|Year : 2020 | Volume
| Issue : 6 | Page : 1180-1188
|Pregnancy-associated hemolytic uremic syndrome
Sami Alobaidi1, Ammar AlDabbagh2, Amany Alamoudi2, Murad Almowarey3, Ahmed Akl4
1 Department of Internal Medicine, University of Jeddah, Jeddah, Saudi Arabia
2 Department of Medicine, Dr. Soliman Fakeeh Hospital, Jeddah, Saudi Arabia
3 Department of Hematology, King Fahad Hospital, Madinah, Saudi Arabia
4 Department of Medicine, Dr. Soliman Fakeeh Hospital, Jeddah, Saudi Arabia; Department of Nephrology, Urology and Nephrology Center, Mansoura, Egypt; Fakeeh College of Medical Sciences, Jeddah, Saudi Arabia
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|Date of Web Publication||29-Jan-2021|
| Abstract|| |
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.
|How to cite this article:|
Alobaidi S, AlDabbagh A, Alamoudi A, Almowarey M, Akl A. Pregnancy-associated hemolytic uremic syndrome. Saudi J Kidney Dis Transpl 2020;31:1180-8
|How to cite this URL:|
Alobaidi S, AlDabbagh A, Alamoudi A, Almowarey M, Akl A. Pregnancy-associated hemolytic uremic syndrome. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2021 Aug 3];31:1180-8. Available from: https://www.sjkdt.org/text.asp?2020/31/6/1180/308326
| Introduction|| |
Thrombotic microangiopathy (TMA) is a relatively rare condition, but is a definite medical emergency and is associated with irreversible organ damage or death if left untreated. In general, the group of diseases that causes TMA has been divided on clinical grounds by affected organs into thrombotic-thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS), the latter being termed atypical if not preceded by diarrhea.
A definitive diagnosis of aHUS is made when the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury are present. Shiga toxins should not be associated with the disease, and TTP should also be excluded. Patients with negative Shiga toxin-producing Escherichia. coli (STEC) are categorized as having atypical HUS (aHUS), which is related to an increased risk of complement mutations and a prognosis compared with typical HUS.
| Pregnancy-associated Atypical Hemolytic Uremic Syndrome|| |
Pregnancy-associated atypical hemolytic uremic syndrome (P-aHUS) is also a rare condition, affecting 1 of every 25,000 pregnancies; P-aHUS is characterized by very high maternal mortality and morbidity, as stated. Published literature suggests that more than 50% of all patients with P-aHUS eventually progress to end-stage renal disease in <1 month if left untreated, with most cases of it (79%) developing in the postpartum period.
Three regulatory proteins prevent the uncontrolled activation of complement during normal pregnancy: DAF, MCP, and CD59. During pregnancy, an increase by 10%–50% of the serum concentrations of C3, C4, and CH50 occurs. Many factors can lead to systemic activation of the alternative pathway such as inflammation during delivery, post-partum infections, hemorrhage, and the release of fetal cells in the maternal circulation, which, in the absence of effective regulatory mechanisms, induces postpartum aHUS., P-aHUS is correlated with uncontrolled activation of complement alternative pathway and complement-mediated damage to the micro-vascular endothelium. Postpartum period in women carrying inherited defects in complement genes or autoantibodies against complement regulatory proteins has been identified as a high-risk period for aHUS development.
Both children and young adults with aHUS have nonspecific symptoms of illness: pallor, poor feeding, vomiting, fatigue, and drowsiness. Anuria or oliguria with or without peripheral edema may be present. Marked hypertension may also be present, either from acute kidney injury or from ischemia caused by TMA. Hypertension may be severe enough to provoke heart failure or posterior reversible encephalopathy. Half of the children and the majority of adults need dialysis at admission. Such symptoms should be addressed and treated with close follow-up by the attending team. Extra-renal involvement during HUS episodes was observed in 10%–30% of patients, with the exception of patients with MCP mutations. The most frequent extra-renal manifestation is central nervous system involvement (10% of patients) with diverse presentations including irritability, drowsiness, seizures, diplopia, cortical blindness, hemiparesis or hemiplegia, stupor, and coma. Myocardial infarction due to cardiac micro-angiopathy has been reported in approximately 3% of patients and is presumed to cause episodes of sudden death, while 5% of patients present with a life-threatening multi-organ failure due to diffuse TMA.,,
P-aHUS is associated with uncontrolled complement alternative pathway activation and complement-mediated damage to the micro-vascular endothelium. As a function of this, pregnancy in the postpartum period has recently been identified as a high-risk period for the development of aHUS in women carrying inherited defects in complement genes or autoantibodies against complement regulatory proteins, as stated earlier.
P-aHUS can mimic several other diseases that cause TMA and to differentiate between them can be challenging. Common features of TMA seen in p-aHUS are also observed in severe pre-eclampsia with hemolysis, elevated liver enzymes, and low platelet count (HELLP syndrome), TTP, and acute fatty liver of pregnancy (AFLP). It is crucial to make the correct diagnosis in a timely manner to treat patients appropriately and prevent further complications. While some clinical features of these syndromes overlap, laboratory studies can help guide the clinician to the right diagnosis; for example, TTP manifests with more neurological symptoms and severe ADAMTS 13 deficiency, while HELLP and AFLP appear to present with high liver dysfunction, nausea, and vomiting; all these syndromes present in the third trimester or late in the second trimester, but P-aHUS occurs mostly post-partum and tends to manifest with a higher degree of renal failure. These syndromes may act as a stimulus for the development of P-aHUS in genetically predisposed patients. The presence of bloody diarrhea or a confirmed positive Shiga toxin test will lead to the diagnosis of STEC-HUS., [Table 1] shows a summary of the clinical and laboratory differentiation between HELLP syndrome, TTP, a-HUS and catastrophic anti-phospholipid syndrome. [Figure 1] shows a suggested algorithm to approach a pregnancy-associated TMA.
|Figure 1: Suggested algorithm to approach a pregnancy associated thrombotic microangiopathy.|
SLE: Systemic lupus erythematosus, HELLP: Hemolysis, elevated liver enzymes, and low platelet count, CNS: Central nervous system, HUS: Hemolytic uremic syndrome, aHUS: atypical hemolytic uremic syndrome.
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|Table 1: Summary of the clinical and laboratory differentiation between HELLP syndrome, TTP, a-HUS and CAPL.,,,|
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A genetic testing for known causative genes and analysis of anti-CFH antibodies is required to confirm a diagnosis of aHUS. However, the absence of causative genetic mutations does not always exclude a diagnosis of aHUS, because specific genetic mutations still could not be detected in 40% of aHUS patients.
Complement pathways and gene mutations
The association between pregnancy, especially in the postpartum period, as a trigger factor for P-aHUS can be explained by several hypotheses: for example, how complement components (C3b, C4b) are detected in the placenta of both normal and pathologic pregnancies.
During pregnancy, an immunological conflict takes place in the placenta, which is potentially subject to complement-mediated immune attacks at the feto-maternal interface, with the potential risk of fetal loss. In the French aHUS cohort, published in 2010 by Fakhouri et al, it was shown that P-aHUS and non-pregnancy-related aHUS share a high incidence of mutations in complement genes (86% with P-aHUS and 76% with non-pregnancy-related aHUS), with CFH mutations being the most frequently encountered gene mutation (48% of patients). The same study showed the occurrence of 75% of cases of P-aHUS in the postpartum period. Furthermore, 21% of aHUS cases among women were P-aHUS and 85% of them carried mutations in the CFH, MCP, CFI, or C3 genes. The results of this comprehensive meta-analysis reviewed 39 articles, and demonstrated strong evidence for an association between CFHR1 deletion, anti-FH autoantibodies, and aHUS. CFHR1 deficiency was significantly correlated with an increased risk of aHUS. This study also identified potential interactions between anti-FH auto-antibodies and CFHR1 deletion in aHUS patients, indicating that the development of aHUS could be exacerbated by the interaction between CFHR1 deficiency and anti -FH auto-antibodies. CFH and CFHR genes present in 4.5% of patients with aHUS, while CFH/ CFHR rearrangements are associated with poor clinical prognosis and a high risk of posttransplant recurrence.
The clinical evidence of how the complement plays a role in the pathogenesis of glomerular disease has several strands. The presence of complement components, identified in renal biopsy samples by immunofluorescence or immunohistochemical staining, is consistent with a pathogenic role, although it may often be incidental. Similarly, the presence of low serum levels of complement components, suggesting activation, and consumption, or of autoantibodies against complement components is suggestive, but not firm evidence, of a contribution to tissue injury. The association of some types of glomerular disease with genetic abnormalities of complement components is stronger evidence, particularly when the situation is familial.
| P-aHUS Management|| |
Supportive care and plasma exchange
Once P-aHUS is suspected, it is mandatory to immediately start management with plasma exchange (PE) within 24 h of diagnosis (after obtaining, but without awaiting for the results, all important laboratories such as ADAMTS 13), along with obtaining a renal biopsy, which pathognomically shows evidence of TMA. However, renal biopsy is not usually indicated if the picture is suggestive of TMA. PE should be performed daily, while duration of PE is usually individualized on the basis of the patient’s response and should be continued until complete normalization of blood parameters [platelets >150,000/mm for two consecutive days as well as the normalization of lactate dehydrogenase (LDH)]. The use of PE in P-aHUS improved survival rates from 10% to 75% to 92%; it is recommend to use pooled plasma from male donors to decrease the chances of transfusion-related lung injury. It is reasonable to start renal replacement therapy as needed for hyperkalemia, pulmonary edema, metabolic acidosis, and uremia. It is advisable to transfuse packed red blood cells as needed to keep hemoglobin level >7 g/dL and to avoid transfusion of platelets prior to central line placement. A multidisciplinary team consisting of intensivists, maternal-fetal medicine specialists, hematologists, nephro-logists, and transfusion medicine pathologists should be involved in the management and long-term therapy of this patient population. If the diagnosis of atypical HUS is confirmed, consider pro-longed therapy with complement inhibitors (eculizumab), due to the fact that despite the initial success of PE in maintaining normal platelet counts and LDH, the persistence of abnormal pattern of complement activation and TMA is likely to continue with the risk of irreversible organ damage, primarily renal, in subsequent weeks to months.
Eculizumab is a recombinant monoclonal IgG2/4 kappa chimeric anticomplement C5 antibody, preventing C5a and C5b products and formation of the membrane attack complex, but does not affect the complement systems up to C3. Although complement regulatory functions are attributed to most of the members of the CFHR protein family, the precise role of each CFHR protein in complement activation and its exact contribution to disease pathology is still unclear. Because of complement involvement in aHUS pathogenesis, and based on two prospective studies in predominantly adults and retrospective data in children, eculizumab, a terminal complement inhibitor, is approved for aHUS treatment.
Recent guidelines recommend treating children and adults with a diagnosis of aHUS with eculizumab within 24 h. Eculizumab should be initiated after no more than five PEs in patients with confirmed diagnosis of aHUS, where further workup is needed, and where no significant improvement of renal and hematological parameters has been observed., A lack of normalization of the platelet count and LDH, or improvement in serum creatinine levels in this time is an additional indicator for a switch to eculizumab; therefore, it is reasonable to start eculizumab in less than a week when patients present with TMA as a consequence of aHUS. It was shown in open-label phase two trials that earlier initiation of eculizumab therapy is associated with greater improvements in kidney disease outcomes, with significant improvements in eGFRs as well. Platelet counts were normalized as early as one week after eculizumab intervention. Similarly, the accumulated clinical experience with multiple prospective studies done in patients with aHUS shows that its use was associated with a fast and sustained interruption of the TMA process and improvement of the hematologic parameters. It was associated with significant long-term improvements in renal function, interruption of plasma therapy, and important reductions/discontinuation after dialysis, plus an improved quality of life and transplant protection.,,
The C5b-9 complex confers protection against encapsulated bacteria, particularly N. meningitidis, and its formation is blocked by eculizumab; encapsulated bacteria have been shown to elevate the risk of meningococcal infection; thus, patients should be immunized with meningococcal vaccine at least two weeks before receiving eculizumab. If the situation requires immediate eculizumab administration in patients who have not been immunized, the physician must administer it with appropriate prophylactic antibiotics (for example, oral penicillin for two weeks after vaccination, or macrolide in case of penicillin allergy).
Eculizumab in pregnancy
The literature of aHUS cases treated with eculizumab in pregnancy is limited. Servais et al analyzed the role of eculizumab for the treatment of aHUS during five pregnancies in three patients and studied an additional pregnancy without it. All pregnant patients with aHUS were closely monitored by both nephrology and obstetric specialists. The study concluded that eculizumab displayed no overt safety issues, but did not appear to prevent adverse outcomes such as HELLP syndrome or pre-eclampsia either. Its effects on the fetus are unknown, since it may cross the placenta, but the level is not high enough to affect complement activation. However, the drug’s safety in pregnancy, in terms of treating paroxysmal nocturnal hemoglobinuria (PNH) has been better described. Previous literature reviewed a small series of pregnant women and newborns, with confirmed PNH or undetectable/very low limits in newborns. More experience of eculizumab, in PNH, from the international registry, provides further evidence for its safe use in pregnancy, with improved fetal survival (although 30% were premature, but it reduced maternal thrombotic complications). Eculizumab was detected in 7/20 cord samples, but not in any breast milk samples from the 10 cases analyzed.
Discontinuation of eculizumab
After administering eculizumab, it is mandatory to follow-up with clinical and laboratory data that demonstrates both hematological and renal remission, for example, normal platelet and red blood cell counts, absence of any signs suggestive of hemolysis, normalization of LDH, and stable serum creatinine. However, in these cases, we believe that performing a renal biopsy, once clinical remission has been achieved, could also play a key role, thereby providing histopathological information and allowing detection of subclinical TMA.,
The optimal duration of eculizumab treatment in aHUS and the decision to stop treatment remains under debate., Fakhouri et al reported the largest retrospective study that included 108 patients with aHUS, all were dialysis-free after discontinuation of eculizumab where the median duration of treatment was 17.5 months. The study concluded that the presence and type of complement gene variants detected do not affect one’s response to it, but are major predictive factors for aHUS relapse after termination. The risk of relapse after eculizumab discontinuation was the highest in patients with CFH variants (72%), reflecting that the decision to discontinue or not should take into account the high risk of relapse, unlike the patient with no identified complement gene or pathogenic variants, or those with MCP pathogenic variants, where discontinuation of the treatment might be considered. However, kidney biopsy still plays a role in assessing subclinical renal damage after treatment discontinuation or subsequent relapse.
We recently reported a case of postpartum atypical HUS with hybrid CFHR1/CFH gene who suffered relapse after discontinuation of the eculizumab due to financial issues. After successful re-induction of remission, we tailored eculizumab interval therapy to every three months instead of monthly dose. We are the first to report this new three-month interval, our patient is doing well for three years with no relapse nor complications. Long-term studies with a large number of patients are needed to confirm our experience.
| Role of Transplantation in Atypical Hemolytic Uremic Syndrome|| |
Until recently, kidney transplantation alone was not recommended in the treatment of aHUS with known anomalies of complement alternative proteins: this is due to the high risk of recurrence of the disease and graft failure. Combined liver-kidney transplantation in combination with extensive pre- and peri-operative PE was applied in some patients with aHUS who had a CFH mutation with a positive outcome. Previously published studies suggested that eculizumab alone, without PE, was sufficient to prevent recurrence of aHUS and maintain long-term graft function.
Another published study included 41 patients diagnosed with aHUS, and clearly showed that no patient with a kidney transplant who entered the study lost the graft after 26 weeks.
Furthermore, with regard to carriers of the hybrid CFHR1/CFH gene, it induced more C5b-9 deposition on the endothelial cells than control serum. Current recommendations suggest that this novel genomic hybrid mediates disease pathogenesis through dysregulation of the complement at the endothelial cell surface. They recommend that genetic screening of aHUS should include analysis of CFH and CFHR rearrangements, particularly before a kidney transplant, because such rearrangements are associated with recurrence and graft loss, which can be prevented by eculizumab prophylaxis. Combined liver/kidney transplantation has been successfully used in patients with CFH mutations and could also be useful for patients with CFH/CFHR and CFHR1/ CFH hybrid genes. The combined transplant provides surgical correction of the genetic abnormality and is considered less expensive than a single kidney transplant with ongoing eculizumab prophylaxis; however, it is associated with higher short-term complications and requires extremely experienced centers.
| Pregnancy-associated-atypical Hemolytic Uremic Syndrome and Future Pregnancies|| |
The risk of P-aHUS is highest during a woman’s second pregnancy., It is difficult to exclude that complement dysregulation could be involved in other pregnancy complications, such as pre-eclampsia and fetal losses. Counseling of young female patients with documented C3 convertase dysregulation who wish to have another pregnancy is crucial. On the basis of the literature review, patients with complement dysregulation should be informed of the relatively high-risk (20%) of P-aHUS, along with the pregnancy being closely monitored.,,
| Conclusion|| |
The diagnosis of p-aHUS can be challenging, as other diseases such as severe pre-eclampsia, HELLP syndrome, TTP, and AFLP need to be excluded first. Genetic testing for known causative genes and analysis of anti-CFH antibodies might confirm a diagnosis of aHUS in the postpartum period. However, the absence of causative genetic mutations does not always exclude a diagnosis of aHUS. In addition to supportive care and immediate initiation of plasmapheresis, Eculizumab has shown 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.
Conflict of interest: None declared.
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Department of Internal Medicine, University of Jeddah, Jeddah
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