Venous and Arterial Thromboembolism in Lung Cancer Patients: A Retrospective Analysis.

Background: Patients with lung cancer face an increased incidence of venous (VTE) and arterial (ATE) thromboembolism. Risk factors for thrombosis remain unclear, particularly the impact of the use of immune checkpoint inhibitors (ICIs). We sought to compare the incidence of VTE and ATE in lung cancer patients receiving platinum-based therapy versus those receiving ICIs alone or in combination with chemotherapy and to validate the Khorana risk score for predicting VTE in the era of ICIs. Methods: A retrospective single-institution data analysis of 173 patients diagnosed with locally advanced or metastatic lung cancer at the Jena University hospital between 2015 and 2021. Results: The study revealed a high incidence of VTE (17.9%) and ATE (5.8%). The VTE risk was higher in patients diagnosed with adenocarcinoma (OR 0.29, 95% CI 0.09-0.93) than in patients with other histological types. A prior venous event was associated with an increased risk of recurrent VTE (OR 4.46, 95% CI 1.20-16.63). The incidence of thrombosis under first-line platinum-based chemotherapy did not differ from the incidence under ICIs (p = 0.19). There were no differences in the subgroup of patients who received ICIs alone or combined immunochemotherapy (p = 0.43). The Khorana score failed to predict the risk of VTE correctly. Conclusions: We did not find evidence supporting the theory that ICI therapy (alone or combined) increases the risk of thrombotic events. Adenocarcinoma and a prior history of VTE were strongly associated with an increased risk of VTE. Other scores for thrombotic risk assessment in lung cancer patients should be tested in prospective studies.

The Diagnostic Value of ACSL1, ACSL4, and ACSL5 and the Clinical Potential of an ACSL Inhibitor in Non-Small-Cell Lung Cancer.

Abnormal expression of ACSL members 1, 3, 4, 5, and 6 is frequently seen in human cancer; however, their clinical relevance is unclear. In this study, we analyzed the expression of ACSLs and investigated the effects of the ACSL inhibitor Triacsin C (TC) in lung cancer. We found that, compared to normal human bronchial epithelial (NHBE) cells, ACSL1, ACSL4, and ACSL6 were highly expressed, while ACSL3 and ACSL5 were lost in the majority of lung cancer cell lines. ACSL activity was associated with the expression levels of the ACSLs. In primary lung tumors, a higher expression of ACSL1, ACSL4, and ACSL5 was significantly correlated with adenocarcinoma (ADC). Moreover, ACSL5 was significantly reversely related to the proliferation marker Ki67 in low-grade tumors, while ACSL3 was positively associated with Ki67 in high-grade tumors. Combination therapy with TC and Gemcitabine enhanced the growth-inhibitory effect in EGFR wild-type cells, while TC combined with EGFR-TKIs sensitized the EGFR-mutant cells to EGFR-TKI treatment. Taken together, the data suggest that ACSL1 may be a biomarker for lung ADC, and ACSL1, ACSL4, and ACSL5 may be involved in lung cancer differentiation, and TC, in combination with chemotherapy or EGFR-TKIs, may help patients overcome drug resistance.

Respiratory Infections in the Aging Lung: Implications for Diagnosis, Therapy, and Prevention.

Respiratory infections pose a significant health problem among elderly individuals, particularly during the COVID-19 pandemic. The increased mortality and morbidity rates among individuals over 65 highlight the criticality of these infections. The normal aging process in the lungs increases vulnerability to respiratory infections due to the accumulation of cellular damage and senescence. Consequently, the lung environment undergoes major changes in mechanical function and other systemic factors. This review aims to examine the influence of aging on respiratory infections from a clinical perspective by analyzing clinical studies. Additionally, the review will emphasize potential prevention and diagnostic developments to enhance therapy options available for elderly patients over 65 years of age.

Long-term interplay between COVID-19 and chronic kidney disease.

PURPOSE: The COVID-19 pandemic may have an impact on the long-term kidney function of survivors. The clinical relevance is not clear. METHODS: This review summarises the currently published data. RESULTS: There is a bidirectional relationship between chronic kidney disease and COVID-19 disease. Chronic kidney diseases due to primary kidney disease or chronic conditions affecting kidneys increase the susceptibility to COVID-19 infection, the risks for progression and critical COVID-19 disease (with acute or acute-on-chronic kidney damage), and death. Patients who have survived COVID-19 face an increased risk of worse kidney outcomes in the post-acute phase of the disease. Of clinical significance, COVID-19 may predispose surviving patients to chronic kidney disease, independently of clinically apparent acute kidney injury (AKI). The increased risk of post-acute renal dysfunction of COVID-19 patients can be graded according to the severity of the acute infection (non-hospitalised, hospitalised or ICU patients). The burden of chronic kidney disease developing after COVID-19 is currently unknown. CONCLUSION: Post-acute COVID-19 care should include close attention to kidney function. Future prospective large-scale studies are needed with long and complete follow-up periods, assessing kidney function using novel markers of kidney function/damage, urinalysis and biopsy studies.

Neutrophil-to-lymphocyte ratio-a new diagnostic and prognostic marker of acute kidney injury. Barriers to broad clinical application.

Hospital-acquired acute kidney injury is a heterogeneous clinical syndrome that has multiple aetiologies, widely differing pathogeneses, variable clinical manifestations, and diverse outcomes. There is a persistent unmet need for novel biomarkers that offer timely diagnosis and accurate prediction of the short- and long-term sequelae of acute kidney injury (AKI). AKI is associated with systemic and intrarenal inflammation. The neutrophil-to-lymphocyte ratio (NLR), a readily available marker of inflammation and physiologic stress, has gained increasing attention as universal marker in AKI patients. Numerous retrospective cross-sectional studies assessed the clinical usefulness of this test in high-risk patients with a known time point of the renal injury (surgery, radiological procedures). Strong associations have been demonstrated between high NLR and early onset, progression or recovery of AKI, and the in-hospital and post-discharge mortality of these patients. However, the results were contradictory. The huge heterogeneity of reporting concerning the timing and numbers of blood samples, calculation of the optimal cut-off and the demographic and clinical features of the patient cohorts were confounders. Uncertainty in the optimal cut-off values defining high NLR, the lack of prospective validation of this test and limited understanding of the strengths of associations between NLR and clinical outcomes were further barriers for the clinical adoption of NLR as a valid diagnostic and prognostic test in AKI patients.

Dimorphic Response of Sex and Hospital-acquired Acute Kidney Injury.

The risk of hospital-acquired acute kidney injury (HA-AKI) depends on a person's intrinsic susceptibility, the presence of risk factors, and on the type and extent of exposure to kidney insults. Older cohort studies have focused on male-only or mostly male populations, assuming a lower incidence of HA-AKI in women. Insufficient statistical power suggested that female sex was a shared susceptibility factor for HA-AKI. It was included as a risk factor in risk prediction models of HA-AKI. With the inclusion of women in clinical research studies, this presumption was challenged. Recent meta-analyses of sex-stratified studies showed that the risk for HA-AKI was significantly higher in men. These results suggested a protective role of female sex hormones. However, these studies were complicated by the inclusion of women across an age spectrum that includes the menopausal shift. Preliminary clinical and basic research data suggest that postmenopausal women lose their protection from HA-AKI. The number, size, and quality of reported clinical studies are low. There is an unmet need to characterize the susceptibility factor sex, to assess its clinical relevance and to evaluate renoprotection by sex hormone administration.

Current Approach to Successful Liberation from Renal Replacement Therapy in Critically Ill Patients with Severe Acute Kidney Injury: The Quest for Biomarkers Continues.

Recovery of sufficient kidney function to liberate patients with severe acute kidney injury (AKI-D) from renal replacement therapy (RRT) is recognized as a vital patient-centred outcome. However, no clinical consensus guideline provides specific recommendations on when and how to stop RRT in anticipation of renal recovery from AKI-D. Currently, wide variations in clinical practice regarding liberation from RRT result in early re-start of RRT to treat uraemia after premature liberation or in the unnecessary prolonged exposure of unwell patients after late liberation. Observational studies, predominantly retrospective in nature, have attempted to assess numerous surrogate markers of kidney function or of biomarkers of kidney damage to predict successful liberation from RRT. However, a substantial heterogeneity in the timing of measurement and cut-off values of most biomarkers across studies allows no pooling of data, and impedes the comparison of outcomes from such studies. The accuracy of most traditional and novel biomarkers cannot be assessed reliably. Currently, the decision to discontinue RRT in AKI-D patients relies on daily clinical assessments of the patient's status supplemented by measurement of creatinine clearance (> 15 ml/min) and 24-h urine output (> 2000 ml/min with diuretics). Clinical trials objectively comparing the success of validated biomarkers for guiding optimal timed liberation from RRT in AKI-D will be required to provide high-quality evidence for guidelines.

Risk of lung cancer and renin-angiotensin blockade: a concise review.

PURPOSE: The blockade of the renin-angiotensin-aldosterone system (RAAS) by angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) is one of the most common treatments for hypertension, heart failure and renal diseases. However, concerns have been raised about a possible link between RAAS-blockers and an increased risk of cancer, particularly of lung cancer. This narrative review aims to give a critical appraisal of current evidence and to help physicians understand potential links between RAAS blockade and de novo lung cancer development. METHODS: Numerous pharmaco-epidemiologic studies, mostly retrospective cohort analyses, evaluated the association of RAAS blockade with lung cancer incidence and reported inconsistent findings. Meta-analyses could not further clarify a possible link between RAAS blockade and the risk of lung cancer. RESULTS: International regulatory agencies (FDA, EMA) have concluded that the use of RAAS blockers is not associated with an increased risk of developing lung cancer. Co-administration of RAAS blockers to systemic therapy of advanced non-small cell lung cancer seems to have positive effects on the outcome. CONCLUSION: Until more comprehensive analyses have been completed, there is no need to change clinical practise. Additional prospective randomized trials with long-term follow-up are needed to investigate the effects of these drugs on the development and progression of lung cancer.

Proton-pump inhibitors and chronic kidney disease: Hidden consequences of an inappropriate drug use?

Proton-pump inhibitors (PPIs) are the most effective therapy for gastric acid- related diseases. They are generally well tolerated with rare, often self-limiting adverse reactions. On the other hand, there is growing concern regarding the increased public access and inappropriate PPI use. This review aims to give a critical appraisal of current literature and to analyze a possible relationship between renal disorders and PPI use. A plethora of observational pharmacoepidemiological studies link PPI therapy to the development of acute interstitial nephritis (AIN). Most of these studies show a higher risk for acute kidney injury, de novo chronic kidney disease, and end-stage renal disease. However, current evidence is inadequate to establish a causal relationship between PPI use and many of the proposed renal syndromes. Residual confounding and bias related to study design and the over extrapolation of quantitatively small treatment effects contributed to the unnecessary controversy about PPI safety. Undoubtedly, PPI use may rarely induce AIN. Given the worldwide use of PPIs, the number of patients with biopsy- proven AIN is extremely small. However, more research is required to explore the underlying pathophysiological mechanisms and possible differences between commercially available PPIs regarding adverse renal effects. Till then, the PPIs should be used in the lowest effective dose, and inappropriate use should be avoided.

Ursodeoxycholic acid attenuates hepatotoxicity of multidrug treatment of mycobacterial infections: A prospective pilot study.

BACKGROUND: Tuberculosis (TB) remains a global health problem. The application of rifampicin-based regimens for antimycobacterial therapy is hampered by its marked hepatotoxicity which results in poor adherence and may contribute to prolonged therapy or treatment failure. The purpose of this prospective investigation was to evaluate the hepatoprotective effectiveness of oral ursodeoxycholic acid (UDCA) (250-500 mg TID) administered to TB- or non-TB mycobacterial (NTM)-infected patients with drug-induced hepatotoxicity and ongoing therapy. METHODS: Study population: During 2009-2017, 27 patients (11 women, 16 men, aged 19-90 years; median age 44 years, 16 Caucasians, 10 Africans, 1 Asian) out of 285 patients with active TB (24/261) or NTM infections (3/24) treated at our TB Center developed clinically relevant hepatotoxicity. Oral UDCA was administered to treat hepatotoxicity. RESULTS: Twenty-one out of 27 patients (77.8%) showed normalization of elevated enzymes (alanine transferase and aspartate aminotransferase), alkaline phosphatase, and bilirubin while continuing TB treatment and 5 patients demonstrated a significant reduction of liver enzymes (18.5%). No change was observed in 1 patient (3.7%). Drug dose was not reduced in all patients; they all showed radiological and clinical improvement. There were no significant side effects. CONCLUSION: Oral administration of UDCA to TB patients developing anti-TB drug-induced liver injury may reverse hepatotoxicity in adults.

Obesity, acute kidney injury and outcome of critical illness.

Acute kidney injury is a heterogeneous clinical syndrome encompassing a spectrum of risk factors and acute insults, occurring in multiple settings and affecting both short-term and long-term outcomes. Obesity has become an epidemic. The available literature suggests that AKI is common in critically ill surgical or medical obese patients and that obesity is a novel risk factor for this acute renal syndrome. The pathophysiology of obesity-associated AKI is not completely understood. Obesity-related factors combined with the burden of other comorbidities in elderly obese patients may interact with known precipitating factors such as hypotension, nephrotoxins or sepsis and increase the susceptibility of this population to AKI. Whether or not obesity may counterintuitively be protective and associated with better survival of critically ill patients with AKI ("reverse epidemiology") is a subject for debate. Further investigations exploring the role of novel biomarkers and optimal management are needed urgently.

Assessment of dialysis dose in critically ill maintenance dialysis patients.

Maintenance dialysis patients are admitted more frequently to the intensive care unit (ICU) and have higher ICU mortality than the general population. It is unclear if such dialysis patients receive adequate dialysis in the ICU setting. Using the Daugirdas formula for calculation of spKt/Vurea, single treatment delivered dialysis dose was assessed in 85 critically ill maintenance hemodialysis patients during their first ICU dialysis session. Weekly delivered spKt/Vurea was determined in the surviving 64 patients and compared with their corresponding delivered outpatient dialysis dosages. Outcome measures were ICU and in-hospital mortality and mortality at 6 and 12 months after discharge. Prescribed dose of the first ICU dialysis was a spKt/Vurea of 1.43 ± 0.11, the single treatment delivered dose was 1.02 ± 0.14. The weekly prescribed ICU Kt/Vurea was 4.25 ± 0.12 and delivered ICU Kt/Vurea was 3.48 ± 0.19. Patients with sepsis had the lowest mean spKt/Vurea values (0.87 ± 0.12). Serial measurements of delivered dialysis dose suggest that this gap is explained by variability of volume of urea distribution. ICU mortality was 25% and was related to APACHE II score, but not to delivered intermittent hemodialysis dose. Critically ill maintenance dialysis patients receive suboptimal dialysis doses. The impact of short-term underdialysis on survival of hospitalized maintenance dialysis patients remains unknown. Assessment of dialysis adequacy should be routinely performed in these patients and delivered dialysis should be tracked through the initial clinical course.

Urinary biomarkers and acute kidney injury in children: the long road to clinical application.

Pediatric acute kidney injury is rising with the advances in technology available for children with chronic conditions or those who are critically ill. Serum creatinine and urine output, traditional markers of renal function, often allow only delayed and unreliable diagnosis of acute kidney injury. Biomarker development in pediatric patients with low disease prevalence is challenging (small cohorts, few analyzable events). In this issue of Pediatric Nephrology, Ivanisevic and colleagues report that urinary liver-type fatty-acid-binding protein (L-FABP) can be used for early identification of pediatric acute kidney injury in a small cohort undergoing cardiac surgery. Addition of the biomarker resulted in an improvement in early diagnosis compared with a clinical model (age, gender, body weight, cardiopulmonary bypass duration, and aortic clamp time). It is noteworthy that the preoperative clinical model performed excellently in predicting postsurgery pediatric acute kidney injury. Further work is needed before this or other novel biomarkers (alone or in combination) can be implemented in clinical practice. Large-scale observational studies are needed to test these biomarkers against hard clinical endpoints, independent of serial measurements of serum creatinine concentrations. Prospective randomized interventional trials using exclusively high biomarker levels to define acute kidney injury should demonstrate improved clinical outcomes.

Severe acute hypophosphatemia during renal replacement therapy adversely affects outcome of critically ill patients with acute kidney injury.

PURPOSE: Hypophosphatemia during renal replacement therapy (RRT) is common in critically ill patients with acute kidney injury (AKI). The clinical consequences of RRT-induced phosphate depletion are not well defined in this patient population, and there is no evidence that intravenous sodium phosphate supplementation (PS) prevents the clinical sequelae of acute hypophosphatemia. The purpose of this retrospective analysis of the Acute Renal Support Registry of the University of Munich was to examine the association between severe hypophosphatemia and severity of and recovery from AKI. METHODS: 289 ICU patients with AKI on intermittent hemodialysis (IHD) were included in the study. One hundred and forty-nine patients received PS during IHD. Outcomes were short-term (at discharge) and long-term (at 1 year) recovery of renal function and mortality. RESULTS: The two patient groups did not differ in demographics, clinical features, renal characteristics, and frequency of hypophosphatemia at initiation of IHD. Without PS, the frequency of hypophosphatemia increased from 20 to 35%. Severe hypophosphatemia was found in 50% of these patients. By comparison, PS was not associated with an increased frequency of hypophosphatemia. Compared with patients with acute phosphate depletion, patients receiving PS developed less oliguria during IHD, had shorter duration of AKI, higher incidence of complete renal recovery at discharge, and a lower risk of de novo chronic kidney disease. Hypophosphatemia was associated with higher all-cause in-hospital mortality and higher risk of long-term mortality. CONCLUSIONS: This multicenter study indicates for the first time that hypophosphatemia during IHD adversely affects short- and long-term outcome of critically-ill patients with AKI. The clinical consequences of the acute hypophosphatemic syndrome may be prevented by PS.

Comparison of portable oxygen concentrators in a simulated airplane environment.

Portable oxygen concentrators (POC) are highly desirable for patients with lung disease traveling by airplane, as these devices allow theoretically much higher travel times if additional batteries can be used. However, it is unclear whether POCs produce enough oxygen in airplanes at cruising altitude, even if complying with aviation regulations. We evaluated five frequently used POCs (XPO2 (Invacare, USA), Freestyle (AirSep C., USA), Evergo (Philipps Healthcare, Germany), Inogen One (Inogen, USA), Eclipse 3 (Sequal, USA)) at an altitude of 2650 m (as simulated airplane environment) in 11 patients with chronic obstructive lung disease (COPD) and compared theses POCs with the standard oxygen system (WS120, EMS Ltd., Germany) used by Lufthansa. Oxygen was delivered by each POC for 30 min to each patient at rest, blood gases were then drawn from the arterialized ear lobe. All POCs were able to deliver enough oxygen to increase the PaO(2) of our subjects by at least 1.40 kPa (10 mmHg). However, to achieve this increase, the two most lightweight POCs (Freestyle and Invacare XPO2) had to be run at their maximum level. This causes a significant reduction of battery life. The three other POCs (EverGo, Inogen One, Eclipse 3) and the WS120 were able to increase the PaO(2) by more than 2.55 kPa (20 mmHg), which provides extra safety for patients with more severe basal hypoxemia. When choosing the right oxygen system for air travel in patients in COPD, not only weight, but also battery life and maximum possible oxygen output must be considered carefully.