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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2019  |  Volume : 30  |  Issue : 3  |  Page : 701-705
Does severe ADAMTS13 deficiency in thrombotic microangiopathy rule out complement-mediated atypical hemolytic uremic syndrome

Department of Pediatrics, Division of Pediatric Nephrology, Christian Medical College, Vellore, Tamil Nadu, India

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Date of Submission08-May-2018
Date of Decision12-Aug-2018
Date of Acceptance14-Aug-2018
Date of Web Publication26-Jun-2019


In evaluating a patient with thrombotic microangiopathy (TMA), it is necessary to rule out thrombotic thrombocytopenic purpura before a diagnosis of atypical hemolytic uremic syndrome (aHUS) is made. There have been reports that mutations of complement factors can coexist with partial A Disintegrin and Metalloproteinase with a ThromboSpondin type 1 motif, member 13 deficiency. Here, we report the case of a 6-year-old girl who was initially diagnosed as nephrotic syndrome and developed TMA after five years of onset of illness. She had poor response to treatment and had multiple relapses due to associated complement factor mutation. Hence, genetic evaluation has to be considered in all children presenting with aHUS.

How to cite this article:
Arumugam V, Bhowmick R, Agarwal I, Arumadi M. Does severe ADAMTS13 deficiency in thrombotic microangiopathy rule out complement-mediated atypical hemolytic uremic syndrome. Saudi J Kidney Dis Transpl 2019;30:701-5

How to cite this URL:
Arumugam V, Bhowmick R, Agarwal I, Arumadi M. Does severe ADAMTS13 deficiency in thrombotic microangiopathy rule out complement-mediated atypical hemolytic uremic syndrome. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2020 Jul 9];30:701-5. Available from: http://www.sjkdt.org/text.asp?2019/30/3/701/261349

   Introduction Top

The term thrombotic microangiopathy (TMA) encompasses a spectrum of disorders presenting with thrombocytopenia, microangio-pathic hemolytic anemia, acute kidney injury [predominantly in atypical hemolytic uremic syndrome (aHUS)], neurological symptoms [predominantly in thrombotic thrombocytopenic purpura (TTP)], and multi-organ involvement. There have been reports of mutations of complement factors which co-exist with partial ADAMTS 13 (ADAMTS 13) deficiency.[1]

   Case Report Top

A 6-year-old female child born to parents of nonconsanguineous marriage presented to our hospital in August 2015 with facial puffiness and pallor of two-week duration, dyspnea on exertion, and decreased urine output of one-week duration. She was diagnosed with steroid-sensitive nephrotic syndrome at the age of 18 months but had been in remission for a period of three years. There was a history of anemia requiring blood transfusion prior to visiting us. Her paternal uncle had succumbed to death at the age of 1½ years with a history of diarrhea followed by facial puffiness and anasarca. On examination, she had pallor, anasarca, and stage II hypertension. Rest of the clinical examination was within normal limits.

On laboratory evaluation, she had features of microangiopathic hemolytic anemia (MAHA) [anemia (hemoglobin: 5.8 gm%), schistocytes of 4% and thrombocytopenia (60,000/mm3) and renal failure (serum creatinine: 3.9 mg%). She also had nephrotic range proteinuria (Up/Uc: 14.05), hypoalbuminemia (albumin: 2.3 g%), hypercholesterolemia (total cholesterol: 328 mg/dL), and raised amylase (206 U/L) and lipase (227 U/L). Her C3 and C4 levels were normal (C3: 93.7 mg%, C4: 28 mg%), and ANA was negative. Blood samples for anticomplement factor H (CFH) antibody and ADAMTS 13 activity were sent. Renal biopsy showed evidence of recurrent TMA.

She was diagnosed with aHUS/TTP and was started on plasma exchange (daily for seven days followed by alternate-day therapy for a total of 14 cycles). As she had acute kidney injury with oliguria, hemodialysis was initiated. She was also concomitantly started on pulse methylprednisolone followed by oral prednisolone. She was started on intravenous pulse cyclophosphamide as pulse cyclophos-phamide is found to induce and maintain remission in antibody-mediated aHUS.[2] She responded well to treatment; her general condition improved and her creatinine decreased to 1.5 mg% at which it remained stable. Anti-CFH antibody level was 212 AU/mL (reported 4 weeks later), and ADAMTS 13 activity (enzyme immuno-assay-fluorometry) was reported to be 4% with the presence of inhibitors (reported 4 weeks later). ADAMTS13 activity was repeated again after four months when the child was in remission, which remained low (<5%) with the presence of inhibitors. Based on this, a diagnosis of TTP was considered.

Two months later in November 2015, the child had relapse with seizures and features of MAHA, supporting the diagnosis of TTP. She also had worsening of renal function. She was restarted on plasma exchange. Despite nine plasma exchanges, she attained only partial hematological remission, and her renal function deteriorated rapidly with loss of residual renal function. She was initiated on peritoneal dialysis in December 2015. In view of refractory TTP, three doses of rituximab were given over a period of six weeks with which she attained hematological remission. In May 2016, she had another relapse during which she attained remission after five daily plasma exchanges.

With intensive plasma exchange and rituximab infusion, ADAMTS13 levels became normal in July 2016. Genetic analysis by targeted gene sequencing was done at a newly available facility MedGenome in Bengaluru, India, in view of the atypical course. This revealed a heterozygous mutation in CFI gene [Table 1]. The same mutation was seen in her unaffected father. The genetic analysis of her mother was normal [Table 1]. Eculizumab being unavailable in this country and with the difficulties of importing it from other countries due to its exorbitant cost, she was started on mycophenolate mofetil. Two months later, in August 2016, she was readmitted with pseudomonas septicemia and shock to our pediatric intensive care unit. She was started on mero-penem and vancomycin and other supportive measures. Her peritoneal fluid culture was sterile. In the course of illness, she developed pericardial effusion with cardiac tamponade, for which pericardiocentesis was done. Despite all supportive measures, she succumbed to her illness on the 4th day of hospitalization.
Table 1: Variation detected by next-generation sequencing.

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   Discussion Top

The term aHUS is now reserved preferentially for hemolytic uremic syndrome without any coexisting disease.[3] Mutations in various complement pathway regulators such as C3, CFH, CFB, CFI, and thrombomodulin have been implicated in the pathogenesis of aHUS.[4] According to the diagnostic algorithm, in evaluating a patient with TMA, it is necessary to rule out TTP before a diagnosis of aHUS is made.[3] There has been previous report of congenital TTP associated with CFH rare variant.[5] The diagnosis of aHUS is considered and mutational screening is recommended when other coexisting diseases such as bone marrow transplantation, Streptococcus pneumoniae and Haemophilus inñuenza infection, TTP, STEC-HUS, and cobalamin C defect have been excluded.[3]

The present case presented with nephrotic syndrome at the onset of the disease. Although children with atypical HUS present with rapid onset of anemia, thrombocytopenia, and renal failure, approximately 20% can present with slowly progressive disease.[6],[7] It was also reported in literature that different types of glomerulopathies can be complicated by atypical HUS.[8] Atypical HUS can present with nephrotic range proteinuria and edema. The child in the present case was found to have severe deficiency of ADAMTS13 which was done twice at an interval of three months. She showed a relapsing course to plasmapheresis. A review of literature revealed that preemptive infusion of rituximab after inducing clinical remission in TTP effectively reduces clinical relapses in acquired TTP.[9] The levels of CFI, CFH, and C5b-9 were not done as these tests were not available at that time.

She continued to have a relapsing course of disease after her ADAMTS13 level normalized. Mutational analysis was sent in view of her relapsing and recurring course about nine months after her presentation to a facility, which had not been previously available. A heterozygous missense variation in exon 2 of the CFI gene (chr4:110687890; G>G/C; Depth: 236x) that results in the amino acid substitution of alanine for proline at codon 50 (p. Pro50Ala; ENST00000394634) was detected in our patient. The same mutation was seen in her unaffected father [Table 1]. The above-reported variation was previously reported as P32A without signal peptide.[10] The Pro32Ala mutant was able to cleave the α-chain of C4b, but the cleavage of the α-chain of C3b was impaired and this resulted in a 60% decrease in the factor I. The Pro32Ala variant is present in the factor I membrane attack complex domain, and structural analysis on the potential consequences of this variant on the protein structure revealed stability and folding problems. The Pro50Ala variant has a minor allele frequency of <0.02% in both the 1000 genomes and ExAC databases. Pro50Ala mutation in CFI gene is also reported in patients with definite Pneumococcus-asso-ciated aHUS.[11]

Homozygous mutations of CFI are associated with immunodeficiency disorders. They may also result in aHUS.[12] CFI mutations are extremely rare and have so far been reported in only 6.7% of children with aHUS.[3] Mutation in complement factor I gene results in deficiency of the complement, leading to uncontrolled cleavage of C3 and activation of the complement pathway. Low C3 levels can be seen in approximately 60% of patients with CFI mutation. Relapsing course can be present in 20%–40% of aHUS with CFI mutation.[13] Progression to end-stage renal disease or death is reported in 50% of the children with CFI mutation. ADAMTS13 cleaves von-Willebrand factor multimers into monomers. Approximately 20% of acquired TTP occur in children aged <9 years.[14],[15] Mutations of both CFI and ADAMTS13 have also been implicated in the pathogenesis of TMA. The confounding presence of low levels of ADAMTS13 delaying the diagnosis and treatment of children with aHUS due to complement mutations has been reported in adults.[16] Fidalgo et al, studied 11 complement genes by next-generation sequencing and found only four rare benign variants of CFI mutation (n = 3) and CFB mutation (n = 1) in a cohort of 40 TTP patients. It was also found in their cohort that additional genetic risk factors with possible impact in the activity of ADAMTS13 were present in patients with aHUS, which may augment the activity of benign variants.[17] Phillips et al, reported no rare genetic variants in complement genes in their cohort of 14 TTP patients.[18] As it is evident from our patient, ADAMTS13 deficiency does not exclude a coexisting underlying complement mutation-associated aHUS and can deny early diagnosis of the underlying complement pathway mutation.

   Conclusion Top

Workup for complement pathway dysregu-lation including mutational analysis may be required in any children with TMA, especially when the severity of renal failure is out of proportion to what may be expected in TTP.

   Acknowledgments Top

The authors would like to thank MedGenome, Bengaluru, India.

   Informed consent Top

Written informed consent was obtained from the parents of the patient for publication of this case report and any additional information.

   Declaration of patient consent Top

The authors certify that they have obtained all appropriate patient consent forms. In the form, the parents have given their consent for their child’s images and other clinical information to be reported in the journal. The parents understands that their child’s name and initial will not be published and due efforts will be made to conceal patient identity, but anonymity cannot be guaranteed.

Conflict of interest: None declared.

   References Top

Feng S, Eyler SJ, Zhang Y, et al. Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome. Blood 2013;122:1487-93.  Back to cited text no. 1
Sana G, Dragon-Durey MA, Charbit M, et al. Long-term remission of atypical HUS with anti-factor H antibodies after cyclophospha-mide pulses. Pediatr Nephrol 2014;29:75-83.  Back to cited text no. 2
Loirat C, Fakhouri F, Ariceta G, et al. An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Pediatr Nephrol 2016;31: 15-39.  Back to cited text no. 3
Lemaire M, Frémeaux-Bacchi V, Schaefer F, et al. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet 2013;45:531-6.  Back to cited text no. 4
Noris M, Bucchioni S, Galbusera M, et al. Complement factor H mutation in familial thrombotic thrombocytopenic purpura with ADAMTS13 deficiency and renal involvement. J Am Soc Nephrol 2005;16:1177-83.  Back to cited text no. 5
Campistol JM, Arias M, Ariceta G, et al. An update for atypical haemolytic uraemic syndrome: Diagnosis and treatment. A consensus document. Nefrologia 2015;35:421-47.  Back to cited text no. 6
Dolcemascolo V, Vivarelli M, Colucci M, et al. Nephrotic-range proteinuria and peripheral edema in a child: Not only idiopathic nephrotic syndrome. Case Rep Nephrol Dial 2016;6:120-7.  Back to cited text no. 7
Manenti L, Gnappi E, Vaglio A, et al. Atypical haemolytic uraemic syndrome with underlying glomerulopathies. A case series and a review of the literature. Nephrol Dial Transplant 2013;28:2246-59.  Back to cited text no. 8
Hie M, Gay J, Galicier L, et al. Preemptive rituximab infusions after remission efficiently prevent relapses in acquired thrombotic thrombocytopenic purpura. Blood 2014;124: 204-10.  Back to cited text no. 9
Bienaime F, Dragon-Durey MA, Regnier CH, et al. Mutations in components of complement influence the outcome of factor I-associated atypical hemolytic uremic syndrome. Kidney Int 2010;77:339-49.  Back to cited text no. 10
Szilágyi A, Kiss N, Bereczki C, et al. The role of complement in Streptococcus pneumoniae-associated haemolytic uraemic syndrome. Nephrol Dial Transplant 2013;28:2237-45.  Back to cited text no. 11
Alba-Domínguez M, López-Lera A, Garrido S, et al. Complement factor I deficiency: A not so rare immune defect: Characterization of new mutations and the first large gene deletion. Orphanet J Rare Dis 2012;7:42.  Back to cited text no. 12
Fremeaux-Bacchi V, Fakhouri F, Garnier A, et al. Genetics and outcome of atypical hemolytic uremic syndrome: A nationwide French series comparing children and adults. Clin J Am Soc Nephrol 2013;8:554-62.  Back to cited text no. 13
Reese JA, Muthurajah DS, Kremer Hovinga JA, Vesely SK, Terrell DR, George JN. Children and adults with thrombotic thrombo-cytopenic purpura associated with severe, acquired adamts13 deficiency: Comparison of incidence, demographic and clinical features. Pediatr Blood Cancer 2013;60:1676-82.  Back to cited text no. 14
Hassenpflug WA, Budde U, Schneppenheim S, Schneppenheim R. Inherited thrombotic thrombocytopenic purpura in children. Semin Thromb Hemost 2014;40:487-92.  Back to cited text no. 15
Ferreira E, Oliveira N, Marques M, et al. Eculizumab for the treatment of an atypical hemolytic uremic syndrome with mutations in complement factor I and C3. Nefrologia 2016; 36:72-5.  Back to cited text no. 16
Fidalgo T, Martinho P, Pinto CS, et al. Combined study of ADAMTS13 and complement genes in the diagnosis of thrombotic microangiopathies using next-generation sequencing. Res Pract Thromb Haemost 2017; 1:69-80.  Back to cited text no. 17
Phillips EH, Westwood JP, Brocklebank V, , et al. The role of ADAMTS-13 activity and complement mutational analysis in differentiating acute thrombotic microangiopathies. J Thromb Haemost 2016;14:175-85.  Back to cited text no. 18

Correspondence Address:
Venkatesh Arumugam
Department of Pediatrics, Division of Pediatric Nephrology, Pediatrics Unit II, Christian Medical College, Vellore, Tamil Nadu
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DOI: 10.4103/1319-2442.261349

PMID: 31249236

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