Discussion
In this report, a young woman presented with acute onset nephrotic syndrome and multi-organ injuries. Her anemia progressed despite stabilized renal function. TMA was clinically indicated based on laboratory findings of microangiopathic hemolytic anemia, thrombocytopenia, increasing LDH, and peripheral red blood cell fragmentation. The biopsy confirmed the presence of TMA in addition to a diffuse proliferative glomerulonephritis with “full-house” deposits. The etiologies of TMA can be divided into primary and secondary causes, the former includes ADAMTS13 deficiency or autoantibodies against ADAMTS13, complement-mediated or factor H autoantibodies-related hemolytic-uremic syndrome, and rare origins of vitamin deficiency. Secondary causes of TMA include infection, malignant hypertension, autoimmune diseases, malignancies, organ transplantation, pregnancy, or medications(1). Thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome were excluded based on her normal ADAMTS13 levels and human complement factor H. Therefore, this patient’s TMA was suspected to be secondary to underlying SLE. However, the current classification criteria for SLE do not provide clear guidance on diagnosing LN in patients with negative ANA but suspicious renal pathology.
“Full-house” immunofluorescence depositions upon renal biopsy is characteristic of LN, but this can be also seen in other types of nephropathy. In the 2019 SLE classification criteria published by EULAR and the American College of Rheumatology, at least one episode of positive ANA is designated as a mandatory entry criterion, followed by weighted values from another 7 clinical indicators (general status, hematology, neuropsychology, mucocutaneous, serosa, musculoskeletal, and renal presentations) as well as 3 immunological indicators (antiphospholipid antibodies, decreased complement levels, and other SLE specific antibodies). A score of ≥ 10 combined with at least one clinical criterion is required for SLE diagnosis. Although this guideline does not exclude the possibility of LN with negative ANA, the algorithm for diagnosing LN with negative ANA remains unavailable currently. Moreover, it remains controversial whether LN can be diagnosed solely by renal pathology. A 2013 literature review suggested that LN could be diagnosed without positive SLE-related autoantibodies, which might emerge during subsequent follow-up. In a case of ANA-negative SLE with vasculitis, prolonged serositis, and glomerulonephritis with “full-house” deposits, patient’s renal function and serum albumin normalized after immunosuppression(2). Other reports also revealed that patients might become serologically positive during follow-up with the diagnosis of SLE being made(3). We propose that the speed of emergence of existing autoantibodies may not parallel that of other clinical presentations in our patient, possibly due to a time lag. It could be worthwhile to explore novel or un-identified autoantibodies exhibiting a closer relationship with disease manifestations in similar patients.
Based on our literature review,the main criteria for diagnosis was negative SLE-related autoantibodies with a renal pathology showing “full-house” immune deposits. Though the diagnosis of LN based on pathology alone is not recommended, biopsy findings combined with other clinical presentations can be very helpful for establishing seronegative LN. There are a few pathology findings considered characteristic for LN: “full-house” immunofluorescence staining; intense C1q staining; extraglomerular deposits; subendothelial & subepithelial deposits; and tubuloreticular inclusions. In this patient’s biopsy findings, all features were identified, with the exception of tubuloreticular inclusions. Combined with clinical presentations of thrombocytopenia, hemolytic anemia, serositis, and multi-system damages, LN was reasonably favored despite negative serologic evidence.
The optimal treatment approach for LN with TMA remains unclear. However, early provision of adequate doses of plasma exchange or infusion may effectively improve renal outcomes in LN patients with TMA(4). A retrospective study focusing on SLE with TMA showed that patients’ survival rate was 33.3% and 92.4% in the conventional and immunosuppressive therapy groups, respectively(5). In addition, treatment responses of seronegative LN are better than those of seropositive ones. Such good responses to immunosuppressants were also observed in our patient. Therefore, we administered plasma exchange in combination with glucocorticoids and immunosuppressants to the index patient. She also received hemodialysis for months and saw an improvement in edema. After 6 months of follow-up, both her hemoglobin (110 g/L) and creatinine (99.3 μmol/L) returned to normal levels.
In summary, this case highlights the diagnostic challenge of seronegative LN with TMA. The current classification criteria for SLE do not provide clear guidance on diagnosing LN in patients with negative ANA but suspicious renal pathology. More cases are needed to establish a standardized diagnostic strategy and to summarize the phenotypic characteristics and treatment responses of patients with seronegative LN.