Cytokines in childhood hemolytic uremic syndrome and thrombotic thrombocytopenic purpura

Serum and urine cytokines were analyzed in children with hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Interleukin-6 (IL-6) was elevated in the serum of 33 of 35 children with HUS (94%) and in 2 of 2 children with recurrent TTP. Serum IL-6 was higher in children with HUS who developed anuria, extrarenal manifestations during the acute phase of illness and/or chronic renal sequelae. Tumor necrosis factor- (TNF-) was detected in the serum of 7 patients with HUS (20%) and 1 patient with TTP. IL-6 and TNF- were elevated in the urine of 4 of 4 children with HUS and 2 of 2 children with TTP. Urinary levels were higher than serum levels, suggesting local production of cytokines in the urinary tract. Sequential serum and urine samples showed that IL-6 levels varied with disease activity. IL-6 and TNF- were not detected in the serum (n=25) and urine (n=15) of healthy children. We conclude that IL-6 in urine may be used to monitor disease activity in HUS and TTP.     

Haemolytic uraemic syndrome following bone marrow transplantation. Case report and review of the literature

Thrombotic microangiopathy (TMA) can be a late complicationof bone marrow transplantation (BMT). A patient is describedin whom the haemolytic uraemic syndrome developed 10 monthsafter BMT and who died of E. coli sepsis while on maintenancehaemodialysis. The literature is reviewed, regarding clinicalpresentation, incidence, pathogenesis and therapy. TMA can beobserved, after an interval of 3–12 months, in about 6–26%of patients following BMT. Reported cases vary considerablyin clinical severity, from mild presentations to severe TMAwith high mortality rates despite intensive therapy. Importantpathogenetic roles are ascribed to the conditioning total bodyirradiation and the use of cyclosporin A, but other factorsmay be involved as well. Next to supportive therapy, plasmaexchange and the use of ACE inhibitors may be of value in treatingBMT-associated TMA.     

Cyclosporine-induced hemolytic uremic syndrome and hemorrhagic colitis following renal transplantation

Nephrotoxicity remains one of the most common side-effects of cyclosporine in the setting of transplantation. Acute reversible decreases in glomerular filtration rate and chronic irreversible renal damage are the most common manifestations, but hemolytic uremic syndrome and thrombotic thrombocytopenic purpura have been reported. Prognosis of cyclosporine-associated de novo hemolytic uremic syndrome (CyA-HUS) is poor, with nearly half of affected patients losing function in the transplanted kidney. Therapeutic options are limited, but good outcomes have been reported by switching patients from cyclosporine to tacrolimus. We report an unusual presentation of CyA-HUS associated with hemorrhagic colitis following renal transplantation. The patient was successfully managed by switching from cyclosporine to tacrolimus.     

Pretransplant‐corrected QT dispersion as a predictor of pericardial effusion after pediatric hematopoietic stem cell transplantation

Pericardial effusion is a potentially fatal complication following hematopoietic stem cell transplantation (HSCT). Therefore, the identification of risk factors could improve the outcome. Prolonged QT dispersion (QTD) and corrected QTD (QTcD) are associated with serious arrhythmias and sudden death in many forms of heart disease. However, no study has evaluated the efficacy of QTD and QTcD to predict pericardial effusion post‐HSCT. We studied 89 pediatric HSCT patients to identify preoperative risk factors for pericardial effusion with particular focus on QTD and QTcD. Pericardial effusion occurred in 15 patients (cumulative onset rate: 17.4%) within one year post‐HSCT, of which 8 (9.2%) were symptomatic. Patients with pericardial effusion following allogeneic HSCT showed significantly lower overall survival; however, pericardial effusion was not the direct cause of death in any patient. Univariate and multivariate analyses revealed that transplantation‐associated thrombotic microangiopathy (TA‐TMA) was an independent risk factor for post‐HSCT pericardial effusion. In addition, pretransplant QTcD was significantly prolonged in the pericardial effusion group. These results suggest that pediatric patients with abnormally prolonged QTcD before the preparative regimen for HSCT should be regularly followed‐up by echocardiography to detect pericardial effusion, particularly when accompanied by complications including TA‐TMA.     

Postoperative thrombotic thrombocytopenic purpura in an infant: case report and literature review

Thrombotic thrombocytopenic purpura is caused by an imbalance of von Willebrand factor and its cleaving protease, which leads to the formation of microthrombi in end-organs. It rarely occurs in the pediatric population. Plasma exchange can significantly reduce mortality and morbidity. We present a 14-month-old infant in whom clinical and laboratory abnormalities compatible with thrombotic thrombocytopenic purpura were noted several days after resection of a large pelvic tumor. Treatment with double volume plasma exchange on postoperative day 5 led to complete resolution of the renal failure, thrombocytopenia, anemia, and neurological manifestations. ADAMTS13 inhibitors were negative and no mutations were found in factor H, factor I, membrane cofactor protein, and thrombomodulin to account for genetic predisposition to thrombotic thrombocytopenic purpura or atypical hemolytic uremic syndrome. Postoperative anemia, thrombocytopenia, fever, and neurological deficits in children should raise the suspicion of thrombotic thrombocytopenic purpura. Early diagnosis is important because the disorder is readily and efficiently treated with plasma exchange.     

Plasmapheresis in a very young infant with atypical hemolytic uremic syndrome

Atypical hemolytic uremic syndrome (HUS) is a heterogeneous group of disorders, the pathogenesis of which is unclear. Plasma transfusions and plasmapheresis are widely used modes of therapy for adults with this life-threatening syndrome. There is very limited experience in using plasmapheresis therapy in children and infants with atypical HUS. Plasmapheresis, which is considered a relatively safe procedure in adults and older children, may be hazardous in neonates and very young infants and can result in severe complications. We report a 2-month-old infant with idiopathic atypical HUS, who was successfully treated with a 1-month course of plasmapheresis during the acute phase of the disease. Appropriate preparations as well as several adjustments were made in order to meet the special needs of this very young infant who, to the best of our knowledge, is the youngest reported patient with atypical HUS to undergo plasmapheresis. Plasmapheresis therapy of the infant was not associated with any complications of the procedure and resulted in marked clinical improvement. We conclude that plasmapheresis in neonates and in very small infants is technically feasible, can be performed without major complications, and may be of benefit in individual cases. Received: 11 November 1999 / Revised: 3 August 2000 / Accepted: 10 August 2000     

The risk of recurrence of hemolytic uremic syndrome after renal transplantation in children

We reviewed the literature to analyze the risk of recurrence of hemolytic uremic syndrome (HUS) after renal transplantation in children. Among 118 children transplanted after post-diarrheal (D+) HUS, 1 (0.8%) had recurrence with graft loss. Among 63 children transplanted after HUS not associated with a prodrome of diarrhea (D–) of unknown mechanism, 13 (21%) had recurrence with graft loss. Of 11 patients with HUS associated with factor H deficiency who were transplanted, 5 lost the graft because of recurrence. Of 7 patients with HUS associated with normal factor H concentration but mutations in factor H gene who were transplanted, probably 2 had recurrence. Three patients with HUS associated with low serum C3, but no factor H deficiency or mutation lost their graft because of recurrence. The risk of recurrence in the autosomal recessive forms of HUS of unknown mechanism is not documented in children, but is around 60% in adults. A similar risk has been reported in the autosomal dominant forms. The only transplant patient with a constitutional deficiency of von Willebrand factor-cleaving protease had recurrence. Further efforts to document the post-transplant course of patients with D– HUS and progress in the understanding of the mechanisms and genetics of the disease are needed to allow more accurate prediction of the recurrence risk and to define therapeutic approaches.     

Simultaneous occurrence of atypical hemolytic uremic syndrome and acute lymphoblastic leukemia: a case report and literature review

A 3.5-year-old girl with fever had a pancytopenic blood smear that also showed schistocytes and blast cells. Bone marrow examination resulted in a diagnosis of acute lymphoblastic leukemia (ALL). Although creatinine on admission was normal, she had mild hematuria and moderate proteinuria. Chemotherapy was started, but she was initially given only steroids (dexamethasone) due to high liver enzymes. Her renal parameters worsened, and her creatinine doubled. She also developed nephrotic-range proteinuria and hypertension. Renal biopsy showed thrombotic microangiopathy that was clinically consistent with hemolytic uremic syndrome (HUS). Some reports of HUS preceding ALL do exist. However, to the best of our knowledge, this is the first case that describes ALL and HUS presenting simultaneously.     

特发性血小板减少性紫癜患者接受肾移植的安全性观察

目的  探讨特发性血小板减少性紫癜(ITP)患者接受肾移植的安全性。 方法  回顾性分析两例ITP肾移植患者的临床资料并结合相关文献进行复习。 结果  两例患者肾移植术前血小板计数分别为41×10⁹/L及34×10⁹/L, 凝血功能正常, 临床无活动性出血表现, 均成功进行肾移植手术, 术中、术后无明显出血。1例患者术后接受氢化可的松冲击治疗3 d并服用以环孢素为基础免疫抑制剂, 术后7 d血小板计数恢复至正常范围并维持稳定。另1例患者术后接受甲泼尼龙冲击治疗3 d并服用以他克莫司为基础的免疫抑制剂, 术后应用多种提升血小板药物并输注血小板治疗, 血小板波动在10×10⁹/L~30×10⁹/L。两例患者移植肾功能均恢复良好。 结论  ITP患者的肾移植手术出血的风险性主要与患者在术前有否活动性出血有关, 术前无活动性出血的尿毒症患者行肾移植是相对安全的。     

肾移植相关血栓性微血管病的诊断及治疗进展

血栓性微血管病（TMA）是肾移植术后较为严重的并发症,以血小板减少、微血管溶血性贫血和急性肾损伤为主要特征,可导致移植肾失功甚至受者死亡。随着我国实体器官移植数量的不断增加,以及对TMA认识的提高,其相关研究也在逐步深入。肾移植相关TMA病因多样,临床表现各异,缺乏特异性的无创检测手段。多数TMA的确诊依赖于肾穿刺活组织检查,但由于TMA多伴随有血小板明显降低,肾穿刺风险较大,明确诊断存在一定困难。针对肾移植相关TMA,目前通常使用血浆置换、静脉注射免疫球蛋白以及停用潜在风险药物等综合治疗方式,但总体预后不佳。本文现就肾移植术后TMA的分类、肾移植相关TMA的诊断及治疗做一综述,以期为临床肾移植相关TMA的诊断和治疗提供参考。     

Cytomegalovirus‐induced thrombotic microangiopathy after renal transplant successfully treated with eculizumab: case report and review of the literature

De novo thrombotic microangiopathy (TMA) after renal transplant is rare. Cytomegalovirus (CMV)‐related post‐transplant TMA has only been reported in 6 cases. We report an unusual case of a 75‐year‐old woman who developed de novo TMA in association with CMV viremia. The recurrence of TMA with CMV viremia, the resolution with treatment for CMV, and the lack of correlation with a calcineurin inhibitor (CNI) in our case support CMV as the cause of the TMA. What is unique is that the use of eculizumab without plasmapheresis led to prompt improvement in renal function. After a failure to identify a genetic cause for TMA and the clear association with CMV, eculizumab was discontinued. This case provides insight into the pathogenesis and novel treatment of de novo TMA, highlights the beneficial effects of complement inhibitors in this disease, and shows that they can be safely discontinued once the inciting etiology is addressed.     

����ֲ���󲢷����ع�������(��6������)

目的总结肝移植术后严重骨髓抑制并发症的临床特点,探讨其发生原因及预防措施。方法回顾性分析2002-2006年天津市第一中心医院收治的肝移植术后并发严重骨髓抑制6例病人的临床资料。结果所有病例均因终末期肝病进行肝脏移植,术后应用标准的免疫抑制剂方案:FK506 骁悉 激素,术后2周常规静脉用更昔洛韦预防巨细胞病毒感染。严重骨髓抑制(白细胞计数<1.0×109/L)发生于术后19~78d,临床表现包括发热伴有或不伴有皮疹、消化道症状、感染以致发生严重的败血症。5例肝功能在治疗过程中始终是正常的。所有病例均死于严重败血症及多脏器功能衰竭。结论肝移植术后严重骨髓抑制的发生可能与免疫反应、药物毒性及严重感染有关,其发生率及确切的发生机制尚不清楚。肝移植术后严重骨髓抑制一旦发生,预后极差,应根据可能的诱发因素采取积极的预防措施。     

Successful management of thrombocytopenia, microangiopathic anemia, and acute renal failure by plasmapheresis

We report on the outcome of six consecutive adult patients who presented with microangiopathic anemia and thrombocytopenia. Clinical parameters on admission included platelet counts less than 45,000/mm3, microangiopathic red blood cell morphology, mental status abnormalities, and in three, rapidly progressive azotemia requiring dialysis. All patients underwent plasma exchange therapy as part of their treatments. Patients with renal failure underwent plasma exchange with a hollow fiber plasma separator, while those without renal failure were treated with a cytocentrifuge. All received fresh frozen plasma as replacement solution and were treated with glucocorticoids as well. For all six patients, plasmapheresis and conventional drug therapy resulted in remission that has lasted for 16 +/- 5 months (range 8 to 24 months). Early cessation of plasmapheresis in two patients resulted in rapid relapse. Patients who required dialysis now have a mean creatinine of 2.0 +/- 0.9 mg/dL (range 1.2 to 3.5). With similar volumes of exchange, and the same number of treatments, less fresh frozen plasma was used in the three patients treated with the hollow fiber separator than in patients treated with the cytocentrifuge (6.3 +/- 3.7 v 14.8 +/- 4.3 U/exchange, P less than 0.05). We conclude that plasmapheresis is a useful therapeutic modality for the treatment of thrombocytopenia and microangiopathic hemolytic anemia. In addition the use of a hollow fiber plasma separator for plasmapheresis is safe and efficient, particularly when concurrent dialysis is required.     

Pure red cell aplasia after major ABO-incompatible bone marrow transplantation: two case reports of treatment with recombinant human erythropoietin

A 34-year-old man with acute myelocytic leukemia (AML: MO) and a 32-year-old woman with AML: M2 developed pure red cell aplasia (PRCA) after receiving a major ABO-incompatible bone marrow transplant (BMT). The first patient responded to recombinant human erythropoietin (rhEPO) therapy, while the second did not. The second patient also received methylprednisolone (m-PSL) but developed reticulocytosis and hemolysis after the administration of m-PSL. Plasmapheresis was then performed and the patient promptly recovered from hemolysis and PRCA. We conclude that close attention must be paid when treating PRCA following major ABO-in-compatible BMT with rhEPO and m-PSL, as there is always the potential for massive hemolysis.     

De novo thrombotic microangiopathy after kidney transplantation

Thrombotic microangiopathy (TMA) is a serious complication of transplantation that adversely affects kidney transplant recipient and allograft survival. Post-transplant TMA is usually classified into two categories: 1) recurrent TMA and 2) de novo TMA. Atypical hemolytic uremic syndrome (aHUS) resulting from dysregulation and over-activation of the alternate complement pathway is a rare disease but the most common diagnosis associated with recurrence in the allografts. De novo TMA, on the other hand, represents an overwhelming majority of the cases of post-transplant TMA and is a substantially more heterogeneous entity than recurrent aHUS. Here, we review the etio-pathogenesis, diagnosis and treatment options for de novo post-transplant TMA. It is usually in the setting of calcineurin inhibitor use, mammalian target of rapamycin inhibitor use, or antibody mediated rejection; recently genetic mutations in complement regulatory genes for Factor H and Factor I similar to those described in aHUS have been reported in up to a third of these patients. Systemic signs of TMA are frequently absent, and a renal allograft biopsy is often needed to establish the diagnosis. Although withdrawal of the offending agents is usually the first line of treatment and resolution of laboratory abnormalities has been documented with this approach in several case reports and case series, available retrospective data demonstrate lack of benefit in long-term graft outcomes. Co-stimulation blockage with belatacept provides an effective alternate immunosuppressive strategy for these patients. Anti-complement therapy with eculizumab is effective in some cases; further work is required to define which patients with TMA (with and without concomitant antibody-mediated rejection) would benefit from receiving this treatment, and what biomarkers can be used to identify them.     

Association of systemic lupus erythematosus and hemolytic uremic syndrome in a child

We describe a 10-year-old girl with systemic lupus erythematosus (SLE) who first presented with hemolytic uremic syndrome (HUS). Diagnoses were based on the classic HUS triad, including the observation of fragmented red blood cells, and on the American College of Rheumatology criteria for SLE. Plasma exchange may have been effective against both HUS and SLE in this patient, as it was associated with improvement of platelet counts, renal function, and serological findings. Received: 24 September 1998 / Revised: 4 January 1999 / Accepted: 4 January 1999     

恶性疟合并溶血尿毒综合征的诊疗探讨

目的探讨恶性疟引起的溶血尿毒综合征（HUS）的诊断及治疗要点。 方法对本院2008至2014年13例恶性疟引起的溶血尿毒综合征患者的临床特点、辅助检查及治疗情况进行回顾性分析。 结果入组患者中男性12例,女性1例,年龄22～60岁,均符合恶性疟疾合并溶血尿毒综合征的诊断。其中10例合并脑型疟,1例合并消化道出血,2例出现呼吸循环衰竭。经抗疟原虫治疗、激素治疗、补液对症治疗以及呼吸机、血液透析滤过等,入组的13例患者中1例死亡,1例自动出院,11例治愈出院,其中5例因急性肾功能衰竭行血液透析滤过治疗肾功能恢复,随访11例治愈患者均未出现慢性肾功能损害,2例病例出现再燃。 结论疟疾的早期诊断及治疗,对控制溶血及阻止脏器损害具有重要作用;大剂量长疗程使用蒿甲醚可增强抗疟原虫效果,早期应用激素可有效阻止溶血,减轻肾脏损害,对严重溶血、急性肾功能衰竭病例应及时采取血液透析滤过治疗,以降低病死率。     

Double bone marrow transplantation for severe aplastic anemia after orthotopic liver transplantation: implications for clinical management and immune tolerance

A 2-year-old boy underwent liver transplantation for fulminant hepatic failure of unknown cause. Four months later the child developed severe aplastic anemia. Allogeneic bone marrow transplantation (BMT) was performed using marrow from his 14-month-old HLA-identical sister. Severe aplastic anemia recurred 2.5 months later. After reconditioning a second BMT was performed using the same donor. Tapering of immunosuppression 2 years after BMT led to biopsy-confirmed rejection of the liver. Therapy with high-dose corticosteroids and an increase in cyclosporine A medication readily reversed rejection and a low-dose immunosuppression reflected by cyclosporine trough levels less than 50 ng/ml has been maintained since. Eight years later the boy is in excellent health with both bone marrow and liver functioning perfectly. In summary, this case demonstrates that even recurrent severe aplastic anemia after OLT can be cured by BMT, and that a transplanted liver can tolerate a double conditioning regimen without problems. Tolerance towards the liver through BMT did not develop.