Specific and Non-specific Aspects and Future Challenges of ICU Care Among COVID-19 Patients with Obesity: A Narrative Review.

PURPOSE OF REVIEW: Since the end of 2019, the coronavirus disease 2019 (COVID-19) pandemic has infected nearly 800 million people and caused almost seven million deaths. Obesity was quickly identified as a risk factor for severe COVID-19, ICU admission, acute respiratory distress syndrome, organ support including mechanical ventilation and prolonged length of stay. The relationship among obesity; COVID-19; and respiratory, thrombotic, and renal complications upon admission to the ICU is unclear. RECENT FINDINGS: The predominant effect of a hyperinflammatory status or a cytokine storm has been suggested in patients with obesity, but more recent studies have challenged this hypothesis. Numerous studies have also shown increased mortality among critically ill patients with obesity and COVID-19, casting doubt on the obesity paradox, with survival advantages with overweight and mild obesity being reported in other ICU syndromes. Finally, it is now clear that the increase in the global prevalence of overweight and obesity is a major public health issue that must be accompanied by a transformation of our ICUs, both in terms of equipment and human resources. Research must also focus more on these patients to improve their care. In this review, we focused on the central role of obesity in critically ill patients during this pandemic, highlighting its specificities during their stay in the ICU, identifying the lessons we have learned, and identifying areas for future research as well as the future challenges for ICU activity.

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.

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.

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.

Gender differences in the susceptibility of hospital-acquired acute kidney injury: more questions than answers.

Hospital-acquired acute kidney injury (HA-AKI) is a heterogeneous renal syndrome which occurs in different clinical settings. It is characterized by multiple aetiologies, various pathogeneses and unpredictable outcomes. HA-AKI, once predominantly viewed as a self-limited and reversible short-term condition, is now recognized as a harbinger for chronic kidney disease and a cause of long-term morbidity with an increased risk of cardiovascular, renal and cancer mortality. Recent clinical studies contradict the generally held belief that female sex is a risk factor for HA-AKI. They show, consistent with basic research performed with experimental models of AKI, that only male sex is associated with HA-AKI. The presence of testosterone, more likely than the absence of estrogen, plays a critical role in sex differences in the susceptibility of ischemia/reperfusion kidney injury. The conflicting data in epidemiological studies related to sex as susceptibility variable for human AKI, underscore the need for more rigorous, well designed observational studies taking into account the menopausal status and hormone therapy.

High-volume online haemodiafiltration treatment and outcome of end-stage renal disease patients: more than one mode.

The reduction of the dismally high mortality of current end-stage renal disease patients maintained on conventional standard haemodialysis (HD) remains an unmet medical need. Online haemodiafiltration (HDF) modes with various sites of fluid substitution (post-, pre-, mixed- and mid-dilution) are increasingly used worldwide as promising alternatives to conventional HD. Large scale cohort studies, post hoc analyses of randomized trials, and individual participant meta-analyses suggest that post-dilution and pre-dilution, especially with high substitution volumes, improve outcomes compared with conventional standard HD. However, there is no definitive proof of a survival advantage of HDF over standard HD. The different modes of high-volume HDF should be considered a therapeutic platform allowing to personalize and tailor routine HDF treatment. The selection of the HDF mode should be made according to individual patient characteristics. Utilizing high retention onset membranes, expanded haemodialysis (HDx) can achieve the same solute removal performance as HDF. Subgroups of high-volume OL-HDF patients could benefit from HDx. Ongoing and future trials should provide definitive proof for the superiority of high-volume OL-HDF over conventional HD or HDx to give guidance for the most favourable mode of dialytic therapy for clinical use.

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.

Obesity and the Survival of Critically Ill Patients with Acute Kidney Injury: A Paradox within the Paradox?

The obesity epidemic is reflected by the rising number of obese patients requiring intensive care. Obesity is a recognized risk factor for the development of acute kidney injury (AKI) in critically ill patients. Both acute critical illness and AKI are associated with higher in-hospital mortality rates, and intensive care unit (ICU) patients suffering from AKI have an elevated risk of death. The relationships between obesity and mortality in critically ill paediatric and adult patients with or without AKI are less clear. Conflicting evidence exists regarding the potential impact of body mass index on the mortality of ICU patients with AKI. Some studies looking at the ICU outcomes of critically ill obese patients with AKI show reduced mortality and others show either no association or elevated mortality. Despite a high biologic plausibility of the proposed causal mechanisms, such as a greater haemodynamic stability and the protective cytokine, adipokine, and lipoprotein defence profiles associated with obesity, the inconsistency of the data suggests that the obesity paradox is a statistical fallacy and the result of chance, bias, and residual confounding variables in retrospective cohort analyses. Further prospective randomized trials are essential to elucidate the role of obesity and the mechanisms underlying a potential survival benefit of obesity in critically ill patients with AKI.

Intensity of renal replacement therapy and outcomes in critically ill patients with acute kidney injury: Critical appraisal of the dosing recommendations.

The current care of critically ill patients with severe acute kidney injury requiring dialysis (AKI-D) is limited to supportive management in which renal replacement therapy (RRT) plays a central role. Renal replacement techniques are invasive bioincompatible procedures and are therefore associated with complications that may prove harmful to fragile patients. Inexperience with the standards and lacking or misinterpreted recommendations for the delivery of the RRT dose increases the risk of serious complications. Neither the optimal doses of intermittent or continuous RRTs nor the minimal or maximal effective doses are known. The Kidney Disease Improving Global outcomes (KDIGO) AKI guidelines for RRT dosing recommendations are inflexible, based on limited research, and may be at least partially outdated. High-intensity therapy may be associated with clinically relevant alterations in systemic and renal hemodynamics, profound electrolyte imbalances, the loss of nutrients or thermal energy, and underdosing of antimicrobial agents. However, higher doses of continuous renal replacement therapy (CRRT) may confer a survival benefit for certain subgroups of intensive care patients with severe AKI. Lower CRRT doses than the recommended adequate dosage may not lead to negative health outcomes, at least in Asian patients. Future research should evaluate the demand-capacity concept, recognizing that the delivery of the RRT dose is dynamic and should be modified in response to patient-related factors. There is a need for large-scale studies evaluating whether precision RRT dose modifications may improve patient-centered outcomes in subgroups of critically ill patients.

Online hemodiafiltration and mortality risk in end-stage renal disease patients: A critical appraisal of current evidence.

The life expectancy of end-stage renal disease patients undergoing regular hemodialysis (HD) remains significantly lower than in the general population. Reducing excess mortality by improving renal replacement options is an unmet medical need. Online post-dilution hemodiafiltration (HDF) has been promoted as the gold standard, offering improved clinical outcomes, based on numerous observational studies that suggest a reduced mortality risk and lower morbidity with HDF compared with standard HD. However, most randomized controlled trials (RCTs) have failed to demonstrate a significant beneficial effect of HDF on all-cause mortality. The effects on secondary outcomes were often negligible or absent. Unfortunately, these RCTs were characterized by a moderate to high risk of bias. In post-hoc analyses of the largest RCTs and meta-analysis of individual participant data from four RCTs, HDF patients receiving the highest convection volume consistently and dose-dependently saw superior outcomes. However, as these studies were not designed a priori to clarify this issue, and there are no indisputable mechanisms underlying reduced mortality risks, we cannot exclude the possibility that the health status of patients (with vascular access as a proxy) may affect outcomes more than the convective technique itself. There is currently insufficient evidence to support the contention that high-volume HDF confers relevant benefits to patients over standard HD. The conflicting data of published RCTs reduce confidence in the superiority of high-volume convective therapy. Hopefully, ongoing large RCTs (for example, CONVINCE) may supply an indisputable answer to the crucial question of high-volume HDF.

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.

Timing of Renal Replacement Therapy in Acute Kidney Injury: Shedding New Light on an Old Controversy.

Critically ill patients with severe acute kidney injury (AKI-D) require renal replacement therapy (RRT) increasingly. However, the optimal timing of initiation of RRT for non-life-threatening indications of AKI remains unknown. There is a debate as to whether different philosophies of RRT initiation (early vs. delayed) confer a survival benefit. Lowering the threshold for RRT initiation, however, inevitably leads to more critically ill patients receiving unnecessary RRT. The relevant proportion of nonprogressing early stage AKI patients with spontaneous kidney recovery is a matter of severe concern because RRT has potentially lethal complications and is expensive. Moreover, these patients should be excluded from randomized trials. The furosemide stress test in critically ill patients with early stages of AKI serves as a novel tubular function test to identify those patients with severe and progressive AKI-D. Future trials to validate findings of a promising pilot study are warranted.

Discontinuation of renal replacement therapy in critically ill patients with severe acute kidney injury: predictive factors of renal function recovery.

INTRODUCTION: Severe acute kidney injury (AKI-D) is common in critically ill patients and contributes substantially to short- and long-term morbidity and mortality. Acute renal replacement therapy (RRT) is an increasingly widely utilized life-sustaining support strategy for AKI-D patients, providing a bridge to renal recovery in many survivors of AKI. However, key aspects (when and how) of this therapy's appropriate cessation remain unclear. Today, wide variation in clinical practice exists regarding the indication for and the timing of RTT discontinuation, likely due to the poor current evidence base. METHODS: Few studies have evaluated the process of weaning or ideal markers (clinical factors or parameters that may suggest renal recovery, such as urine output, urine chemistry, and creatinine clearance) to predict sufficient recovery of renal function following AKI and to avoid re-institution of RRT. However, translation of the current evidence to clinical practice is hampered by considerable limitations of the retrospective, post hoc secondary design of cohort studies, small sample sizes, heterogeneity across study populations and illness severity, variations of the thresholds of predictive markers and conflicting results for given markers. Currently, 24-h creatinine clearance greater than 20 ml/min combined with spontaneously decreasing serum creatinine concentrations in the context of fixed RRT and a clinically stable intensive care unit (ICU) patient may be the best predictor of recovery of excretory renal function. CONCLUSION: The decision regarding the appropriate time to wean acute RRT is complex, integrating numerous clinical variables and renal functional parameters. Cessation of RRT should largely be individualized in critically ill patients. Large randomized multicentre trials are needed to definitively answer the vitally important question of whether inappropriate discontinuation of RRT in ICU patients with AKI-D impacts patient outcomes. Future work should integrate novel kidney damage and repair biomarkers and techniques to measure real-time glomerular filtration rates.