How I diagnose and treat atypical hemolytic uremic syndrome.

Our understanding and management of atypical hemolytic uremic syndrome (aHUS) have dramatically improved in the last decade. aHUS has been established as a prototypic disease resulting from a dysregulation of the complement alternative C3 convertase. Subsequently, prospective nonrandomized studies and retrospective series have shown the efficacy of C5 blockade in the treatment of this devastating disease. C5 blockade has become the cornerstone of the treatment of aHUS. This therapeutic breakthrough has been dulled by persistent difficulties in the positive diagnosis of aHUS, and the latter remains, to date, a diagnosis by exclusion. Furthermore, the precise spectrum of complement-mediated renal thrombotic microangiopathy is still a matter of debate. Nevertheless, long-term management of aHUS is increasingly individualized and lifelong C5 blockade is no longer a paradigm that applies to all patients with this disease. The potential benefit of complement blockade in other forms of HUS, notably secondary HUS, remains uncertain.

An expert discussion on the atypical hemolytic uremic syndrome nomenclature-identifying a road map to precision: a report of a National Kidney Foundation Working Group.

The term atypical hemolytic uremic syndrome has been in use since the mid-1970s. It was initially used to describe the familial or sporadic form of hemolytic uremic syndrome as opposed to the epidemic, typical form of the disease. Over time, the atypical hemolytic uremic syndrome term has evolved into being used to refer to anything that is not Shiga toxin-associated hemolytic uremic syndrome. The term describes a heterogeneous group of diseases of disparate causes, a circumstance that makes defining disease-specific natural history and/or targeted treatment approaches challenging. A working group of specialty-specific experts in the thrombotic microangiopathies was convened to review the validity of this broad term in an era of swiftly advancing science and targeted therapeutics. A Delphi approach was used to define and interrogate some of the key issues related to the atypical hemolytic uremic syndrome nomenclature.

A case-based narrative review of pregnancy-associated atypical hemolytic uremic syndrome/complement-mediated thrombotic microangiopathy.

Atypical hemolytic uremic syndrome is a complement-mediated thrombotic microangiopathy caused by uncontrolled activation of the alternative complement pathway in the setting of autoantibodies to or rare pathogenic genetic variants in complement proteins. Pregnancy may serve as a trigger and unmask atypical hemolytic uremic syndrome/complement-mediated thrombotic microangiopathy (aHUS/CM-TMA), which has severe, life-threatening consequences. It can be difficult to diagnose aHUS/CM-TMA in pregnancy due to overlapping clinical features with other thrombotic microangiopathy syndromes including hypertensive disorders of pregnancy. However, the distinction among thrombotic microangiopathy etiologies in pregnancy is important because each syndrome has specific disease management and treatment. In this narrative review, we discuss 2 cases to illustrate the diagnostic challenges and evolving approach in the management of pregnancy-associated aHUS/CM-TMA. The first case involves a 30-year-old woman presenting in the first trimester who was diagnosed with aHUS/CM-TMA and treated with eculizumab from 19 weeks' gestation. Genetic testing revealed a likely pathogenic variant in CFI. She successfully delivered a healthy infant at 30 weeks' gestation. In the second case, a 22-year-old woman developed severe postpartum HELLP syndrome, requiring hemodialysis. Her condition improved with supportive management, yet investigations assessing for aHUS/CM-TMA remained abnormal 6 months postpartum consistent with persistent complement activation but negative genetic testing. Through detailed case discussion describing tests assessing for placental health, fetal anatomy, complement activation, autoantibodies to complement regulatory proteins, and genetic testing for aHUS/CM-TMA, we describe how these results aided in the clinical diagnosis of pregnancy-associated aHUS/CM-TMA and assisted in guiding patient management, including the use of anticomplement therapy.

Constipation and hemolytic uremic syndrome.

BACKGROUND: Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) classically presents with diarrhea. Absence of diarrheal prodrome increases suspicion for atypical HUS (aHUS). Inability to obtain a fecal specimen for culture or culture-independent testing limits the ability to differentiate STEC-HUS and aHUS. CASE-DIAGNOSIS/TREATMENT: Our patient presented with abdominal pain and constipation, and evaluation of pallor led to a diagnosis of HUS. There was a complete absence of diarrhea during the disease course. Lack of fecal specimen for several days delayed testing for STEC. Treatment for atypical HUS was initiated with complement-blockade therapy. PCR-testing for Shiga toxin from fecal specimen later returned positive. Alternative complement-pathway testing did not identify a causative genetic variant or anti-Factor H antibody. A diagnosis of STEC-HUS was assigned, and complement-blockade therapy was stopped. CONCLUSION: Diagnosis of aHUS remains a diagnosis of exclusion, whereby other causes of HUS are eliminated with reasonable certainty. Exclusion of STEC is necessary and relies on testing availability and recognition of testing limitations. Diarrhea-negative STEC-HUS remains a minority of cases, and future research is needed to explore the clinical characteristics of these patients.

Anti-CFH-associated hemolytic uremic syndrome: do we still need plasma exchange?

BACKGROUND: Between 5 and 50% of atypical hemolytic uremic syndrome (aHUS) cases in children are caused by autoantibodies against complement factor H (CFH). Given the acquired autoimmune nature of the disease, plasma exchange (PE) and various immunosuppressive treatments have been used. More recently, eculizumab has been proposed. METHODS: In this multicenter, retrospective study, we report outcomes of 12 children with anti-FH antibody-associated HUS treated with eculizumab associated with various immunosuppressive regimens. RESULTS: Patients were treated with eculizumab for 15.5 [9.5;23.0] months and 3 received PE or IgG adsorption. Three patients received mycophenolate mofetil (MMF) alone, 1 patient received MMF and steroids, 1 patient received MMF and rituximab, 3 patients received MMF/steroids and rituximab, and 4 patients did not receive any immunosuppression. Anti-FH antibody levels significantly decreased but no difference was observed based on the immunosuppressive regimen. Eculizumab was discontinued in 7/10 patients after 11 [7.5;15.5] months and MMF in 6/8 patients after 36 [35;40] months. Anti-FH titers at MMF discontinuation ranged from 257 to 3425 UI/L. None of these patients relapsed and eGFR at last follow-up was above 70 mL/min/1.73 m2 in all patients. CONCLUSIONS: Eculizumab is effective and safe in inducing and maintaining remission in aHUS secondary to anti-FH antibodies and renders reduction of anti-FH titers less urgent. Anti-FH antibody titers decreased in most patients irrespective of the immunosuppressive treatment chosen, so that a strategy consisting of combining eculizumab with MMF monotherapy seems sufficient at least in non-Indian or less severe forms of anti-FH antibody-associated HUS.

Characterization of patients with aHUS and associated triggers or clinical conditions: A Global aHUS Registry analysis.

INTRODUCTION: Atypical haemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) associated with complement dysregulation; aHUS may be associated with other 'triggers' or 'clinical conditions'. This study aimed to characterize this patient population using data from the Global aHUS Registry, the largest collection of real-world data on patients with aHUS. METHODS: Patients enrolled in the Global aHUS Registry between April 2012 and June 2021 and with recorded aHUS-associated triggers or clinical conditions prior/up to aHUS onset were analysed. aHUS was diagnosed by the treating physician. Data were classified by age at onset of aHUS (< or ≥18 years) and additionally by the presence/absence of identified pathogenic complement genetic variant(s) and/or anti-complement factor H (CFH) antibodies. Genetically/immunologically untested patients were excluded. RESULTS: 1947 patients were enrolled in the Global aHUS Registry by June 2021, and 349 (17.9%) met inclusion criteria. 307/349 patients (88.0%) had a single associated trigger or clinical condition and were included in the primary analysis. Malignancy was most common (58/307, 18.9%), followed by pregnancy and acute infections (both 53/307, 17.3%). Patients with an associated trigger or clinical condition were generally more likely to be adults at aHUS onset. CONCLUSION: Our analysis suggests that aHUS-associated triggers or clinical conditions may be organized into clinically relevant categories, and their presence does not exclude the concurrent presence of pathogenic complement genetic variants and/or anti-CFH antibodies. Considering a diagnosis of aHUS with associated triggers or clinical conditions in patients presenting with TMA may allow faster and more appropriate treatment.

Systemic lupus erythematosus presenting with atypical hemolytic uremic syndrome: a case report and review of the literature.

Systemic lupus erythematosus (SLE) can present with a diverse array of hematologic manifestations, among which atypical hemolytic uremic syndrome (aHUS) is a rare entity. SLE-triggered aHUS has significant morbidity and mortality without timely intervention, yet its frequency remains uncertain and optimal strategies for complement-directed therapies are largely expert-driven. We performed a comprehensive literature review and present a case of a 23-year-old female newly diagnosed with SLE/class IV lupus nephritis who developed aHUS that rapidly responded to the C5 antagonist, eculizumab. Review of the current literature identified forty-nine published cases of SLE with concurrent aHUS and revealed a predilection for aHUS in younger SLE patients, concurrent presentation with lupus nephritis, anti-dsDNA positivity, and complement system abnormalities. Over seventy percent of cases used eculizumab as complement-directed therapy with a trend towards faster time to improvement in laboratory parameters, though reported outcomes were highly variable. Early recognition of aHUS in SLE is pivotal in guiding appropriate therapeutic interventions, and prompt initiation of eculizumab may reduce the potential morbidity associated with plasmapheresis and additional immunosuppression. While eculizumab showcases promising results, its optimal timing and duration remain elusive. An understanding of a patients' complement genetics could aid management strategies, and ongoing research into complement-targeted therapies offers promising avenues for both SLE and aHUS treatment.

Pregnancy-associated atypical hemolytic uremic syndrome. Case report.

Pregnancy-associated atypical hemolytic uremic syndrome (P-aHUS) is a rare disease. There are only few reports in the literature, and most are in the puerperium period. It is a thrombotic microangiopathy (TMA) characterized for microangiopathic hemolytic anemia, thrombocytopenia, and renal dysfunction. We report the case of a pregnant patient at 26.3 gestation weeks, who developed clinical features of TMA, neurological alterations, and septic shock; then after fetus and placental delivery, no clinical improvement was observed; a diagnostic protocol was performed due to suspicion of P-aHUS, showing improvement after the plasma exchange sessions and eculizumab. We present here a brief review of the case since it is an entity that needs to be suspected during pregnancy when TMA features and requires an immediate diagnosis to provide timely treatment.

Atypical Hemolytic Uremic Syndrome Occurring After Receipt of mRNA-1273 COVID-19 Vaccine Booster: A Case Report.

Atypical hemolytic uremic syndrome (aHUS) is a subtype of thrombotic microangiopathy (TMA) characterized by a dysregulation of the alternative complement pathway. Here, we report a previously healthy 38-year-old woman in whom aHUS developed after a COVID-19 vaccine booster. One day after receipt of a booster dose of mRNA-1273 vaccine, she felt ill. Because of persistent headache, nausea, and general malaise, she went to her general practitioner, who referred her to the hospital after detecting hypertension and acute kidney injury. A diagnosis of TMA was made. Her treatment consisted of blood pressure control, hemodialysis, plasma exchange, and respiratory support. Kidney biopsy confirmed the diagnosis of acute TMA. The patient was referred for treatment with eculizumab, and kidney function improved after initiation of this therapy. Genetic analysis revealed a pathogenic C3 variant. SARS-CoV-2 infection as a trigger for complement activation and development of aHUS has been described previously. In addition, there is one reported case of aHUS occurring after receipt of the adenovirus-based COVID-19 vaccine ChAdOx1 nCoV-19, but, to our knowledge, this is the first case of aHUS occurring after a booster dose of an mRNA COVID-19 vaccine in a patient with an underlying pathogenic variant in complement C3. Given the time frame, we hypothesize that the vaccine probably was the trigger for development of aHUS in this patient.

CFH-CFHR1 hybrid genes in two cases of atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a rare complement-mediated disease that manifests as the triad of thrombotic microangiopathy. We identified two aHUS patients with neither anti-complement factor H (CFH) antibodies nor causative variants of seven aHUS-related genes (CFH, CFI, CFB, C3, MCP, THBD, and DGKE); however, their plasma showed increased levels of hemolysis by hemolytic assay, which strongly suggests CFH-related abnormalities. Using a copy number variation (CNV) analysis of the CFH/CFHR gene cluster, we identified CFH-CFHR1 hybrid genes in these patients. We verified the absence of aHUS-related abnormal CNVs of the CFH gene in control genomes of 2036 individuals in the general population, which suggests that pathogenicity is related to these hybrid genes. Our study emphasizes that, for patients suspected of having aHUS, it is important to perform an integrated analysis based on a clinical examination, functional analysis, and detailed genetic investigation.

The nailfold dermoscopy findings of patients with atypical haemolytic uremic syndrome.

INTRODUCTION: Hemolytic uremic syndrome (HUS) is a severe disease characterized by microangiopathic anemia, thrombocytopenia, and acute renal failure. OBJECTIVES: Atypical HUS (aHUS) that results due to genetic disorders of the alternative complement pathway results in inflammation, endothelial damage, and kidney injury. Therefore, simple and non-invasive tests are needed to evaluate the activity of the disease by assessing the microvascular structure in aHUS. METHODS: A dermoscope (×10) is an inexpensive and easily portable device used to visualize nailfold capillaries and has high clinical performance and interobserver reliability. In this study, the nailfold capillaries of patients with aHUS who were in remission under eculizumab treatment were examined, and the findings were compared to those of a healthy control group to evaluate disease characteristics. RESULTS: All children with aHUS had decreased capillary densities even if they were in remission. This may be indicative of ongoing inflammation and microvascular damage in aHUS. CONCLUSION: A dermoscopy can be used as a screening tool for disease activity in patients with aHUS.

Eculizumab for paediatric patients with atypical haemolytic uraemic syndrome: full dataset analysis of post-marketing surveillance in Japan.

BACKGROUND: Eculizumab was approved for atypical haemolytic uraemic syndrome (aHUS) in Japan in 2013. Post-marketing surveillance (PMS) was mandated by regulatory authorities to assess the safety and effectiveness of eculizumab in patients with aHUS in a real-world setting. METHODS: Paediatric patients in the PMS cohort who were <18 years of age at the first administration of eculizumab and diagnosed with aHUS [excluding Shiga toxin-producing Escherichia coli HUS, thrombotic thrombocytopaenic purpura and secondary thrombotic microangiopathy (TMA)] were included in the effectiveness and safety analysis. Clinical endpoints of effectiveness [complete TMA response, TMA event-free status, platelet (PLT) count and lactate dehydrogenase (LDH) normalization, serum creatinine (sCr) decrease and estimated glomerular filtration rate (eGFR) improvement] were analysed in patients treated with at least one dose of eculizumab. Serious adverse events (SAEs) were also evaluated. RESULTS: A total of 40 paediatric patients (median age 5 years) were included. The median eculizumab treatment duration was 66 weeks. PLT count, LDH and eGFR significantly improved at 10 days post-treatment. Complete TMA response, haematologic normalization, sCr decrease, eGFR improvement and TMA event-free status were achieved by 73.3%, 73.3%, 70.0%, 78.3% and 77.5% of patients, respectively. Discontinuation criteria were met by 18 patients: 13 patients maintained treatment discontinuation at the end of observation and 5 patients, including 1 patient with aHUS relapse, continued the treatment but extended the treatment interval. During eculizumab treatment, 59 SAEs (0.66/person-year) were reported. Although four deaths were reported, none of them were related to eculizumab. CONCLUSION: Eculizumab was well tolerated and effective for paediatric patients with aHUS in the real-world setting in Japan.

Thrombotic microangiopathy in patients with malignant hypertension.

BACKGROUND: Thrombotic microangiopathy (TMA) is a complication of malignant hypertension (mHTN) attributed to high blood pressure (BP). However, no studies have investigated in patients with mHTN of different aetiologies whether the presence of TMA is associated with specific causes of mHTN. METHODS: We investigated the presence of TMA (microangiopathic haemolytic anaemia and thrombocytopenia) in a large and well-characterized cohort of 199 patients with mHTN of different aetiologies [primary HTN 44%, glomerular diseases 16.6%, primary atypical haemolytic uraemic syndrome (aHUS) 13.1%, renovascular HTN 9.5%, drug-related HTN 7%, systemic diseases 5.5%, endocrine diseases 4.5%]. Outcomes of the study were kidney recovery and kidney failure. RESULTS: Patients with TMA [40 cases (20.1%)] were younger, were more likely female and had lower BP levels and worse kidney function at presentation. Their underlying diseases were primary aHUS (60%), drug-related mHTN (15%), glomerular diseases [all of them immunoglobulin A nephropathy (IgAN); 10%], systemic diseases (10%) and primary HTN (5%). The presence of TMA was 92.3% in primary aHUS, 42.9% in drug-related HTN, 36.4% in systemic diseases, 12.1% in glomerular diseases and 2.3% in primary HTN. No patient with renovascular HTN or mHTN caused by endocrine diseases developed TMA, despite BP levels as high as patients with TMA. A higher proportion of TMA patients developed kidney failure as compared with patients without TMA (56.4% versus 38.9%, respectively). CONCLUSIONS: The presence of TMA in patients with mHTN should guide the diagnosis towards primary aHUS, drug-related mHTN, some systemic diseases and IgAN, while it is exceptional in other causes of mHTN.

The treatment of atypical hemolytic uremic syndrome with eculizumab in pediatric patients: a systematic review.

BACKGROUND: The atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy associated with high morbidity and high mortality. Eculizumab, a humanized anti-C5 monoclonal antibody, was the first medication approved for treating aHUS in 2011. OBJECTIVE: The objective of this study is to evaluate the efficacy and safety of eculizumab treatment in pediatric patients with aHUS. DATA SOURCES: We consulted PubMed, Scopus, SciELO, and Cochrane Library databases in July 2021. The descriptors were as follows: "Atypical Hemolytic Uremic Syndrome," "aHUS," "eculizumab," "Pediatrics," "Pediatric," "Child," "Children," "Adolescent." STUDY ELIGIBILITY CRITERIA: The study eligibility criteria are as follows: clinical trials and observational studies that included pediatric patients with aHUS diagnosis and who were treated with eculizumab. PARTICIPANTS AND INTERVENTIONS: The participants are pediatric patients, up to 18 years old, with aHUS. The intervention was eculizumab treatment. STUDY APPRAISAL: For quality assessment, we used the Newcastle-Ottawa Scale, the National Institutes of Health (NIH) quality assessment tool for case series studies, and the Risk of Bias In Non-Randomized Studies of Interventions (ROBINS-I) tool. RESULTS: The initial search retrieved 433 studies, from which 15 were selected after complete assessment: 9 cohorts, 4 case series, and 1 clinical trial. The publication date ranged from 2015 to 2021. In total, 940 pediatric patients were included, and 682 received eculizumab. All studies reported improvements in renal and hematological parameters in most of the patients treated with eculizumab. The mortality rate was 1.6% for all patients treated with eculizumab. LIMITATIONS: The number of studies is limited, and the included studies were methodologically heterogeneous. The studies were mostly observational and many had small sample sizes. CONCLUSIONS: Eculizumab appears to be safe and effective for the treatment of aHUS in pediatric patients. More research is necessary to establish long-term efficacy, safety, and time of discontinuation. SYSTEMATIC REVIEW REGISTRATION NUMBER: CRD42021266255.

Better late than never: Diagnosis of recurrent atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) comprising microangiopathic hemolytic anemia, consumptive thrombocytopenia, and end-organ damage. Risk of end-stage renal disease is increased as HUS usually manifests in native and transplanted kidneys. In transplants, while de novo disease can be seen, recurrent disease is more common. The etiology is variable, being either primary or secondary. aHUS often constitutes a diagnostic and therapeutic challenge, which may lead to a considerable delay in the diagnosis and treatment. During the last decades, great progress has been made in understanding the mechanisms and therapeutic options of this devastating condition. We present a case of a 50-year-old female who received her first kidney transplant from her mother at the age of 9 years. She experienced recurrent losses of transplants, and only after the loss of her fourth transplant did the diagnosis of aHUS become evident.

Atypical haemolytic uremic syndrome with refractory multiorgan involvement and heterozygous CFHR1/CFHR3 gene deletion.

BACKGROUND: We present this challenging case report of Atypical Haemolytic Uremic Syndrome (aHUS) presenting with multi-organ involvement in a patient and heterozygous CFHR1/CFHR3 gene variant, which was refractory to initial eculizumab therapy. CASE PRESENTATION: A forty-three year old female presented with aHUS and had heterozygous disease-associated deletions in the complement genes CFHR1/CFHR3. She had progressive kidney failure and severe extra-renal manifestations including cardiomyopathy and haemorrhagic cystitis; as well as pulmonary, gastrointestinal and neurological involvement. The initial kidney biopsy revealed thrombotic microangiopathy (TMA) changes involving all glomeruli. Clinical improvement was initially seen during eculizumab initiation with suppressed CH50 level, but a new rhinovirus/enterovirus upper respiratory tract infection triggered further severe multi-organ disease activity. The extra-renal manifestations stabilised, then ultimately improved after a period of eculizumab dose intensification. However, the impact on dose intensification on this improvement is unclear. Despite the extra-renal clinical improvement, she ultimately progressed to end-stage kidney disease (ESKD), commencing peritoneal dialysis for three years before undergoing a successful uncomplicated cadaveric kidney transplant without prophylactic eculizumab. Two years after transplant, she has excellent transplant graft function without any further disease recurrence. CONCLUSIONS: This case highlights the concept of extra-renal manifestations in aHUS initially resistant to eculizumab, which potentially responded to dose intensification. Whilst organ injuries are potentially reversible with timely targeted treatment, it appears that the kidneys are most vulnerable to injury.

Clinical features of women with thrombotic microangiopathy in pregnancy: A case series from a single Japanese tertiary perinatal care center.

AIM: Although perinatal thrombotic microangiopathy has become increasingly understood, the racial characteristics of patients with this condition remain unclear. Herein, we report the characteristics of patients with perinatal thrombotic microangiopathy at a single institution in Japan. METHODS: We conducted a retrospective study over a 5-year period from January 1, 2017, to December 31, 2021, using the electronic medical records of pregnant women who delivered at the perinatal center of our hospital. We extracted the data of those who developed perinatal thrombotic microangiopathy and evaluated their characteristics at the time of disease onset, final diagnosis, and maternal and fetal outcomes. RESULTS: Of the 10 224 deliveries that occurred during the 5-year period, only seven patients (0.06%) had perinatal thrombotic microangiopathy. The median pre-pregnant body mass index was 18.65 kg/m2 (minimum 17.3 kg/m2 , maximum 20.7 kg/m2 ). More than half of the patients were conceived by in-vitro fertilization, and 42% these had twin deliveries. Four patients had a history of rheumatic disease. The other three patients without underlying diseases developed thrombotic microangiopathy with HELLP syndrome, and one patient transitioned to atypical hemolytic uremic syndrome. CONCLUSIONS: Based on low body mass index and in-vitro fertilization, which are characteristic of Japanese women, medical complications and twin pregnancies may be a risk for thrombotic microangiopathy. Additionally, depending on the cause of thrombotic microangiopathy, its timing and onset differed.

Atypical hemolytic uremic syndrome: Consensus of diagnosis and treatment in Taiwan.

Atypical hemolytic uremic syndrome (aHUS), characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, is a rare but life-threatening systemic disorder caused by the dysregulation of the complement pathway. Current advances in molecular analysis and pathogenesis have facilitated the establishment of diagnosis and development of effective complement blockade. Based on this recent consensus, we provide suggestions regarding the diagnosis and management of aHUS in Taiwan. The diagnosis of aHUS is made by the presence of TMA with normal ADAMTS13 activity without known secondary causes. Although only 60% of patients with aHUS have mutations in genes involving the compliment and coagulation systems, molecular analysis is suggestive for helping establish diagnosis, clarifying the underlying pathophysiology, guiding the treatment decision-making, predicting the prognosis, and deciding renal transplantation. Complement blockade, anti-C5 monoclonal antibody, is the first-line therapy for patients with aHUS. Plasma therapy should be considered for removing autoantibody in patients with atypical HUS caused by anti-CFH or complement inhibitor is unavailable.

Dysregulation of Immune Cell Subpopulations in Atypical Hemolytic Uremic Syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening thrombotic microangiopathy. Definitive biomarkers for disease diagnosis and activity remain elusive, making the exploration of molecular markers paramount. We conducted single-cell sequencing on peripheral blood mononuclear cells from 13 aHUS patients, 3 unaffected family members of aHUS patients, and 4 healthy controls. We identified 32 distinct subpopulations encompassing 5 B-cell types, 16 T- and natural killer (NK) cell types, 7 monocyte types, and 4 other cell types. Notably, we observed a significant increase in intermediate monocytes in unstable aHUS patients. Subclustering analysis revealed seven elevated expression genes, including NEAT1, MT-ATP6, MT-CYB, VIM, ACTG1, RPL13, and KLRB1, in unstable aHUS patients, and four heightened expression genes, including RPS27, RPS4X, RPL23, and GZMH genes, in stable aHUS patients. Additionally, an increase in the expression of mitochondria-related genes suggested a potential influence of cell metabolism on the clinical progression of the disease. Pseudotime trajectory analysis revealed a unique immune cell differentiation pattern, while cell-cell interaction profiling highlighted distinctive signaling pathways among patients, family members, and controls. This single-cell sequencing study is the first to confirm immune cell dysregulation in aHUS pathogenesis, offering valuable insights into molecular mechanisms and potential new diagnostic and disease activity markers.

Ischemic cerebrovascular complications with initial presentation of genetic atypical hemolytic uremic syndrome.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare disease, with scarce reports of neurologic manifestations in the acute setting. Ischemic cortical infarcts concurrently with aHUS presentation have not been described in adult patients. CASE DESCRIPTION: A 46-year-old male presented with acutely declining mental status and progressive weakness, in the setting of longstanding hypertension and known type B aortic dissection. Urgent neuroimaging showed bilateral multifocal multiterritorial ischemic infarcts, concerning for an embolic source or hypercoagulable state. Systemic workup was notable for microangiopathic hemolytic anemia and acute kidney injury. Empiric plasmapheresis was initiated for presumed thrombotic thrombocytopenic purpura. Broad workup did not support such a diagnosis, and kidney biopsy showed findings compatible with aHUS. Additional blood testing showed increased complement pathway activity. Shiga toxin was negative, and overall clinical picture fit with aHUS as diagnosis. Treatment with complement inhibitor was started and patient gradually recovered. Genetic testing confirmed a pertinent pathogenic mutation, CFHR1 homozygous deletion. CONCLUSION: Acute multifocal multiterritorial ischemic infarcts and systemic thrombotic microangiopathy may be a manifestation of aHUS, and with associated genetic mutation, even in adult population.