De novo donor-specific anti-HLA antibodies after kidney transplantation are associated with impaired graft outcome independently of their C1q-binding ability.

Many aspects of post-transplant monitoring of donor-specific (DSA) and non-donor-specific (nDSA) anti-HLA antibodies on renal allograft survival are still unclear. Differentiating them by their ability to bind C1q may offer a better risk assessment. We retrospectively investigated the clinical relevance of de novo C1q-binding anti-HLA antibodies on graft outcome in 611 renal transplant recipients. Acute rejection (AR), renal function, and graft survival were assessed within a mean follow-up of 6.66 years. Post-transplant 6.5% patients developed de novo DSA and 11.5% de novo nDSA. DSA (60.0%; P < 0.0001) but not nDSA (34.1%, P = 0.4788) increased rate of AR as compared with controls (27.4%). C1q-binding anti-HLA antibodies did not alter rate of AR in both groups. Renal function was only significantly diminished in patients with DSAC1q+ . However, DSA significantly impaired 5-year graft survival (65.2%; P < 0.0001) in comparison with nDSA (86.7%; P = 0.0054) and controls (90.7%). While graft survival did not differ between DSAC1q- and DSAC1q+ recipients, 5-year allograft survival was reduced in nDSAC1q+ (80.9%) versus nDSAC1q- (90.7%, P = 0.0251). De novo DSA independently of their ability to bind C1q are associated with diminished graft survival.

Real-world data confirm the effectiveness of caplacizumab in acquired thrombotic thrombocytopenic purpura.

Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare but life-threatening condition. In 2018, the nanobody caplacizumab was approved for the treatment of adults experiencing an acute episode of aTTP, in conjunction with plasma exchange (PEX) and immunosuppression for a minimum of 30 days after stopping daily PEX. We performed a retrospective, observational analysis on the use of caplacizumab in 60 patients from 29 medical centers in Germany during acute disease management. Caplacizumab led to a rapid normalization of the platelet count (median, 3 days; mean 3.78 days). One patient died after late treatment initiation due to aTTP-associated complications. In 2 patients with initial disease presentation and in 4 additional patients with laboratory signs of an exacerbation or relapse after the initial therapy, PEX-free treatment regimens could be established with overall favorable outcome. Caplacizumab is efficacious in the treatment of aTTP independent of timing and ancillary treatment modalities. Based on this real-world experience and published literature, we propose to administer caplacizumab immediately to all patients with an acute episode of aTTP. Treatment decisions regarding the use of PEX should be based on the severity of the clinical presentation and known risk factors. PEX might be dispensable in some patients.

ADAMTS13 and VWF activities guide individualized caplacizumab treatment in patients with aTTP.

Introduction of the nanobody caplacizumab was shown to be effective in the treatment of acquired thrombotic thrombocytopenic purpura (aTTP) in the acute setting. The official recommendations include plasma exchange (PEX), immunosuppression, and the use of caplacizumab for a minimum of 30 days after stopping daily PEX. This study was a retrospective, observational analysis of the use of caplacizumab in 60 patients from 29 medical centers in Germany. Immunosuppressive treatment led to a rapid normalization of ADAMTS13 activities (calculated median, 21 days). In 35 of 60 patients, ADAMTS13 activities started to normalize before day 30 after PEX; in 11 of 60 patients, the treatment was extended beyond day 30; and in 5 patients, it was extended even beyond day 58 due to persistent autoimmune activity. In 34 of 60 instances, caplacizumab was stopped before day 30 with a favorable outcome whenever ADAMTS13 activities were >10%. In contrast, 11 of 34 patients with ADAMTS13 activities <10% at the time of stopping caplacizumab treatment developed a nonfavorable outcome (disease exacerbation or relapse). In some cases, prolongation of the treatment interval to every other day was feasible and resulted in a sustained reduction of von Willebrand factor activity. ADAMTS13 activity measurements are central for a rapid diagnosis in the acute setting but also to tailor disease management. An ADAMTS13 activity-guided approach seems safe for identifying the individual time point when to stop caplacizumab to prevent overtreatment and undertreatment; this approach will result in significant cost savings without jeopardizing the well-being of patients. In addition, von Willebrand factor activity may serve as a biomarker for drug monitoring.

Truncating Wilms Tumor Suppressor Gene 1 Mutation in an XX Female with Adult-Onset Focal Segmental Glomerulosclerosis and Streak Ovaries: A Case Report.

About 30% of children with nephrotic syndrome (NS) have inherited forms. Among them, mutations in Wilms tumor suppressor gene 1 (WT1) are a well characterized cause associated with steroid-resistant NS, Wilms tumor, and urogenital malformation in males. However, the role of WT1 mutations in adult-onset focal segmental glomerulosclerosis (FSGS) is unclear. We report the case of a 38-year-old female with FSGS. She had been diagnosed with streak ovaries during diagnostic workup for infertility. Mutational analysis identified the heterozygous mutation c.1372C>T (p.Arg458*) in WT1 and the heterozygous non-neutral polymorphism c.868G>A (p.Arg229Gln) in NPHS2. Chromosomal analysis revealed a normal 46,XX female karyotype. Our case highlights that WT1 mutations should be considered in XX females with adult-onset FSGS, especially if urogenital abnormalities are present.

Nucleosomal DNA fragments in autoimmune diseases.

The inadequate response of immune cells to circulating apoptotic products, such as nucleosomal DNA fragments, is assumed to be a potent stimulus for the production of autoantibodies during the pathogenesis and progression of systemic lupus erythematosus (SLE). Here, we analyzed the levels of circulating nucleosomes, caspases, and C-reactive protein in sera of 244 individuals with various autoimmune diseases (155 with autoimmune hepatic disorders, 25 with ANCA-associated vasculitis, and 64 with various connective tissue diseases), and 32 healthy controls. Nucleosomes and caspase activities were significantly elevated in sera of patients with hepatic autoimmune diseases, connective tissue diseases, and particularly in ANCA-associated vasculitis when compared with healthy individuals. Nucleosomes showed a correlation with caspases, and caspases with C-reactive protein, but nucleosomes did not correlate with C-reactive protein. Serum levels of the apoptotic products, nucleosomes, and caspases are increased in various autoimmune diseases but may not be solely responsible for antinucleosome antibody production in SLE patients. It remains to be clarified whether qualitative changes in nucleosomes are linked with pathogenesis and disease progression in SLE.

Outcome after Desensitization in HLA or ABO-Incompatible Kidney Transplant Recipients: A Single Center Experience.

BACKGROUND: The shortage of deceased donors led to an increase of living donor kidney (LDK) transplantations performed in the presence of donor-specific antibodies (DSA) or ABO incompatibility (ABOi) using various desensitization protocols. METHODS: We herein analyzed 26 ABOi and 8 Luminex positive DSA patients who were successfully desensitized by anti-CD20, antigen-specific immunoadsorption and/or plasmapheresis to receive an LDK transplant. Twenty LDK recipients with non-donor-specific HLA-antibodies (low risk) and 32 without anti-HLA antibodies (no risk) served as control groups. RESULTS: 1-year graft survival rate and renal function was similar in all 4 groups (creatinine: 1.63 ± 0.5 vs 1.78 ± 0.6 vs 1.64 ± 0.5 vs 1.6 ± 0.3 mg/dl in ABOi, DSA, low risk and no risk group). The incidence of acute T-cell mediated rejections did not differ between the 4 groups (15% vs 12, 5% vs 15% vs 22% in ABOi, DSA, low risk and no risk), while antibody-mediated rejections were only found in the DSA (25%) and ABOi (7.5%) groups. Incidence of BK nephropathy (BKVN) was significantly more frequent after desensitization as compared to controls (5/34 vs 0/52, p = 0.03). CONCLUSION: We demonstrate favorable short-term allograft outcome in LDK transplant recipients after desensitization. However, the desensitization was associated with an increased risk of BKVN.