A 3-month-old male infant developed an extremely severe episode of atypical hemolytic uremic syndrome (aHUS) associated with partial deﬁciencies of full-length complement factor H (FH; 15% of infant normal) and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) (39% of normal) and autoantibodies reactive with both proteins. His FH and ADAMTS13 genes were normal, indicating that the partial deﬁciencies were acquired, probably as the result of autoantibodies against full-length FH and ADAMTS13. The child also had a homozygous deletion of the complement factor H–related (CFHR)3–CFHR1 portion in the complement factor H (CFH) gene cluster. He therefore had deﬁciency of CFHR proteins and autoantibody-positive hemolytic uremic syndrome (DEAP-HUS) with an unusual early onset associated with a partial deﬁciency of ADAMTS13 and an anti-ADAMTS13 autoantibody. His clinical episode of aHUS responded to plasma infusion and subsequent treatment with mycophenolate and rituximab. We believe that this is the ﬁrst report of DEAP-HUS in an infant with partial deﬁciencies in both ADAMTS13 and full-length FH acquired in association with autoantibodies to both proteins. Key words: acute kidney injury, atypical HUS, autoantibody to ADAMTS13, factor H autoantibody, thrombotic microangiopathy Received: 11.7.2017. Editorial decision: 23.1.2018 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact email@example.com Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy010/4924409 by Ed 'DeepDyve' Gillespie user on 12 July 2018 2| M. Michael et al. history of diarrhea, lethargy, fever (101 F), hypertension [blood Introduction pressure (BP) 150/90 mmHg] and decreased oral intake. Initial Atypical hemolytic uremic syndrome (aHUS) is a thrombotic evaluation (Day 1) showed acute renal failure (oliguria with creati- microangiopathy (TMA) characterized by thrombocytopenia, nine 2.2 mg/dL and blood urea nitrogen (BUN) 47 mg/dL), microan- microangiopathic hemolytic anemia and renal failure. It is a giopathic hemolytic anemia (hemoglobin 6.5 g/dL, schistocytosis, complication of excessive alternative pathway (AP) activation lactate dehydrogenase (LDH) elevated at 5063 IU/L, decreased that results in damage or perturbation of renal endothelial cells haptoglobin), thrombocytopenia (platelet count 102 000/mL) and (ECs) and episodes of acute renal failure . Prominent causes leukocytosis (total white blood cell count 20 000/mL, neutrophils of aHUS are heterozygous loss-of-regulatory-function muta- 10 010/mL). Stool and urine culture were negative for Escherichia tions in the gene for complement factor H [CFH; full-length fac- coli. tor H protein with 20 short consensus repeats (SCRs)]. Full- Plasma complement C3 level was reduced on Day 1 [16 mg/ length FH is a negative AP regulator that prevents amplification dL (normal pediatric range 63–179)] and complement C4 level of the C3 and C5 convertases and acts as a cofactor for factor I was within normal limits, suggesting overactivation of the AP. (FI)-mediated conversion of C3b to inactive C3b (iC3b) [2–4]. The patient initially received therapeutic plasma exchange Approximately 10–16% of aHUS patients have homozygous (TPE) (1.5 plasma volume) after blood samples were obtained deletions CFHR1–CFHR3 (both with five SCR domains) within the for genetic testing of complement components and ADAMTS13. CFH gene cluster, resulting in the absence of these plasma pro- His treatment was subsequently changed to plasma infusion teins . When this latter entity is associated with an acquired (PI). Although TPE is superior to PI in most studies of TMA , autoantibody against FH, it is known as deficiency of CFHR pro- TPE is technically difficult and clinically dangerous in infants. PI teins and autoantibody-positive HUS (DEAP-HUS) [5–7]. These alone, nevertheless, has therapeutic effectiveness and has been FH autoantibodies frequently bind to the C-terminal portion of used successfully as treatment in some TMA patients . In our full-length FH that contains the binding recognition site . patient, the PI (containing both ADAMTS13 and FH) increased Recent in vitro data show that AP initiation can occur on EC- antigen levels of the two proteins and was probably capable of secreted and anchored ultralarge von Willebrand factor partially overcoming the negative effects of the autoantibodies. (ULVWF) strings . The attachment of C3b, Bb and C5b to EC- Computed tomography and electroencephalography studies secreted/anchored ULVWF strings occurs in quantitative pat- of the patient were normal and a T-antigen test for neuramini- terns consistent with the assembly of active complexes of C3 dase was negative. Pre-TPE ADAMTS13 activity showed a partial and C5 convertases. ADAMTS13 (a disintegrin and metallopro- deficiency (39%). Daily PI was begun on Day 5 because of 2þ teinase with a thrombospondin type 1 motif 13) is the Ca / ongoing hemolysis and thrombocytopenia and continued until 2þ Zn -metalloprotease responsible for cleaving EC-secreted/ Day 12. At this time (2010), eculizumab was not US Food and anchored ULVWF multimeric strings. Drug Administration (FDA)-approved for the treatment of aHUS. It has been hypothesized  that even partial deficiencies Platelet count and C3 progressively increased and LDH progres- of ADAMTS13 (e.g. 50% of normal) may result in platelet adhe- sively decreased (Figure 1). The patient initially received labetalol sion/aggregation and AP activation in excess of normal on intravenous infusion for control of hypertension. Because of his secreted ULVWF strings that are uncleaved by ADAMTS13 and excellent clinical response, PI was tapered to once weekly by Day remain anchored to ECs after secretion. In this report we 20. He received intermittent red cell transfusion and hemodialysis describe an infant with a severe episode of TMA correlated with until creatinine was normalized by Day 30. Three months after the an initial partial deficiency of plasma ADAMTS13 and full- episode he was discharged on once a week PI. He had normal crea- length FH associated with homozygous gene deletions of CFHR1 tinine and BUN values (0.3 mg/dL and 15 mg/dL, respectively), and CFHR3 and antibodies against both FH and ADAMTS13. hemoglobin of 9.7 g/dL and platelet count of 357 000/mL. Total plasma FH levels were 56 mg/mL on Day 1 and 72 mg/mL on Day 7 (normal infant range 170–397). A plasma FI level Case report obtained on Day 1 was normal. The enzyme-linked immuno- The patient, a 3-month-old African American male who was in sorbent assay (ELISA) used for FH measures the total quantity of foster care due to history of child abuse, presented with a 2-day plasma proteins that cross-react with a polyclonal antibody FIGURE 1: Patient response to treatment. The x-axis shows the number of days since initial presentation. Hemoglobin at presentation was 6.5 g/dL, platelet count was 100 000/mL, C3 was 16 mg/dL and LDH was 5000 IU/L. The patient improved in all parameters with plasma therapy. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy010/4924409 by Ed 'DeepDyve' Gillespie user on 12 July 2018 DEAP-HUS in infants and associated deficiencies | 3 that identifies all forms of FH, including FH-like protein and the standard deviations (SD) and the black dashed line indicates the five FH-related proteins. In a normal adult, FHR-1 protein levels average fluorescent antibody intensity from nine normal adult are 10–20% of FH levels  and FHR-3 levels are extremely plasma samples plus 2 SD. low . Complete deficiency of FHR-1 and FHR-3 proteins can Citrated plasma obtained pre-TPE showed a subnormal level therefore potentially reduce modestly the total plasma FH anti- of functional ADAMTS13 (39% by fluorescence resonance energy gen levels measured by the anti-FH antibody . transfer assay). Patient plasma ADAMTS13 antigen level (by An antibody against FH was detected in each of six patient ELISA) on Day 7 was 55% of normal and 65% on Day 10 [nor- samples collected on Day 7 through Day 45 and on Day 440 mal infant level 713 ng/mL (n¼ 3)]. The slightly higher antigenic using a specific antibody detection ELISA (Figure 2A). The assay values on Days 7 and 10 were obtained during daily PI. An anti- used immobilized, plasma purified, full-length FH to capture body detection ELISA showed that the patient had autoantibod- patient, normal adult and normal infant plasma antibodies. In ies to ADAMTS13 (Figure 2B). In Figure 2B, the gray dashed line Figure 2A, the gray dashed line shows the average fluorescent shows the average fluorescent ADAMTS13 antibody intensity of FH antibody intensity of three normal infant samples plus 2 three normal infant samples plus 2 SD and the black dashed FIGURE 2: Detection of autoantibodies against full-length FH and ADAMTS13 in patient plasma. Autoantibodies against (A) immobilized human full-length FH and (B) immobilized EC-released ADAMTS13 were detected in patient plasma samples using an ELISA. The relative antibody levels were detected with goat antihuman-IgG- horseradish peroxidase plus a ﬂuorescent substrate. Control plasma samples from three normal newborns are shown for comparison. The gray dashed line shows the average ﬂuorescent antibody intensity of the newborn samples plus 2 SD and the black dashed line indicates the average ﬂuorescent antibody intensity from nine (A) and ﬁve (B) normal adult plasma samples plus 2 SD. In (A), the black circles show patient full-length FH antigen levels (mg/mL, right side y-axis). Newborn FH antigens were 290, 293 and 192 mg/mL, respectively. In (B), ADAMTS13 antigen levels (ng/mL) are shown for Days 7 and 10 and patient ADAMTS13 activity levels (% normal by ﬂu- orescence resonance energy transfer) are shown for Days 3 and 440. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy010/4924409 by Ed 'DeepDyve' Gillespie user on 12 July 2018 4| M. Michael et al. line indicates the average fluorescent antibody intensity from Homozygous CFHR1 and CFHR3 deletions have been found in five normal adult plasma samples plus 2 SD. We could not 2–4% of clinically normal individuals . This indicates that a determine conclusively if the antibodies caused a modest complete absence of circulating FHR-1 and FHR-3 does not reduction in ADAMTS13 activity or in ADAMTS13 survival time. cause clinical disease in the absence of an autoantibody to full- VWF multimer patterns that were analyzed in patient samples length FH, additional complement mutations or other autoanti- collected on Days 7, 10, 17, 38, 39 and 45 after hospital admis- bodies against complement proteins . It has been reported sion were similar to normal newborns and adult plasma VWF that 87% of aHUS patients with autoantibodies against full- multimers analyzed in parallel. length FH have homozygous CFHR1 and CFHR3 gene deletions Genetic testing showed that CFH, thrombomodulin (THBD), com- . It is not known, however, how these observations might plement factor B (CFB), membrane cofactor protein (CD46), complement explain the appearance of these autoantibodies in association factor H-related protein 5 (CFHR5), complement factor I (CFI), component with CFHR1/CFHR3 gene deletions. One possibility is that one 3(C3) and ADAMTS13 were normal . There was a homozygous (or both) of these molecules normally impairs the antibody pro- deletion of CFHR3–CFHR1 within the CFH gene cluster on chromo- duction by B-lymphocytes . Therefore, in the absence of some 1 . It was not until 2 years later that a recessive mutation CFHR-1 and/or CFHR-3 proteins, autoantibody production by of the gene encoding diacylglycerol kinase e (DGKE) was found to B-lymphocytes may be inadequately controlled. There are sev- be associated with aHUS in children < 1 year of age. Although eral case series [23, 24] reporting successful treatment of FH testing for a DGKE mutation has not been performed in our autoantibody-associated HUS with plasma exchange, predni- patient, it should be noted that most of DGKE aHUS patients do sone and immunosuppression with cyclophosphamide or ritux- not have complement abnormalities . imab, with or without maintenance immunosuppression. We Eleven months after initial presentation, the frequency of therefore chose to use the immunosuppressive treatment PI was reduced to once every 2 weeks. Transient attempts to detailed above for our patient. reduce PI to once every 3 weeks were unsuccessful (LDH The association of DGKE mutations and aHUS was not increased to 1150 U/L), possibly because the replenishment of known 6 years ago when our patient initially presented . FH and ADAMTS13 using an every 3-week regime was inad- Genetic testing demonstrated homozygous deletion of CFHR1– equate to counteract the effect of autoantibody-mediated CFHR3 and associated autoantibodies to FH and ADAMTS13. decreases in FH (and ADAMTS13) survival. At 14 months of age Because of his clinical response to plasma therapy, and later he remained dependent on biweekly PI and autoantibodies immunosuppression, testing for DGKE mutations was not con- were still detectable. At that time, our therapeutic goal was to sidered clinically important during later follow-up (after the induce a decrease in FH (and ADAMTS13) autoantibodies to association between DGKE mutations and aHUS became levels that would allow a reduction in the frequency of PIs. known). Although eculizumab had been FDA-approved by this time, In our patient, deletion of the CFHR1 and CFHR3 genes was the continued presence of the two types of autoantibodies led also associated with autoantibodies to ADAMTS13, as well as to to our decision to treat him with 2 weekly doses of rituximab full-length FH and initial ADAMTS13 activity level that was 39% (375 mg/m ), 3 months of oral prednisone (1 mg/kg daily 4 of normal. This lower ADAMTS13 activity would likely have weeks, then weaned over 2 months), 6 additional weeks of PI compromised his capacity to cleave EC-anchored ULVWF and mycophenolate (200 mg twice daily) for 24 months. At this strings. Increased numbers of ULVWF multimeric strings are point his FH level was normal without detectable FH autoanti- secreted and anchored to ECs in the presence of inflammatory body and mycophenolate was discontinued. Four months later cytokines (TNF and interleukin (IL)-8)  or during trauma and/ the FH autoantibody was again positive and he was restarted or hypoxia . Increased secreted/anchored hyperadhesive on mycophenolate. This has continued to the present time ULVWF strings are sites of platelet adhesion/aggregation in the without adverse reaction. He is now 6.5 years old with height microvasculature. Binding of C3 (as C3b) to secreted/anchored 121 cm (74%) and weight 25.1 kg (84%), with normal renal func- ULVWF strings that remain uncleaved when ADAMTS13 is tion [serum creatinine 0.51 mg/dL and estimated glomerular subnormal would be expected to increase AP activation, filtration rate (eGFR) 97 mL/min/1.73 m ], normal BP (108/ especially in the presence of reduced levels of full-length FH. In 53 mmHg), negative urine protein, hemoglobin 12 g/dL, LDH a previous study, Strauss et al.  showed that neonates with 214 IU/L, haptoglobin 106 mg/dL and platelet count 320 000/mL. stressful conditions such as intrauterine growth restriction, ret- inopathy of prematurity and necrotizing enterocolitis had lower levels of ADAMTS13. Our patient was born full term but did Discussion have a history of child abuse (a serious stressful event) that may have contributed to his lower level of ADAMTS13. The 3-month-old infant described in this report had a severe epi- Normal infant and adult plasmas were tested routinely for sode of acute renal failure in association with both reduced FH autoantibodies against ADAMTS13 and FH along with the antigen levels (25% of normal infant levels) and reduced func- patient plasma samples. As shown in Figure 2, the autoantibody tional ADAMTS13 activity (39%)  ADAMTS13 activity levels in levels against both antigens in the patient samples were higher aHUS studies are typically >10%. Patients with <10% plasma than levels obtained in normal plasma samples (and more than ADAMTS13 usually have severe thrombotic thrombocytopenic double the values for autoantibodies against ADAMTS13). These purpura (TTP), however, ADAMTS13 levels of 11–25% and 11– results indicate that the autoantibodies detected in the patient 70%  have been reported in two large TMA patient studies. plasma are unlikely to be false positives. Inverse correlations Genetic studies showed normal full-length CFH and ADAMTS13 between ADAMTS13 and FH autoantibodies and corresponding genes combined with a homozygous deletion of the CFHR1 and antigen levels are not possible to determine because of the fre- CFHR3 genes of the CFH gene cluster. These deletions and the con- quent PIs received by the patient. We did not determine the spe- sequent absence of FHR-1 and FHR-3 proteins from the patient’s cific subset of the autoantibodies. plasma did not explain the 75% reduction in total plasma FH Autoantibodies against ADAMTS13 have been previously antigen . The additional reduction was likely to be associated evaluated almost exclusively in TTP patients with<10% activity with the autoantibody that was detected in full-length FH. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy010/4924409 by Ed 'DeepDyve' Gillespie user on 12 July 2018 DEAP-HUS in infants and associated deficiencies | 5 10. Turner N, Sartain S, Moake J. Ultralarge von Willebrand levels. The findings in our patient of combined acquired defi- ciencies of both ADAMTS13 and FH, in association with autoan- factor-induced platelet clumping and activation of the alter- tibodies against both, have rarely (if ever) been subjected to native complement pathway in thrombotic thrombocyto- laboratory testing. The autoantibodies against ADAMTS13 in penic purpura and the hemolytic-uremic syndromes. the patient’s plasma are likely to be of pathophysiological Hematol Oncol Clin North Am 2015; 29: 509–524 importance because his ADAMTS13 genes are normal. It is prob- 11. Rock GA, Shumak KH, Buskard NA. et al. Comparison of plasma exchange with plasma infusion in the treatment of able that these antibodies against ADAMTS13 were binding to the patient’s plasma ADAMTS13 and subsequently removed thrombotic thrombocytopenic purpura. N Engl J Med 1991; from circulation. The autoantibody reactive with ADAMTS13 325: 393–397 may have decreased survival of the enzyme in the blood of the 12. Coppo P, Bussel A, Charrier S. et al.High-dose plasma infusion versus plasma exchange as early treatment of throm- patient (rather than directly inhibiting ADAMTS13 activity using in vitro testing). Noninhibitory autoantibodies reactive with botic thrombocytopenic purpura/hemolytic-uremic syndrome. ADAMTS13 have been described in several studies [28–30]. Medicine (Baltimore) 2003; 82: 27–38 In summary, the infant described had a severe episode of 13. Jozsi M, Zipfel PF. Factor H family proteins and human dis- eases. Trends Immunol 2008; 29: 380–387 TMA resulting from acquired partial deficiencies of both FH and ADAMTS13 associated with autoantibodies to both proteins and 14. Pouw RB, Brouwer MC, Geissler J. et al. Complement factor H-related protein 3 serum levels are low compared to factor with a homozygous deletion of the CFHR1 and CFHR3 genes. H and mainly determined by gene copy number variation in CFHR3. PLoS One 2016; 11: e0152164 Funding 15. de Cordoba SR, Tortajada A, Harris CL. et al. Complement dysregulation and disease: from genes and proteins to diag- Funding of N.T. and J.M. was provided by the Mary R. Gibson nostics and drugs. Immunobiology 2012; 217: 1034–1046 Foundation and the Mabel and Everett Hinkson Memorial 16. Lemaire M, Fre ´ meaux-Bacchi V, Schaefer F. et al. Recessive Fund. R.J.S. was supported in part by the U.S. National mutations in DGKE cause atypical hemolytic-uremic syn- Institutes of Health (DK110023). drome. Nat Genet 2013; 45: 531–536 17. Kavakli K, Canciani MT, Mannucci PM. Plasma levels of the von Willebrand factor-cleaving protease in physiological Conflict of interest statement and pathological conditions in children. Pediatr Hematol None declared. Oncol 2002; 19: 467–473 18. Vesely SK, George JN, La ¨ mmle B. et al. 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Clinical Kidney Journal – Oxford University Press
Published: Mar 7, 2018
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