Signs Of Thrombotic Microangiopathy Research Articles

Divergent cardiac and renal effects of miR-181c-5p inhibition in a rodent heart failuremodel.

MiR-181c-5p overexpression associates with heart failure (HF) and cardiac damage, but the underlying pathophysiology remains unclear. This study investigated the effect of miR-181c-5p inhibition on cardiac function and fibrosis in a rodent model of diastolic dysfunction, and evaluated additional effects on kidney as relevant comorbid organ. Diastolic dysfunction was induced in male C57/BL6J mice (n = 20) by combining high-fat diet, L-NG-nitroarginine methyl ester, and angiotensin II administration, and was compared to sham controls (n = 18). Mice were randomized to subcutaneous miR-181c-5p antagomiR (INH) or scrambled antagomiR injections (40 mg/kg/week). HF mice demonstrated diastolic dysfunction and increased fibrosis, which was attenuated by INH treatment. Remarkably, HF + INH animals had a threefold higher mortality rate (60%) compared to HF controls (20%). Histological examination revealed increased glomerular damage in all INH treated mice, and signs of thrombotic microangiopathy (TMA) in mice who died prematurely. Quantitative polymerase chain reaction demonstrated a miR-181c-5p-related downregulation of cardiac but not renal Tgfbr1 in HF + INH mice, while INH treatment reduced renal but not cardiac Vegfa expression in all mice. This study demonstrates cardiac anti-fibrotic effects of miR-181c-5p inhibition in a rodent HF model through targeting of Tgfbr1 in the heart. Despite improved diastolic function, HF + INH mice had higher mortality due to increased predisposition for TMA, increased renal fibrosis and glomerular damage, associated with Vegfa downregulation in kidneys.

Ex vivo C5b-9 Deposition Test to Monitor Complement Activity in Clinical and Subclinical Atypical Hemolytic Uremic Syndrome and in Transplantation-Associated Thrombotic Microangiopathy

IntroductionAtypical Haemolytic Uremic Syndrome (aHUS) is a complement system (CS)-mediated ultrarare disease that manifests as thrombotic microangiopathy (TMA) with preferential small kidney vessels involvement. Transient CS activation is also observed in secondary TMA or in patients at risk to develop aHUS. There is no gold standard test to monitor disease activity but the ex vivo C5b-9 deposition test to be a better approach. MethodsWe assessed the C5b-9 deposition induced by serum samples of patients with aHUS (n=8) and with TMA associated to kidney (n=2), lung (n=1) or hematopoietic stem cell (HSC) transplantation (n=2) during the acute phase of the disease or in remission. As control for transplant associated (TA)-TMA we have analyzed samples of clinically stable kidney and HSC-transplanted patients without signs of TMA. Additionally, we studied one child with genetic risk of aHUS during an acute infection. ResultsIn the acute disease phase or in patients with disease activity despite C5 blockade, a significant increase of C5b-9 deposition was detected. In all patients with clinical response to C5 blockade but one, levels of C5b-9 deposition were within the normal range. Finally, we detected increased C5b-9 deposition levels in an asymptomatic child with genetic risk of aHUS when a concomitant otitis episode was ongoing. ConclusionThe ex vivo C5b-9 deposition test is an auspicious tool to monitor CS activity in aHUS and TA-TMA. In addition, we demonstrate that the test may also be useful to detect subclinical increase of CS activity which expands the spectrum of patients that would benefit from a better CS activity assessment.

MO175: Association between Thrombotic Microangiopathy, ADAMTS13 Activity and Development of AKI, ARDS, AND Poor Outcomes in COVID-19 Patients (Pilot Study)

BACKGROUND AND AIMSCases of microangiopathy associated with COVID-19 are not fully understood. We aimed to clarify in these patients the presence of thrombotic microangiopathy (TMA) and decreased ADAMTS13 activity, the possible influence of these factors on kidney and lung damage, and outcomes.METHODThe study involved 90 patients with COVID-19 and viral pneumonia, who were treated at the Pavlov First St. Petersburg State Medical University. Patients undergoing plasma transfusion were excluded. In addition to the standard examination, activity of ADAMTS13 was determined in admission (ELISA, normal range 30–160%).RESULTSMedian level ADAMTS13 was 92%, IQR 27.9%. The presence of TMA took place in 26.7% of patients, in 41.5% patients with TMA the level of activity of ADAMTS13 was less than 60%. In patients with respiratory failure, the ADAMTS13 level was significantly lower–78.4%, IQR 32.1% versus 108.6%, IQR 26.7%. In patients with respiratory failure (P < .01), the incidence of TMA was significantly higher–34.2% versus 19.3%, respectively (P < .01). The ADAMTS13 level neg. correlated with the risk of developing TMA (ρ = –0.486, P < .01), AKI of any stage (KDIGO2012 criteria) (ρ = –0.288, P < .01), acute respiratory distress syndrome (ARDS, ‘Berlin definition’) (ρ = –0.304, P < .01), the duration of hospitalization (ρ = –0.342, P < .01) and the probability of death (ρ =–0.278, P < .01). In the case of five patients, an extremely low level of ADAMTS13 (less than 30%) was noted, which in all cases was accompanied by laboratory signs of TMA and the development of ARDS; two patients had a fatal outcome.CONCLUSIONTMA and low ADAMTS13 activity are associated with progression to severe COVID-19 disease and development of AKI. Some of the cases of TMA in these patients may be due to low ADAMTS13 activity. Further research is needed to assess the potency of treating these patients with TMA associated with low ADAMTS activity.

Projected Cost Savings of a Plasmic Score-Based Approach to Patients with Suspected Thrombotic Thrombocytopenic Purpura

Background: Thrombotic thrombocytopenic purpura (TTP) is a rare but deadly thrombotic microangiopathy (TMA) that is caused by a severe acquired deficiency in the ADAMTS13 enzyme. The PLASMIC clinical scoring system categorizes patients with suspected TTP as being at low (score <5), intermediate (score = 5), or high (score >5) risk of severe ADAMTS13 deficiency. Here we have modeled the potential cost savings of a management approach that incorporates the PLASMIC score to defer testing and treatment for low risk patients and compared this approach to one in which ADAMTS13 testing requests require pre-approval by the blood transfusion service.Methods: We utilized an expanded dataset from the Harvard TMA Research Collaborative, a multi-institutional registry consisting of all consecutive patients with TMA and suspected TTP seen at three large academic medical centers between 2004-2015 (n=372). We leveraged existing differences in practice patterns between participating institutions to identify hospitals that do not regulate ADAMTS13 testing (Group A, N=278) and those that employed a restrictive strategy in which requests for ADAMTS13 testing were subject to approval by the blood transfusion service (Group B, N=94). A decision tree-based cost analysis algorithm was utilized to assess the potential cost savings from utilizing the PLASMIC score to defer ADAMTS13 testing in low-risk patients in Group A. We also compared total TTP-related costs (diagnosis and treatment) between Group A (both the unregulated and PLASMIC-based approach) and Group B.Results: Different practice patterns between Groups A and B provided a “natural experiment” to study the cost implications of different management approaches for TTP. In Group A, we noted a 435% increase in ADAMTS13 assays sent between 2004-2015 (test for trend p<0.0001), driven largely by patients without signs of TMA and/or with low-risk PLASMIC scores. This growth in testing was absent in Group B (test for trend p=0.98). The number of TTP cases per 100,000 admissions did not differ the two groups (p=0.19) and remained unchanged over time (p=0.67 and p=0.31 for Groups A and B, respectively). To assess the cost differences between management approaches, we generated a decision tree containing nodes with important clinical choices such as ADAMTS13 testing, expert consultation, and initiation of therapeutic plasma exchange (TPE). The tree excluded patients without thrombocytopenia or schistocytes at its first branch point. In projecting the number of ADAMTS13 tests through 2025, we found that Group A's TTP-related costs were significantly higher and would result in over $11 million in increased costs between 2004-2025 compared to Group B (Figure 1). Under a PLASMIC score-based approach, patients at Group A institutions with a low risk score would not receive upfront ADAMTS13 testing or downstream care for TTP and instead be closely observed while being worked up for alternative causes of TMA. Considering 2015, the latest year for which complete data are available, applying a PLASMIC-score based approach to the Group A institutions was projected to reduce TTP-related costs from $610,471 to $473,058 (23%) per 100,000 admissions (Table 1). By comparison, in 2015 Group B TTP-related costs were $152,000 per 100,000 admissions. Assuming current trends, a PLASMIC score-based strategy within Group A would result in over $3.2 million (23%) saved between 2004-2025 compared to the current unregulated approach, primarily due to decreased rates of testing, expert consultation, and TPE.Conclusions: Our data suggest that institutions with an unregulated approach to ADAMTS13 testing could potentially realize cost savings by implementing a strategy based on risk stratification of suspected TTP cases by PLASMIC score. In terms of normalized costs, a PLASMIC-score based strategy would be intermediate between an unregulated testing approach and one that employs live oversight of ADAMTS13 testing by the blood transfusion service. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

P0392AHUS ASSOCIATED WITH IGA NEPHROPATHY

Abstract Background and Aims IgAN is characterized by the presence of intense deposits of C3 accompanying IgA. As documented in several studies this is due to the activation of the complement system by pathological IgA; the mechanism of IgA–mediated complement activation remains poorly understood but is thought to act with different mechanisms such as the stabilization of the C3 convertase, the activation of the lectin pathway through polymeric IgA and eventually inherited partial deficiencies of complement regulatory genes [Maillard N, Wyatt RJ, Julian BA, Kiryluk K, Gharavi A, Fremeaux-Bacchi V, Novak J.J Current Understanding of the Role of Complement in IgA Nephropathy.Am Soc Nephrol 26:, 2015] . Dysregulation of the C3 convertase is a recognized cause of thrombotic microangiopathy (TMA) in atypical hemolytic uremic syndrome (aHUS). The association between aHUS and IgAN has been sporadically described . In this study we report a series of 6 patients, observed in our department, with biopsy proven IgAN, who developed aHUS during the follow-up. We report a series of aHUS associated IgA nephropathy. Method This report describes 6 patients with aHUS IgAN who were identified among all patients with biopsy proven IgAN observed at the Department of Nephrology, University of Parma, from March 2010 to March 2015. The diagnosis of aHUS was suspected in the presence of renal biopsy with documented typical signs of TMA (glomerular or arteriolar thrombi, onion skin lesions) associated with non-immune microangiopathic haemolytic anemia, increased reticulocyte count, negative Coomb test, thrombocytopenia (platelets &amp;lt;150000/mm3). Results Data collected on the 6 patients with IgA nephropathy associated with aHUS are described in Figure 1. All the cases of aHUS-IgAN were characterized by worsening of nephrotic proteinuria and reduced serum C3. Pathogenetic variant of CFH, predisposing for aHUS were identified in 2/6 cases; in the remaining patients a predisposing risk aplotype for aHUS was documented. All patients were treatment resistant for IgA nephropathy, had persistent proteinuria and progressed to ESRD. Conclusion It is known that most cases of aHUS are associated with the presence of genetic or acquired alterations of the regulation of the complement AP. However overlapping of other triggering conditions was documented in 70% of aHUS cases [Noris M, Caprioli J, Bresin E, et al. Relative Role of Genetic Complement Abnormalities in Sporadic and Familial aHUS and Their Impact on Clinical Phenotype. Clin J Am Soc Nephrol. 2010;5: 1844–1859]. Our case series shows that the presence of genetic factors predisposing to uncontrolled activation of the C3 convertase associated to continuous activation of the same enzyme from pathological IgA, could lead to sC3 consumption, development of aHUS and consequent rapid progression towards ESRD. In conclusion during the natural history of IgAN, appearance of hemolysis, thrombocytopenia, serum C3 reduction and increasing proteinuria would suggest to search for aHUS, allowing to early treatment with plasmapheresis and/or new available complement targeted inhibitors to prevent renal failure.

Pig-to-non-human primate heart transplantation: The final step toward clinical xenotransplantation?

The demand for donated human hearts far exceeds the number available. Xenotransplantation of genetically modified porcine organs provides an alternative. In 2000, an Advisory Board of the International Society for Heart and Lung Transplantation set the benchmark for commencing clinical cardiac xenotransplantation as consistent 60% survival of non-human primates after life-supporting porcine heart transplantations. Recently, we reported the stepwise optimization of pig-to-baboon orthotopic cardiac xenotransplantation finally resulting in consistent success, with 4 recipients surviving 90 (n = 2), 182, and 195 days. Here, we report on 4 additional recipients, supporting the efficacy of our procedure. The first 2 additional recipients succumbed to porcine cytomegalovirus (PCMV) infections on Days 15 and 27, respectively. In 2 further experiments, PCMV infections were successfully avoided, and 3-months survival was achieved. Throughout all the long-term experiments, heart, liver, and renal functions remained within normal ranges. Post-mortem cardiac diameters were slightly increased when compared with that at the time of transplantation but with no detrimental effect. There were no signs of thrombotic microangiopathy. The current regimen enabled the prolonged survival and function of orthotopic cardiac xenografts in altogether 6 of 8 baboons, of which 4 were now added. These results exceed the threshold set by the Advisory Board of the International Society for Heart and Lung Transplantation. The results of our current and previous experimental cardiac xenotransplantations together fulfill for the first time the pre-clinical efficacy suggestions. PCMV-positive donor animals must be avoided.

Immunoadsorption Combined with Membrane Filtration to Counteract Early Treatment-Refractory Antibody-Mediated Rejection

Introduction: Immunoadsorption (IA) represents a therapeutic option for acute antibody-mediated rejection (ABMR) after kidney transplantation. The addition of membrane filtration (MF) to enhance elimination of macromolecular components that potentially contribute to rejection, such as key complement component C1q and alloreactive IgM, may be an effective strategy to further improve its therapeutic efficiency. Results: Here we present 4 consecutive patients with episodes of HLA donor-specific antibody-positive ABMR nonresponsive to cycles of 6–16 sessions of IA treatment. Rejection episodes were characterized by severe microvascular injury (high-grade microcirculation inflammation and/or signs of thrombotic microangiopathy) and evidence of intense complement activation in peritubular capillaries (diffuse C4d-positivity). IA combined with MF led to substantial morphologic improvement (follow-up biopsies: g + ptc and C4d scores ≤1) and stabilization of allograft function. Conclusions: Our findings provide evidence for an effect of combination of IA + MF in refractory early acute/active ABMR in kidney transplant recipients.

302. Preeclampsia, HELLP-syndrome after kidney transplantation

Preeclampsia (PE) and HELLP -syndrome often complicates pregnancies after maternal kidney transplantation. Moreover, women who become pregnant after renal transplantation are at higher risk of any TMA(thrombotic microangiopathy)-disorders. Objective We aimed to assess frequency of TMA, PE, HELLP –syndrome and negative obstetric outcomes, kidney function decline during the pregnancy. Methods An retrospective single-center cohort study 01/2014– 12/2017: 19 patients with renal allograft, 29 ± 4.35 years old (24–39). Renal function at conception and after delivery, pregnancy outcomes, clinical and laboratory parameters were collected from women who were pregnant after renal transplantation and had transplant and obstetric care. Results 10 of 19(52,6%) have had laboratory signs of TMA during pregnancy –gr.1. All of them had normal levels of calcineurin inhibitor concentration. Symptoms of TMA were wavy, alternating with spontaneous improvement and were not regarded as manifestations of a possible PE in 6 (sFlt-1 were normal). 4 of 19 (21.3%) had full HELLP-syndrome. Without TMA 9/19- gr.2. Only patients with HELLP or PE had elevated sFlt-1/PlGF ratio. There were no ”pure” PE(without signs of partial HELLP). In patients without signs of TMA, the sFlt-1 / PIGF ratio did not exceed the 4.95. Anemia was detected in all patients, but the signs of TMA showed anemia more pronounced. Thrombocytopenia was noted only in patients with signs of TMA. GFR was significantly reduced in all patients with signs of TMA. Conclusion Signs of TMA during pregnancy after kidney transplantation have had every second woman. Pregnancy outcomes were worse in TMA, newborns had lower Apgar scores, growth and birth weights. Pregnancy after kidney transplantation is independent risk factor of the development of HELLP syndrome, rather than ”pure” PE. Patients with TMA demonstrate the most pronounced impairment of kidney function and an unfavorable outcome of pregnancy.

A simple prognostic index for Shigatoxin-related hemolytic uremic syndrome at onset: data from the ItalKid-HUS network.

Shigatoxin Escherichia coli-related hemolytic uremic syndrome (eHUS) is a severe thrombotic microangiopathy (TMA) burdened by life-threatening complications and long-term sequelae. Since hemoconcentration is associated with worse outcome, we tried to develop a reliable and easy-to-calculate index for predicting complications and sequelae based on hemoglobin (Hb) at presentation. The first laboratory examinations with signs of TMA in eHUS patients were analyzed in relation to the outcomes with the receiver operating characteristic curves and their areas under the curve (AUC) for Hb and creatinine (sCr). A total of 197 eHUS patients were identified of whom 24% did not have anemia at presentation. Hb level was the best predictor of a poor outcome (AUC 0.67) but the combination of Hb with sCr, in the formula [(Hb in g/dL + (sCr in mg/dL × 2)], showed an even better AUC of 0.75. The described scoring system was also strongly associated and predictive of all complications and health care needs (8% of patients with scoring > 13 died or entered a permanent vegetative state compared with 0% of those with ≤ 13).Conclusion: The presented score is a simple and early predictor of both short- and long-term outcomes and identifies patients who should undergo rapid volume expansion to counteract hemoconcentration, the spreading of microvascular thrombosis, and the consequent increased organ damage. What is Known: • In eHUS, hemoconcentration is associated with worse short- and long-term outcome. • A prognostic index to identify patients at higher risk for complications at presentation is not available. What is New: • We developed a simple and early prognostic index for eHUS outcome with the combination of Hb and sCr at onset, in the following formula [(Hb in g/dL + (sCr in mg/dL × 2)]. • The proposed HUS Severity Score can promptly identify patients with good outcome and those with high risk of worse short- and long-term outcome.

Pre-clinical heterotopic intrathoracic heart xenotransplantation: a possibly useful clinical technique.

As a step towards clinical cardiac xenotransplantation, our experimental heterotopic intrathoracic xenotransplantation model offers a beating and ejecting donor heart while retaining the recipient's native organ as a backup in case of graft failure. Clinically applicable immunosuppressive regimens (IS) were investigated first, then treatments known to be effective in hypersensitized patients or those with recalcitrant rejection reactions. Consecutive experiments were carried out between 2009 and 2013. Twenty-one genetically modified pigs (GGTA1-knockout/hCD46/± thrombomodulin, in one case HLA-E instead) were used as donors. In all experiments, two cycles of immunoabsorption reduced preformed antibodies. Recipient baboons were divided into two groups according to IS regimen: In group one (n = 10), pre-treatment started either one (anti-CD20) or four weeks (anti-CD20 plus the proteasome inhibitor bortezomib) prior to transplantation. The extended conventional (as for allotransplantation) immunosuppressive maintenance regimen included anti-thymocyte globuline, tacrolimus, mycophenolate mofetil, methylprednisolone and weekly anti-CD20. In group two (n = 11), myeloablative pre-treatment as in multiple myeloma patients (long and short regimens) was added to extended conventional IS; postoperative total thoracic and abdominal lymphoid irradiation (TLI; single dose of 600 cGY) was used to further reduce antibody-producing cells. In the perioperative course, the surgical technique was safely applied: 19 baboons were weaned off extracorporeal circulation and 17 extubated. Nine animals were lost in the early postoperative course due to causes unrelated to surgical technique or IS regimen. Excluding these early failures, median graft survival times of group 1 and 2 were 18.5 (12-50) days and 16 (7-35) days. Necropsy examination of group 1 donor organs revealed hypertrophy of the left ventricular wall in the six longer-lasting grafts; myocardial histology confirmed pre-clinical suspicion of humoral rejection, which was not inhibited by the extended conventional IS including intensified treatments, and signs of thrombotic microangiopathy. Grafts of group 2 presented with only mild-to-moderate features of humoral rejection and thrombotic microangiopathy, except in one case of delayed rejection on day 17. The other experiments in this group were terminated because of untreatable pulmonary oedema, recurring ventricular fibrillation, Aspergillus sepsis, as well as a combination of a large donor organ and late toxic side effects due to TLI. Longer-term results were difficult to achieve in this model due to the IS regimens used. However, we conclude that heterotopic intrathoracic heart transplantation may be an option for clinical xenotransplantation.

Seasonal Flu as a Triggering Factor for Acquired Thrombotic Thrombocytopenic Purpura

A 47 years old woman was admitted to our intensive care unit for acute asthma. An infection by influenza virus A was diagnosed and the patient presented during her hospitalization signs of thrombotic microangiopathy. Biologic analysis showed low A Desintegrin and Metalloproteinase with ThromboSpondin 1 - motifs - member 13 (ADAMTS13) activity and positive anti-A Desintegrin And Metalloproteinase with ThromboSpondin 1 - motifs - member 13 antibodies. Diagnosis of Acquired Thrombotic Thrombocytopenic Purpura was considered and a specific treatment was started with plasma exchange and intravenous administration of rituximab for relapse. Acquired Thrombotic Thrombocytopenic Purpura is considered an auto-immune disease. As such, it can be triggered by bacterial or viral infection. Many triggering factors have been described. Testing for influenza virus should be considered in epidemic situations when a Thrombotic Thrombocytopenic Purpura is diagnosed.

Hämolytisch-urämisches Syndrom nach EHEC-Infektion – Fall 9/2011

We report on four patients treated for typical hemolytic uremic syndrome (HUS) at our hospital during the outbreak in Germany in May 2011. Three out of four patients had previously travelled to northern Germany, one patient was exposed within the family. All patients were tested positive for enterohemorrhagic E.coli of the type O104:H4 in stool cultures and presented with signs of thrombotic microangiopathy and fragmented erythrocytes. Due to strong hemolytic activity (LDH >600 U/l), thrombocytopenia (< 60,000/µl) und acute kidney injury (creatinine >1.2 mg/dl) plasma separation with fresh frozen plasma was commenced in three out of four patients with the fourth patient exhibiting a self-limiting course. Altogether, it took 7 to 13 treatments until disease activity was stopped. During treatment, kidney injury recovered and all patients had negative stool cultures. The HUS-outbreak 2011 in Germany was associated with a severe course in many patients, particularly in women. Treatment with plasma separation was successful to stop hemolysis and end disease activity.

Pulmonary-renal syndrome in systemic sclerosis: a report of three cases and review of the literature

We describe three cases of acute renal failure with diffuse alveolar hemorrhage, which is designated pulmonary-renal syndrome (PRS), in systemic sclerosis (SSc) and review the literature to better define this rare but severe complication of SSc. The clinical course of three SSc patients with acute renal failure and concomitant diffuse alveolar hemorrhage are reported, and the literature published between 1967 and 2005 is reviewed following a PubMed search. Including our cases, a total of 19 SSc patients with acute renal failure and concomitant diffuse alveolar hemorrhage have been reported. Pulmonary-renal syndrome developing in SSc patients can be categorized clinicopathologically into three entities: PRS with thrombotic microangiopathy, PRS with small vessel vasculitides accompanied with SSc, and d-penicillamine-induced Goodpasture-like syndrome. Patients with scleroderma PRS with thrombotic microangiopathy, to which group our all patients belong, often developed diffuse alveolar hemorrhage after receiving high-dose corticosteroid therapy. Pulmonary-renal syndrome is a fatal complication of SSc and results from different pathogenic processes. Prompt differential diagnosis between the subsets is critical, because therapeutic strategy may differ in the use of high-dose corticosteroid and plasma exchange between the subsets of PRS. Clinical courses of the patients with PRS with thrombotic microangiopathy suggest that high-dose corticosteroid therapy is a trigger of diffuse alveolar hemorrhage in patients with diffuse SSc with signs of thrombotic microangiopathy.

Pulmonary-renal syndrome in systemic sclerosis: a report of three cases and review of the literature

We describe three cases of acute renal failure with diffuse alveolar hemorrhage, which is designated pulmonary-renal syndrome (PRS), in systemic sclerosis (SSc) and review the literature to better define this rare but severe complication of SSc. The clinical course of three SSc patients with acute renal failure and concomitant diffuse alveolar hemorrhage are reported, and the literature published between 1967 and 2005 is reviewed following a PubMed search. Including our cases, a total of 19 SSc patients with acute renal failure and concomitant diffuse alveolar hemorrhage have been reported. Pulmonary-renal syndrome developing in SSc patients can be categorized clinicopathologically into three entities: PRS with thrombotic microangiopathy, PRS with small vessel vasculitides accompanied with SSc, and d-penicillamine-induced Goodpasture-like syndrome. Patients with scleroderma PRS with thrombotic microangiopathy, to which group our all patients belong, often developed diffuse alveolar hemorrhage after receiving high-dose corticosteroid therapy. Pulmonary-renal syndrome is a fatal complication of SSc and results from different pathogenic processes. Prompt differential diagnosis between the subsets is critical, because therapeutic strategy may differ in the use of high-dose corticosteroid and plasma exchange between the subsets of PRS. Clinical courses of the patients with PRS with thrombotic microangiopathy suggest that high-dose corticosteroid therapy is a trigger of diffuse alveolar hemorrhage in patients with diffuse SSc with signs of thrombotic microangiopathy.