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.