Platelet concentrate (PC) transfusions are a lifesaving adjunct to control and prevent bleeding in cancer, hematologic, surgical, and trauma patients. Platelet concentrate availability and safety are limited by the development of platelet storage lesions (PSLs) and risk of bacterial contamination. Platelet storage lesions are a series of biochemical, structural, and functional changes that occur from blood collection to transfusion. Understanding of PSLs is key for devising interventions that prolong PC shelf life to improve PC access and wastage. This article will review advancements in clinical and mechanistic PSL research. In brief, exposure to artificial surfaces and high centrifugation forces during PC preparation initiate PSLs by causing platelet activation, fragmentation, and biochemical release. During room temperature storage, enhanced glycolysis and reduced mitochondrial function lead to glucose depletion, lactate accumulation, and product acidification. Impaired adenosine triphosphate generation reduces platelet capacity to perform energetically demanding processes such as hypotonic stress responses and activation/aggregation. Storage-induced alterations in platelet surface proteins such as thrombin receptors and glycoproteins decrease platelet aggregation. During storage, there is an accumulation of immunoactive proteins such as leukocyte-derive cytokines (tumor necrosis factor α, interleukin (IL) 1α, IL-6, IL-8) and soluble CD40 ligand which can participate in transfusion-related acute lung injury and nonhemolytic transfusion reactions. Storage-induced microparticles have been linked to enhanced platelet aggregation and immune system modulation. Clinically, stored PCs have been correlated with reduced corrected count increment, posttransfusion platelet recovery, and survival across multiple meta-analyses. Fresh PC transfusions have been associated with superior platelet function in vivo; however, these differences were abrogated after a period of circulation. There is currently insufficient evidence to discern the effect of PSLs on transfusion safety. Various bag and storage media changes have been proposed to reduce glycolysis and platelet activation during room temperature storage. Moreover, cryopreservation and cold storage have been proposed as potential methods to prolong PC shelf life by reducing platelet metabolism and bacterial proliferation. However, further work is required to elucidate and manage the PSLs specific to these storage protocols before its implementation in blood banks.

SUMMARY Four young Chinese women took daily doses of an unidentified 'Indian' herbal tea as treatment for psoriasis. Three (one of whom died), developed ascites, hepatomegaly and biochemical abnormalities within 19-45 days. The fourth patient discontinued herbal tea after 21 days when she developed a skin rash. Two patients had portal hypertension, while all had liver histology showing features of veno-occlusive disease. Pyrrolizidine alkaloids were identified spectrophotometrically in the brewed tea, and in the chopped leaves of the herbal mixture; the mean dose in the tea prepared for consumption being 12 mg/day of alkaloid base and 18 mg/day of N-oxide. The mean cumulative dose of alkaloids (base + N-oxide) before onset of symptoms (three patients), was estimated to be 18 mg/kg. In the asymptomatic patient with histological liver disease only, the corresponding dose was 15 mg/kg. These cases thus provide some measure of pyrrolizidine alkaloid toxicity in adults.

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Although literature presents a concerning picture of potential storage complications, current findings are too inconsistent to drive changes in clinical practice. Results from current RCTs will likely play a role in PRBC age guidelines for cardiac surgery and ICU patients. However, these studies may be less efficacious at detecting small effects that are limited to specific subpopulations.

Observational studies address packed red blood cell effects at the end of shelf life and have larger sample sizes compared to randomized control trials. Meta-analyses combining data from observational studies have been complicated by differences in aggregate transfused packed red blood cell age and outcome reporting. This study abrogated these issues by taking a pooled patient data approach. Observational studies reporting packed red blood cell age and clinical outcomes were identified and patient-level data sets were sought from investigators. Odds ratios and 95% confidence intervals for binary outcomes were calculated for each study, with mean packed red blood cell age or maximum packed red blood cell age acting as independent variables. The relationship between mean packed red blood cell age and hospital length of stay for each paper was analyzed using zero-inflated Poisson regression. Random effects models combined paper-level effect estimates. Extremes analyses were completed by comparing patients transfused with mean packed red blood cell aged less than ten days to those transfused with mean packed red blood cell aged at least 30 days. sixteen datasets were available for pooled patient data analysis. Mean packed red blood cell age of at least 30 days was associated with an increased risk of in-hospital mortality compared to mean packed red blood cell of less than ten days (odds ratio: 3.25, 95% confidence interval: 1.27–8.29). Packed red blood cell age was not correlated to increased risks of nosocomial infection or prolonged length of hospital stay.

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Understanding the molecular mechanisms underlying mammalian kidney function requires transcriptome profiling of the interplay between cells comprising nephron segments. Traditional transcriptomics requires cell dissociation, resulting in loss of the spatial context of gene expression within native tissue. To address this problem, we performed spatial transcriptomics (ST) to retain the spatial context of the transcriptome in human and mouse kidneys. The generated ST data allowed spatially resolved differential gene expression analysis, spatial identification of functional nephron segments, cell-to-cell interaction analysis, and chronic kidney disease-associated genetic variant calling. Novel ST thus provides an opportunity to enhance kidney diagnostics and knowledge, by retaining the spatial context of gene expression within intact tissue.

Inflammasomes are multiprotein platforms responsible for the release of pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Mouse studies have identified inflammasome activation within dendritic cells (DC) as pivotal for driving tubulointerstitial fibrosis and inflammation, the hallmarks of chronic kidney disease (CKD). However, translation of this work to human CKD remains limited. Here, we examined the complex tubular cell death pathways mediating inflammasome activation in human kidney DC and, thus, CKD progression. Ex vivo patient-derived proximal tubular epithelial cells (PTEC) cultured under hypoxic (1% O2) conditions modelling the CKD microenvironment showed characteristics of ferroptotic cell death, including mitochondrial dysfunction, reductions in the lipid repair enzyme glutathione peroxidase 4 (GPX4) and increases in lipid peroxidation by-product 4-hydroxynonenal (4-HNE) compared with normoxic PTEC. The addition of ferroptosis inhibitor, ferrostatin-1, significantly reduced hypoxic PTEC death. Human CD1c+ DC activated in the presence of hypoxic PTEC displayed significantly increased production of inflammasome-dependent cytokines IL-1β and IL-18. Treatment of co-cultures with VX-765 (caspase-1/4 inhibitor) and MCC950 (NLRP3 inflammasome inhibitor) significantly attenuated IL-1β/IL-18 levels, supporting an NLRP3 inflammasome-dependent DC response. In line with these in vitro findings, in situ immunolabelling of human fibrotic kidney tissue revealed a significant accumulation of tubulointerstitial CD1c+ DC containing active inflammasome (ASC) specks adjacent to ferroptotic PTEC. These data establish ferroptosis as the primary pattern of PTEC necrosis under the hypoxic conditions of CKD. Moreover, this study identifies NLRP3 inflammasome signalling driven by complex tubulointerstitial PTEC-DC interactions as a key checkpoint for therapeutic targeting in human CKD.