Atypical Hemolytic Uremic Syndrome Research Articles

Thrombotic Microangiopathy in Solid Organ Transplantation

Thrombotic Microangiopathy (TMA) is a syndrome characterized by microangiopathic hemolytic anemia (MAHA) and thrombocytopenia. The presence of schistocytes on peripheral smear, a negative Coombs test, elevated lactate dehydrogenase, increased reticulocyte count and low haptoglobin are often the clues for MAHA. The microvascular process often targets vasculature in kidneys, brain, gastrointestinal system, heart, and skin. A timely diagnosis and treatment are often crucial to prevent severe end organ damage and death. TMA is classified into primary and secondary forms. Primary TMA includes TTP and complement mediated or atypical hemolytic uremic syndrome (aHUS), often related to a mutation or deficiency and clinically expressed in the setting of a precipitant condition. Secondary TMA is a manifestation of underlying disorder and can occur in clinical scenarios associated with autoimmune disease, malignancy, infections, SOT (Solid Organ Transplant), pregnancy, HSCT (Hematopoietic Stem Cell Transplantation), medications, or methylmalonic acidemia. Transplant associated TMA (TA-TMA) can be complement mediated or aHUS and could be related to the ischemic reperfusion injury, induction regimen, calcineurin inhibitor (CNI) use, mammalian target of rapamycin (MTOR) inhibitor use, or could be infection related. Cost, access, and turnaround time are often the limitations for certain TTP and complement specific testing. Treatment should not be delayed while waiting for such tests. Treatment must be individualized based on the underlying cause of TMA. Terminal complement blockade utilizing monoclonal antibodies directed against C5 complement is the treatment for complement mediated TMA. C5 inhibitors have also been used successfully in treatment of secondary HUS cases where, unlike aHUS, defects in complement cannot be demonstrated. Such treatment has demonstrated improvement in renal function, MAHA and platelet counts.

Diagnostic Challenges and Emerging Pathogeneses of Selected Glomerulopathies.

Recent progress in glomerular immune complex and complement-mediated diseases have refined diagnostic categories and informed mechanistic understanding of disease development in pediatric patients. Herein, we discuss selected advances in 3 categories. First, membranous nephropathy antigens are increasingly utilized to characterize disease in pediatric patients and include phospholipase A2 receptor (PLA2R), Semaphorin 3B (Sema3B), neural epidermal growth factor-like 1 (NELL1), and protocadherin FAT1, as well as the lupus membranous-associated antigens exostosin 1/2 (EXT1/2), neural cell adhesion molecule 1 (NCAM1), and transforming growth factor beta receptor 3 (TGFBR3). Second, we examine advances in techniques for paraffin and light chain immunofluorescence (IF), including the former's function as a salvage technique and their necessity for diagnosis in adolescent cases of membranous-like glomerulopathy with masked IgG kappa deposits (MGMID) and proliferative glomerulonephritis with monotypic Ig deposits (PGNMID), respectively. Finally, progress in understanding the roles of complement in pediatric glomerular disease is reviewed, with specific attention to overlapping clinical, histologic, and genetic or functional alternative complement pathway (AP) abnormalities among C3 glomerulopathy (C3G), infection-related and post-infectious GN, "atypical" post-infectious GN, immune complex mediated membranoproliferative glomerulonephritis (IC-MPGN), and atypical hemolytic uremic syndrome (aHUS).

Post-transplant CFHR5 mutation-related atypical HUS: The need for pre-transplant diagnosis

Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) affecting multiple organs and can be sporadic or familial. It is most commonly caused by dysregulation of the alternative complement pathway. aHUS can occur at any age with a high rate of progression to end-stage kidney disease. We describe the case of a 24-year-old man with chronic kidney disease, severe hypertension, and antineutrophilic antibody by IF positive. On biopsy, diffuse global glomerulosclerosis with TMA and IF findings of full house pattern suggestive of lupus nephritis were present. Considering a lupus nephritis case, after 2 years of hemodialysis underwent live-related renal transplant (Father Donor). Immediate post-transplant period developed severe cortical necrosis and TMA. An etiological workup was done to ascertain the cause of post-transplant TMA. After excluding common causes of antibody-mediated rejection (C4d and donor-specific alloantibody neg), calcineurin inhibitor toxicity, and infection, we detected an abnormal complement CFHR5 mutation with an autosomal dominant pattern of inheritance. Pre-transplant diagnosis could have prevented taking the kidney from the father for transplant and further prevented recurrence. Systemic lupus erythematosus and TMA both can have alternate complement pathway dysregulation leading to full house IF pattern and misdiagnosis.

Living with Atypical Hemolytic Uremic Syndrome in the Netherlands: Patient and Family Perspective

IntroductionAtypical hemolytic uremic syndrome (aHUS) poses a significant health challenge due to its rarity and severity within the spectrum of thrombotic microangiopathy (TMA). Despite efforts to optimize and personalize health care for aHUS patients, understanding the individual experiences, needs and desires of aHUS patients and relatives remains limited. MethodsHere we present a nationwide, exploratory, qualitative interview study with a direct content analysis approach. In-depth interviews and a six-week evaluation were audio-recorded and conducted using a semi-structured topic guide, based on the Institute for Positive Health (IPH) model. ResultsAnalysis of ten interviews involving six aHUS patients and thirteen relatives revealed the prevalence of long-term disease symptoms in adult patients, notably fatigue, which significantly impacted daily functioning. Moreover, the resilience demonstrated by patients and their relatives was noteworthy, yet the acute phase of aHUS and the unpredictable nature of disease recurrence could profoundly affect mental well-being. The emotional toll of aHUS is pervasive, with feelings of fear, guilt and trauma persisting across disease phases in both patients and relatives. Challenges in medical care, including delays in diagnosis and the need for personalized and uniform protocols, were highlighted. Support was deemed crucial, indicating the necessity for enhancements in the accessibility of comprehensible disease information and psychological counselling. At last, complexities surrounding genetic testing and carriership were discussed. ConclusionThis study underscores the profound, enduring and multifaced impact of aHUS. The insights gleaned from the experiences and needs of aHUS patients and their relatives could lay the foundation for development and implementation of more personalized innovations in aHUS healthcare.

196 Patience is Key: Renal Recovery in Atypical Hemolytic Uremic Syndrome After 3 Months of Eculizumab Treatment

196 Patience is Key: Renal Recovery in Atypical Hemolytic Uremic Syndrome After 3 Months of Eculizumab Treatment

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.

207 Postpartum-associated atypical hemolytic uremic syndrome: From dialysis-dependent acute kidney injury (AKI-D) to recovery

207 Postpartum-associated atypical hemolytic uremic syndrome: From dialysis-dependent acute kidney injury (AKI-D) to recovery

62 Case of In Vitro Fertilization-associated Atypical Hemolytic Uremic Syndrome

62 Case of In Vitro Fertilization-associated Atypical Hemolytic Uremic Syndrome

Bilateral Retinal Venous Occlusion in Atypical Hemolytic-Uremic Syndrome Due to Complement Factor H Mutation

ABSTRACT Purpose Atypical hemolytic uremic syndrome (aHUS) is a rare progressive thrombotic microangiopathy caused by overactivation in the alternative complement pathway. A wide spectrum of environmental triggers, such as viruses, vaccination, drugs, pregnancy, neoplasms, transplant, and autoimmune diseases can cause aHUS in genetically susceptible individuals. In this report, the diagnosis and treatment process of aHUS and bilateral retinal venous occlusion (RVO) will be presented. Methods Single-case, retrospective management of ophthalmological and systemic manifestations. Results A 28-year-old G2P2 female with acute blurred vision and history of acute renal failure. She was diagnosed with preeclampsia in her gestation history. After the laboratory work-up, the diagnosis of aHUS was confirmed. She was treated with eculizumab following 14 days of plasmapheresis. However, her visual acuity was 20/20 on the right and 20/60 on the left at the time of admission. Retinal examination revealed flame-shaped hemorrhages, exudation, and macular edema. The patient was diagnosed with branch RVO in the right eye. Subsequently, central RVO was occurred in the left eye. Intravitreal dexamethasone implant was administered for both eyes since there was no reasonable regression in retinal findings with bevacizumab treatment. She went into remission and her BCVA reached 20/25 during the 12-month follow-up period under the eculizumab therapy. Conclusion Diagnosis of aHUS is challenging especially during pregnancy and the postpartum period. Although ocular involvement is quite rare, we described bilateral RVO in aHUS case with homozygous nonsense mutation (c.2134 G > T p.G712). Dexamethasone implant should be considered for the treatment of RVO in aHUS cases.

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.

Eculizumab for pregnancy-related atypical hemolytic uremic syndrome.

Eculizumab for pregnancy-related atypical hemolytic uremic syndrome.

What came first, atypical hemolytic uremic syndrome or malignant hypertension: a clinical dilemma

What came first, atypical hemolytic uremic syndrome or malignant hypertension: a clinical dilemma

Thrombotic Microangiopathy as a Life-Threatening Complication of Long-Term Interferon Beta Therapy for Multiple Sclerosis: Clinical Phenotype and Response to Treatment-A Literature Review.

Thrombotic microangiopathy (TMA) has been observed in some patients receiving interferon beta (IFNβ) therapy for relapsing-remitting multiple sclerosis, but little is known about its clinical features and outcomes. We searched the literature to identify cases with IFNβ-related TMA and assessed their pattern of organ involvement, the presence of prodromal manifestations, the treatments used, and the outcomes. Thirty-five articles met the inclusion criteria, and data of 67 patients were collected. The median duration of IFNβ therapy before the diagnosis of TMA was 8 years, and 56/67 (84%) presented with acute kidney injury (AKI), of which 33 required acute dialysis. All but three patients had manifestations during the four weeks before TMA onset, including flu-like symptoms, headache, and worsening blood pressure control. In only two patients, ADAMTS13 activity was reduced, while 27% had low C3 levels. However, none showed causative genetic mutations associated with development of atypical hemolytic uremic syndrome. All patients discontinued IFNβ, 34 (55%) also received plasma exchange, and 12 (18%) received eculizumab. Complete renal recovery was achieved by 20 patients (30%), while 13 (20%) developed end-stage renal disease. Among those with AKI requiring dialysis, eculizumab therapy was associated with a significantly reduced risk of ESRD compared with plasma exchange. Therefore, TMA with features of aHUS mainly occurs after prolonged treatment with IFNβ and is preceded by prodromes, which may lead to an early diagnosis before life-threatening complications occur. Eculizumab appears beneficial in cases with severe kidney involvement, which supports a role of the complement system in the pathogenesis of these forms.

Suspected pregnancy-associated atypical hemolytic uremic syndrome treated with eculizumab: a case report

Suspected pregnancy-associated atypical hemolytic uremic syndrome treated with eculizumab: a case report

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 represent a very high proportion of patients with TMA and results from virtually all known causes of TMA, 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.

Management of pediatric hemolytic uremic syndrome.

Classical clinical triad of hemolytic uremic syndrome (HUS) is microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury associated with endothelial cell injury. Several situations, including infections, medications, malignancies, and transplantation can trigger endothelial damage. On the HUS spectrum, atypical hemolytic uremic syndrome (aHUS) deserves special attention in pediatric patients, as it can cause endstage kidney disease and mortality. A dysfunction in the alternative complement pathway, either acquired or genetic, has been shown to be the main underlying cause. In the last decades, breathtaking advances have been made in understanding the pathophysiology of this rare disease, which has led to more efficient treatment. Recent studies have implicated genes in pathways beyond the alternative complement system, such as DGKE, TSEN2, and INF2 highlighting the importance of personalized management. Eculizumab has brought about dramatic improvements in the treatment of aHUS. Beyond eculizumab, there are many alternative therapeutics in the pipeline that target the complement system. Because of the rarity of aHUS, data from multiple patient registries are very important. The present report aimed to summarize the most important aspects of diagnosing and treating aHUS based on the Turkish national registry and the literature so as to improve clinical practice.

Клинические особенности течения и исходы атипичного гемолитико-уремического синдрома, ассоциированного с антителами к Фактору H

Atypical hemolytic-uremic syndrome (aHUS) is an ultra-rare life-threatening disease from the group of thrombotic microangiopathies (TMA) with genetic predisposition factors associated with uncontrolled activation of the alternative complement pathway. In 10% of cases aHUS is acquired and associated with antibodies to factor H (CFH-Ab-aHUS), among which 90% of cases are also determined by a deficiency of plasma proteins related to factor H (CFHR). Information on the course, therapeutic approaches and outcomes of CFH-Ab-aHUS varies Worldwide and is presented by series of clinical observations. The purpose of the research was to determine the patterns of the course and outcomes of CFH-Ab-aHUS to substantiate methods of effective treatment and improve prognosis. Methods used: retro- and prospective analysis of the course and outcomes of CFH-Ab-aHUS in 43 patients in Jan. 2010-Feb. 2022. The sample is continuous. In the development of microangiopathic hemolytic anemia (MAHA), thrombocytopenia and acute kidney injury (AKI), the diagnosis of CFH-Ab-aHUS was established after exclusion of other forms of TMAs and determination of immunoglobulin class G (IgG) in serum against factor H by enzyme-linked immunosorbent assay (ELISA-VIDITEST anti-complement factor H, Czech Republic). In 41 cases molecular genetic study by NGS (next generation sequencing) for aHUS panel and Sanger sequencing were performed. Results: the incidence of CFH-Ab-aHUS was 20.6% among all cases of aHUS. In 88.4% of children the disease debuted at the age of above 4 y/o. It was associated with a trigger (infections, vaccination, trauma, etc.) in 76.7% of cases. The median (Me) level of antibodies to factor H was 12400 [4187; 22181] AU/ml, which was more than 8 times higher than the normal upper limit. The acute period was characterized by the development of the TMA triad (MAGA, thrombocytopenia, AKI) in 100%, hemorrhagic syndrome (69.8%), arterial hypertension (69.8%), C3 consumption (77.8%) and dysfunction of more than 2 systems (83.7%). Neoliguric form of AKI was diagnosed in 44.2%, cardiac involvement in 65.1%, CNS in 55.8%, GI in 51.2%, pulmonary in 23.3%, and visual organ in 16.3% of cases. CFHR1/CFHR3 deletions were found in 87.8% (36/41) of cases (77.8% homozygous/ 22.2% heterozygous). Relapses were noted in 34.9%. Remission of CFH-Ab-aHUS was achieved in 11.6% of cases using plasma therapy and immunosuppressants, in 88.4% - with complement-blocking therapy (eculizumab). The outcome of the disease was characterized by the development of arterial hypertension (65.1%), CKD (60.5%), hypertrophic (25.6%) and dilated cardiomyopathy (16.3%). Conclusion: thus, in the Russin pediatric population with aHUS, every fifth child is diagnosed with CFH-Ab-aHUS associated with a risk of recurrence in every third child. The most important components of the management of patients with CFH-Ab-aHUS are its timely diagnosis and initiation of pathogenetic therapy (plasma therapy with immunosuppressants/eculizumab).

Eculizumab dose tapering should take into account the nonlinearity of its pharmacokinetics.

Eculizumab is a monoclonal antibody targeting complement protein C5 used in renal diseases. As recommended dosing regimen leads to unnecessarily high concentrations in some patients, tailored dosing therapeutic drug monitoring was proposed to reduce treatment cost. The objectives of the present work were (i) to investigate the target-mediated elimination of eculizumab and (ii) whether a pharmacokinetic model integrating a nonlinear elimination allows a better prediction of eculizumab concentrations than a linear model. We analysed 377 eculizumab serum concentrations from 44 patients treated for atypical haemolytic uraemic syndrome and C3 glomerulopathy with a population pharmacokinetic approach. Critical concentrations (below which a non-log-linear decline of concentration over time is evidenced) were computed to estimate the relevance of the target-mediated elimination. Simulations of dosing regimens were then performed to predict probabilities of target attainment (i.e. trough >100 mg/L). Pharmacokinetics of eculizumab was nonlinear and followed a mixture of first-order (CL = 1.318 mL/day/kg) and Michaelis-Menten elimination (Vmax = 26.07 mg/day, Km = 24.06 mg/L). Volume of distribution (72.39 mL/kg) and clearance were weight-dependent. Critical concentrations (Vmax /CL) ranged from 144.7 to 759.7mg/L and were inversely related to body weight (P = .013). Nonlinearity was thus noticeable at therapeutic concentrations. Simulations predicted that 1200 mg of eculizumab every 21 days would allow 85% and 76% of patients to maintain a therapeutic exposure, for 50 or 90 kg body weight, respectively. Our study investigates the nonlinear elimination of eculizumab and discusses the importance of accounting for eculizumab target-mediated elimination in therapeutic drug monitoring.

Genetic Diagnosis of Adult Hemodialysis Patients With Unknown Etiology

Kidney disease of unknown etiology accounts for 1 in 10 adult end-stage renal disease (ESRD) cases worldwide. The aim of this study is to clarify the genetic background of patients with chronic kidney disease (CKD) of unknown etiology who initiated renal replacement therapy (RRT) in adulthood. This is a multicenter cross-sectional cohort study. Of the 1164 patients who attended 4 dialysis clinics in Japan, we first selected patients who started RRT between the ages of 20 and 49 years. After excluding patients with apparent causes of CKD (e.g., diabetic nephropathy, polycystic kidney disease (PKD) with family history, patients who underwent renal biopsy), 90 patients with CKD of unknown cause were included. The 298 genes associated with CKD were analyzed using capture-based targeted next-generation sequencing. Of the 90 patients, 10 (11.1%) had pathogenic variants in CKD-causing genes and 17 (18.9%) had variant of unknown significance (VUS). Three patients had PKD1 pathogenic variants, and 1 patient had PKD1 and COL4A4 pathogenic variants. In addition, 2 patients were diagnosed with atypical hemolytic uremic syndrome (aHUS) due to C3 or CFHR5. One patient each was diagnosed with Alport syndrome due to COL4A4 and COL4A3 variants, nephronophthisis due to NPHP1 variants, Fabry disease due to GLA variants, and autosomal-dominant tubulointerstitial kidney disease due to UMOD variants. Genetic diagnoses were not concordant with clinical diagnoses, except for patients with PKD1 variant. This largest study on genetic analysis in hemodialysis-dependent adults revealed the presence of undiagnosed inherited kidney diseases.

Atypical Hemolytic Uremic Syndrome: A Therapeutic Challenge When Eculizumab is Not Available

Atypical Hemolytic Uremic Syndrome: A Therapeutic Challenge When Eculizumab is Not Available