|Year : 2017 | Volume
| Issue : 2 | Page : 63-66
Pregnancy-associated atypical hemolytic uremic syndrome: A case report and literature review
Yu Qiang Chen, Qin Xue, Nian Song Wang
Department of Nephrology, Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200233, China
|Date of Web Publication||20-Jun-2017|
Nian Song Wang
Department of Nephrology, Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, 600 Yishan Road, Shanghai 200233
Source of Support: None, Conflict of Interest: None
Atypical hemolytic uremic syndrome (aHUS) is a rare disease of uncontrolled alternative pathway complement activation and pregnancy-associated aHUS (P-aHUS) is a more rare but life-threatening disorder. Besides gene screening, ADAMTS-13 detection and renal biopsy is helpful to establish diagnosis and prognosis assessment when kidney is involved. Combined liver-kidney transplant and eculizumab therapy has generally been the initial approach to this disease management besides therapeutic plasma exchange and plasma infusion. Though transplant and eculizumab therapy may be more effective than traditional therapy, it is much more expensive and not easily available. Herein we report a case of P-aHUS and our case indicates that plasma exchange and hemodialysis may be effective to P-aHUS for those not suitable/available for eculizumab treatment or transplant.
Keywords: ADAMTS-13, atypical hemolytic uremic syndrome, hemodialysis, plasma exchange, pregnancy-associated atypical hemolytic uremic syndrome
|How to cite this article:|
Chen YQ, Xue Q, Wang NS. Pregnancy-associated atypical hemolytic uremic syndrome: A case report and literature review. J Integr Nephrol Androl 2017;4:63-6
|How to cite this URL:|
Chen YQ, Xue Q, Wang NS. Pregnancy-associated atypical hemolytic uremic syndrome: A case report and literature review. J Integr Nephrol Androl [serial online] 2017 [cited 2023 Mar 24];4:63-6. Available from: http://www.journal-ina.com/text.asp?2017/4/2/63/208577
| Introduction|| |
Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening, chronic, genetic disease of uncontrolled alternative pathway complement activation. The understanding of the pathophysiology and genetics of this disease has expanded over recent decades and thus promising new developments in the management of aHUS have emerged.,, However, this disease is still associated with a very high rate of mortality and progression to end-stage kidney disease (ESKD). The most common cause of thrombotic microangiopathy (TMA) and hemolytic uremic syndrome (HUS) is associated with Shiga-toxin-producing infections (now termed STEC-HUS). The term aHUS has been used to describe the entity of cases of TMA not caused by Shiga toxin-associated microorganisms and bacterial infections in general, and in which thrombotic thrombocytopenic purpura (TTP) has been excluded in the differential diagnosis by demonstrating levels of ADAMTS-13 activity more than 5%–10%. Some researchers insisted that aHUS was a form of TMA, but some others disagreed with it.,,, Severe kidney impairment is a prominent but not an essential feature of the disease. Nevertheless, the ultimate diagnosis of aHUS does not require a formal demonstration of its underlying genetic cause. Herein, we report one case of pregnancy-associated aHUS (P-aHUS).
| Case Report|| |
Our patient was an Asian female aged 21 who was hospitalized on April 19, 2016, for oliguria and azotemia after her cesarean section. Before her pregnancy, her menstruation was quite normal (lasting for about 5 days every 28 days and the volume was medium without menorrhalgia), her last menstruation started on July 11, 2015, and the expected date of confinement was April 18, 2016. She had no pregnancy history, and during her pregnancy, she had a minor morning sickness. She had no influenza, no exposure to radiation, toxicity or pets such as cats and dogs. There were no abnormal findings in Down syndrome screening and major malformotion screening in routine examinations and tests in the duration of pregnancy. Moreover, her blood pressure, blood sugar, and liver and kidney function, blood coagulation index were in normal range. The creatinine level was 63 μmol/L, and urea nitrogen was 2.84 mmol/L on January 27, 2016. However, the patient presented with discernible lower extremities edema in both legs in late gestation with normotension and no signs of urinary protein. On April 11, 2016, the patient was hospitalized in Anhui Province for premature rupture of membrane, there she had to receive a cesarean section and delivered a female infant (weight 3780 g, Apgar scores = 10) after an unsuccessfully induced labor. The patient presented with oliguria soon after the surgery and anuria on the 2nd day, accompanied by promptly reduced liver and kidney function. Meanwhile, disseminated intravascular coagulation was highly suggested as D-dimer surged out of the detection margin, and her hemoglobin (Hb) dropped promptly from 104 g/L to 87 g/L in 3 days, accompanied by elevated white blood cell (WBC) of 26.63 × 109/L and decreased platelets (PLT) of 75 × 109/L. She also presented with insufferable nausea and vomiting but no diarrhea this time. On April 13, 2016, hemodialysis was initiated for continuing anuria and aggressively reduced liver-kidney functions (blood UN = 15.1 mmol/L, creatinine = 300.3 μmol/L, UA = 576 μmol/L, alanine aminotransferase (ALT) =187 U/L, aspartate aminotransferase (AST) =193 U/L, posttransfusion hepatitis = 354.00 pg/mL). Before hemodialysis, autoantibodies were screened with negative results. After five cycles of daily hemodialysis, the patient was still in MODS (ALT = 65 IU/L, AST = 56 IU/L, albumin (Alb) =25.2 g/L, UN = 13.02 mmol/L, creatinine = 361 μmol/L) and thus was transferred to our hospital for further treatment.
In our hospital, she was still normotensive and had no urinary protein. The laboratory test results on April 19, 2016, were as follows: WBC = 12.5 × 109/L, PLT = 130 × 109/L, Hb = 69 g/L, ALT = 9 U/L, AST = 34 U/L, β-GT = 46 U/L, TBil = 16 μmol/L, LDH = 4048 U/L, T-protein = 48 g/L, Alb = 24 g/L, ceatinine = 891 μmol/L, BUN = 12.0 mmol/L, UA = 404 μmol/L. Plasma concentrations of complement factor H (CFH), CFI, and CFB were in normal range and the expression of membrane cofactor protein (MCP) on leukocytes was normal, too. No anti-factor H antibodies were found, and no mutations in the genes for CFH, CFI, or MCP were identified. The peripheral blood smear was negative for schistocytes, and C3 value was 61.2 mg/dL. It was notable that ADAMTS-13 activity was <5%, which was quite below the normal range of 75.60% ±10.07% using residual-collagen binding assay. Autoantibodies were tested for the second time, negative again.
Ultrasonography showed normal morphous of liver, gallbladder, and pancreas but thinning in renal cortex and echo enhancement of kidneys, color Doppler flow imaging showed reduced bloodstream delivery in kidneys. Computed tomography (CT) scan of upper abdomen detected bilateral pulmonary interstitial edema and pleural effusion, hydroperitoneum as well as renomegaly and perirenal exudation. Kidney biopsy was conducted on April 26, 2016, and the LM results showed prevalent ischemic infarct in glomerulus (20 out of 21 glomerulus), foliated infarct in kidney tubules accompanied by hemorrhage, multiple thrombopoiesis in renal arteries and veins, and massive phlogocyte infiltration in renal interstitium [Figure 1]. Meanwhile, the immunofluorescence findings of IgG, IgA, IgM and C3 were all negative. Immunohistochemistry results were as following: HBsAg(−), HBcAg(−), SMA(+), LCA(+), CD3(+), CD20(−), CD31(+), CD34(+), CD10(+), and ERG(+). Moreover, periodic acid-Schiff stain and Masson stain were both positive.
|Figure 1: (a and b) Kidney biopsy result. LM results showed prevalent ischemic infarct in glomerulus (20 out of 21 glomerulus), foliated infarct in kidney tubules accompanied by hemorrhage, multiple thrombopoiesis in renal arteries and veins, and massive phlogocyte infiltration in renal interstitium (H and E, ×400)|
Click here to view
Thus, based on the patient's clinical manifestations and laboratory tests, we established the diagnosis as follows: Elective cesarean section, postpartum HUS, acute kidney injury and renal insufficiency, pulmonary interstitial edema and acute respiratory failure.
LM results showed prevalent ischemic infarct in glomerulus (20 out of 21 glomeruli), foliated infarct in kidney tubules accompanied by hemorrhage, multiple thrombopoiesis in renal arteries and veins, and massive phlogocyte infiltration in renal interstitium.
We used BiPAP ventilation (FiO2 50%, PEEP 3 cmH2O, PS 6 cmH2O) to relieve hyoxemia and continuous renal replacement therapy (the mode is continuous venovenous hemofiltration [CVVH]) and plasma exchange to retrieve the renal function, pulsed with basic symptomatic and supportive therapies. After six sessions of plasma exchange and CVVH, the patient's urine output increased gradually and her laboratory results improved greatly. Hence, she went back to her hometown for subsequent treatment. Now, she still had a deficient renal function (the urine output is about 800 mL/day) and relied on maintenance hemodialysis (twice every week).
| Discussion|| |
aHUS is a challenging disease process to manage with a relatively poor prognosis, as many patients develop ESKD or die within the 1st year of diagnosis. Mutations have been described in CFH, CFI, MCP, CFB, C3, and thrombomodulin. In addition, autoantibodies to CFH can cause aHUS and are commonly associated with deletions of CFH-related proteins (CFHR1) and CFHR3. Mutations in either CFH, CFI, MCP, thrombomodulin and/or CFHR1/3 with autoantibodies to CFH are associated with loss of regulatory control of the alternative pathway of the complement cascade.,, Mutations in CFB and C3 are gain-of-function mutations leading to complement overactivation. Loss-of-function mutations in CFH are most common and have the worst prognosis based on registry data, with 60%–70% of patients progressing to ESKD or death within a year of disease onset. The prognosis for patients with CFI mutations appears slightly better, followed by patients with MCP mutations, of whom 20% require renal replacement therapy. However, patients without demonstrated mutations have similar dire outcomes, raising the idea that the presence or absence of a given mutation may have limited prognostic value, except for the MCP mutation that may not recur after a kidney transplant. Until recently, there have been no specific therapies for aHUS.
P-aHUS is a very rare disorder with an estimated incidence of approximately 1 in 25,000 pregnancies. However, it is associated with a significant perinatal or maternal morbidity and mortality. P-aHUS is defined by the occurrence of fibrin and/or platelet thrombi in the microvasculature, resulting in hemolytic mechanical hemolysis and thrombocytopenia during the antepartum or postpartum period. In recent years, two major findings have significantly improved our understanding of TMA. Notably, an acquired or constitutional deficiency in ADAMTS-13, a von Willebrand factor (vWF)-processing enzyme, has emerged as a cause of a peculiar type of TMA with profound thrombocytopenia and minor renal involvement-TTP. The complement system, a part of the innate immune system, is a complex multiproteic cascade involved in protection against invading microorganisms, removal of debris from plasma and tissues, and enhancement of cell-mediated immune responses. Pregnancy may trigger the onset or subsequent relapses of ADAMTS-13 deficiency-related TTP as well as complement dysregulation associated-aHUS. More recently, complement dysregulation was also associated with another pregnancy disorder, hemolysis elevated liver enzymes and low platelet count syndrome, which shares several features with P-aHUS. To the best of our knowledge, there are not adequate studies to date that have specifically assessed the implication for alternative complement pathway dysregulation in P-aHUS.
Therapeutic plasma exchange or plasma infusion has generally been the initial approach to disease management, although there are no randomized controlled trials of plasma therapy in aHUS to establish its effectiveness. Plasma exchange may only be beneficial to aHUS in the short-term since long-term kidney outcomes are uniformly poor with a varying short-term response in hematological parameters. Patients who do respond to plasma exchange frequently become plasma dependent, requiring long-term therapy to maintain remission. Kidney transplant, then, would be expected to halt the disease process. Other mutations or unknown ones have led to high relapse rates of aHUS in the transplanted kidney. These circulating proteins are primarily synthesized in the liver. Not unexpectedly, aHUS recurs in 80% of patients with CFH mutations and 90% of patients with CFI mutations after an isolated kidney transplant. Combined liver-kidney transplant has been attempted for patients with CFH and CFI mutations to address the abnormal protein synthesis in the liver and its downstream effect on the kidney. Simultaneous liver-kidney transplant with prophylactic use of plasma therapy has been successful in patients with CFH mutations. A pathophysiologic-based treatment for aHUS is available now with eculizumab, through inhibiting the formation of the common terminal complement complex (C5b-9). Due to the impaired capacity for opsonization and clearance of encapsulated organisms, meningococcal disease is a risk with the use of eculizumab and has been reported among patients receiving eculizumab for paroxysmal nocturnal hemoglobinuria. Early initiation of eculizumab, before significant kidney injury, has been associated with improved renal outcomes. Our patient, however, who presented with acute kidney failure for P-aHUS, recovered partial kidney function without eculizumab or transplant.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understand that her name and initial will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed.
We thank Zhang Lisha for clinical data collecting.
Financial support and sponsorship
This work was supported by grants from the National Natural Science Foundation of China (81300602).
Conflicts of interest
There are no conflicts of interest.
| References|| |
Koskinen AR, Tukiainen E, Arola J, Nordin A, Höckerstedt HK, Nilsson B, et al.
Complement activation during liver transplantation-special emphasis on patients with atypical hemolytic uremic syndrome. Am J Transplant 2011;11:1885-95.
Moore I, Strain L, Pappworth I, Kavanagh D, Barlow PN, Herbert AP, et al.
Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic uremic syndrome. Blood 2010;115:379-87.
Goodship TH, Kavanagh D. Pulling the trigger in atypical hemolytic uremic syndrome: The role of pregnancy. J Am Soc Nephrol 2010;21:731-2.
Davin JC, Groothoff J, Gracchi V, Bouts A. Long-term renal function under plasma exchange in atypical hemolytic uremic syndrome. Pediatr Nephrol 2011;26:1915-6.
Kohli R, Gulati S. Plasma infusion therapy in atypical hemolytic uremic syndrome long term outcome. Indian Pediatr 2006;43:164-6.
Hodgkins KS, Bobrowski AE, Lane JC, Langman CB. Clinical grand rounds: Atypical hemolytic uremic syndrome. Am J Nephrol 2012;35:394-400.
Dorresteijn EM, van de Kar NC, Cransberg K. Eculizumab as rescue therapy for atypical hemolytic uremic syndrome with normal platelet count. Pediatr Nephrol 2012;27:1193-5.
Kavanagh D, Richards A, Fremeaux-Bacchi V, Noris M, Goodship T, Remuzzi G, et al.
Screening for complement system abnormalities in patients with atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol 2007;2:591-6.
Saad AF, Roman J, Wyble A, Pacheco LD. Pregnancy-associated atypical hemolytic-uremic syndrome. AJP Rep 2016;6:e125-8.
Saland JM, Ruggenenti P, Remuzzi G; Consensus Study Group. Liver-kidney transplantation to cure atypical hemolytic uremic syndrome. J Am Soc Nephrol 2009;20:940-9.