Early Diagnosis and Treatment of Subclinical AMR Is Vital for Improving Clinical Outcomes

Despite remarkable improvements in short-term outcomes of kidney grafts over the last decade, long-term outcomes have not significantly changed. About one-third of all transplanted patients will lose their graft within 10 years.1 We now know that the majority of late allograft loss results from cumulative effects of underlying subacute immunological injury and that such processes often remain undetected until irreversible damage has already occurred.2 Late irreversible graft failure is typically associated with antibody-mediated responses, which are now the greatest unsolved problem in improving kidney transplant outcomes. None of the current treatment options for clinical antibody-mediated rejection (AMR) (including steroids, plasmapheresis, application of IVIGs or rituximab) have been able to significantly improve outcomes; therefore, new diagnostic and therapeutic strategies are urgently needed.3 Subclinical antibody-mediated rejection is defined by histological signs of AMR without impairment of graft function, with or without detection of donor-specific antibodies. In the largest reported cohort of 1001 kidney transplant recipients, 14% were diagnosed with subclinical AMR.4 Diagnosis of subclinical AMR is associated with poor long-term outcomes and independently associated with graft loss.4 In this issue of Transplantation, a paper by Parajuli et al5 investigates whether early diagnosis and treatment of subclinical AMR can slow progression to clinical AMR. In their study, protocol biopsies were performed at 3 months and 1 year posttransplant, which allowed patients with stable graft function to be classified as subclinical AMR or nonrejecting. Twenty-five patients with subclinical AMR were treated with intravenous steroids, IVIG, plasmapheresis, and rituximab, according to the standard of care for patients with clinical AMR. Graft function and failure rates were similar between treated subclinical AMR and the rejection-negative control group, whereas both were significantly worse in the clinical AMR group. Although the study did not randomize subclinical AMR patients to intervention versus nonintervention, considering the known deleterious effects of subclinical AMR, the authors claim that early diagnosis and intensified treatment are beneficial for long-term outcomes. If these results can be confirmed in a prospective, randomized clinical trial, they could lead to a change in treatment strategy. On the other hand, one must consider the potential risk of overimmunosuppression and associated side effects like infectious complications in patients with a stable graft function. This is an important question that could also be addressed by an adequately designed prospective study. Parajuli's study emphasizes the importance of early detection of histological changes before irreversible graft damage occurs. Some predictive biomarkers like donor-specific cell-free DNA have shown very promising results and could potentially serve as predictors of AMR and success of treatment in the near future.6 But as long as these markers have not been validated in larger cohorts to be accepted as a standard diagnostic approach, protocol biopsies are the only way to detect such early changes in patients with serologically normal graft function. A recent survey of US transplant centers showed that only 17% perform regular surveillance biopsies on all patients.7 Unexpectedly, Parajuli's report also suggests that early intervention in subclinical AMR improves outcomes, whereas the course of clinical AMR cannot be altered. In future prospective studies, it would be valuable if the success of treatment were confirmed by follow-up biopsies. Notably, in cases of cellular rejection, it is reported that patients with recurrent subclinical changes (meaning that the histological signs are found in a follow-up biopsy despite adequate initial therapy) do worse than patients with resolved signs of rejection. Although the detrimental impact of de novo donor-specific antibody (dnDSA) and subclinical AMR on kidney graft outcomes is well-described,4 the significance of dnDSA in the setting of stable transplant function without histological signs of AMR is still discussed as being controversial. In some studies, emergence of dnDSA has been associated with higher rates of subclinical and clinical AMR and worse long-term outcomes8,9; however, others report dnDSA is a benign finding that is not associated with deterioration in graft function as long as there are no signs of rejection.10 Importantly, Parajuli's study included a control group of donor-specific antibody-positive patients (both de novo and preexisting) and did not receive treatment. This subgroup had better outcomes than patients with clinical AMR but worse than patients with treated subclinical AMR (figure 2). Hence, the presence of dnDSA seems to have an impact on graft function even in patients with stable graft function at the time of detection. In summary, Parajuli et al's work speaks to the importance of early diagnosis and treatment of subclinical AMR, but the results must be further confirmed by a prospective trial in which patients with subclinical AMR are randomized to continued or intensified treatment arms.