Antibody-mediated rejection is a leading cause of kidney-transplant failure. The targeting of CD38 to inhibit graft injury caused by alloantibodies and natural killer (NK) cells may be a therapeutic option. In this phase 2, double-blind, randomized, placebo-controlled trial, we assigned patients with antibody-mediated rejection that had occurred at least 180 days after transplantation to receive nine infusions of the CD38 monoclonal antibody felzartamab (at a dose of 16 mg per kilogram of body weight) or placebo for 6 months, followed by a 6-month observation period. The primary outcome was the safety and side-effect profile of felzartamab. Key secondary outcomes were renal-biopsy results at 24 and 52 weeks, donor-specific antibody levels, peripheral NK-cell counts, and donor-derived cell-free DNA levels. A total of 22 patients underwent randomization (11 to receive felzartamab and 11 to receive placebo). The median time from transplantation until trial inclusion was 9 years. Mild or moderate infusion reactions occurred in 8 patients in the felzartamab group. Serious adverse events occurred in 1 patient in the felzartamab group and in 4 patients in the placebo group; graft loss occurred in 1 patient in the placebo group. After week 24, resolution of morphologic antibody-mediated rejection was more frequent with felzartamab (in 9 of 11 patients [82%]) than with placebo (in 2 of 10 patients [20%]), for a difference of 62 percentage points (95% confidence interval [CI], 19 to 100) and a risk ratio of 0.23 (95% confidence interval [CI], 0.06 to 0.83). The median microvascular inflammation score was lower in the felzartamab group than in the placebo group (0 vs. 2.5), for a mean difference of -1.95 (95% CI, -2.97 to -0.92). Also lower was a molecular score reflecting the probability of antibody-mediated rejection (0.17 vs. 0.77) and the level of donor-derived cell-free DNA (0.31% vs. 0.82%). At week 52, the recurrence of antibody-mediated rejection was reported in 3 of 9 patients who had a response to felzartamab, with an increase in molecular activity and biomarker levels toward baseline levels. Felzartamab had acceptable safety and side-effect profiles in patients with antibody-mediated rejection. (Funded by MorphoSys and Human Immunology Biosciences; ClinicalTrials.gov number, NCT05021484; and EUDRACT number, 2021-000545-40.).

Background: Nephrectomy is the management of choice for the treatment of renal tumors. Surgical pathologists primarily focus on tumor diagnosis and investigations relating to prognosis or therapy. Pathological changes in non-neoplastic tissue may, however, be relevant for further management and should be thoroughly assessed. Methods: Here, we examined the non-neoplastic renal parenchyma in 206 tumor nephrectomy specimens for the presence of glomerular, tubulo-interstitial, or vascular lesions, and correlated them with clinical parameters and outcome of renal function. Results: We analyzed 188 malignant and 18 benign or pseudo-tumorous lesions. The most common tumor type was clear cell renal cell carcinoma (CCRCC, n = 106) followed by papillary or urothelial carcinomas (n = 25). Renal pathology examination revealed the presence of kidney disease in 39 cases (18.9%). Glomerulonephritis was found in 15 cases (7.3%), and the most frequent was IgA nephropathy (n = 6; 2.9%). Vasculitis was found in two cases (0.9%). In 15 cases we found tubulo-interstitial nephritis, and in 9 severe diabetic or hypertensive nephropathy. Partial nephrectomy was not linked to better eGFR at follow-up. Age, vascular nephropathy, glomerular scarring and interstitial fibrosis were the leading independent negative factors influencing eGFR at time of surgery, whereas proteinuria was associated with reduced eGFR at 1 year. Conclusion: Our large study population indicates a high incidence of renal diseases potentially relevant for the postoperative management of patients with renal neoplasia. Consistent and systematic reporting of non-neoplastic renal pathology in tumor nephrectomy specimens should therefore be mandatory.

Early progression of chronic histologic lesions in kidney allografts represents the main finding in graft attrition. The objective of this retrospective cohort study was to elucidate whether HLA histocompatibility is associated with progression of chronic histologic lesions in the first year post-transplant. Established associations of de novo donor-specific antibody (dnDSA) formation with HLA mismatch and microvascular inflammation (MVI) were calculated to allow for comparability with other study cohorts. We included 117 adult kidney transplant recipients, transplanted between 2016 and 2020 from predominantly deceased donors, who had surveillance biopsies at 3 and 12 months. Histologic lesion scores were assessed according to the Banff classification. HLA mismatch scores [i.e. eplet, predicted indirectly recognizable HLA-epitopes algorithm (PIRCHE-II), HLA epitope mismatch algorithm (HLA-EMMA), HLA whole antigen A/B/DR] were calculated for all transplant pairs. Formation of dnDSAs was quantified by single antigen beads. More than one-third of patients exhibited a progression of chronic lesion scores by at least one Banff grade in tubular atrophy (ct), interstitial fibrosis (ci), arteriolar hyalinosis (ah) and inflammation in the area of interstitial fibrosis and tubular atrophy (i-IFTA) from the 3- to the 12-month biopsy. Multivariable proportional odds logistic regression models revealed no association of HLA mismatch scores with progression of histologic lesions, except for ah and especially HLA-EMMA DRB1 [odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.03–1.18]. Furthermore, the established associations of dnDSA formation with HLA mismatch and MVI (OR = 5.31, 95% CI 1.19–22.57) could be confirmed in our cohort. These data support the association of HLA mismatch and alloimmune response, while suggesting that other factors contribute to early progression of chronic histologic lesions.

Substaging of T1 urothelial cancer is associated with tumor progression and its reporting is recommended by international guidelines. However, it has not been integrated in risk stratification tools and there is no agreement on the best method to use for its reporting. We aimed to investigate the applicability, interobserver variability, and prognostic value of histological landmark based and micrometric (aggregate linear length of invasive carcinoma (ALLICA), microscopic vs. extensive system, Rete Oncologica Lombarda (ROL) system) substaging methods. A total of 79 patients with the primary diagnosis of T1 urothelial cancer treated with conventional transurethral resection and adjuvant BCG therapy between 2000 and 2020 at the Medical University of Vienna were included. The anatomical and metrical substaging systems were evaluated using agreement rate, Cohen’s kappa, Kendall’s tau, and Spearman rank correlation. Prognostic value for high-grade recurrence or T2 progression was evaluated in uni- and multivariable analysis. Applicability and reproducibility were good to moderate and varied between substaging methods. Obstacles are mainly due to fragmentation of samples. Anatomical substaging was associated with progression in univariable and multivariable analysis. In our cohort, we could only identify anatomical landmark–based substaging to be prognostic for T2 progression. A major obstacle for proper pathological assessment is fragmentation of samples due to operational procedure. Avoiding such fragmentation might improve reproducibility and significance of pathological T1 substaging of urothelial cancer.

Background Gene expression profiling of renal allograft biopsies revealed the Duffy antigen receptor for chemokines (DARC) as being strikingly upregulated in antibody‐mediated rejection (ABMR). DARC has previously been shown to be associated with endothelial injury. This study aimed at assessing the value of DARC immunohistochemistry as diagnostic marker in ABMR. Methods The study was performed on 82 prospectively collected biopsies of a clinically well‐defined population (BORTEJECT trial, NCT01873157) of DSA positive patients with gene expression data available for all biopsies. Diagnostic histological assessment of biopsies was performed according to the Banff diagnostic scheme. Results DARC expression was focally accentuated, on peritubular capillaries (PTC) mostly in areas of interstitial fibrosis and/or inflammation. DARC positivity was associated with diagnosis of ABMR and correlated with DARC gene‐expression levels detected by microarray analysis. Still, as previously described, a substantial number of biopsies without signs of rejection showed DARC‐positive PTC. However, DARC positivity in patients with ABMR was associated with significantly reduced graft survival, as compared to patients with DARC‐negative ABMR or DARC‐positivity without ABMR. Conclusions In summary, the upregulation of DARC, detected by immunohistochemistry, is associated with but not specific for ABMR. We did not observe reduced graft survival in DARC positive patients.

BACKGROUND: Arterial hypertension (HTN) and type 2 diabetes (T2DM) are contributors to chronic kidney disease leading to glomerulomegaly and podocyte loss. Enlarged glomeruli and podocyte depletion are associated with kidney disease progression. This retrospective study aimed to investigate morphometric changes in patients with HTN and the contribution of coexisting T2DM in HTN. METHODS: Glomerular and podocyte structure was estimated stereologically in unaffected areas of tumor nephrectomies in 99 patients. Morphometric features between subjects with HTN (n=47), HTN+T2DM (n=32), and controls without HTN and T2DM (n=20) were compared by ANOVA. Linear regression models evaluated the effect of morphometric parameters on renal compensation after nephrectomy (change of estimated glomerular filtration rate from pre-nephrectomy to 12 months post-nephrectomy). RESULTS: In total, 36% of the HTN and 50% of the patients with T2DM exhibited dipstick-positive proteinuria. Glomerular volume in HTN+T2DM was similar compared with controls (2.7±0.8 versus 2.3±0.8×10 ⁶ µm³; P =0.16) and to HTN only (2.7±0.9×10 ⁶ µm³; P =0.95). Podocyte density was reduced in HTN+T2DM versus controls (217±66 versus 279±75 per 10 ⁶ µm³; P =0.02) and not different to HTN only (233±87 per 10 ⁶ µm³; P =0.67). Podocyte nuclear volume was larger in HTN+T2DM versus controls (230±28 versus 201±32 µm³; P =0.004) and similar to HTN (221±33 µm³; P =0.39). Larger glomerular volume ( P =0.009), reduced podocyte density ( P =0.003), and nuclear hypertrophy ( P =0.01) were associated with impaired compensation. CONCLUSION: The patterns of podocyte depletion and nuclear hypertrophy were independently observed in both HTN and HTN+T2DM versus controls. Coexisting T2DM exhibited no additional contribution to glomerular and podocyte alterations.