A 36-year-old woman developed general weakness with bilateral lower limb edema and dizziness, without fever, rash, joint pain, abdominal pain, diarrhea, or melena. She tested positive for COVID-19, and initial examination in a local hospital revealed inflammation (leukocytes 17.93×109 /L; reference range, 4–10×109/L), acute kidney injury (AKI) (serum creatinine 618 µmol/L; reference range, 53–115 µmol/L), anemia (hemoglobin 58 g/L; reference range, 114–154 g/L), and thrombocytopenia (platelet 48×109/L; reference range, 150–407×109 /L). She also had increased indirect bilirubin (48.4 µmol/L), aspartate aminotransferase 191 U/L, creatine kinase 1,429 U/L, lactate dehydrogenase 5,384 U/L, and decreased complement C3 (0.54 g/L; reference range, 0.79–1.17 g/L) levels. Her serum creatinine progressively increased up to 1,141 µmol/L. She was diagnosed as having hemolytic uremic syndrome, pulmonary infection, and COVID-19. After treatment with diuretic agents, hemodialysis, antibiotics, anemia correction, and intensifying blood pressure control, her condition gradually stabilized but remained hemodialysis-dependent after discharge. One week later, her urine output decreased further to approximately 20 mL per day, and she was re-hospitalized.
Upon admission, her physical examination showed anemia and mild bilateral lower extremity edema. Laboratory findings revealed hemoglobin 75 g/L, platelet 70×109/L, and serum albumin 40 g/L. Her serum creatinine level was 1,058 µmol/L. Her urinalysis results showed proteinuria (2+) and hematuria (2+), and the urine protein-to-creatinine ratio was 3,728 mg/g. Rheumatologic survey disclosed positive antinuclear antibody but a normal erythrocyte sedimentation rate, glucose-6-phosphate dehydrogenase activity, and negative lupus anticoagulant, cryoglobulin, urinary hemoglobin, and bound globin. Blood smear revealed the presence of schistocytes, suggesting MAHA. Her LDH (588 U/L; reference range, 114–240 U/L) and direct bilirubin (10.1 µmol/L; reference range, ≤5 µmol/L) levels were elevated, but the direct Coombs test was negative. During the initial 10 days of hospitalization, her urine output was 20–90 ml daily and blood pressure fluctuated between 120/70 mmHg and 145/90 mmHg. Abdominal ultrasound showed increased bilateral kidney echogenicity. Her C3 was low (0.58 g/L; reference range, 0.79–1.17 g/L) and C4 was high (0.55 g/L; reference range, 0.17–0.31 g/L), with normal C1q, factor I, factor H, factor B, and terminal complement complex C5b-9. Complement factor H (CFH) antibody was high (1943.22 ng/mL; reference range, 474.38–1346.75 ng/mL). No significant abnormalities were observed in ADAMTS13 enzyme activity or inhibitory antibodies. Genetic testing did not reveal variants associated with hereditary hematological diseases. Whole-exome sequencing detected an unknown variant of the C3 gene associated with hemolytic uremic syndrome susceptibility type 5/complement C3 deficiency.
Kidney biopsy was performed after one week of hospitalization, the findings of which showed prominent renal artery lesions, including small arteriole endothelial swelling, intimal thickening, mucinous degeneration, an "onion skin"–like change, substantial luminal occlusion, and small arterial wall necrosis. The small arterial wall was found to have red blood cell accumulation with debris, and the artery lumen exhibited obvious stenosis and even occlusion with transparent degeneration (Figs. 1A and 1C). Tissue staining with hematoxylin & eosin, periodic acid Schiff, periodic Schiff-Methenamine (PASM), and Masson trichrome showed 19 glomeruli without spherical sclerosis nor segmental sclerosis, and significant mesangial or endothelial proliferation. Capillary loops showed significant ischemia without balloon adhesion. PASM staining showed subendothelial widening (Fig. 1B). We also found minimal tubular atrophy (about 5%), modest tubular epithelial brush border and cell flattening, residual tubular vacuolation, and granular degeneration. Interstitial fibrosis and edema with a few mononuclear cell infiltrates were noted. Immunofluorescence was negative for IgG, IgA, IgM, C3, C1q, and Fibrinogen. Her IgG1, IgG2, IgG3, IgG4, and PLA2R antibodies were all negative. The pathological diagnosis was kidney TMA. Electron microscopy showed TMA-compatible glomerular changes without an electron-dense deposition (Fig 1D).
The patient then received hemodialysis, blood pressure lowering agents, antacids, antibiotics, and antiplatelet therapies. On the 13th day of hospitalization, she began four sessions of plasma exchange and received 25 mg oral glucocorticoids daily. Follow-up laboratory data showed decreasing serum creatinine and gradually increased urine output (Fig. 2). She discontinued hemodialysis on the 15th day. Two weeks after discharge, she felt less fatigue without edema, hematuria, or foamy urine. Her daily urine volume was 1,500–2,000 mL. Laboratory data showed that her hemoglobin, platelet count, and serum creatinine were 98 g/L, 142×109/L, and 238 µmol/L, respectively. She continued to receive hormonal therapy, antacid, blood pressure lowering agents, antiplatelet therapy, and treatment for anemia. Two months later, her serum creatinine decreased further to 168 µmol/L. At the most recent follow-up (May 24, 2023), her hemoglobin, platelet, and serum creatinine were 112 g/L, 375×109 /L, and 145 µmol/L, respectively.