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.

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.

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.

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.

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.

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.

Daily hemodialysis and the outcome of acute renal failure.

BACKGROUND: Intermittent hemodialysis is widely used as renal-replacement therapy in patients with acute renal failure, but an adequate dose has not been defined. We performed a prospective study to determine the effect of daily intermittent hemodialysis, as compared with conventional (alternate-day) intermittent hemodialysis, on survival among patients with acute renal failure. METHODS: A total of 160 patients with acute renal failure were assigned to receive daily or conventional intermittent hemodialysis. Survival was the primary end point of the study. The duration of acute renal failure and the frequency of therapy-related complications were secondary end points. RESULTS: The two study groups were similar with respect to age, sex, cause and severity of acute renal failure, medical or surgical intensive care setting, and the score on the Acute Physiology, Age, and Chronic Health Evaluation. Daily hemodialysis resulted in better control of uremia, fewer hypotensive episodes during hemodialysis, and more rapid resolution of acute renal failure (mean [+/-SD], 9+/-2 vs. 16+/-6 days; P=0.001) than did conventional hemodialysis. The mortality rate, according to the intention-to-treat analysis, was 28 percent for daily dialysis and 46 percent for alternate-day dialysis (P=0.01). In a multiple regression analysis, less frequent hemodialysis (on alternate days, as opposed to daily) was an independent risk factor for death. CONCLUSIONS: The high mortality rate among critically ill patients with acute renal failure who require renal-replacement therapy is related to both coexisting conditions and uremic damage to other organ systems. Intensive hemodialysis reduces mortality without increasing hemodynamically induced morbidity.

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.

Acute effects of hemodialysis on lung function in patients with end-stage renal disease.

Impaired lung function in hemodialysis patients may be caused by an underlying pulmonary disease; however, the impact of uremia and the effects of dialysis treatment are not well understood. Our investigation aimed to characterize the acute effects of bicarbonate hemodialysis using membranes differing in biocompatibility on various parameters of lung function in unselected uremic patients maintained on regular hemodialysis. Fourteen clinically stable hemodialysis patients without acute lung disease were included in the study. Restrictive lung disease was present in eight of 14 cases and obstructive lung disease in one patient. A cellulose dialyzer membrane and a synthetic high-flux dialyzer membrane were each tested twice (two sessions one week apart). Spirometry (VCmax, FEV1, FEF(25-75%), PEF) was carried out before and after hemodialysis. Resistance was determined with the interrupter technique and with the impulse oscillation system (R5Hz, R20Hz) before, during and after hemodialysis. Our comparative investigation of two dialyzer membranes found that bioincompatibility of dialysis had no acute adverse effects on lung function in our heterogeneous population of dialysis patients. None of our patients experienced bronchoconstriction or aggravation of obstructive lung disease as a result of poor biocompatibility of the dialyzer membrane. Spirometric data and resistance measurements by two different methods showed no relevant changes during the dialysis procedure. There was no correlation between lung function parameters and interdialytic changes in body weight or duration on hemodialysis. Regardless of the membrane used, the hemodialysis procedure does not acutely affect lung function in uremic patients on maintenance hemodialysis. Hemodialysis is a safe procedure even in uremic patients with pre-existing lung disease.

Detection of cancerous endobronchial lesions by autofluorescence bronchoscopy combined with mutation analysis of p53.

Early lung cancer screening failed to reduce lung cancer mortality. New techniques such as autofluorescence bronchoscopy (AF) and the identification of specific genetic alteration might change future outcomes of lung cancer screening. It was the aim of our study to combine p53 analysis with white-light bronchoscopy (WL) or WL and AF to improve the diagnostic yield in a series of 36 patients with histologically proven lung cancer, pulmonary metastasis or suspected lung cancer. - Endobronchial sites were analysed by WL (n = 71), AF (Storz) (n = 34), histopathology (n = 71) and p53 mutations were examined by SSCP analysis on additional biopsies (n = 69). The overall frequency of cancerous lesions was 19, of which 14 were macroscopically visible lesions. The addition of p53 and autofluorescence improved the yield to 17 of 19 cases. In 7 preinvasive lesions (dysplasia/metaplasia) 4 were identified macroscopically and 5 of 7 lesions by all 3 methods. In the WL/p53 group the diagnostic yield was 7 of 9 cancerous lesions compared to 10 of 10 cancerous lesions in the AF group. It should be noted that all methods were associated with false positive results. However, the combination of conventional with autofluorescence bronchoscopy and mutation analysis is a promising approach which is applicable to clinical routine and may be further enhanced by the inclusion of a panel of markers of tumour progression.