Endoscopic manifestation of intestinal transplant-associated microangiopathy after stem cell transplantation.

BACKGROUND: Endoscopic features of intestinal transplant-associated microangiopathy (iTAM) have not been comprehensively investigated. This study aimed to examine the endoscopic characteristics of patients diagnosed with iTAM. METHODS: This retrospective analysis included 14 patients pathologically diagnosed with iTAM after stem cell transplantation for hematolymphoid neoplasms (n = 13) or thalassemia (n = 1). The sex, age at diagnosis, endoscopic features, and prognosis of each patient were assessed. Serological markers for diagnosing transplant-associated thrombotic microangiopathy were also evaluated. RESULTS: The mean age at the time of iTAM diagnosis was 40.2 years. Patients diagnosed based on the pathognomonic pathological changes of iTAM presented with diverse symptoms at the times of endoscopic examinations, including diarrhea (n = 10), abdominal pain (n = 5), nausea (n = 4), appetite loss (n = 2), bloody stools (n = 2), abdominal discomfort (n = 1), and vomiting (n = 1). At the final follow-up, six patients survived, while eight patients succumbed, with a median time of 100.5 days (range: 52-247) post-diagnosis. Endoscopic manifestations included erythematous mucosa (n = 14), erosions (n = 13), ulcers (n = 9), mucosal edema (n = 9), granular mucosa (n = 9), and villous atrophy (n = 4). Erosions and/or ulcers were primarily observed in the colon (10/14, 71%), followed by the ileum (9/13, 69%), stomach (4/10, 40%), cecum (5/14, 36%), duodenum (3/10, 30%), rectum (4/14, 29%), and esophagus (1/10, 10%). Cytomegalovirus infection (n = 4) and graft-versus-host disease (n = 2) coexisted within the gastrointestinal tract. Patients had de novo prolonged or progressive thrombocytopenia (6/14, 43%), decreased hemoglobin concentration (4/14, 29%), reduced serum haptoglobin level (3/14, 21%), and a sudden and persistent increase in lactate dehydrogenase level (2/14, 14%). Peripheral blood samples from 12 patients were evaluated for schistocytes, with none exceeding 4%. CONCLUSIONS: This study provides a comprehensive exploration of the endoscopic characteristics of iTAM. Notably, all patients exhibited erythematous mucosa throughout the gastrointestinal tract, accompanied by prevalent manifestations, such as erosions (93%), ulcers (64%), mucosal edema (64%), granular mucosa (64%), and villous atrophy (29%). Because of the low positivity for serological markers of transplant-associated thrombotic microangiopathy in patients with iTAM, endoscopic evaluation and biopsy of these lesions are crucial, even in the absence of these serological features.

Assessment of epidemiology and outcomes of adult patients with kidney-limited thrombotic microangiopathies.

Thrombotic microangiopathies (TMA) are usually associated with hematological features (RH-TMA). The epidemiology of TMA limited to kidneys (RL-TMA) is unclear Therefore, patients with TMA and native kidney biopsies were identified during 2009-2022 in 20 French hospitals and results evaluated. RL-TMA was present in 341/757 (45%) patients and associated with lower creatinine levels (median 184 vs 346 µmol/L) than RH-TMA. RL-TMA resulted from virtually all identified causes, more frequently from anti-VEGF treatment and hematological malignancies but less frequently from shigatoxin-associated hemolytic uremic syndrome (HUS), systemic sclerosis, gemcitabine and bacterial infection, and even less frequently when three or more causes/triggers were combined (RL-TMA: 5%; RH-TMA: 12%). RL-TMA was associated with significantly lower major cardiovascular events (10% vs 20%), kidney replacement therapy (23% vs 43%) and death (12% vs 20%) than RH-TMA during follow-up (median 28 months). Atypical HUS (aHUS) was found in 326 patients (RL-TMA: 43%, RH-TMA: 44%). Among the 69 patients with proven complement-mediated aHUS, eculizumab (anti-C5 therapy) was used in 43 (62%) (RL-TMA: 35%; RH-TMA: 71%). Among the 257 other patients with aHUS, including 51% with RL-TMA, eculizumab was used in 29 but with unclear effects of this treatment. Thus, RL-TMA represents a very high proportion of patients with TMA and results from virtually all known causes of TMA and includes 25% of patients with complement-mediated aHUS. Adverse outcomes of RL-TMA are lower compared to RH-TMA but remain significant. Anti-C5 therapy was rarely used in RL-TMA, even in proven complement-mediated aHUS, and its effects remain to be assessed.

Spectrum of renal vascular lesions among patients with lupus nephritis: An experience from a tertiary care center.

Background: Lupus nephritis (LN) is the assemblage of glomerular, tubulointerstitial and vascular changes. Despite the fact that glomerular changes are overemphasized in pathological classification and scoring system, but the existence of vascular damage negatively impact the clinical course. Aims and Objective: This study was conducted to determine the clinicopathological spectrum of renal vascular lesions in lupus nephritis. Materials and Methods: Renal microvascular lesions in biopsy proven lupus nephritis were classified into 5 major categories-thrombotic microangiopathy, true vasculitis; lupus vasculopathy, uncomplicated vascular immune deposits, and arterial. Clinical details, laboratory parameters and histopathological variables were compared among all groups. Summary of chronic changes was also assessed. Results: Biopsies from 56 patients revealed thrombotic microangiopathy (2), lupus vasculopathy (3), uncomplicated vascular immune deposit (6), PAN type vasculitis (1) and arterial sclerosis (13). No renal vascular lesions were found in 35.18% of patients. At the time of biopsy, arterial sclerosis or lupus vasculopathy patients were older Nephritis subtype. Activity indices were higher in lupus vasculopathy group whereas patients with arteriosclerosis showed highest chronicity index. Conclusions: Renal vascular lesions are common in systemic lupus erythematosus patients with nephritis and may be associated with aggressive clinical course.

[Clinicopathological features and prognosis of kidney injury in patients after hematopoietic stem cell transplantation].

To summarize the clinicopathological features and prognosis of kidney injury after hematopoietic stem cell transplantation (HSCT), to provide basis for preventing its occurrence and development. By using a retrospective cohort study method, we collected the clinical and renal biopsy pathological data of all the patients who hospitalized in the Department of Nephrology of Peking University First Hospital from June 2011 to June 2021 with renal injury after HSCT and underwent renal biopsy, and prognosis was followed up by telephone. The clinical laboratory characteristics, renal pathology and prognosis, and their association were analyzed. The results showed that the most common clinical phenotype was chronic kidney disease (CKD,69.2%, 18/26), in this term 13/18 patients received stem cells from haploidentical donors, and 11/18 patients experienced with extrarenal graft-versus-host disease (GVHD). The most common pathologic phenotype was thrombotic microangiopathy (TMA, 61.5%, 16/26). Renal function returned to baseline level in 6 patients, and the kidney survival at 2 years and 5 years were 95.7% (22/23) and 87.5% (14/16), respectively. In conclusion, the clinical phenotype of renal injury after HSCT were mainly CKD, and the most common pathologic phenotype was TMA, the long-term prognosis was favourable.

Surufatinib-induced renal thrombotic microangiopathy: first case report and review of literature.

Angiogenesis inhibitors such as tyrosine kinase inhibitors (TKIs) are common therapeutics currently used to treat oncologic disease. Surufatinib is a novel, small-molecule multiple receptor TKI approved by the National Medical Products Administration (NMPA) for the treatment of progressive, advanced, and well-differentiated pancreatic and extrapancreatic neuroendocrine tumours (NETs). Thrombotic microangiopathy (TMA) is a well-documented complication of TKIs targeting the VEGF-A/VEGFR2 signalling pathway. Here, we describe a 43-year-old female patient with biopsy-proven TMA and nephrotic syndrome due to surufatinib treatment for adenoid cystic carcinoma. Histological lesions included glomerular endothelial swelling, widening of subendothelial spaces, mesangiolysis, and double contour, which caused nephrotic proteinuria. Effective management was achieved by drug withdrawal and oral anti-hypertensive regents. The management of surufatinib-related nephrotoxicity without compromising its anticancer effects is challenging. Hypertension and proteinuria must be closely monitored during drug use to reduce or stop the dose in a timely manner before severe nephrotoxicity occurs.

Proteinuria in thrombotic microangiopathy is associated with partial podocytopathy.

BACKGROUND: Thrombotic microangiopathy (TMA) results in acute kidney injury, but the cause of heavy proteinuria in this disorder is puzzling. The goal of this study was to determine if there were significant effacement of foot processes and CD133-positive hyperplastic podocytes in TMA to explain the proteinuria. METHODS: The study included 12 negative controls (renal parenchyma removed from renal cell carcinoma) and 28 thrombotic microangiopathy due to different etiologies. The percent of foot process effacement was estimated, and proteinuria level was obtained for each TMA case. Both groups of cases were stained for CD133 by immunohistochemical method, and the number of positive CD133 in hyperplastic podocytes was counted and analyzed. RESULTS: Nineteen (19) of 28 (68%) TMA cases had nephrotic range proteinuria (urine protein/creatinine >3). Twenty-one (21) of 28 (75%) TMA cases showed positive CD133 staining in scattered hyperplastic podocytes within Bowman's space but was absent in control cases. The percent of foot process effacement (56 ± 4%) correlated with proteinuria (protein/creatinine ratio 4.4 ± 0.6) (r = 0.46, p = .0237) in TMA group. CONCLUSION: Our data indicate that the proteinuria in TMA can be associated with significant effacement of foot processes. CD133-positive hyperplastic podocytes can be seen in the majority of TMA cases of this cohort, indicating a partial podocytopathy.

Pulmonary tumor thrombotic microangiopathy caused by metastatic ovarian high-grade serous carcinoma: a case report and literature review.

BACKGROUND: Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare entity with poor prognosis, and often diagnosed postmortem. PTTM is resulting from tumor emboli induced activation of coagulation cascade, fibrin clot formation and fibrocellular intimal proliferation in pulmonary microvasculature. CASE: The patient was a 65-year-old female, with past medical history of ovarian high-grade serous carcinoma, presented with chest pain and shortness of breath. The chest computed tomography (CT) revealed innumerable new lung nodules as well as small hazy and patchy opacities compared to the chest CT 2 months before current presentation. She developed progressive respiratory failure and expired. A lung-restricted autopsy showed diffuse subcentimetric nodules in bilateral lungs grossly. Microscopic examination revealed the lung parenchyma demonstrated numerous tumor emboli consisting of pleomorphic tumor cells with varying degrees of fibrin deposition and fibrocellular intimal proliferation in the pulmonary arterioles, small arteries, and capillaries in the alveolar septa. Immunohistochemistry confirmed the ovarian origin of the tumor cells. The findings were consistent with PTTM secondary to metastasis of ovarian high-grade serous carcinoma. Literature review of PTTM caused by ovarian cancer was conducted. CONCLUSION: PTTM is a fatal entity with rare association with primary ovarian malignancy. This case study demonstrates the clinicopathological features of PTTM associated with high-grade serous carcinoma, and it will be the second case of PTTM with this association in the literature.

Clinical value of the renal pathologic scoring system in complement-mediated thrombotic microangiopathy.

OBJECTIVES: This study was initiated to establish a renal thrombotic microangiopathy (TMA) scoring system based on clinical needs and investigate its predictive value for patients' long-term outcomes. METHODS: Kidney biopsy-proven Complement-mediated TMA (C-TMA) patients from January 2000 to December 2017 in Peking University First Hospital were retrospectively studied. Both acute and chronic TMA-related lesions, including 15 pathologic indices, were semiquantitatively scored. The interobserver and intraobserver reproducibility and correlation between the pathologic indices and clinical parameters were analyzed. Furthermore, the patients were divided into 2 groups by dialysis use at baseline, and the association of these pathologic indices with their prognostic outcomes was assessed between the two groups. RESULTS: Ninety-two patients with renal biopsy-proven C-TMA were enrolled. All fifteen included pathology indices showed good or moderate interobserver and intraobserver reproducibility and correlated well with several clinical parameters. Several clinicopathological indices were worse in the dialysis group than in the nondialysis group, such as serum creatinine, hemoglobin, platelet count, and estimated glomerular filtration rate. Moreover, morphologic features in the dialysis group presented with more severe vascular lesions. Interstitial fibrosis and chronic tubulointerstitial lesions were related to a trend of high risk of continuous dialysis in the dialysis group. Based on univariate and multivariable Cox regression analysis, more severe glomerular lesions, including glomerular mesangiolysis, glomerular basement membrane double contours and glomerular mesangial proliferation, were identified as risk factors predicting worse prognosis. CONCLUSIONS: Our renal C-TMA semiquantitative scoring system is reliable with good reproducibility and prognostic value in clinical practice, which needs further validation.

Harmonizing Definitions for Diagnostic Criteria and Prognostic Assessment of Transplantation-Associated Thrombotic Microangiopathy: A Report on Behalf of the European Society for Blood and Marrow Transplantation, American Society for Transplantation and Cellular Therapy, Asia-Pacific Blood and Marrow Transplantation Group, and Center for International Blood and Marrow Transplant Research.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic cell transplantation (HCT) associated with significant morbidity and mortality. However, TA-TMA is a clinical diagnosis, and multiple criteria have been proposed without universal application. Although some patients have a self-resolving disease, others progress to multiorgan failure and/or death. Poor prognostic features also are not uniformly accepted. The lack of harmonization of diagnostic and prognostic markers has precluded multi-institutional studies to better understand incidence and outcomes. Even current interventional trials use different criteria, making it challenging to interpret the data. To address this urgent need, the American Society for Transplantation and Cellular Therapy, Center for International Bone Marrow Transplant Research, Asia-Pacific Blood and Marrow Transplantation, and European Society for Blood and Marrow Transplantation nominated representatives for an expert panel tasked with reaching consensus on diagnostic and prognostic criteria. The panel reviewed literature, generated consensus statements regarding diagnostic and prognostic features of TA-TMA using the Delphi method, and identified future directions of investigation. Consensus was reached on 4 key concepts: (1) TA-TMA can be diagnosed using clinical and laboratory criteria or tissue biopsy of kidney or gastrointestinal tissue; however, biopsy is not required; (2) consensus diagnostic criteria are proposed using the modified Jodele criteria with additional definitions of anemia and thrombocytopenia. TA-TMA is diagnosed when ≥4 of the following 7 features occur twice within 14 days: anemia, defined as failure to achieve transfusion independence despite neutrophil engraftment; hemoglobin decline by ≥1 g/dL or new-onset transfusion dependence; thrombocytopenia, defined as failure to achieve platelet engraftment, higher-than-expected transfusion needs, refractory to platelet transfusions, or ≥50% reduction in baseline platelet count after full platelet engraftment; lactate dehydrogenase (LDH) exceeding the upper limit of normal (ULN); schistocytes; hypertension; soluble C5b-9 (sC5b-9) exceeding the ULN; and proteinuria (≥1 mg/mg random urine protein-to-creatinine ratio [rUPCR]); (3) patients with any of the following features are at increased risk of nonrelapse mortality and should be stratified as high-risk TA-TMA: elevated sC5b-9, LDH ≥2 times the ULN, rUPCR ≥1 mg/mg, multiorgan dysfunction, concurrent grade II-IV acute graft-versus-host disease (GVHD), or infection (bacterial or viral); and (4) all allogeneic and pediatric autologous HCT recipients with neuroblastoma should be screened weekly for TA-TMA during the first 100 days post-HCT. Patients diagnosed with TA-TMA should be risk-stratified, and those with high-risk disease should be offered participation in a clinical trial for TA-TMA-directed therapy if available. We propose that these criteria and risk stratification features be used in data registries, prospective studies, and clinical practice across international settings. This harmonization will facilitate the investigation of TA-TMA across populations diverse in race, ethnicity, age, disease indications, and transplantation characteristics. As these criteria are widely used, we expect continued refinement as necessary. Efforts to identify more specific diagnostic and prognostic biomarkers are a top priority of the field. Finally, an investigation of the impact of TA-TMA-directed treatment, particularly in the setting of concurrent highly morbid complications, such as steroid-refractory GVHD and infection, is critically needed.

Clinicopathological features and prognosis of kidney injury in patients after hematopoietic stem cell transplantation / 中华预防医学杂志

To summarize the clinicopathological features and prognosis of kidney injury after hematopoietic stem cell transplantation (HSCT), to provide basis for preventing its occurrence and development. By using a retrospective cohort study method, we collected the clinical and renal biopsy pathological data of all the patients who hospitalized in the Department of Nephrology of Peking University First Hospital from June 2011 to June 2021 with renal injury after HSCT and underwent renal biopsy, and prognosis was followed up by telephone. The clinical laboratory characteristics, renal pathology and prognosis, and their association were analyzed. The results showed that the most common clinical phenotype was chronic kidney disease (CKD,69.2%, 18/26), in this term 13/18 patients received stem cells from haploidentical donors, and 11/18 patients experienced with extrarenal graft-versus-host disease (GVHD). The most common pathologic phenotype was thrombotic microangiopathy (TMA, 61.5%, 16/26). Renal function returned to baseline level in 6 patients, and the kidney survival at 2 years and 5 years were 95.7% (22/23) and 87.5% (14/16), respectively. In conclusion, the clinical phenotype of renal injury after HSCT were mainly CKD, and the most common pathologic phenotype was TMA, the long-term prognosis was favourable.

Thrombotic microangiopathy mediates poor prognosis among lupus nephritis via complement lectin and alternative pathway activation.

Objective: The pathogenesis of thrombotic microangiopathy (TMA) in lupus nephritis (LN) remains complicated. This study aimed to detect the deposition of complement lectin pathway (LP) and alternative pathway (AP) components in renal tissues, then evaluate the clinicopathological characteristics and risk factors for renal survival between patients with or without TMA in LN cohorts. Methods: We included 79 patients with biopsy-proven LN-associated TMA and matched the same number of LN patients without TMA as the control group. The deposition of mannose binding lectin (MBL), MBL-associated serine proteases 1/3 (MASP1/3), complement factor B (CFB), complement factor D (CFD), C4d, and von Willebrand factor (VWF) in renal tissue was assessed by immunohistochemistry and immunofluorescence. Besides, co-localization of C5b-9 and CD34 was detected by confocal microscopy. Results: In our retrospective cohort, the incidence of acute kidney injury (30% vs. 14%, p = 0.013), acute hemodialysis (35% vs. 5%, p < 0.001), and interstitial fibrosis (43% vs. 13%, p < 0.001) is higher in the TMA, compared with the control group. Despite aggressive steroids pulse, plasma exchange, and immunosuppressive therapy among TMA group, they still had significantly inferior 3-year renal survival rates (68% vs. 89%, p = 0.002) than those in the non-TMA group. COX regression analysis identified that TMA (HR 4.807, 95% CI [2.052, 11.263], p < 0.001) is a risk factor in LN. MBL, MASP1/3, CFB, CFD, C4d, and VWF deposited along the glomerulus among LN, while TMA had stronger staining intensity and deposition. The co-localized expression of CD34 and C5b-9 in the endothelial cells was also observed in the renal tissues. Conclusions: TMA is an independent risk factor for renal survival in LN patients. Moreover, LP and AP activation are involved in the pathogenesis of LN-associated TMA.

[Biomarkers of retinal ischemia in thrombotic microangiopathy associated with malignant arterial hypertension on optical coherence tomography]. / Markery retinal'noi ishemii pri tromboticheskoi mikroangiopatii, assotsiirovannoi so zlokachestvennoi arterial'noi gipertenziei, po dannym opticheskoi kogerentnoi tomografii.

Malignant arterial hypertension is a clinical syndrome characterized by severe diastolic arterial hypertension with signs of ischemic damage to various organs. In some malignant arterial hypertension cases, thrombotic microangiopathy occurs - a rare life-threatening condition characterized by multiple systemic thrombosis of the microvasculature, including in the eyes, which can be clarified by optical scanning of the retina. PURPOSE: To determine markers of retinal ischemia in the eyes with thrombotic microangiopathy associated with malignant arterial hypertension. MATERIAL AND METHODS: The study included 6 patients (12 eyes) with thrombotic microangiopathy associated with malignant arterial hypertension who were examined by optical coherence tomography (OCT) and OCT angiography (OCT-A). All patients suffered from renal dysfunction, which etiology was determined by renal biopsy verifying the presence of renal thrombotic microangiopathy in all cases. RESULTS: According to OCT findings, there were bilateral local foci of thinning of the inner nuclear layer with elevation of the outer plexiform and outer nuclear layers of the retina in 5 out of 6 patients (83%). OCT-A revealed that in most cases (67%), these changes had perivascular localization and corresponded to the areas of attenuation of the deep capillary plexus. A statistically significant thinning of the inner nuclear layer of the retina was found in thrombotic microangiopathy associated with malignant arterial hypertension in comparison with the control group. CONCLUSION: Presence of renal thrombotic microangiopathy confirmed by renal biopsy and the anatomical similarity of the microvasculature of the kidneys and the eyes, give basis to consider the foci of «chronic¼ paracentral acute middle maculopathy detected with OCT in patients with malignant arterial hypertension as biomarkers of thrombotic microangiopathy of the eye.

[The role of optical coherence tomography angiography in the assessment of retinal microcirculation in thrombotic microangiopathy associated with malignant arterial hypertension]. / Rol' opticheskoi kogerentnoi tomografii s funktsiei angiografii v otsenke retinal'noi mikrotsirkulyatsii pri tromboticheskoi mikroangiopatii, assotsiirovannoi so zlokachestvennoi arterial'noi gipertenziei.

Optical coherence tomography angiography (OCT-A) allows detailed assessment of the state of local blood flow in various systemic ischemic diseases, which include thrombotic microangiopathy (TMA) associated with malignant arterial hypertension (MAH). PURPOSE: To evaluate retinal microcirculation using OCT-A imaging data in the group of patients with TMA associated with MAH. MATERIAL AND METHODS: The study consisted of a qualitative and quantitative analysis of OCT-A data from 7 patients (14 eyes) with TMA associated with MAH and verified by renal biopsy. The control group included 7 healthy individuals (14 eyes). The following parameters were analyzed: area size of the foveal avascular zone FAZ, mm, vessel density (VD, %) and vessel skeleton density (VSD, %). The indicators were measured separately in the deep and superficial vascular plexuses and divided by localization into: the total density of the entire measured area, central density, density by quadrants (superior, inferior, nasal and temporal). All quadrants were subdivided into inner (corresponding to parafovea) and outer (corresponding to perifovea). RESULTS: Local foci of vascular attenuation of the deep retinal capillary plexus, pathological tortuosity of blood vessels in the deep and superficial retinal capillary plexuses were found in 100% of study group patients. Per-quadrant analysis of OCT-A finding in the macular zone revealed a statistically significant decrease in VD of the deep retinal capillary plexus (p<0.05). A direct correlation was found between glomerular filtration rate and the VD index in the outer inferior (r=0.567; p=0.034) and inner temporal quadrants (r=0.613; p=0.020) of the deep retinal capillary plexus, as well as the level of hemoglobin in blood serum and VD in inner temporal quadrant of the deep vascular plexus (r=0.596; p=0.025). CONCLUSION: Changes revealed with OCT-A are the symptoms of TMA in MAH patients spreading to the retinal microvasculature, mainly at the level of the deep retinal capillary plexus.

A Case of Pulmonary Tumor Thrombotic Microangiopathy: A Rare and Fatal Phenomenon.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a pulmonary hypertensive arteriopathy thought to be caused by activation of the coagulation cascade at the surface of circulating tumor microemboli along with intimal proliferation in small pulmonary arteries in patients with metastatic carcinomas. The subsequent stenosis of the pulmonary vasculature leads to pulmonary hypertension (PH) and, cor pulmonale with eventual respiratory compromise leading to respiratory failure. PTTM is always a nearly fatal disease with most cases diagnosed postmortem. Most cases reported on this condition are from Japan where the incidence of gastric malignancy is relatively higher than other parts of the world. We report a case of a Caucasian man with a classic presentation of PTTM to help make physicians aware of this rare, rapidly progressive and usually fatal phenomenon.

Antemortem Diagnosis of Pulmonary Tumor Thrombotic Microangiopathy in a Patient with Recurrent Breast Cancer: An Autopsy Case Report.

OBJECTIVE: Herein, we report a case of a patient with recurrent breast cancer who was diagnosed antemortem with pulmonary tumor thrombotic microangiopathy (PTTM) using wedge aspiration cytology of the pulmonary artery after breast cancer surgery. CASE SUMMARY: The patient was a 50-year-old woman who underwent mastectomy and axillary lymph node dissection for stage IIIA (T3N2M0) triple-negative left breast cancer. Postoperative follow-up was performed with radiotherapy and anticancer chemotherapy. Seventeen months after the surgery, the patient was hospitalized for right heart failure and diagnosed with pulmonary arterial hypertension. The patient was diagnosed with PTTM following the detection of malignant cells in the pulmonary artery using wedge aspiration cytology. Anti-pulmonary hypertension therapy was administered; however, the patient did not respond and died 26 days after admission. Autopsy revealed multiple microscopic tumor emboli in the pulmonary artery. In portions of the pulmonary artery without embolization, fibro-cellular intimal hyperplasia and stenosis were observed. Tumor embolism was expressed for CK7+/CK20-, consistent with the primary breast cancer. DISCUSSION: Since the primary pathophysiology of PTTM entails narrowing due to fibro-cellular intimal hyperplasia rather than multiple tumor thrombi, the efficacy of chemotherapy combined with vasodilators is discussed.

Endothelial-specific loss of Krüppel-Like Factor 4 triggers complement-mediated endothelial injury.

Thrombotic microangiopathy (TMA) in the kidney represents the most severe manifestation of kidney microvascular endothelial injury. Despite the source of the inciting event, the diverse clinical forms of kidney TMA share dysregulation of endothelial cell transcripts and complement activation. Here, we show that endothelial-specific knockdown of Krüppel-Like Factor 4 (Klf4)ΔEC, an anti-inflammatory and antithrombotic zinc-finger transcription factor, increases the susceptibility to glomerular endothelial injury and microangiopathy in two genetic murine models that included endothelial nitric oxide synthase knockout mice and aged mice (52 weeks), as well as in a pharmacologic model of TMA using Shiga-toxin 2. In all models, Klf4ΔEC mice exhibit increased pro-thrombotic and pro-inflammatory transcripts, as well as increased complement factors C3 and C5b-9 deposition and histologic features consistent with subacute TMA. Interestingly, complement activation in Klf4ΔEC mice was accompanied by reduced expression of a key KLF4 transcriptional target and membrane bound complement regulatory gene, Cd55. To assess a potential mechanism by which KLF4 might regulate CD55 expression, we performed in silico chromatin immunoprecipitation enrichment analysis of the CD55 promotor and found KLF4 binding sites upstream from the CD55 transcription start site. Using patient-derived kidney biopsy specimens, we found glomerular expression of KLF4 and CD55 was reduced in patients with TMA as compared to control biopsies of the unaffected pole of patient kidneys removed due to kidney cancer. Thus, our data support that endothelial Klf4 is necessary for maintenance of a quiescent glomerular endothelial phenotype and its loss increases susceptibility to complement activation and induction of prothrombotic and pro-inflammatory pathways.

Pulmonary Tumor Embolism and Pulmonary Tumor Thrombotic Microangiopathy Causing Rapidly Progressive Respiratory Failure: A Case Series.

Pulmonary tumor embolism (PTE) and pulmonary tumor thrombotic microangiopathy (PTTM) are rare etiologies for rapidly progressive dyspnea in the setting of undiagnosed metastatic cancer. They occur most frequently in association with adenocarcinomas, with PTE being most frequently associated with hepatocellular carcinoma and PTTM being most commonly reported with gastric adenocarcinoma. Pulmonary tumor embolism and PTTM appear to be a disease spectrum where PTTM represents an advanced form of PTE. Pulmonary tumor embolism and PTTM are mostly identified postmortem during autopsy as the antemortem diagnosis remains a clinical challenge due to the rapidly progressive nature of these rare diseases. We report 2 cases of rapidly progressive respiratory failure leading to death, due to tumoral pulmonary hypertension resulting from PTE and PTTM, diagnosed postmortem. Both of the patients were middle-aged females, nonsmokers, and had a gastrointestinal source of their primary malignancy.

Nephrotic syndrome as a manifestation of thrombotic microangiopathy due to long-term use of sunitinib.

Nephrotic syndrome in patients with cancer may be related to the primary malignancy or chemotherapeutic therapy. Solid organ cancers may cause membranous glomerulonephritis which is manifested by nephrotic syndrome; other less common histologic presentations include focal and segmental glomerulosclerosis and minimal change disease. In addition, chemotherapy agents may cause renal toxicity by affecting the small blood vessels, glomeruli, tubules, and interstitium. Tyrosine kinase inhibitors such as sunitinib may cause endothelial and podocyte damage leading to thrombotic microangiopathy affecting only the kidney and manifested by proteinuria and hypertension. We report a case of an elderly man with gastrointestinal stromal tumor (GIST) on treatment with sunitinib who had as a complication a thrombotic microangiopathy manifested with nephrotic syndrome and a hypertension of difficult control, which was finally controlled by stopping this drug but had a fatal outcome due to its malignancy.

The roles of homocysteinemia and methylmalonic acidemia in kidney injury in atypical hemolytic uremic syndrome caused by cobalamin C deficiency.

BACKGROUND: Cobalamin C (cblC), a vitamin B12 processing protein, plays a crucial role in metabolism for the conversion of homocysteine to methionine and methylmalonyl-CoA to succinyl-CoA. CblC deficiency, an inborn error of cobalamin processing, is a rare cause of atypical hemolytic-uremic syndrome (aHUS) and results in hyperhomocysteinemia and methylmalonic aciduria. Both substances are thought to contribute to thrombotic microangiopathy (TMA) in cblC deficiency patients. However, the roles of homocysteine and methylmalonic acid (MMA) in these patients remain unclear. We want to shed more light on the contributions of homocysteine and MMA levels as contributing factors for thrombotic microangiopathy (TMA)/aHUS by a follow-up of a cblC deficiency patient over 6 years. CASE DIAGNOSIS: A 27-day-old Hispanic female presented with abnormal C3-carnitine on her newborn screen, poor feeding, decreased activity, and oligouria. She was diagnosed with cblC deficiency after laboratory results revealed elevated serum homocysteine, and serum MMA along with genetic testing showing a homozygous pathogenic frameshift variant in MMACHC. The patient developed aHUS and acute kidney injury (AKI), which resolved after appropriate therapy. Over 6 years, she continued to have normal kidney function with no thrombocytopenia despite persistently elevated homocysteine and MMA levels. CONCLUSION: We question the roles of homocysteine and MMA as causative of aHUS/TMA in cblC deficiency as they remained elevated during follow-up but did not result in aHUS/TMA or AKI. Hyperhomocysteinemia and/or MMA caused by other metabolic diseases do not result in aHUS/TMA or AKI. This suggests that other nephrotoxic factors may trigger aHUS/TMA in cblC patients.