Pierre Merville

Antibody-mediated rejection (ABMR) is the leading cause of allograft failure in kidney transplantation. Defined by the Banff classification, its gold standard diagnosis remains a challenge, with limited inter-observer reproducibility of the histological scores and efficient immunomarker availability. We performed an immunohistochemical analysis of 3 interferon-related proteins, WARS1, TYMP and GBP1 in a cohort of kidney allograft biopsies including 17 ABMR cases and 37 other common graft injuries. Slides were interpreted, for an ABMR diagnosis, by four blinded nephropathologists and by a deep learning framework using convolutional neural networks. Pathologists identified a distinctive microcirculation staining pattern in ABMR with all three antibodies, displaying promising diagnostic performances and a substantial reproducibility. The deep learning analysis supported the microcirculation staining pattern and achieved similar diagnostic performance from internal validation, with a mean area under the receiver operating characteristic curve of 0.89 (± 0.02) for WARS1, 0.80 (± 0.04) for TYMP and 0.89 (± 0.04) for GBP1. The glomerulitis and peritubular capillaritis scores, the hallmarks of histological ABMR, were the most highly correlated Banff scores with the deep learning output, whatever the C4d status. These novel immunomarkers combined with a CNN framework could help mitigate current challenges in ABMR diagnosis and should be assessed in larger cohorts.

Key Points: Magnetic resonance elastography–derived stiffness does not directly reflect the extent of fibrosis in kidney transplantation. Mean magnetic resonance elastography–derived stiffness displays high interpatient variability, even in allografts without significant fibrosis, suggesting a strong influence of confounding factors. Background: Fibrosis progression is a major prognosis factor in kidney transplantation. Its assessment requires an allograft biopsy, which remains an invasive procedure at risk of complications. Methods: We assessed renal stiffness by magnetic resonance elastography (MRE) as a surrogate marker of fibrosis in a prospective cohort of kidney transplant recipients compared with the histologic gold standard. Interstitial fibrosis was evaluated by three methods: the semi-quantitative Banff ci score, a visual quantitative evaluation by a pathologist, and a computer-assisted quantitative evaluation. MRE-derived stiffness was assessed at the superior, median, and inferior poles of the allograft. Results: We initially enrolled 73 patients, but only 55 had measurements of their allograft stiffness by MRE before an allograft biopsy. There was no significant correlation between MRE-derived stiffness at the biopsy site and the ci score (ρ=–0.25, P=0.06) or with the two quantitative assessments (pathologist: ρ=–0.25, P=0.07; computer assisted: ρ=–0.21, P=0.12). We observed negative correlations between the stiffness of both the biopsy site and the whole allograft, with either the glomerulosclerosis percentage (ρ=–0.32, P=0.02 and ρ=–0.31, P=0.02, respectively) and the overall nephron fibrosis percentage, defined as the mean of the percentages of glomerulosclerosis and interstitial fibrosis (ρ=–0.30, P=0.02 and ρ=–0.28, P=0.04, respectively). At patient level, mean MRE-derived stiffness was similar across the three poles of the allograft (±0.25 kPa). However, a high variability of mean stiffness was found between patients, suggesting a strong influence of confounding factors. Finally, no significant correlation was found between mean MRE-derived stiffness and the slope of eGFR (P=0.08). Conclusions: MRE-derived stiffness does not directly reflect the extent of fibrosis in kidney transplantation.

Antibody-mediated rejection (ABMR) is the leading cause of allograft failure in kidney transplantation. Its histological hallmark is represented by lesions of glomerulitis i.e., inflammatory cells within glomeruli. Current therapies for ABMR fail to prevent chronic allograft damage i.e., transplant glomerulopathy, leading to allograft loss. We used laser microdissection of glomeruli from formalin-fixed allograft biopsies combined with mass spectrometry-based proteomics to describe the proteome modification of 11 active and 10 chronic active ABMR cases compared to 8 stable graft controls. Of 1335 detected proteins, 77 were deregulated in glomerulitis compared to stable grafts, particularly involved in cellular stress mediated by interferons type I and II, leukocyte activation and microcirculation remodeling. Three proteins extracted from this protein profile, TYMP, WARS1 and GBP1, showed a consistent overexpression by immunohistochemistry in glomerular endothelial cells that may represent relevant markers of endothelial stress during active ABMR. In transplant glomerulopathy, 137 proteins were deregulated, which favor a complement-mediated mechanism, wound healing processes through coagulation activation and ultimately a remodeling of the glomerular extracellular matrix, as observed by light microscopy. This study brings novel information on glomerular proteomics of ABMR in kidney transplantation, and highlights potential targets of diagnostic and therapeutic interest.

Introduction Although living kidney donation is not a high-risk surgery, there is still a need to identify situations at risk of kidney disease after uninephrectomy. Estrogens exhibit a protective role against various nephropathies. The aim of this study was to assess renal adaptation following nephrectomy according to menopausal status in women. Methods A prospective bicentric study including living women donors measured glomerular filtration rate (GFR) (inulin or ⁵¹⁻Cr-EDTA clearances) and kidney volume (using CT-scan and 3-dimensional reconstruction), before and after 1-year post-uninephrectomy. Renal adaptation was compared according to menopausal status. Results Sixteen non-menopausal women and 18 menopausal women were included. One year following uninephrectomy, the mean decrease in GFR (global population) was − 32 ± 12 ml/min/1.73 m², and the mean increase in remnant kidney volume was + 32 ± 13 cm³/1.73 m². No significant difference was observed between the two groups for both the decrease in GFR (-32.9 ± 13.3 in non-menopausal vs − 31.5 ± 9.9 in menopausal, ml/min/1.73 m², p = 0.84), and the increase in kidney volume (+ 36.1 ± 13.4 in non-menopausal vs + 28.1 ± 12.5 in menopausal, cm³/1.73 m², p = 0.09). Discussion Menopausal status did not influence kidney adaptation following uninephrectomy, and in this respect is not a potential limiting factor for living kidney donation. Graphic abstract

Background: Non-adherence with immunosuppressant medication (MNA) fosters development of de novo donor-specific antibodies (dnDSA), rejection, and graft failure (GF) in kidney transplant recipients (KTRs). However, there is no simple tool to assess MNA, prospectively. The goal was to monitor MNA and analyze its predictive value for dnDSA generation, acute rejection and GF. Methods: We enrolled 301 KTRs in a multicentric French study. MNA was assessed prospectively at 3, 6, 12, and 24 months (M) post-KT, using the Morisky scale. We investigated the association between MNA and occurrence of dnDSA at year 2 post transplantation, using logistic regression models and the association between MNA and rejection or graft failure, using Cox multivariable models. Results: The initial percentage of MNA patients was 17.7%, increasing to 34.6% at 24 months. Nineteen patients (8.4%) developed dnDSA 2 to 3 years after KT. After adjustment for recipient age, HLA sensitization, HLA mismatches, and maintenance treatment, MNA was associated neither with dnDSA occurrence, nor acute rejection. Only cyclosporine use and calcineurin inhibitor (CNI) withdrawal were strongly associated with dnDSA and rejection. With a median follow-up of 8.9 years, GF occurred in 87 patients (29.0%). After adjustment for recipient and donor age, CNI trough level, dnDSA, and rejection, MNA was not associated with GF. The only parameters associated with GF were dnDSA occurrence, and acute rejection. Conclusions: Prospective serial monitoring of MNA using the Morisky scale does not predict dnDSA occurrence, rejection or GF in KTRs. In contrast, cyclosporine and CNI withdrawal induce dnDSA and rejection, which lead to GF.

Hannah Kaminski, Julie Belliere, Lionel Couzi, Nassim Kamar, Pierre Merville; Reply to Coussement et al, Clinical Infectious Diseases, , ciab022, https://doi.or