In patients with PLA2R-associated pMN, clinical and laboratory criteria are used to assess the risk of progressive loss of kidney function. According to the KDIGO guideline, PLA2Rab should be measured at 3- to 6-month intervals, with the shorter interval advised for patients with a high PLA2Rab titre at baseline. The PLA2Rab titre reflects the clinical activity of pMN, whereby an increase or decrease in the antibody level usually precedes the clinical change by months (Fig. 2). Disappearance of PLA2ab is mostly followed by clinical remission. Continued presence of PLA2Rab indicates persistent disease activity. High initial titres are associated with a lower likelihood of spontaneous remission and a higher likelihood of a non-response to low-dose therapy.
Treatment for pMN follows a risk-based strategy. Owing to potential adverse effects, immunosuppressive treatment is restricted to patients at risk of progressive kidney injury. Medications include rituximab, calcineurin inhibitor, cyclophosphamide, glucocorticoids and combinations thereof, depending on the patient’s risk profile.
PLA2Rab-positive pMN patients who successfully respond to treatment show a strong reduction in the antibody titre several months before the reduction in the clinical parameter proteinuria. Therefore, monitoring of PLA2Rab levels at 6 months after start of therapy is recommended for early evaluation of treatment response in patients and is useful for guiding adjustments to therapy. In most cases the treatment response occurs within 3 months after the start of therapy.
Immunological monitoring is particularly valuable in patients with initial relapse after therapy-induced remission. Positive PLA2Rab in a period of clinical remission is evidence for resistant disease. Therefore, in patients with PLA2Rab, the antibody titre should be evaluated at the time of remission and relapse.
Resistant disease can be defined by the persistence of PLA2Rab at high or unchanged levels after the first line of immunosuppressive therapy. In this case, further treatments should be evaluated. Persistent proteinuria is not sufficient to define resistance, as it can persist for 12 to 24 months after start of therapy. Some patients demonstrate partial remission of proteinuria and persistent low-level PLA2Rab. These patients can often refrain from immunosuppressive therapy but should be followed carefully.
Kidney transplant recipients
In pMN patients who require a kidney transplant, KDIGO recommends measuring PLA2Rab both pre-transplantation for risk assessment and every 1 to 3 months post-transplantation for monitoring the disease course and deciding on the requirement for immunosuppressive therapy. An absence of PLA2Rab at the time of transplantation predicts a low risk of disease recurrence. Persistently high or increasing titres of PLA2Rab following transplantation are associated with a high risk of recurrence.
Autoantibodies in pMN can be determined using test systems available exclusively from EUROIMMUN (Fig. 3). The indirect immunofluorescence test (IIFT) enables qualitative to semiquantitative detection of PLA2Rab or THSD7Aab using transfected cells expressing the corresponding antigen on their surface. A control substrate comprising non-transfected cells serves as an internal control. Determining both antibodies in parallel or via a two-step strategy, in which PLA2Rab-negative sera are subsequently tested for THSD7Aab, can increase the serological detection rate for pMN.
PLA2Rab can be measured quantitatively using ELISA or chemiluminescence immunoassay (ChLIA). In the ELISA, purified recombinant receptor is coated onto the wells of a microplate, whereas the ChLIA uses magnetic particles coated with the antigen. The quantitative antibody measurement with ELISA or ChLIA is highly suited to disease and therapy monitoring and can be performed efficiently at high throughput.
The IIFT, ELISA and ChLIA procedures can be automated using different devices according to the laboratory’s requirements, providing increased standardization and streamlining of the analyses.
Incorporation of PLA2Rab into the KDIGO guidelines has enriched the diagnosis and monitoring of pMN, reducing the number of costly and arduous biopsies required. Further research will aim to elucidate the role of PLA2Rab as a pre-clinical marker. A deeper understanding of THSD7Aab will clarify the clinical usefulness of this parameter in diagnosis and follow-up. In particular, THSD7Aab may be associated with a higher risk of malignant tumours than PLA2Rab. Patients who are double negative for PLA2Rab and THSD7Aab are likely to harbour other pathogenic antibodies. A variety of potential antigenic targets has been discovered by scientific research in recent years. Thus, additional serological parameters for pMN will probably enter the diagnostic scene in the coming years.