Alberto Mella

Complement cascade and kidney transplantation: The rediscovery of an ancient enemy

The identification of complement activity in serum and immunohistochemical samples represents a core element of nephropathology. On the basis of this observation, different experimental models and molecular studies have shown the role of this cascade in glomerular disease etiology, but the absence of inhibiting drugs have limited its importance. Since 2006, the availability of target-therapies re-defined this ancient pathway, and its blockage, as the new challenging frontier in renal disease treatment. In the graft, the complement cascade is able to initiate and propagate the damage in ischemia-reperfusion injury, C3 glomerulopathy, acute and chronic rejection, atypical hemolytic uremic syndrome and, probably, in many other conditions. The importance of complement-focused research is revealed by the evidence that eculizumab, the first complement-targeting drug, is now considered a valid option in atypical hemolytic uremic syndrome treatment but it is also under investigation in all the aforementioned conditions. In this review we evaluate the importance of complement cascade in renal transplantation diseases, focusing on available treatments, and we propose a speculative identification of areas where complement inhibition may be a promising strategy.

Assessment of Platelet Function Analyzer (PFA-100) in Kidney Transplant Patients Before Renal Allograft Biopsy: A Retrospective Single-Center Analysis

BACKGROUND Kidney biopsy (KB) represents the criterion standard to obtain information on diagnosis and prognosis of renal allograft dysfunctions. However, it can be associated with bleeding complications (BCs). Bleeding time test (BTT), the best predictive indicator of post-biopsy BCs, is not a very reproducible test and is invasive. Therefore, the aim of this study was to evaluate whether the platelet function analyzer (PFA-100), a very reliable test to investigate primary hemostasis, could be useful in predicting the risk of bleeding complications in transplant patients undergoing KB. METHODS We carried out a retrospective analysis of PFA-100 collagen-epinephrine (C-EPI) and collagen-adenosine diphosphate (C-ADP) closure times in 119 patients undergoing KB in our center. Data regarding BTT, age, sex, blood pressure, number of renal allograft punctures for each biopsy procedure, thromboplastin time, prothrombin time, complete blood count, and prophylactic therapy with desmopressin were also collected. Major (need for blood transfusion) or minor (no need for any intervention) BCs (hematoma and hematuria) were recorded. RESULTS Indications for KB were: delayed graft function (n=23), allograft dysfunction (n=40), proteinuria (n=27), allograft dysfunction plus proteinuria (n=19), and protocol biopsy (n=10). Nine of the 119 patients (7.5%) developed minor BCs (6 macrohematuria, 3 hematoma), major BCs did not develop. No significant differences were found in any of the clinical and laboratory data, including BTT and PFA-100 (C-EPI and C-ADP) between patients who developed BCs compared with those who did not. In addition, there was no correlation between PFA-100 test (C-EPI and C-ADP) values and BTT data [R2=0.002; P=.6]. CONCLUSIONS The PFA-100 test was not useful in predicting the risk of BCs in kidney transplant patients undergoing renal allograft biopsy.

Treatment with plasmapheresis, immunoglobulins and rituximab for chronic-active antibody-mediated rejection in kidney transplantation: Clinical, immunological and pathological results

AIM To evaluate the role of a therapeutic regimen with plasma exchange, intravenous immunoglobulins and rituximab in chronic-active antibody-mediated rejection (cAMR) settings. METHODS We compared 21 kidney transplant recipients (KTRs) with a diagnosis of cAMR in a retrospective case-control analysis: nine KTRs treated with plasmapheresis, intravenous immunoglobulins and rituximab (PE-IVIG-RTX group) vs 12 patients (control group) not treated with antibody-targeted therapies. We examined kidney survival and functional outcomes 24 mo after diagnosis. Histological features and donor-specific antibody (DSA) characteristics (MFI and C1q-fixing ability) were also investigated. RESULTS No difference in graft survival between the two groups was noted: three out of nine patients in the PE-IVIG-RTX group (33.3%) and 4/12 in the control group (33.3%) experienced loss of allograft function at a median time after diagnosis of 14 mo (min 12-max 18) and 15 mo (min 7-max 22), respectively. Kidney functional tests and proteinuria 24 mo after cAMR diagnosis were also similar in both groups. Only 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 and/or DSA characteristics. No functional or histological parameter at diagnosis was predictive of clinical outcome. CONCLUSION Our data showed no difference in the two year post-treatment outcome of kidney grafts treated with PE-IVIG-RTX for cAMR diagnosis, however there were notable improvements in microvascular inflammation in post-therapy protocol biopsies. Further studies, especially involving innovative therapeutic approaches, are required to improve the management and long-term results of this severe condition.

Detection of angiotensin ii type i-receptor antibodies in transplant glomerulopathy

Transplant glomerulopathy (TG) is an important cause of late graft loss. The role of angiotensin type 1‐receptor antibodies (AT1R‐Ab) in TG is not known.