Published online Sep 10, 2018. doi: 10.5500/wjt.v8.i5.178
Peer-review started: May 3, 2018
First decision: May 22, 2018
Revised: June 14, 2018
Accepted: June 28, 2018
Article in press: June 28, 2018
Published online: September 10, 2018
Chronic-active antibody-mediated rejection (cAMR) due to de novo or pre-formed donor specific antibody (DSA) is now considered the most important cause of allograft losses. Treatment is focused on reducing or eliminating DSA, antagonizing their detrimental effects on the graft with different approaches, without available guidelines.
An antibody-directed treatment combining high-dose immunoglobulin and rituximab showed beneficial effects (reduction in allograft losses and/or stabilization of glomerular filtration rate) in some patients with cAMR, but these results have now been partially questioned. The role of functional and histological parameters (i.e., GFR proteinuria at diagnosis, microvascular inflammation) in predicting response to antibody-targeted therapy is also a matter of debate.
To evaluate the role of a therapeutic regimen with plasma exchange, intravenous immunoglobulins and rituximab in cAMR settings. To identify in which cases these protocols should be adopted (in all patients or only in specific histopathological and functional settings).
Retrospective case-control analysis in 21 kidney transplant recipients with a diagnosis of cAMR, 9 treated with plasmapheresis, intravenous immunoglobulins and rituximab and 12 patients not treated with antibody-targeted therapies. Primary outcomes were kidney survival and functional outcomes 12 and 24 mo after diagnosis. Histological features (according to BANFF 2015 criteria) and donor specific antibodies characteristics (MFI and C1q-fixing ability) were also evaluated.
No difference in graft survival was noted 12 and 24 mo after cAMR diagnosis. Three out of nine patients in the PE-IVIG-RTX group (33.3%) and 4/12 in the control group (33.3%) lost their allograft, at a median time after diagnosis of 14 mo (min 12 - max 18) and 15 mo (min 7 - max 22), respectively. Kidney functional tests (serum creatinine and eGFR) and proteinuria 24 mo after cAMR diagnosis were strictly similar in both groups. Microvascular inflammation (glomerulitis + peritubular capillaritis score) was significantly reduced after PE-IVIG-RTX in seven out of eight patients (87.5%) in the PE-IVIG-RTX group (median score 3 in pre-treatment biopsy vs 1.5 in post-treatment biopsy; P = 0.047), without any impact on kidney survival. Two out of nine patients had a negative post-treatment Luminex test. However, considering the entire cohort, the median MFI of immunodominant DSA (9800 pre-treatment vs 8200 post-treatment; P = NS) and the percentage of C1q-fixing ability (4/9 - 44.4% - pre-treatment vs 3/9 - 33.3% - post-treatment) were unchanged after treatment with PE-IVIG-RTX. No functional or histological parameter at diagnosis was predictive of clinical outcome.
No clinical improvement after therapy with PE-IVIG-RTX, either in graft survival or in renal functional tests (serum creatinine, eGFR, proteinuria) was observed. In addition, the reduction in the MVI score was not supported by an amelioration in kidney outcomes. Considering our results, we are unable to define any functional or histological characteristics at diagnosis that could influence prognosis.
Future prospective studies that involve innovative therapeutic approaches, longer follow-ups and protocol biopsies are required to: (1) Improve the management and long-term results of this severe condition; and (2) identify a certain population who would benefit from therapy.