Pregnancy-associated Hemolytic Uremic Syndrome Research Articles

Pregnancy-Associated Hemolytic Uremic Syndrome: Two Case Series From the University of Vermont Medical Center

Pregnancy-Associated Hemolytic Uremic Syndrome: Two Case Series From the University of Vermont Medical Center

High prevalence of CFHR deletions in Indian women with pregnancy-associated hemolytic uremic syndrome.

Pregnancy-associated hemolytic uremic syndrome (P-aHUS) is an important cause of peripartum acute kidney injury. Studies from Europe have described mutations in complement regulator genes, and data in Indian patients is scarce. Hence this study used multiplex ligation-dependent probe amplification (MLPA) to identify variants in complement genes in P-aHUS patients. We present 17 patients of P-aHUS who were investigated for complement protein levels and genetic analysis with MLPA for complement genes. Plasma exchange therapy was offered to all patients presenting in acute phase. Mean age 26.74 (3.36) years with 15/17 delivered by caesarean section. Eleven patients received early (within 7 days) plasma exchange, three were dialysis-dependent at 3months and seven were dialysis-free. Only one of the three patients receiving late (after 7 days) plasma exchange was dialysis-free. MLPA showed that 11 patients had heterozygous deletions of exons 3, 5, 6 of CFHR1 and upstream region of exons 1, 2, 3, 6 and intron 4 of CFHR3 gene while four patients had homozygous deletions at the same loci. Two patients had no MLPA-detectable variations. This study reports a high proportion of deletions of exons of CFHR1 & CFHR3 genes in Indian P-aHUS patients detectable by MLPA by copy number variations. This needs confirmation in large multicentre studies. Plasma exchange can be an effective therapy in the non-availability of Eculizumab.

Acute Kidney Injury in Obstetric Patients.

Obstetric-related acute kidney injury (obstetric AKI) is an important and complex public health problem; its early recognition and proper treatment are key in preventing maternal and fetal adverse outcomes. While the incidence of obstetric AKI has drastically declined in some developing countries due to reduction of sepsis-related causes, the opposite has been observed in other developed nations in the last decade due to advanced maternal age and the presence of comorbidities. The diagnosis of obstetric AKI has been made difficult by the physiologic decrease in serum creatinine of pregnancy as well as the absence of a uniform definition for AKI in this population. The most common causes of obstetric AKI include pre-renal etiologies such as hyperemesis gravidarum and post-abortal sepsis, intra-renal causes which comprise the thrombotic microangiopathies (preeclampsia/HELLP, thrombotic thrombocytopenic purpura, pregnancy associated-hemolytic uremic syndrome, lupus nephritis), and post-renal causes due to obstruction from kidney stones or iatrogenic injuries during delivery. A kidney biopsy is rarely required and should be reserved for cases where the diagnosis will change management, preferably before the third trimester. A multidisciplinary approach with the maternal-fetal-medicine specialist and nephrologist, along with the intensivist and hematologist may be needed. In this review, we will present the latest updates on the global epidemiology, focus on the most challenging thrombotic microangiopathy diagnoses, summarize treatment recommendations, and delineate the ongoing challenges as well as novel strategies to tackle this public health burden which does not seem to be disappearing.

Complement-Mediated Disorders in Pregnancy.

Complement-mediated disorders in pregnancy span a large spectrum and have been implicated in all three complement pathways: classical, lectin, and alternative. Our understanding of these disorders in recent years has advanced due to a better understanding of complement regulatory proteins, such as complement factor H, complement factor I, membrane cofactor protein, and thrombomodulin that particularly affect the alternative complement pathway. Enthusiasm in genotyping for mutations that encode these proteins has allowed us to study the presence of genetic variants which may predispose women to develop conditions such as pregnancy-associated hemolytic uremic syndrome (P-aHUS), thrombotic thrombocytopenic purpura, preeclampsia/hemolysis, elevated liver enzymes, low platelets (HELLP), systemic lupus erythematosus/antiphospholipid syndrome, and peripartum cardiomyopathy. The advent of the anti-C5-antibody eculizumab to quench the complement cascade has already proven in small case series to improve maternal kidney outcomes in complement-mediated obstetric catastrophes such as P-aHUS and HELLP. In this review, we will detail the pathogenesis behind these complement-mediated pregnancy disorders, the role of complementvariants in disease phenotype, and the most up-to-date experience with eculizumab in this population.

Pregnancy-associated hemolytic uremic syndrome.

Pregnancy-associated hemolytic uremic syndrome (P-aHUS) is not an uncommon condition. It is considered a medical emergency that is associated with a high risk of mortality and serious morbidity. End-stage renal disease as a consequence of P-aHUS occurs in >50% of the patients if left untreated; the majority of identified cases (79%) are during the postpartum period. Its mechanism of action is related mainly to the disturbance in the activation of the complement alternative pathway, leading to damage of the microvascular endothelium. The clinical picture of P-aHUS mimics several conditions occurring during post-partum thrombotic microangiopathy, for example, severe pre-eclampsia, hemolysis, elevated liver enzymes, and low platelet count, thrombotic-thrombocytopenic purpura, and acute fatty liver of pregnancy. Genetic analysis of known genetic mutations together with the analysis of anti-CFH antibodies might confirm the diagnosis of aHUS in the post-partum period. The absence of causative genetic mutations does not always exclude a diagnosis of aHUS, since 40% of patients show no known genetic abnormalities. The mainstay of management is supportive care and immediate initiation of plasmapheresis. Eculizumab has been proved to be both safe and effective in inducing and maintaining remission in P-aHUS and it is recommended to be started as soon as the diagnosis is established.

Атипичный гемолитико-уремический синдром: современные представления о патогенезе, клинике, подходах к диагностике и лечению

Атипичный гемолитикоуремический синдром (аГУС) ультраредкое (орфанное) заболевание прогрессирующего течения, представляющее собой системную тромботическую микроангиопатию (ТМА) вследствие хронической неконтролируемой активации альтернативного пути комплемента. В настоящее время установлено, что генетические аномалии комплемента, которые раньше рассматривали как основную причину заболевания, являются лишь фактором, предрасполагающим к возникновению ТМА. Классическую триаду клинических проявлений аГУС составляют тромбоцитопения, микроангиопатическая гемолитическая анемия и острое повреждение почек. У большинства пациентов независимо от возраста отмечается артериальная гипертензия, основными причинами которой являются гиперренинемия вследствие ишемии ткани почек, обусловленной ТМА, и перегрузка объемом при наличии олиго/анурии. Атипичный ГУС представляет собой системную ТМА, при которой могут поражаться не только почки, но и другие жизненно важные органы головной мозг, сердце, легкие, пищеварительный тракт, глаза и др. Диагноз аГУС это диагноз исключения. Он устанавливается на основании характерной клинической картины после исключения других форм ТМА, как первичных, так и вторичных. Для исключения тромботической тромбоцитопенической пурпуры (ТТП) всем больным с ТМА необходимо определение активности ADAMTS13: снижение ее до 10 и менее является диагностическим маркером ТТП. У пациентов с аГУС и другими ТМА активность ADAMTS13 может быть снижена, однако всегда превышает 10. Инновационным подходом к лечению аГУС, используемым в клинической практике в течение последнего десятилетия, стало применение экулизумаба препарата группы комплеменингибирующих антител, который является препаратом патогенетической терапии аГУС. Экулизумаб является средством первой линии для лечения детей с установленным диагнозом аГУС, при семейном характере заболевания, наличии экстраренальных проявлений. Совершенствование методов диагностики и внедрение новых подходов к лечению позволяет быстрее заподозрить и купировать проявления аГУС, добиться стойкой ремиссии и улучшить прогноз. Atypical hemolytic uremic syndrome (aHUS) is an ultra rare (orphan) progressive disease that is a systemic thrombotic microangiopathy (TMA) due to chronic uncontrolled activation of the alternative complement pathway. It is currently established that complement genetic abnormalities that were previously considered the main cause of the disease, are only a factor predisposing to TMA occurrence. The classic triad of aHUS clinical manifestations is thrombocytopenia, microangiopathic hemolytic anemia andacute kidney damage. Most patients, regardless of age, have arterial hypertension the main reasons of hypertension are hyperreninemia (due to kidney tissue ischemia because of TMA) and volume overload in the presence of oligo/anuria. Atypical HUS is a systemic TMA that affected not only the kidneys, but also other vital organs brain, heart, lungs, digestive tract, eyes, etc. The diagnosis of aHUS is a diagnosis of exclusion that is established on the basis of specifi c clinical picture after exclusion of other forms of TMA, both primary and secondary. To exclude thrombotic thrombocytopenic purpura (TTP), all patients with TMA need to determine ADAMTS13 activity: its reducing to 10 or less is a diagnostic marker of TTP. In patients with aHUS and other TMA, ADAMTS13 activity may be reduced, but always exceeds 10. The innovative pathogenetic approach to aHUS treatment over the last decade became the application of eculizumab that is a drug from complementinhibitory antibodies group. Eculizumab is a fi rstline treatment for children with proven aHUS diagnosis, with familial disease, with extrarenal manifestations. Progress in diagnostic methods and new treatment approaches allows us to quickly suspect and stop the manifestations of aHUS, achieve stable remission and improve the prognosis.

Use of eculizumab in pregnancy-associated atypical hemolytic uremic syndrome

Abstract Pregnancy-associated atypical hemolytic uremic syndrome (p-aHUS) is a rare disorder, with an estimated incidence of 1 in 25,000 pregnancies [Fakhouri F, Roumenina L, Provot F, Sallee M, Caillard S, Couzi L, et al. Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations. J Am Soc Nephrol. 2010;21:859–67.]. Unlike classic hemolytic uremic syndrome (HUS), aHUS is not related to Escherichia coli 0157:H7 infections. Rather, it arises from uncontrolled alternative complement pathway activation leading to diffuse endothelial damage. The formation of the resulting fibrin and platelet microthrombi in the vasculature leads to hemolysis, thrombocytopenia and ischemic end-organ damage in the form of acute kidney injury [Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:1676–87; Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013;368:2169–81; Loirat C, Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60; Shen YM. Clinical evaluation of thrombotic microangiopathy: identification of patients with suspected atypical hemolytic uremic syndrome. Thromb J. 2016;14(Suppl 1):19.]. Triggers for hyperactivation of the complement pathway include infection, inflammation, malignancy, endothelium-affecting drugs, maternal-fetal hemorrhage and pre-eclampsia [Shen YM. Clinical evaluation of thrombotic microangiopathy: identification of patients with suspected atypical hemolytic uremic syndrome. Thromb J. 2016;14(Suppl 1):19.]. Thirty percent of individuals with aHUS are found to have mutations in the genes encoding complement regulatory proteins, such as protein factor H, complement factor I and complement 3 [Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:1676–87; Loirat C, Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60.]. Outcomes of an untreated aHUS are poor: up to 50% of patients with aHUS progress to end-stage renal disease within a year and 25% die during the acute phase [Loirat C, Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60; Laurence J, Haller H, Mannucci PM, Nangaku M, Praga M, Rodriguez de Cordoba S. Atypical hemolytic uremic syndrome (aHUS): essential aspects of an accurate diagnosis. Clin Adv Hematol Oncol. 2016;14(Suppl 11):2–15.]. We present an unusual case of a 37-year-old primigravida who developed p-aHUS in the setting of hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. She was successfully treated with a relatively novel medication; eculizumab, a terminal complement inhibitor. In contrast to previous reports of long-term treatment, she received a total of six doses of eculizumab and remained in remission at 12 months postpartum.

Hemolytic Uremic Syndrome in Pregnancy and Postpartum.

Pregnancy is associated with various forms of thrombotic microangiopathy, including hemolytic uremic syndrome. A previous small French study suggested that pregnancy-associated hemolytic uremic syndrome was to be included in the spectrum of atypical hemolytic uremic syndrome linked to complement alternative pathway dysregulation. We sought to retrospectively analyze the presentation, outcome, and frequency of complement alternative pathway gene variants in a larger international (France, United Kingdom, Italy) cohort of patients with pregnancy-associated hemolytic uremic syndrome. Eighty-seven patients with pregnancy-associated hemolytic uremic syndrome were included. Hemolytic uremic syndrome occurred mainly during the first pregnancy (58%) and in the postpartum period (76%). At diagnosis, 56 (71%) patients required dialysis. Fifty-six (78%) patients underwent plasma exchanges, 21 (41%) received plasma infusions, and four (5%) received eculizumab. During follow-up (mean duration of 7.2 years), 41 (53%) patients reached ESRD, 15 (19%) had CKD, and 18 (28%) patients experienced hemolytic uremic syndrome relapse. Twenty-four patients (27%) received a kidney transplant and a recurrence of hemolytic uremic syndrome occurred in 13 (54%) patients. Variants in complement genes were detected in 49 (56%) patients, mainly in the CFH (30%) and CFI genes (9%). Pregnancy-associated hemolytic uremic syndrome and atypical hemolytic uremic syndrome nonrelated to pregnancy have the same severity at onset and during follow-up and the same frequency of complement gene variants.

Pregnancy-Associated Hemolytic Uremic Syndrome Revisited in the Era of Complement Gene Mutations

In contrast to pregnancy-associated thrombotic thrombocytopenic purpura, the pathogenesis and presentation of pregnancy-associated atypical hemolytic uremic syndrome (P-aHUS) remain ill-defined. We conducted a retrospective study to assess the presentation and outcomes of patients presenting with P-aHUS and the prevalence of alternative C3 convertase dysregulation. P-aHUS occurred in 21 of the 100 adult female patients with atypical HUS, with 79% presenting postpartum. We detected complement abnormalities in 18 of the 21 patients. The outcomes were poor: 62% reached ESRD by 1 month and 76% by last follow-up. The risk for P-aHUS was highest during a second pregnancy. Thirty-five women, 26 (74%) of whom had complement abnormalities, had at least one pregnancy before the onset of a non-pregnancy-related aHUS. Outcomes did not differ between patients with pregnancy-related and non-pregnancy-related aHUS. Mutations in the SCR19-20 domains of factor H were less frequent in P-aHUS patients compared with non-pregnancy-related aHUS. Pregnancies in female patients with complement abnormalities (n = 44) were complicated by fetal loss and preeclampsia in 4.8% and 7.7%, respectively. Better understanding of complement dysregulation in pregnancy complications is essential, especially to guide development of pharmacologic agents to modulate this system.

Hemolytic Uremic Syndrome

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy defined by thrombocytopenia, nonimmune microangiopathic hemolytic anemia, and acute renal failure. The most frequent form is associated with infections by Shiga-like toxin-producing bacteria (STEC-HUS). Rarer cases are triggered by neuraminidase-producing Streptococcus pneumoniae (pneumococcal-HUS). The designation of aHUS is used to refer to those cases in which an infection by Shiga-like toxin-producing bacteria or S. pneumoniae can be excluded. Studies performed in the last two decades have documented that hyperactivation of the complement system is the pathogenetic effector mechanism leading to the endothelial damage and the microvascular thrombosis in aHUS. Recent data suggested the involvement of the complement system in the pathogenesis of STEC-HUS and pneumococcal-HUS as well. Clinical signs and symptoms may overlap among the different forms of HUS; however, pneumococcal-HUS and aHUS have a worse prognosis compared with STEC-HUS. Early diagnosis and identification of underlying pathogenetic mechanism allows instating specific support measures and therapies. In clinical trials in patients with aHUS, complement inhibition by eculizumab administration leads to a rapid and sustained normalization of hematological parameters with improvement in long-term renal function. This review summarizes current concepts about the epidemiological findings, the pathological and clinical aspects of STEC-HUS, pneumococcal-HUS, and aHUS, and their diagnosis and management.

Current understanding of severe preeclampsia, pregnancy-associated hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, hemolysis, elevated liver enzymes, and low platelet syndrome, and postpartum acute renal failure: different clinical syndromes or just different names?

Endothelial cell injury, with subsequent vasospasm, platelet activation, unbalanced prostacyclin-thromboxane ratio, and decreased release of endothelium-derived relaxing factor, play a central role in the pathogenesis of several disorders such as preeclampsia, hemolysis, elevated liver enzymes, and low platelet syndrome, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, acute fatty liver of pregnancy, and acute renal failure. It is possible that all these diseases are part of a spectrum of the same illness. Although the cause remains unknown, the pathophysiology of these diseases is important for an early diagnosis. Differential diagnosis is often difficult due to the overlap of these syndromes. The purpose of this review is to clarify the differences and similarities among these pregnancy-related complications.