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.

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.

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.

Persistent nasal methicillin-resistant staphylococcus aureus carriage in hemodialysis outpatients: a predictor of worse outcome.

BACKGROUND: Nasal colonization with methicillin-resistant Staphylococcus aureus (MRSA) is a well defined risk factor for subsequent bacteremia and death in various groups of patients, but its impact on outcome in patients receiving long-term hemodialysis (HD) is under debate. METHODS: This prospective interventional cohort study (performed 2004 to 2010) enrolled 289 HD outpatients of an urban dialysis-unit. Nasal swab cultures for MRSA were performed in all patients upon first admission, at transfer from another dialysis facility or readmission after hospitalisation. Nasal MRSA carriers were treated in a separate ward and received mupirocin nasal ointment. Concomitant extra-nasal MRSA colonization was treated with 0.2% chlorhexidine mouth rinse (throat) or octenidine dihydrochloride containing antiseptic soaps and 2% chlorhexidine body washes (skin). Clinical data and outcome of carriers and noncarriers were systematically analyzed. RESULTS: The screening approach identified 34 nasal MRSA carriers (11.7%). Extra-nasal MRSA colonization was observed in 11/34 (32%) nasal MRSA carriers. History of malignancy and an increased Charlson Comorbidity Index were significant predictors for nasal MRSA carriers, whereas traditional risk factors for MRSA colonization or markers of inflammation or malnutrition were not able to discriminate. Kaplan-Meier analysis demonstrated significant survival differences between MRSA carriers and noncarriers. Mupirocin ointment persistently eliminated nasal MRSA colonization in 26/34 (73.5%) patients. Persistent nasal MRSA carriers with failure of this eradication approach had an extremely poor prognosis with an all-cause mortality rate >85%. CONCLUSIONS: Nasal MRSA carriage with failure of mupirocin decolonization was associated with increased mortality despite a lack of overt clinical signs of infection. Further studies are needed to demonstrate whether nasal MRSA colonization represents a novel predictor of worse outcome or just another surrogate marker of the burden of comorbid diseases leading to fatal outcome in HD patients.

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.

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.

Erythropoiesis-stimulating agents, hypertension and left ventricular hypertrophy in the chronic kidney disease patient.

PURPOSE OF REVIEW: Left-ventricular hypertrophy (LVH) represents an important marker of cardiovascular morbidity and mortality. Numerous noninterventional studies in patients with chronic kidney disease (CKD) revealed a consistent relationship of LVH with modifiable risk factors attributable to failing renal function, particularly anemia and hypertension. RECENT FINDINGS: Given the clear role for anemia in initiating or accelerating LVH, it seems imperative to correct renal anemia with erythropoiesis-stimulating agents (ESAs). A few nonrandomized studies have described a regression of LVH with correction of anemia, but prospective randomized trials showed no evidence that ESA treatment is able to improve cardiac prognosis in the CKD patient. Current data alert physicians that normalization of hemoglobin in patients with advanced CKD is harmful. Recent studies are now trying to clarify the mechanisms for harm focussing on the influence of comorbidities, ESA doses, and hemoglobin variability. The pathogenesis of hypertension in CKD is multifactorial and only a small percentage of CKD patients have controlled their blood pressure, indicating poor medication adherence, insufficient control of volume overload and undertreatment. SUMMARY: This review provides an update of ESA treatment, hypertension and LVH in the CKD patient, indicating that pathogenesis of LVH in this population is currently not completely understood. In addition, the impact of pharmacological interventions targeted to prevent or reduce LVH in anemic or hypertensive CKD patients is not well defined. As adoption of the Framingham approach seems not feasible in the CKD patient, evidence from large-scale randomized clinical trials is mandatory to resolve this dilemma.

High-flux dialyzers, backfiltration, and dialysis fluid quality.

Currently, high-flux hemodialysis is the most common mode of dialysis therapy worldwide. Its steadily increasing use is largely based on the desire to reduce the excessively high morbidity and mortality of end-stage renal disease patients maintained on conventional dialysis (low-flux, mostly cellulosic membranes) by offering better biocompatibility and enhanced removal of uremic toxins. Two large randomized trials suggest a survival benefit for selected subgroups of high-flux dialysis patients such as diabetics, patients with hypoalbuminemia, or patients who have been on dialysis for a long period (>3.7 years). The major disadvantage of high-flux hemodialysis relates to the use of dialysis fluid, which is commonly not pure and may endanger patients treated with high-flux hemodialysis. Endotoxin fragments and other bacterial substances derived from bacteriologically contaminated dialysis fluid may, even at bacterial counts or endotoxin concentrations within the limits of accepted standards of dialysis fluid purity, enter from the dialysate into the patient's blood either by convective transfer (backfiltration) or by movement down the concentration gradient (backdiffusion). Repeated exposure of high-flux hemodialysis patients to backtransport of dialysate contaminants aggravates the uremia-associated inflammatory response syndrome and contributes to long-term morbidity. At present, the only solution to circumvent the risks of backtransport is the use of dry powder cartridges for bicarbonate concentrate and the use of bacteria- and endotoxin-retentive filters for the online production of ultrapure dialysis fluid. Use of ultrapure dialysis fluid (bacteria <0.1 CFU/ml and endotoxin <0.03 IU/ml) has been found to reduce inflammation and comorbidities in clinical investigations compared to commercial dialysis fluid. The European Renal Association and a number of national societies in Europe or in Japan strongly recommend the use of ultrapure dialysis for high-flux hemodialysis.

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.

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.

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.

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.