Quiz Ref ID Sepsis, defined as a dysregulated immune response to infection that leads to acute organ dysfunction, affects millions of individuals per year, and carries a high risk of death even when care is provided promptly.^1,2 Although the understanding of the host immune response has advanced considerably, it has not translated into new therapies. A major barrier to progress is the overly broad definition of the syndrome, which encompasses a vast, multidimensional array of clinical and biological features. Different combinations of these features may naturally cluster into previously undescribed subsets or phenotypes that may have different risks for a poor outcome and may respond differently to treatments. However, efforts to determine such phenotypes have remained limited and have focused primarily on patients in the intensive care unit.^3-5 In addition, these phenotypes must be identifiable at or soon after hospital presentation to guide treatment.

About one-third of critically ill patients with acute kidney injury (AKI) develop persistently decreased kidney function, known as acute kidney disease (AKD), which may progress to chronic kidney disease (CKD). Although sepsis is the most common cause of AKI, little is known about sepsis-associated AKD. Using data from a large randomized trial including 1341 patients with septic shock, we studied patients with stage 2 or 3 AKI on day 1 of hospitalization. We defined AKD as a persistently reduced glomerular filtration rate for >7 days. In addition to clinical data, we measured several urinary biomarkers (tissue inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein 7 [TIMP-2∗IGFBP7], neutrophil gelatinase-associated lipocalin [NGAL], kidney injury molecule-1 [KIM-1], liver-type fatty acid binding protein, and type 4 collagen) at 0, 6, and 24 hours, to predict AKD. Of 598 patients, 119 (19.9%) died within 7 days, 318 (53.2%) had early reversal of AKI within the first 7 days, whereas 161 (26.9%) developed AKD. In patients with early reversal, 45 (14.2%) had relapsed AKI after early reversal, and only about one-third of these recovered. Among patients developing AKD, only 15 (9.3%) recovered renal function prior to discharge. Male sex, African American race, and underlying CKD were more predominant in patients developing AKD. None of the biomarkers tested performed well for prediction of AKD, although NGAL modestly increased the performance of a clinical model. AKD is common in patients with septic shock, especially among African American males and those with underlying CKD. Existing AKI biomarkers have limited utility for predicting AKD but might be useful together with clinical variables. Novel predictive biomarkers for renal recovery are needed.

Several studies have shown that long-term survival after acute kidney injury (AKI) is reduced even if there is clinical recovery. However, we recently reported that in septic shock patients those that recover from AKI have survival similar to patients without AKI. Here, we studied a cohort with less severe sepsis to examine the effects of AKI on longer-term survival as a function of recovery by discharge. We analyzed patients with community-acquired pneumonia from the Genetic and Inflammatory Markers of Sepsis (GenIMS) cohort. We included patients who developed AKI (KDIGO stages 2–3) and defined renal recovery as alive at hospital discharge with return of SCr to within 150% of baseline without dialysis. Our primary outcome was survival up to 3 years analyzed using Gray’s model. Of the 1742 patients who survived to hospital discharge, stage 2–3 AKI occurred in 262 (15%), of which 111 (42.4%) recovered. Compared to recovered patients, patients without recovery were older (75 ±14 vs 69 ±15 years, p<0.001) and were more likely to have at least stage 1 AKI on day 1 (83% vs 52%, p<0.001). Overall, 445 patients (25.5%) died during follow-up, 23.4% (347/1480) for no AKI, 28% (31/111) for AKI with recovery and 44.3% (67/151) for AKI without recovery. Patients who did not recover had worse survival compared to no AKI (HR range 1.05–2.46, p = 0.01), while recovering patients had similar survival compared to no AKI (HR 1.01, 95%CI 0.69–1.47, p = 0.96). Absence of AKI on day 1, no in-hospital renal replacement therapy (RRT), higher Apache III score and higher baseline SCr were associated with recovery after AKI. In patients with sepsis, recovery by hospital discharge is associated with long-term survival similar to patients without AKI.

Objectives: Acute kidney injury is a common complication of major surgery. However, acute kidney injury occurring within the first 48 hours after surgery (early acute kidney injury) and therefore likely related to the surgery itself is possibly different from acute kidney injury occurring after 48 hours (late acute kidney injury). The aim of this study was to describe the epidemiology and identify differences in risk factors and outcomes between early and late acute kidney injury following major surgery. Design: Retrospective cohort study. Setting: Academic Medical Center. Patients: Patients admitted to ICU following noncardiac major surgery. Interventions: None. Measurements and Main Results: We analyzed data from 3,499 patients and defined acute kidney injury according to full Kidney Disease: Improving Global Outcomes criteria and classified as early (48 hr or less) or late (> 48 hr to 7 d) based on time from surgery. Separate multivariable logistic regression models were fit to identify risk factors of early acute kidney injury compared with no acute kidney injury and risk factors of late acute kidney injury compared with no acute kidney injury. Overall 41.7% (1,459/3,499) developed early acute kidney injury versus 14.4% (504/3,499) late acute kidney injury. Most acute kidney injury occurred within 48 hours following surgery and 12 hours was the peak interval. Risk factors for early acute kidney injury included increased age, body mass index, decreased estimated glomerular filtration rate, and anemia, whereas late acute kidney injury cases were closely associated with postoperative factors, like sepsis, mechanical ventilation, positive fluid balance, blood transfusions and exposure to diuretics, vasopressors, and nonsteroidal anti-inflammatory drugs. After adjusting for age, body mass index, estimated glomerular filtration rate, comorbidities, surgery type, both early acute kidney injury (odds ratio [95% CI], 1.84 [1.50–2.27]) and late acute kidney injury (odds ratio [95% CI], 1.42 [1.09–1.85]) were associated with higher 1-year mortality compared with patients without acute kidney injury. We found similar results in a validation cohort of 10,723 patients admitted between 2008 and 2014. Conclusions: Most surgery-related acute kidney injury occurred within 48 hours of surgery. Acute kidney injury occurring within the first 48 hours was associated with underlying health, whereas acute kidney injury occurring after 48 hours was related to postoperative complications or drugs. Design of clinical and experimental interventions for acute kidney injury in this population should consider these differences.

Electrically excitable cells such as neurons transmit long-distance calcium or electrical signals to regulate their physiological functions. While the molecular underpinnings and down-stream effects of these intercellular communications in excitable cells have been well appreciated, little is known about whether and how non-excitable cancer cells spontaneously initiate and transmit long-distance intercellular signals. Here we report that non-excitable human colon and prostate cancer cells spontaneously initiate and spread intercellular calcium waves, in vitro and ex vivo. Xenograft model studies suggest that these calcium signals promote the growth rate of tumors in mice. Pharmacological studies elucidated that the inositol-trisphosphate-receptor (IP₃R)-regulated calcium release from endoplasmic reticulum (ER), which is activated by the G_q-PLC-IP₃R pathway, is a major cause for the initiation of spontaneous calcium transients. Further, the spatial-temporal characteristics of calcium dynamics can be tuned by the culture substrates of different mechanical stiffnesses. Our results provide evidence that calcium dynamics enables long-distance functional communication in non-excitable cancer cells and offer the potential to modulate calcium signaling for new cancer therapies.

During the first year of the coronavirus disease 2019 (COVID-19) pandemic, prevention measures included quarantining and facility closures. Because cancer screening is dependent on interventions in facilities, the extent of the COVID-19 impact on screening was questioned. A claims registry from a large health system was queried for colorectal and prostate cancer screening. A screening gap and screening loss ratio were calculated by comparing 2020 screening to historical reference years. All cancer screenings decreased in the first four months of the pandemic. Colorectal cancer screening returned to baseline in the latter six months of 2020. Prostate cancer screening exceeded baseline in the latter six months, but with a lesser gain than previous years. Populations disproportionately affected by decreased cancer screening included men and black people. To catch-up after the initial deficit in screening, it is estimated that the rate of colorectal cancer screening needs to increase by 50%.