Introduction: Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy (TMA) disease entity primarily attributed to genetic or acquired abnormalities in the alternative complement pathway. TMA can manifest in kidney transplant (KT) recipients owing to various factors, resulting in diverse clinical presentations. Given its adverse effects on allograft function and patient prognosis, genetic diagnostic approaches for aHUS are essential. Although rarely associated with diffuse alveolar hemorrhage, only a few mild cases have been reported to date. In this report, we present a case of the patient who experienced recurrent and life-threatening diffuse alveolar hemorrhage shortly after KT accompanied by graft failure. Case Presentation: An 18-year-old girl who underwent deceased donor KT developed recurrent diffuse alveolar hemorrhage with acute kidney injury, leading to graft failure. Microangiopathic hemolytic anemia, thrombocytopenia, and schistocytes in blood smears suggested the presence of TMA. The patient underwent therapeutic plasma exchange, and clinical condition improved during the procedure. Genetic testing confirmed a heterozygous c.1273C>T mutation in C3 gene, leading to the diagnosis of aHUS. However, after discontinuing the plasma exchange, the patient experienced seizures, recurrent pulmonary hemorrhage, and oliguria with recurring TMA features. The patient subsequently underwent eculizumab treatment, which resulted in complete remission, although hemodialysis was continued after graft nephrectomy. Conclusion: In patients presenting with unexplained pulmonary hemorrhage and kidney injury following KT, genetic aHUS should be considered as a potential differential diagnosis for TMA.

Thrombotic microangiopathy (TMA) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and pathological evidence of endothelial cell damage resulting in end-organ injuries [1]. According to its pathogenic mechanism, TMA is classified as primary TMA, including Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS), atypical HUS (aHUS), thrombocytopenic purpura, and secondary TMA syndrome [1, 2].

aHUS is caused by genetic or acquired abnormalities in the alternative complement pathway, resulting in overactivation and dysregulation of the complement system [1]. Secondary TMA syndrome is characterized by clinical manifestations similar to those of aHUS but typically has a specific cause [2]. Especially in kidney transplant (KT) recipients, approximately 0.8–14% recipients develop TMA, which can be caused by various factors, including antibody-mediated rejection, infections (cytomegalovirus, human immunodeficiency virus, and parvovirus B19), medications (calcineurin inhibitors, mechanistic target of rapamycin inhibitors, and valacyclovir), and antiphospholipid syndrome [3]. aHUS, confirmed by complement genetic mutations, is observed in approximately 29% of TMA cases after KT [4]. Early recognition and diagnosis of TMA in KT recipients are critical because it adversely affects allograft function and patient prognosis.

We encountered a complex case of a patient who presented with a critical condition marked by life-threatening diffuse alveolar hemorrhage and acute kidney injury following KT. Although pulmonary hemorrhage is recognized as an extrarenal manifestation of aHUS, the occurrence of a life-threatening diffuse alveolar hemorrhage in this context is exceedingly rare. In this report, we present the clinical details of a challenging case of an aHUS patient with a C3 gene mutation who developed life-threatening TMA following KT.

An 18-year-old girl, who had been undergoing peritoneal dialysis for end-stage kidney disease (ESKD) 2 years ago, presented for a deceased donor KT. The primary kidney disease that led to ESKD was unknown as a kidney biopsy had not been performed because of the atrophic changes observed during kidney ultrasonography. The patient had no other relevant medical or family history. No complications were encountered during surgery, and the patient exhibited sufficient urine output. The immunosuppressive induction regimen for the KT included steroids, tacrolimus, mycophenolate mofetil, and basiliximab.

On postoperative day (POD) 2, the patient presented with hemoptysis and oliguria (<1 mL/kg/h). Vital signs indicated instability, with blood pressure at 70/30 mm Hg, a heart rate of 162 beats/min, respiratory rate of 38 beats/min, and a temperature of 39°C. Chest radiography and computed tomography revealed diffuse alveolar hemorrhage with pulmonary edema (Fig. 1,a, b). The patient received mechanical ventilation and continuous kidney replacement therapy. Figure 1 c shows laboratory results obtained during hospitalization. The decrease in hemoglobin levels began on POD 1, and a significant decrease in platelet count and an increase in lactate dehydrogenase levels were observed on POD 6. Blood test results were as follows: hemoglobin levels, 6.3 g/dL; platelet count, 47,000/μL; lactate dehydrogenase, 1,142 IU/L; schistocytes on peripheral blood smear; haptoglobin level, <10; and normal coagulation panel. Complement levels were within normal limits, with C3 levels of 100 mg/dL (88–135 mg/dL) and C4 of 18.6 mg/dL (14–44 mg/dL). Tacrolimus levels were adjusted based on trough levels of approximately 5–10 mg/dL, and the panel reactive antibody was negative. Cultures of sputum, blood, and urine were negative, and polymerase chain reaction (PCR) for cytomegalovirus, BK virus, and Epstein-Barr virus was negative. We found negative results for autoantibodies, including antineutrophilic cytoplasmic antibodies, anti-double-stranded DNA immunoglobulin G, anti-glomerular basement membrane antibodies, antiphospholipid antibodies, and cryoglobulins. Negative stool STEC PCR results and normal activity of ADAMTS-13 (a disintegrin-like metalloprotease with thrombospondin type 1 repeats) (40.04%) ruled out STEC-HUS and thrombocytopenic purpura.

Fig. 1.

a Chest X-ray showing pulmonary edema with bilateral pleural effusion. b Computed tomography of the chest without contrast revealing diffuse alveolar hemorrhage. c Trends in LDH, platelet count, and hemoglobin levels with the patient's treatment course. CKRT, continuous kidney replacement therapy; MV, mechanical ventilation; LDH, lactate hydrogenase; Hb, hemoglobin; red arrowheads, plasma exchange.

Fig. 1.

a Chest X-ray showing pulmonary edema with bilateral pleural effusion. b Computed tomography of the chest without contrast revealing diffuse alveolar hemorrhage. c Trends in LDH, platelet count, and hemoglobin levels with the patient's treatment course. CKRT, continuous kidney replacement therapy; MV, mechanical ventilation; LDH, lactate hydrogenase; Hb, hemoglobin; red arrowheads, plasma exchange.

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Therapeutic plasma exchange for the treatment of TMA was performed ten times over the course of 20 days, and the patient’s clinical condition, including pulmonary hemorrhage, oliguria, and laboratory findings, improved significantly. However, on POD 53, 10 days after discontinuation of plasma exchange, the patient presented with generalized tonic-clonic seizures, recurrent pulmonary hemorrhage, and oliguria with gross hematuria, and laboratory results worsened again. Plasma exchange was performed again, and the patient’s clinical condition and laboratory findings improved, except for oliguria. Mechanical ventilator support was discontinued, but continuous kidney replacement therapy was switched to intermittent hemodialysis. On POD 70, the patient underwent a nephrectomy of the transplanted kidney due to no visualization of arterial flow and diffuse cortical swelling on ultrasonography. The pathological examination of the graft revealed severe necrotic changes.

A missense mutation (R425C) in the C3 gene has been identified as a potential cause of HUS [5‒7]. Subsequently, heterozygous mutations c.1273C>T (p.Arg425Cys) in C3 (NM_000064.4) were identified and confirmed through Sanger sequencing (Fig. 2). This variant is notable for its minor allele frequency in the Korean population, ranging from 0.05% to 0.48%, as indicated by dbSNP151 data [8]. Polyphen-2 (v2.2.3r406) and SIFT (v6.2.0) were predicted to be damaging (HVarPred score: 0.993) and deleterious (score: 0.01; median: 2.66), respectively [9, 10]. The R425C variant is located at 19p13.3-p13.2 and is situated between the macroglobulin-like domains 4 and 5 in the beta chain of C3, providing the binding/dimerization interface [11‒13]. Unfortunately, a family study could not be conducted because of parents’ refusal.

Fig. 2.

Sequencing analysis of the C3 gene. The heterozygous missense mutation c.1273C>T (p.Arg425Cys) of C3 (NM_000064.4) was detected by targeted sequencing (a) and confirmed through Sanger sequencing (b). Arrows denote the mutation site (hg19 chr19:6,711,204) in the coverage plot (a) and electropherogram (b).

Fig. 2.

Sequencing analysis of the C3 gene. The heterozygous missense mutation c.1273C>T (p.Arg425Cys) of C3 (NM_000064.4) was detected by targeted sequencing (a) and confirmed through Sanger sequencing (b). Arrows denote the mutation site (hg19 chr19:6,711,204) in the coverage plot (a) and electropherogram (b).

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As the patient was diagnosed with aHUS with a C3 gene mutation, 900 mg of eculizumab was administered four times weekly. Subsequently, the patient achieved complete remission and was discharged on POD 102. However, 2 months later, the patient died from duodenal perforation unrelated to aHUS.

Herein, we presented a case of aHUS with a C3 gene mutation that developed into severe pulmonary hemorrhage following KT. The patient's ESKD remained unexplained owing to inadequate prior testing, prompting the consideration of aHUS as a potential underlying cause.

Distinguishing between aHUS and secondary TMA in KT recipients is crucial because of the different therapeutic approaches. Although the diagnosis of aHUS is an exclusion criterion [2], various treatment-relevant causes of TMA can emerge early after KT [3]. aHUS, confirmed by complement genetic mutations, is observed in approximately 29% of TMA cases after KT, particularly in newly emerging cases [4]. This underscores the significance of considering an early genetic diagnostic approach for aHUS if TMA persists, even after effectively managing factors such as antibody-mediated rejection, infections, and medications.

Genetic mutations have been reported in a significant percentage (40–60%) of aHUS patients [14], including C3 gene mutations in 4–10% of the cases [15]. In our patient, we identified a c.1273C>T (Arg425Cys) mutation in the C3 gene, primarily located in the binding regions of C3b, which interact with complement factor H (CFH), membrane cofactor protein (MCP), and complement receptor 1 [11‒13]. Consequently, the mutated proteins display resistance to inactivation by complement regulators. This mutation has also been documented in other cases, such as in a Japanese infant with aHUS following cardiovascular surgery [6] and in a Korean woman who presented with an altered mental status [7].

According to the Korean TMA registry, aHUS accounts for 3.4% (66/1,915) of TMA cases, with 60% (40/66) of these patients showing genetic variant [16]. Among these cases, the three most frequently detected genes were CFH (32%), THBD (20%), and CD46 (18%). Additionally, two missense C3 variants (Arg425Cys and Ser562Leu) were identified in 3 patients (4.5%). It is noteworthy that while CFH, CFI, and MCP gene mutations were more common in the European international registry [14], the frequency of C3 gene mutations in the Korean registry was similar to that in the European study but significantly lower than the 31% reported in a Japanese study [17]. In patients with C3 gene mutations after KT, recurrence and graft failure rates of aHUS have been reported to be 53% and 75%, respectively [18]. This was comparable to patients with CFH mutations (64% and 82%) and MCP mutations (18% and 66%, respectively). Therefore, it is believed that the patient’s prognosis may vary depending on the specific gene mutation.

In KT recipients, TMA presents with a wide range of clinical manifestations. This spectrum encompasses cases with only graft dysfunction and abnormal urinalysis, lacking the typical features of TMA, and with severe and extensive involvement. In a study examining biopsy-confirmed post-KT TMA cases, approximately 38% of these cases were confined solely to the graft, with none resulting in graft loss [19]. It appears that the severity of the involvement and the presence of severe symptoms, as observed in our patient, are associated with a higher risk of graft loss. Consequently, early recognition and diagnosis of TMA are of the utmost importance in KT recipients.

aHUS can potentially affect multiple organs as all organs are vascularized and consist of endothelial cells. In a pediatric study, pulmonary involvement, including pulmonary hemorrhage, embolism, and edema, was documented in 7% of the patients [20], and a small number of patients with respiratory failure requiring mechanical ventilation were noted [21]. However, no cases of life-threatening diffuse alveolar hemorrhage have been reported, as observed in our patient. However, this rare and severe manifestation of TMA after KT has not been documented.

The treatment of TMA after KT hinges on addressing the potential etiology, which may involve reducing or withdrawing immunosuppressive agents, controlling infections, or managing antibody-mediated rejection [3]. When clinical signs of TMA are suspected, prompt initiation of diagnostic investigations and immediate plasma exchange therapy are recommended [22]. Plasma exchange therapy, which replaces functional complement control proteins and removes autoantibodies (such as factor H) or excess complement activation factors (such as mutated C3 or factor B), is considered the standard treatment before a definitive diagnosis is established [2]. However, in cases of aHUS, transitioning to eculizumab is advised because of its superior effectiveness compared with plasma therapy [2]. Eculizumab, which functions as a terminal complement inhibitor by binding to C5, is the primary treatment for aHUS, and its early administration has been linked to reduced mortality rates and decreased risk of progression to ESKD [22]. In our patient, initial plasma exchange was performed, but TMA recurred shortly after treatment discontinuation, ultimately leading to graft resection. With timely genetic confirmation, the early administration of eculizumab could help prevent TMA recurrence and graft failure.

Herein, we presented a case of aHUS with a C3 gene mutation that manifested as life-threatening TMA following KT. In KT recipients, unexplained pulmonary hemorrhage or seizures with laboratory findings of hemolytic anemia can serve as potential indicators of aHUS. Timely recognition, etiological assessment, and appropriate management are pivotal for enhancing allograft survival and patient outcomes.

This study was approved by the Institutional Review Board in Pusan National University Yangsan Hospital (No. 05-2022-036). The Ethics Committee waived the requirement for written informed consent for this case report.

The authors declare no conflict of interest.

This study was supported by a 2022 research grant from Pusan National University Yangsan Hospital.

Conceptualization and writing – original draft: J.Y.S. Genetic analysis: S.H.O. Writing – review and editing: Y.K.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

1.
Moake JL. Thrombotic microangiopathies. N Engl J Med. 2002;347(8):589–600.
2.
Lee H, Kang E, Kang HG, Kim YH, Kim JS, Kim HJ, et al. Consensus regarding diagnosis and management of atypical hemolytic uremic syndrome. Korean J Intern Med. 2020;35(1):25–40.
3.
Avila A, Gavela E, Sancho A. Thrombotic microangiopathy after kidney transplantation: an underdiagnosed and potentially reversible entity. Front Med. 2021;8:642864.
4.
Le Quintrec M, Lionet A, Kamar N, Karras A, Barbier S, Buchler M, et al. Complement mutation-associated de novo thrombotic microangiopathy following kidney transplantation. Am J Transplant. 2008;8(8):1694–701.
5.
Fan X, Yoshida Y, Honda S, Matsumoto M, Sawada Y, Hattori M, et al. Analysis of genetic and predisposing factors in Japanese patients with atypical hemolytic uremic syndrome. Mol Immunol. 2013;54(2):238–46.
6.
Matsukuma E, Imamura A, Iwata Y, Takeuchi T, Yoshida Y, Fujimura Y, et al. Postoperative atypical hemolytic uremic syndrome associated with complement C3 mutation. Case Rep Nephrol. 2014;2014:784943.
7.
Cho HJ, Kim JO, Huh JY, Park Y, Kim MG, Oh D. A case of atypical hemolytic uremic syndrome associated with the c.1273C[{GT}]T mutation in the complement C3 gene. Blood Res. 2016;51(3):210–3.
8.
Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001;29(1):308–11.
9.
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7(4):248–9.
10.
Ng PC, Henikoff S. SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003;31(13):3812–4.
11.
Schramm EC, Roumenina LT, Rybkine T, Chauvet S, Vieira-Martins P, Hue C, et al. Mapping interactions between complement C3 and regulators using mutations in atypical hemolytic uremic syndrome. Blood. 2015;125(15):2359–69.
12.
Sfyroera G, Ricklin D, Reis ES, Chen H, Wu EL, Kaznessis YN, et al. Rare loss-of-function mutation in complement component C3 provides insight into molecular and pathophysiological determinants of complement activity. J Immunol. 2015;194(7):3305–16.
13.
Geisbrecht BV, Lambris JD, Gros P. Complement component C3: a structural perspective and potential therapeutic implications. Semin Immunol. 2022;59:101627.
14.
Bresin E, Rurali E, Caprioli J, Sanchez-Corral P, Fremeaux-Bacchi V, Rodriguez de Cordoba S, et al. Combined complement gene mutations in atypical hemolytic uremic syndrome influence clinical phenotype. J Am Soc Nephrol. 2013;24(3):475–86.
15.
Frémeaux-Bacchi V, Miller EC, Liszewski MK, Strain L, Blouin J, Brown AL, et al. Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome. Blood. 2008;112(13):4948–52.
16.
Yun JW, Oh J, Lee KO, Lee SJ, Kim JO, Kim NK, et al. Distinct genetic profile with recurrent population-specific missense variants in Korean adult atypical hemolytic uremic syndrome. Thromb Res. 2020;194:45–53.
17.
Fujisawa M, Kato H, Yoshida Y, Usui T, Takata M, Fujimoto M, et al. Clinical characteristics and genetic backgrounds of Japanese patients with atypical hemolytic uremic syndrome. Clin Exp Nephrol. 2018;22(5):1088–99.
18.
Noris M, Remuzzi G. Managing and preventing atypical hemolytic uremic syndrome recurrence after kidney transplantation. Curr Opin Nephrol Hypertens. 2013;22(6):704–12.
19.
Reynolds JC, Agodoa LY, Yuan CM, Abbott KC. Thrombotic microangiopathy after renal transplantation in the United States. Am J Kidney Dis. 2003;42(5):1058–68.
20.
Fidan K, Göknar N, Gülhan B, Melek E, Yildirim ZY, Baskin E, et al. Extra-Renal manifestations of atypical hemolytic uremic syndrome in children. Pediatr Nephrol. 2018;33(8):1395–403.
21.
Johnson S, Stojanovic J, Ariceta G, Bitzan M, Besbas N, Frieling M, et al. An audit analysis of a guideline for the investigation and initial therapy of diarrhea negative (atypical) hemolytic uremic syndrome. Pediatr Nephrol. 2014;29(10):1967–78.
22.
Kher KKG, Larry A, Schnaper HW. Clinical pediatric nephrology; 3rd ed.2016.