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Thrombocytopenia and MAHA are frequently absent in atypical HUS (aHUS). Thus, renal TMA is easy to miss, especially when a concurrent different renal pathology is more apparent. TMA is, however, associated with worse renal prognosis when superimposed to other pathologies.
A 34-year-old female was seen in the office for a second opinion regarding her kidney disease. Past medical history was significant for nephrotic range proteinuria, HTN, and pre-eclampsia during 2 pregnancies. She had a kidney biopsy at 18 and vaguely remembers a diagnosis of glomerulonephritis. Previous diagnosis included IgM and IgA nephropathy. She was treated with steroids which were discontinued after renal function worsened. She endorsed a strong family history of ESKD across three generations on her maternal side. Review of outside labs revealed a fast deterioration of her kidney function. Her creatinine clearance decreased from 38 to 14 mL/min/1.73m2 in less than a year and 24-hr protein was 5.6 gr at time of evaluation. She was referred for transplant evaluation, supportive care was initiated, and dialysis education was provided. Her kidney function continued to rapidly deteriorate despite supportive measures. Her eGFR was 6 mL/min/1.73m2 within 4 months of her initial evaluation. She was admitted urgently for dialysis initiation. On admission, new thrombocytopenia (Platelets 90 k/uL) and anemia (Hemoglobin 7 g/dL from a baseline of 11.5g/dL) were discovered. Urine analysis was positive for RBCs and protein.
Work up for TMA was started and revealed: Haptoglobin < 10mg/dL, LDH elevated at 344 U/L, C3/C4 within normal limits, ANA and reflex negative, ADAMTS13 inhibitor levels < 0.4 and activity of 99%. B2 Microglobulin was positive at 15 mg/L and anti-cardiolipin antibody was negative. A peripheral smear was negative for schistocytes, but complement workup was sent. The patient refused a repeat kidney biopsy, so the initial biopsy slides were reviewed. Unfortunately, the samples were limited to 5 glomeruli only, read as unremarkable and EM did not reveal electron dense deposits. The complement panel resulted with CH50 at 241 (101-300), SC5b-9 levels at 282 ng/mL (< 244), Factor H autoantibody at 38 U/mL (<22). Factor B and H were within normal limits, while Factor I was low. Genetic testing revealed one variant of unknown significance in INF2 gene (c.134C>T) and she was also positive for the MCP haplotype. Familial variant test was suggested but patient declined. We elected to treat for aHUS with Eculizumab, and she received 4 doses pre living donor kidney transplant. Her renal transplant was uneventful, and she remains with good graft function and no recurrence 4 years out.
Mutations in the INF2 gene are associated with monogenic FSGS and have been reported in patients with aHUS with poor response to Eculizumab. This was likely a case of two very rare entities: familial FSGS with a superimposed smoldering aHUS and highlights the importance of recognizing concurrent renal pathologies as one may be amenable to treatment. Further studies are needed in this case to clarify the significance of the c.134C>T variant.