Development of the 2023 ACR/EULAR Antiphospholipid Syndrome Classification Criteria, Phase III-D Report: Multi Criteria Decision Analysis.

BACKGROUND: The 2023 ACR/EULAR Antiphospholipid Syndrome (APS) Classification Criteria development, aiming to identify patients with high likelihood of APS for research, employed a four-phase methodology. Phase I and II resulted in 27 proposed candidate criteria, organized into laboratory and clinical domains. Here, we summarize the last stage of Phase III efforts employing a consensus-based multi-criteria decision analysis (MCDA) to weigh candidate criteria and identify an APS classification threshold score. METHODS: We evaluated 192 unique, international real-world cases referred for "suspected APS" with a wide range of APS manifestations. Using proposed candidate criteria, subcommittee members rank-ordered 20 representative cases from highly unlikely to highly likely APS. During an in-person meeting, the subcommittee refined definitions and participated in an MCDA exercise to identify relative weights of candidate criteria. Using consensus decisions and pairwise criteria comparisons, 1000Minds™ software assigned criteria weights, and we rank ordered 192 cases by their additive scores. A consensus-based threshold score for APS classification was set. RESULTS: Pre-meeting evaluation of 20 representative cases demonstrated variability in APS assessment. MCDA resolved 81 pairwise decisions; relative weights identified domain item hierarchy. After assessing 192 cases by weights and additive scores, the Steering Committee reached consensus that APS classification should require separate clinical and laboratory scores, rather than a single aggregate score, to ensure high specificity. CONCLUSION: Using MCDA, candidate criteria preliminary weights were determined. Unlike other disease classification systems using a single aggregate threshold score, separate clinical and laboratory domain thresholds were incorporated into the new APS classification criteria.

Paraneoplastic Glomerular Diseases.

Paraneoplastic glomerular disease (PGD) develops from tumor cell products, leading to renal dysfunction. Unlike direct tumor effects, PGD illustrates the complex association between cancer and diverse clinical presentations and outcomes. Initially detected in a Hodgkin's disease patient, current research has defined diagnostic criteria based on PGD symptoms and cancer progression. PGDs, although rare (found in <1% of adult cancer patients with overt renal manifestations), are crucial, as they can signal cancer onset and frequently resist standard glomerulonephritis treatments. The emerging field of onconephrology studies this relationship between kidney disorders and cancers. The exact cause of many PGD cases remains unknown. This review examines PGDs, their clinicopathological features, related cancers, and mechanisms, emphasizing the need for early diagnosis and tailored treatment for kidney disease and linked cancer.

Fanconi-Bickel syndrome complicated by nephrocalcinosis and GFR decline.

Fanconi-Bickel syndrome (FBS) is a rare genetic disorder of carbohydrate metabolism due to pathogenic variants in SLC2A2, a gene encoding glucose transporter 2 (GLUT2), which leads to accumulation of glycogen in the kidney and liver. While consequential complex proximal tubular dysfunction is well acknowledged in the literature, long-term trajectories of kidney function in patients with FBS have not been well characterized, and kidney biopsy is performed infrequently. Here, we report on a patient with FBS followed from infancy through young adulthood who presented early on with hypercalciuria, phosphaturia, and hypophosphatemia, complicated by chronic kidney disease development during childhood. Kidney biopsy, in addition to a widespread glycogen accumulation in proximal tubular epithelial cells, demonstrated medullary nephrocalcinosis. Screening for nephrocalcinosis may be warranted in pediatric patients with FBS, along with close surveillance of their kidney function.

RNA-sequencing of Human Kidney Allografts and Delineation of T-Cell Genes, Gene Sets, and Pathways Associated With Acute T Cell-mediated Rejection.

BACKGROUND: Delineation of T-cell genes, gene sets, pathways, and T-cell subtypes associated with acute T cell-mediated rejection (TCMR) may improve its management. METHODS: We performed bulk RNA-sequencing of 34 kidney allograft biopsies (16 Banff TCMR and 18 no rejection [NR] biopsies) from 34 adult recipients of human kidneys. Computational analysis was performed to determine the differential intragraft expression of T-cell genes at the level of single-gene, gene set, and pathways. RESULTS: T-cell signaling pathway gene sets for plenary T-cell activation were overrepresented in TCMR biopsies compared with NR biopsies. Heightened expression of T-cell signaling genes was validated using external TCMR biopsies. Pro- and anti-inflammatory immune gene sets were enriched, and metabolism gene sets were depleted in TCMR biopsies compared with NR biopsies. Gene signatures of regulatory T cells, Th1 cells, Th2 cells, Th17 cells, T follicular helper cells, CD4 tissue-resident memory T cells, and CD8 tissue-resident memory T cells were enriched in TCMR biopsies compared with NR biopsies. T-cell exhaustion and anergy were also molecular attributes of TCMR. Gene sets associated with antigen processing and presentation, and leukocyte transendothelial migration were overexpressed in TCMR biopsies compared with NR biopsies. Cellular deconvolution of graft infiltrating cells by gene expression patterns identified CD8 T cell to be the most abundant T-cell subtype infiltrating the allograft during TCMR. CONCLUSIONS: Our delineation of intragraft T-cell gene expression patterns, in addition to yielding new biological insights, may help prioritize T-cell genes and T-cell subtypes for therapeutic targeting.