Thrombotic microangiopathy after kidney transplantation: Expanding etiologic and pathogenetic spectra

Thrombotic microangiopathy(TMA)is an uncommon but serious complication that not only affects native kidneys but also transplanted kidneys.This review is specifically focused on post-transplant TMA(PT-TMA)involving kidney transplant recipients.Its reported prevalence in the latter population varies from 0.8%to 14%with adverse impacts on both graft and patient survival.It has many causes and associations,and the list of etiologic agents and associations is growing constantly.The pathogenesis is equally varied and a variety of pathogenetic pathways lead to the development of microvascular injury as the final common pathway.PT-TMA is categorized in many ways in order to facilitate its management.Ironically,more than one causes are contributory in PT-TMA and it is often difficult to pinpoint one particular cause in an individual case.Pathologically,the hallmark lesions are endothelial cell injury and intravascular thrombi affecting the microvasculature.Early diagnosis and classification of PT-TMA are imperative for optimal outcomes but are challenging for both clinicians and pathologists.The Banff classification has addressed this issue and has developed minimum diagnostic criteria for pathologic diagnosis of PT-TMA in the first phase.Management of the condition is also challenging and still largely empirical.It varies from simple maneuvers,such as plasmapheresis,drug withdrawal or modification,or dose reduction,to lifelong complement blockade,which is very expensive.A thorough understanding of the condition is imperative for an early diagnosis and quick treatment when the treatment is potentially effective.This review aims to increase the awareness of relevant stakeholders regarding this important,potentially treatable but under-recognized cause of kidney allograft dysfunction.

Pulmonary tumor thrombotic microangiopathy of hepatocellular carcinoma: A case report and review of literature

BACKGROUND Pulmonary tumor thrombotic microangiopathy(PTTM)is a rare condition in patients with hepatocellular carcinoma(HCC);to date,few cases have been reported.While hepatic dysfunction has been focused on the later stages of HCC,the management of symptoms in PTTM is important for supportive care of the cases.For the better understanding of PTTM in HCC,the information of our recent case and reported cases have been summarized.CASE SUMMARY A patient with HCC exhibited acute and severe respiratory failure.Radiography and computed tomography of the chest revealed the multiple metastatic tumors and a frosted glass–like shadow with no evidence of infectious pneumonia.We diagnosed his condition as acute respiratory distress syndrome caused by the lung metastases and involvement of the pulmonary vessels by tumor thrombus.Administration of prednisolone to alleviate the diffuse alveolar damages including edematous changes of alveolar wall caused by the tumor cell infiltration and ischemia showed mild improvement in his symptoms and imaging findings.An autopsy showed the typical pattern of PTTM in the lung with multiple metastases.CONCLUSION PTTM is caused by tumor thrombi in the arteries and thickening of the pulmonary arterial endothelium leading to the symptoms of dyspnea in terminal staged patients.Therefore,supportive management of symptoms is necessary in the cases with PTTM and hence we believe that the information presented here is of great significance for the diagnosis and management of symptoms of PTTM with HCC.

Acute liver failure with thrombotic microangiopathy due to sodium valproate toxicity:A case report

BACKGROUND Sodium valproate is widely used in the treatment of epilepsy in clinical practice.Most adverse reactions to sodium valproate are mild and reversible,while serious idiosyncratic side effects are becoming apparent,particularly hepatotoxicity.Herein,we report a case of fatal acute liver failure(ALF)with thrombotic microangiopathy(TMA)caused by treatment with sodium valproate in a patient following surgery for meningioma.CASE SUMMARY A 42-year-old man who received antiepileptic treatment with sodium valproate after surgery for meningioma exhibited extreme fatigue,severe jaundice accompanied by oliguria,soy sauce-colored urine,and ecchymosis.His postoperative laboratory values indicated a rapid decreased platelet count and hemoglobin level,severe liver and kidney dysfunction,and disturbance of the coagulation system.He was diagnosed with drug-induced liver failure combined with TMA.After plasma exchange combined with hemoperfusion,pulse therapy with high-dose methylprednisolone,and blood transfusion,his liver function deteriorated,and finally,he died.CONCLUSION ALF with TMA is a rare and fatal adverse reaction of sodium valproate which needs to be highly valued.

Thrombotic microangiopathy-like disorder after living-donor liver transplantation:A single-center experience in Japan

AIM:To investigate thrombotic microangiopathy (TMA)in liver transplantion,because TMA is an infrequent but life-threatening complication in the transplantation field. METHODS:A total of 206 patients who underwent living-donor liver transplantation (LDLT) were evaluated,and the TMA-like disorder (TMALD) occurred in seven recipients. RESULTS:These TMALD recipients showed poor outcomes in comparison with other 199 recipients. Although two TMALD recipients successfully recovered,the other five recipients finally died despite intensive treatments including repeated plasma exchange (PE) and re-transplantation. Histopathological analysis of liver biopsies after LDLT revealed obvious differences according to the outcomes. Qualitative analysis of antibodies against a disintegrin-like domain and metalloproteinase with thrombospondin type 1 motifs (ADAMTS-13) were negative in all patients. The fragmentation of red cells,the microhemorrhagic macules and the platelet counts were early markers for the suspicion of TMALD after LDLT. Although the absolute values of von Willebrand factor (vWF) and ADAMTS-13 did not necessarily reflect TMALD,the vWF/ADAMTS-13 ratio had a clear diagnostic value in all cases. The establishment of adequate treatments for TMALD,such as PE for ADAMTS-13 replenishment or treatments against inhibitory antibodies,must be decided according to each case. CONCLUSION:The optimal induction of adequate therapies based on early recognition of TMALD by the reliable markers may confer a large advantage for TMALD after LDLT.

Glucocorticoid-induced thrombotic microangiopathy in paroxysmal nocturnal hemoglobinuria:A case report and review of literature

BACKGROUND Thrombotic microangiopathy(TMA)is a group of disorders that converge on excessive platelet aggregation in the microvasculature,leading to consumptive thrombocytopenia,microangiopathic hemolysis and ischemic end-organ dysfunction.In predisposed patients,TMA can be triggered by many environmental factors.Glucocorticoids(GCs)can compromise the vascular endothelium.However,GC-associated TMA has rarely been reported,which may be due to the lack of awareness of clinicians.Given the high frequency of thrombocytopenia during GC treatment,particular attention should be given to this potentially fatal complication.CASE SUMMARY An elderly Chinese man had a 12-year history of aplastic anemia(AA)and a 3-year history of paroxysmal nocturnal hemoglobinuria(PNH).Three months earlier,methylprednisolone treatment was initiated at 8 mg/d and increased to 20 mg/d to alleviate complement-mediated hemolysis.Following GC treatment,his platelet counts and hemoglobin levels rapidly decreased.After admission to our hospital,the dose of methylprednisolone was increased to 60 mg/d in an attempt to enhance the suppressive effect.However,increasing the GC dose did not alleviate hemolysis,and his cytopenia worsened.Morphological evaluation of the marrow smears revealed increased cellularity with an increased percentage of erythroid progenitors without evident dysplasia.Cluster of differentiation(CD)55 and CD59 expression was significantly decreased on erythrocytes and granulocytes.In the following days,platelet transfusion was required due to severe thrombocytopenia.Observation of platelet transfusion refractoriness indicated that the exacerbated cytopenia may have been caused by the development of TMA due to GC treatment because the transfused platelet concentrates had no defects in glycosylphosphatidylinositol-anchored proteins.We examined blood smears and found a small number of schistocytes,dacryocytes,acanthocytes and target cells.Discontinuation of GC treatment resulted in rapidly increased platelet counts and steady increases in hemoglobin levels.The patient’s platelet counts and hemoglobin levels returned to the levels prior to GC treatment 4 weeks after GC discontinuation.CONCLUSION GCs can drive TMA episodes.When thrombocytopenia occurs during GC treatment,TMA should be considered,and GCs should be discontinued.

Changes in macrophage infiltration and podocyte injury in lupus nephritis patients with repeated renal biopsy: Report of three cases

BACKGROUND In this study,we retrospectively analysed macrophage infiltration and podocyte injury in three patients with diffuse proliferative lupus nephritis(LN)who un-derwent repeated renal biopsy.CASE SUMMARY Clinical data of three diffuse proliferative LN patients with different pathological characteristics(case 1 was LN IV-G(A),case 2 was LN IV-G(A)+V,and case 3 was LN IV-G(A)+thrombotic microangiopathy)were reviewed.All patients underwent repeated renal biopsies 6 mo later,and renal biopsy specimens were studied.Macrophage infiltration was assessed by CD68 expression detected by immunohistochemical staining,and an immunofluorescence assay was used to detect podocin expression to assess podocyte damage.After treatment,Case 1 changed to LN III-(A),Case 2 remained as type V LN lesions,and Case 3,which changed to LN IV-S(A),had the worst prognosis.We observed reduced macro-phage infiltration after therapy.However,two of the patients with active lesions after treatment still showed macrophage infiltration in the renal interstitium.Before treatment,the three patients showed discontinuous expression of podocin.Notably,the integrity of podocin was restored after treatment in Case 1.CONCLUSION It may be possible to reverse podocyte damage and decrease the infiltrating ma-crophages in LN patients through effective treatment.

Update on hemolytic uremic syndrome:Diagnostic and therapeutic recommendations

Hemolytic uremic syndrome （HUS） is a rare disease. In this work the authors review the recent findings on HUS, considering the different etiologic and patho-genetic classifications. New findings in genetics and, in particular, mutations of genes that encode the complement-regulatory proteins have improved our understanding of atypical HUS. Similarly, the comple-ment proteins are clearly involved in all types of thrombotic microangiopathy： typical HUS, atypical HUS and thrombotic thrombocytopenic purpura （TTP）. Fur-thermore, several secondary HUS appear to be related to abnormalities in complement genes in predisposed patients. The authors highlight the therapeutic as-pects of this rare disease, examining both “traditional therapy” （including plasma therapy, kidney and kidney-liver transplantation） and “new therapies”. The latter include anti-Shiga-toxin antibodies and anti-C5 mono-clonal antibody “eculizumab”. Eculizumab has been recently launched for the treatment of the atypical HUS, but it appears to be effective in the treatment of typical HUS and in TTP. Future therapies are in phases Ⅰ and Ⅱ. They include anti-C5 antibodies, which are more purifed, less immunogenic and absorbed orally and, anti-C3 antibodies, which are more powerful, but potentially less safe. Additionally, infusions of recombinant complement-regulatory proteins are a potential future therapy.

LUPUS NEPHRITIS COMPLICATED WITH MALIGNANT HYPERTENSION:FROM RENAL VASCULAR PATHOLOGY TO CLINICAL RELEVANCE

Objective To investigate the clinical and pathological characteristics of lupus nephritis patients complicated with malignant hypertension.Methods We retrospectively studied 19 patients with lupus nephritis complicated with malignant hypertension who underwent renal biopsy between January 2002 and December 2006.Results Of 19 patients,3 were men and 16 were women,with a mean age of 24.4±7.7 years old.All had positive antinuclear antibodies and low serum complement was found in 13 patients.All were anemic and 12 of them were thrombocytopenic.Impaired renal function was found in 17 patients with an average serum creatinine of 184.5±88.9 μmol/L.Severe intrarenal arteriolar lesion was found in all patients.Six patients had lupus vasculopathy,11 patients had renal thrombotic microangiopathy lesion,2 had severe arteriosclerosis.All patients received steroids and immunosuppressive drugs,15 received angiotensin-converting enzyme inhibitor(ACEI)/angiotensin receptor blocker(ARB)with resultant well-controlled blood pressure.Thrombocytopenia and hemolytic anemia resolved remarkably.The renal function improved or recovered in 14 of 17 patients,and 3 developed end-stage renal disease on maintenance dialysis.Conclusions Severe intrarenal vascular lesion complicated with renal nephritis parallels clinical manifestation of malignant hypertension.Renal pathology is the key of treatment strategy emphasizing on the significance of renal vascular involvement and type.On the basis of immunosuppressive drugs and steroids to control systemic lupus activity,timely initiation of ACEI/ARB could be of benefit to blood pressure control and long term renal survival.

Diagnostic Approach of Thrombocytopenia in Pregnancy: A Review

Thrombocytopenia (defined as platelet count 9/L) is present in 7% - 12% of pregnant women at delivery. Although there are mild etiologies of this condition that are often diagnosed incidentally, there are more severe causes that can be life threating. Thrombocytopenia also has a great implication in surgical risk and regional anesthesia. A structured evaluation of thrombocytopenia is necessary to allow an adequate diagnostic approach. Here we summarized the current knowledge of thrombocytopenia in pregnancy.

Atypical hemolytic-uremic syndrome due to complement factor Ⅰ mutation

Atypical hemolytic-uremic syndrome(a HUS) is a rare disease of complement dysregulation leading to thrombotic microangiopathy(TMA). Renal involvement and progression to end-stage renal disease are common in untreated patients. We report a 52-year-old female patient who presented with severe acute kidney injury, microangiopathic hemolytic anemia, and thrombocytopenia. She was managed with steroid, plasma exchange, and dialysis. Kidney biopsy shows TMA and renal cortical necrosis. Genetic analysis reveals heterozygous complement factor Ⅰ(CFI) mutation. Eculizumab was initiated after 3 mo of presentation, continued for 9 mo, and stopped because of sustained hematologic remission, steady renal function, and cost issues. Despite this, the patient continued to be in hematologic remission and showed signs of renal recovery, and peritoneal dialysis was stopped 32 mo after initiation. We report a case of a HUS due to CFI mutation, which, to the best of our knowledge, has not been reported before in Saudi Arabia. Our case illustrates the challenges related to the diagnosis and management of this condition, in which a high index of suspicion and prompt treatment are usually necessary.

Complement-mediated microvascular injury and thrombosis in the pathogenesis of severe COVID-19: A review

Coronavirus disease 2019(COVID-19)causes acute microvascular thrombosis in both venous and arterial structures which is highly associated with increased mortality.The mechanisms leading to thromboembolism are still under investigation.Current evidence suggests that excessive complement activation with severe amplification of the inflammatory response(cytokine storm)hastens disease progression and initiates complement-dependent cytotoxic tissue damage with resultant prothrombotic complications.The concept of thromboinflammation,involving overt inflammation and activation of the coagulation cascade causing thrombotic microangiopathy and end-organ damage,has emerged as one of the core components of COVID-19 pathogenesis.The complement system is a major mediator of the innate immune response and inflammation and thus an appealing treatment target.In this review,we discuss the role of complement in the development of thrombotic microangiopathy and summarize the current data on complement inhibitors as COVID-19 therapeutics.

Iatrogenic scleroderma renal crisis:A case report and mini literature review for renal crisis

Background:Systemic sclerosis is a connective tissue disease characterized by fibrosis of the skin and organs,marked changes in microvascular structure,cellular and humoral immune disorders.Renal involvement is more frequent and mainly characterized by moderate proteinuria,elevated serum creatinine levels,and hypertension.The most common kidney involvement in SSc is scleroderma renal crisis(SRC)that is fatal without prompt intervention.Case report:A 52-year-old Caucasian male with known diffuse cutaneous systemic sclerosis was hospitalized with communityacquired pneumonia.On the fifth day after appropriate antibiotic therapy and 60 mg/day methylprednisolone,decreased urine output,arterial hypertension,decreased renal function and pulmonary edema developed.The patient was diagnosed with a scleroderma renal crisis.Emergency hemodialysis was applied to the patient,and captopril 6×25 mg/day and nifedipine 2*60 mg/day treatment were given.He received a routine hemodialysis program for about three months.The hemodialysis program was terminated when the patient’s urine quality and quantity increased.Conclusions:SRC,characterized by malignant hypertension,azotemia,microangiopathic hemolytic anemia,and kidney failure,is one of the most important complications of systemic sclerosis with a poor prognosis without prompt intervention.Steroid use is one of the important risk factors that precipitate SRC development.With angiotensin-converting enzyme inhibitors,survival increased after SRC,the need for dialysis decreased,and usually allowed the discontinuation of dialysis treatment within about 6-18 months.Suspicion of SRC in the presence of the above-mentioned findings in patients with a diagnosis or suspected systemic sclerosis can be considered the most important treatment step.

Haploidentical hematopoietic stem cell transplantation for pediatric patients with chronic active Epstein-Barr virus infection:a retrospective analysis of a single center

Background This study aimed to evaluate the feasibility and clinical effect of haploidentical hematopoietic stem cell transplantation(haplo-HSCT)for the treatment of pediatric patients with chronic active Epstein-Barr virus infection(CAEBV).Methods Children with CAEBV who did not have matched donors and underwent haplo-HSCT in Beijing Children's Hospital,Capital Medical University,from October 2016 to June 2020 were analyzed retrospectively.Data relating to the clinical manifestations,engraftment,and prognosis of the children were extracted from medical records.Results Twenty-five patients,including 16 males and 9 females,with an onset age of 5.0±2.6 years and a transplantation age of 6.9±2.9 years,were enrolled irnhis study.The mean time from diagnosis to transplantation was 3.8(2.0-40.2)months.The mean observation time was 19.0±12.0 months.Three patients received the reduced intensity conditioning regimen,and the remaining patients all received the modified myeloablative conditioning regimen.By the end of the follow-up,23 patients were characterized by disease-free survival(DFS),22 were characterized by event-free survival(EFS).and two died.One of the patients died of thrombotic microangiopathy(TMA),and another died of graft versus host disease(GVHD);this patient discontinued the treatment for economic reasons.The 3-year overall survival(OS)rate was estimated to be 92.0%±5.4%,and the 3-year EFS rate was estimated to be 87.4%±6.8%.All active patients survived after HSCT event-free.Acute GVHD degrees 1-3 were observed in ten patients(40.0%),and degree IV was observed in six(24.0%),who were all cured except for one patient.Chronic GVHD was observed in nine(36.0%),and most of these cases were mild.The incidence of TMA and veno-occlusive disease(VOD)was 28.0%and 4.0%.Conclusions Haploidentical hematopoietic stem cell transplantation is safe and effective in the treatment of pediatric CAEBV and can be used as an alternative therapy without matched donors or emergency transplantation.Patients with active disease before HSCT also benefited from haplo-HSCT.Haplo-HSCT requires careful monitoring for complications,such as GVHD and TMA.Early detection of TMA and timely treatment can reduce mortality and can improve the survival rate.

A case of severe preeclampsia diagnosed as post-partum hemolytic uremic syndrome

Post-partum hemolytic uremic syndrome （PHUS） is a severe thrombotic microangiopathy clinically characterized by hemolytic anemia, renal dysfunction, and low platelets after birth with rapid progression and poor prognosis. Here, we reported a rare case of severe preeclampsia diagnosed as hemolytic uremic syndrome after birth. The patient was diagnosed with PHUS and underwent intermittent plasma exchange with supportive treatment including glucocorticoid injections and transfusion of suspended red blood cells. After these treatments, the patient experienced no apparent remission and chronic renal dysfunction occurred on her. PHUS is a severe emergency with acute onset, rapid progress, and poor prognosis. Early detection, diagnosis, and treatment can significantly improve the prognosis.