Nicolas Kozakowski

Export Late antibody-mediated rejection (ABMR) is a leading cause of kidney allograft failure. Uncontrolled studies have suggested efficacy of the proteasome inhibitor bortezomib, but no systematic trial has been undertaken to support its use in ABMR. In this randomized, placebo-controlled trial (the Bortezomib in Late Antibody-Mediated Kidney Transplant Rejection [BORTEJECT] Trial), we investigated whether two cycles of bortezomib (each cycle: 1.3 mg/m2 intravenously on days 1, 4, 8, and 11) prevent GFR decline by halting the progression of late donor-specific antibody (DSA)–positive ABMR. Forty-four DSA-positive kidney transplant recipients with characteristic ABMR morphology (median time after transplant, 5.0 years; pretransplant DSA documented in 19 recipients), who were identified on cross-sectional screening of 741 patients, were randomly assigned to receive bortezomib (n=21) or placebo (n=23). The 0.5-ml/min per 1.73 m2 per year (95% confidence interval, −4.8 to 5.8) difference detected between bortezomib and placebo in eGFR slope (primary end point) was not significant (P=0.86). We detected no significant differences between bortezomib- and placebo-treated groups in median measured GFR at 24 months (33 versus 42 ml/min per 1.73 m2; P=0.31), 2-year graft survival (81% versus 96%; P=0.12), urinary protein concentration, DSA levels, or morphologic or molecular rejection phenotypes in 24-month follow-up biopsy specimens. Bortezomib, however, associated with gastrointestinal and hematologic toxicity. In conclusion, our trial failed to show that bortezomib prevents GFR loss, improves histologic or molecular disease features, or reduces DSA, despite significant toxicity. Our results reinforce the need for systematic trials to dissect the efficiency and safety of new treatments for late ABMR.

The XVI-th Banff Meeting for Allograft Pathology was held at Banff, Alberta, Canada, from 19th to 23rd September 2022, as a joint meeting with the Canadian Society of Transplantation. To mark the 30th anniversary of the first Banff Classification, premeeting discussions were held on the past, present, and future of the Banff Classification. This report is a summary of the meeting highlights that were most important in terms of their effect on the Classification, including discussions around microvascular inflammation and biopsy-based transcript analysis for diagnosis. In a postmeeting survey, agreement was reached on the delineation of the following phenotypes: (1) "Probable antibody-mediated rejection (AMR)," which represents donor-specific antibodies (DSA)-positive cases with some histologic features of AMR but below current thresholds for a definitive AMR diagnosis; and (2) "Microvascular inflammation, DSA-negative and C4d-negative," a phenotype of unclear cause requiring further study, which represents cases with microvascular inflammation not explained by DSA. Although biopsy-based transcript diagnostics are considered promising and remain an integral part of the Banff Classification (limited to diagnosis of AMR), further work needs to be done to agree on the exact classifiers, thresholds, and clinical context of use.

Significance Statement There is no proven effective treatment for a major cause of graft failure, late antibody-mediated rejection, but IL-6, a cytokine known to promote B cell immunity, may be a promising therapeutic target. The authors describe the results of a phase 2 randomized clinical trial involving 20 patients, designed to evaluate the safety (primary endpoint) and efficacy (secondary endpoint analysis) of an anti–IL-6 antibody, clazakizumab, versus placebo in late antibody-mediated rejection. Although the occurrence of serious infections and diverticulitis presented important safety signals, clazakizumab was associated with an early decrease in donor-specific antibody levels, modulated antibody-mediated rejection activity, and slowed the decline of renal function. Preliminary efficacy results suggest a potentially beneficial effect of clazakizumab and may therefore support the design of larger trials with a longer duration of follow-up. Background Late antibody-mediated rejection (ABMR) is a leading cause of transplant failure. Blocking IL-6 has been proposed as a promising therapeutic strategy. Methods We performed a phase 2 randomized pilot trial to evaluate the safety (primary endpoint) and efficacy (secondary endpoint analysis) of the anti–IL-6 antibody clazakizumab in late ABMR. The trial included 20 kidney transplant recipients with donor-specific, antibody-positive ABMR ≥365 days post-transplantation. Patients were randomized 1:1 to receive 25 mg clazakizumab or placebo (4-weekly subcutaneous injections) for 12 weeks (part A), followed by a 40-week open-label extension (part B), during which time all participants received clazakizumab. Results Five (25%) patients under active treatment developed serious infectious events, and two (10%) developed diverticular disease complications, leading to trial withdrawal. Those receiving clazakizumab displayed significantly decreased donor-specific antibodies and, on prolonged treatment, modulated rejection-related gene-expression patterns. In 18 patients, allograft biopsies after 51 weeks revealed a negative molecular ABMR score in seven (38.9%), disappearance of capillary C4d deposits in five (27.8%), and resolution of morphologic ABMR activity in four (22.2%). Although proteinuria remained stable, the mean eGFR decline during part A was slower with clazakizumab compared with placebo (−0.96; 95% confidence interval [95% CI], −1.96 to 0.03 versus −2.43; 95% CI, −3.40 to −1.46 ml/min per 1.73 m 2 per month, respectively, P =0.04). During part B, the slope of eGFR decline for patients who were switched from placebo to clazakizumab improved and no longer differed significantly from patients initially allocated to clazakizumab. Conclusions Although safety data indicate the need for careful patient selection and monitoring, our preliminary efficacy results suggest a potentially beneficial effect of clazakizumab on ABMR activity and progression.

CONTEXT: Sclerostin serum levels are increased in patients with chronic kidney disease (CKD). Osteoporosis and CKD often occur simultaneously. Currently antisclerostin antibodies are in clinical development for the treatment of osteoporosis. OBJECTIVE: The objective of this study was to study the renal handling of sclerostin. DESIGN: This was a cross-sectional study. SETTING: The study was conducted at a university hospital and outpatient renal clinic. PATIENTS: One hundred twenty men and women with CKD stage 1-5 participated in the study. INTERVENTION: Measurements of sclerostin in urine and serum (ELISA), renal function [estimated glomerular filtration rate (eGFR)], electrolytes, α1-microglobulin, PTH, vitamin D, and markers of bone turnover were conducted. Eight human kidney biopsies were stained for sclerostin using immunohistochemistry. MAIN OUTCOME MEASURE: Urinary excretion of sclerostin was measured. RESULTS: Urinary sclerostin excretion increased with declining eGFR (R=-0.75, P<.001), from 10.4 (±12.7) pmol/L in patients with eGFR greater than 90 mL/min per 1.73 m2 (CKD stage 1) to 117.9 (±65.4) pmol/L in patients with eGFR less than 15 mL/min per 1.73 m2 (CKD stage 5, P<.001). Fractional excretion of sclerostin increased with declining eGFR (R=-0.83, P<.001) from 0.45% (±0.6%) in CKD 1 to 26.3% (±17.6%) in CKD 5 (P<.001). Fractional excretion of sclerostin correlated with fractional excretion of α1-microglobulin (R=0.82, P<.001). No association between serum sclerostin and fractional excretion of phosphorus was found in a multivariate analysis. Sclerostin was detected in proximal tubular cells, showing a diffuse cytoplasmic staining pattern. CONCLUSION: Increased sclerostin serum levels in CKD patients are not due to decreased renal elimination. On the contrary, renal elimination increases with declining kidney function. Whether this has consequences on antisclerostin antibody dosing, efficacy, or safety in patients with CKD remains to be determined.