Identifying Candidate Protein Markers of Acute Kidney Injury in Acute Decompensated Heart Failure

One-quarter of patients with acute decompensated heart failure (ADHF) experience acute kidney injury (AKI)—an abrupt reduction or loss of kidney function associated with increased long-term mortality. There is a critical need to identify early and real-time markers of AKI in ADHF; however, to date, no protein biomarkers have exhibited sufficient diagnostic or prognostic performance for widespread clinical uptake. We aimed to identify novel protein biomarkers of AKI associated with ADHF by quantifying changes in protein abundance in the kidneys that occur during ADHF development and recovery in an ovine model. Relative quantitative protein profiling was performed using sequential window acquisition of all theoretical fragment ion spectra–mass spectrometry (SWATH–MS) in kidney cortices from control sheep (n = 5), sheep with established rapid-pacing-induced ADHF (n = 8), and sheep after ~4 weeks recovery from ADHF (n = 7). Of the 790 proteins quantified, we identified 17 candidate kidney injury markers in ADHF, 1 potential kidney marker of ADHF recovery, and 2 potential markers of long-term renal impairment (differential abundance between groups of 1.2–2.6-fold, adjusted p < 0.05). Among these 20 candidate protein markers of kidney injury were 6 candidates supported by existing evidence and 14 novel candidates not previously implicated in AKI. Proteins of differential abundance were enriched in pro-inflammatory signalling pathways: glycoprotein VI (activated during ADHF development; adjusted p < 0.01) and acute phase response (repressed during recovery from ADHF; adjusted p < 0.01). New biomarkers for the early detection of AKI in ADHF may help us to evaluate effective treatment strategies to prevent mortality and improve outcomes for patients.     

Longitudinal Analysis of Urinary Cytokines and Biomarkers in COVID-19 Patients with Subclinical Acute Kidney Injury

In hospitalized COVID-19 patients, disease progression leading to acute kidney injury (AKI) may be driven by immune dysregulation. We explored the role of urinary cytokines and their relationship with kidney stress biomarkers in COVID-19 patients before and after the development of AKI. Of 51 patients, 54.9% developed AKI. The principal component analysis indicated that in subclinical AKI, epidermal growth factor (EGF) and interferon (IFN)-α were associated with a lower risk of AKI, while interleukin-12 (IL-12) and macrophage inflammatory protein (MIP)-1β were associated with a higher risk of AKI. After the manifestation of AKI, EGF and IFN-α remained associated with a lower risk of AKI, while IL-1 receptor (IL-1R), granulocyte-colony stimulating factor (G-CSF), interferon-gamma-inducible protein 10 (IP-10) and IL-5 were associated with a higher risk of AKI. EGF had an inverse correlation with kidney stress biomarkers. Subclinical AKI was characterized by a significant up-regulation of kidney stress biomarkers and proinflammatory cytokines. The lack of EGF regenerative effects and IFN-α antiviral activity seemed crucial for renal disease progression. AKI involved a proinflammatory urinary cytokine storm.     

Extracellular Vesicles in Acute Kidney Injury and Clinical Applications

Acute kidney injury (AKI)––the sudden loss of kidney function due to tissue damage and subsequent progression to chronic kidney disease––has high morbidity and mortality rates and is a serious worldwide clinical problem. Current AKI diagnosis, which relies on measuring serum creatinine levels and urine output, cannot sensitively and promptly report on the state of damage. To address the shortcomings of these traditional diagnosis tools, several molecular biomarkers have been developed to facilitate the identification and ensuing monitoring of AKI. Nanosized membrane-bound extracellular vesicles (EVs) in body fluids have emerged as excellent sources for discovering such biomarkers. Besides this diagnostic purpose, EVs are also being extensively exploited to deliver therapeutic macromolecules to damaged kidney cells to ameliorate AKI. Consequently, many successful AKI biomarker findings and therapeutic applications based on EVs have been made. Here, we review our understanding of how EVs can help with the early identification and accurate monitoring of AKI and be used therapeutically. We will further discuss where current EV-based AKI diagnosis and therapeutic applications fall short and where future innovations could lead us.     

Acute Kidney Injury in COVID-19

COVID-19 is mainly considered a respiratory illness, but since SARS-CoV-2 uses the angiotensin converting enzyme 2 receptor (ACE2) to enter human cells, the kidney is also a target of the viral infection. Acute kidney injury (AKI) is the most alarming condition in COVID-19 patients. Recent studies have confirmed the direct entry of SARS-CoV-2 into the renal cells, namely podocytes and proximal tubular cells, but this is not the only pathomechanism of kidney damage. Hypovolemia, cytokine storm and collapsing glomerulopathy also play an important role. An increasing number of papers suggest a strong association between AKI development and higher mortality in COVID-19 patients, hence our interest in the matter. Although knowledge about the role of kidneys in SARS-CoV-2 infection is changing dynamically and is yet to be fully investigated, we present an insight into the possible pathomechanisms of AKI in COVID-19, its clinical features, risk factors, impact on hospitalization and possible ways for its management via renal replacement therapy.     

Oxidative Stress and Inflammatory Biomarkers for the Prediction of Severity and ICU Admission in Unselected Patients Hospitalized with COVID-19

Objective: We aimed to investigate the prognostic performances of oxidative stress (OS), inflammatory and cell activation biomarkers measured at admission in COVID-19 patients. Design: retrospective monocentric study. Setting: patients with suspected SARS-CoV-2 infection (COVID-19) admitted to the hospital. Patients: One hundred and sixty documented and unselected COVID-19-patients. Disease severity (from mild to critical) was scored according to NIH’s classification. Interventions: none. Measurements and main results: We measured OS biomarkers (thiol, advanced oxidation protein products (AOPP), ischemia-modified albumin (IMA)), inflammation biomarkers (interleukin-6 (IL-6), presepsin) and cellular activation biomarkers (calprotectin) in plasma at admission. Thiol concentrations decreased while IMA, IL-6, calprotectin and PSEP increased with disease severity in COVID-19 patients and were associated with increased O₂ needs and ICU admission. The best area under the receiver-operating-characteristics curve (AUC) for the prediction of ICU admission was for thiol (AUC = 0.762). A thiol concentration <154 µmol/L was predictive for ICU admission (79.7% sensitivity, 64.6% specificity, 58.8% positive predictive value, 78.9% negative predictive value). In a stepwise logistic regression, we found that being overweight, having dyspnoea, and thiol and IL-6 plasmatic concentrations were independently associated with ICU admission. In contrast, calprotectin was the best biomarker to predict mortality (AUC = 0.792), with an optimal threshold at 24.1 mg/L (94.1% sensitivity, 64.9% specificity, 97.1% positive predictive value and 98.9% negative predictive value), and survival curves indicated that high IL-6 and calprotectin concentrations were associated with a significantly increased risk of mortality. Conclusions: Thiol measurement at admission is a promising tool to predict ICU admission in COVID-19-patients, whereas IL-6 and calprotectin measurements effectively predict mortality.     

Predictive Ability of Procalcitonin for Acute Kidney Injury: A Narrative Review Focusing on the Interference of Infection

Acute kidney injury (AKI) is a common yet complicated clinical entity with high morbidity and mortality. An essential strategy to improve AKI patients’ prognoses is finding optimal biomarkers to identify AKI in a timely manner. Procalcitonin (PCT), a well-recognized biomarker for diagnosing infection and guiding antibiotics therapy, has been proposed to predict AKI development and recovery in many clinical settings. The current review provides comprehensive and updated information from relevant studies to evaluate PCT’s AKI-predictive ability and the influence of infection on this predictive ability. PCT has demonstrated optimal predictive ability for AKI in various populations irrespective of infection. However, the predictive ability seems to be blunted by infection since infection and inflammation have a more potent influence than AKI on PCT elevation. We furthermore explain the complicated association between elevated PCT levels and AKI in infection and inflammation situations and recommend directions for further investigations to clarify the essential issue. In conclusion, although conflicting data exist, serum PCT level is a potential biomarker for predicting AKI in many clinical settings regardless of infection. Nevertheless, further studies are warranted to clarify the association between PCT, infection, and AKI and to confirm the utilization of PCT for AKI prediction.     

Molecular Mechanisms and Biomarkers Associated with Chemotherapy-Induced AKI

Acute kidney injury (AKI) is a life-threatening condition characterized by a rapid and transient decrease in kidney function. AKI is part of an array of conditions collectively defined as acute kidney diseases (AKD). In AKD, persistent kidney damage and dysfunction lead to chronic kidney disease (CKD) over time. A variety of insults can trigger AKI; however, chemotherapy-associated nephrotoxicity is increasingly recognized as a significant side effect of chemotherapy. New biomarkers are urgently needed to identify patients at high risk of developing chemotherapy-associated nephrotoxicity and subsequent AKI. However, a lack of understanding of cellular mechanisms that trigger chemotherapy-related nephrotoxicity has hindered the identification of effective biomarkers to date. In this review, we aim to (1) describe the known and potential mechanisms related to chemotherapy-induced AKI; (2) summarize the available biomarkers for early AKI detection, and (3) raise awareness of chemotherapy-induced AKI.     

The Perspective of Vitamin D on suPAR-Related AKI in COVID-19

The coronavirus disease 2019 (COVID-19) pandemic has claimed the lives of millions of people around the world. Severe vitamin D deficiency can increase the risk of death in people with COVID-19. There is growing evidence that acute kidney injury (AKI) is common in COVID-19 patients and is associated with poorer clinical outcomes. The kidney effects of SARS-CoV-2 are directly mediated by angiotensin 2-converting enzyme (ACE2) receptors. AKI is also caused by indirect causes such as the hypercoagulable state and microvascular thrombosis. The increased release of soluble urokinase-type plasminogen activator receptor (suPAR) from immature myeloid cells reduces plasminogen activation by the competitive inhibition of urokinase-type plasminogen activator, which results in low plasmin levels and a fibrinolytic state in COVID-19. Frequent hypercoagulability in critically ill patients with COVID-19 may exacerbate the severity of thrombosis. Versican expression in proximal tubular cells leads to the proliferation of interstitial fibroblasts through the C3a and suPAR pathways. Vitamin D attenuates the local expression of podocyte uPAR and decreases elevated circulating suPAR levels caused by systemic inflammation. This decrease preserves the function and structure of the glomerular barrier, thereby maintaining renal function. The attenuated hyperinflammatory state reduces complement activation, resulting in lower serum C3a levels. Vitamin D can also protect against COVID-19 by modulating innate and adaptive immunity, increasing ACE2 expression, and inhibiting the renin–angiotensin–aldosterone system. We hypothesized that by reducing suPAR levels, appropriate vitamin D supplementation could prevent the progression and reduce the severity of AKI in COVID-19 patients, although the data available require further elucidation.     

Subclinical Acute Kidney Injury in COVID-19: Possible Mechanisms and Future Perspectives

Since the outbreak of COVID-19 disease, a bidirectional interaction between kidney disease and the progression of COVID-19 has been demonstrated. Kidney disease is an independent risk factor for mortality of patients with COVID-19 as well as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leading to the development of acute kidney injury (AKI) and chronic kidney disease (CKD) in patients with COVID-19. However, the detection of kidney damage in patients with COVID-19 may not occur until an advanced stage based on the current clinical blood and urinary examinations. Some studies have pointed out the development of subclinical acute kidney injury (subAKI) syndrome with COVID-19. This syndrome is characterized by significant tubule interstitial injury without changes in the estimated glomerular filtration rate. Despite the complexity of the mechanism(s) underlying the development of subAKI, the involvement of changes in the protein endocytosis machinery in proximal tubule (PT) epithelial cells (PTECs) has been proposed. This paper focuses on the data relating to subAKI and COVID-19 and the role of PTECs and their protein endocytosis machinery in its pathogenesis.     

Repeated Episodes of Ischemia/Reperfusion Induce Heme-Oxygenase-1 (HO-1) and Anti-Inflammatory Responses and Protects against Chronic Kidney Disease

Preconditioning episodes of ischemia/reperfusion (IR) induce protection against acute kidney injury (AKI), however their long-term effect still unknown. We evaluated AKI to chronic kidney disease (CKD) transition, after three-mild or three-severe episodes of IR. AKI was induced by single bilateral IR (1IR), or three episodes of IR separated by 10-day intervals (3IR) of mild (20 min) or severe (45 min) ischemia. Sham-operated rats served as controls. During 9-months, the 1IR group (20 or 45 min) developed CKD evidenced by progressive proteinuria and renal fibrosis. In contrast, the long-term adverse effects of AKI were markedly ameliorated in the 3IR group. The acute response in 3IR, contrasted with the 1IR group, that was characterized by an increment in heme oxygenase-1 (HO-1) and an anti-inflammatory response mediated by a NFkB-p65 phosphorylation and IL-6 decrease, together with an increase in TGF-β, and IL-10 expression, as well as in M2-macrophages. In addition, three episodes of IR downregulated endoplasmic reticulum (ER) stress markers expression, CHOP and BiP. Thus, repeated episodes of IR with 10-day intervals induced long-term renal protection accompanied with HO-1 overexpression and M2-macrophages increase.     

SARS-CoV-2 RNA Testing Using Different Assays—Impact on Testing Strategies in a Clinical Setting

In order to assess SARS-CoV-2 real time quantitative polymerase chain reaction (RT-qPCR) results in a real-life setting, three independent laboratories in Graz (Austria) set up a continuous cross comparison schedule. The following test systems were used: The QIAGEN NeuMoDx SARS-CoV-2 Assay, the Allplex™ 2019-nCoV Assay (Seegene) on a MicroLab Nimbus (Hamilton) platform combined with RealStar SARS-CoV-2 RT-PCR Assay (Altona Diagnostics GmbH), and the cobas SARS-CoV-2 test on a fully automated cobas 6800 system (Roche). A total of 200 samples were analysed, 184 (92%) were found to be concordant with all testing platforms, 14 (7%) discordant. Two (1%) samples tested invalid on a single platform and were excluded from further analysis. Discordant results were distributed randomly across the assays. The Ct values from all assays correlated closely with each other. All discordant samples showed Ct values ≥ 26. SARS-CoV-2 RT-qPCR assays may show considerable variability, especially in samples with low viral RNA concentrations. Decision makers should thus balance the advantages and disadvantages of RT-qPCR for mass screening and adopt suitable strategies that ensure a rational management of positive samples with high Ct values.     

Assessment of Renal Function in Head and Neck Cancer Patients Treated with Cisplatin: Different Biomarkers and Acute Kidney Injury Classifications

Cisplatin is associated with dose-limiting nephrotoxicity, and the timely detection of acute kidney injury (AKI) can affect morbimortality. Therefore, this study aimed to investigate the tools for monitoring renal function in AKI. This was a retrospective, cohort study. Cisplatin-treated patients with head and neck cancer were included. Nephrotoxicity was assessed using serum creatinine, estimated creatinine clearance, serum electrolytic alterations, and plasma kidney injury molecule-1 (KIM-1). The toxicity severity was classified according to Common Terminology Criteria for Adverse Events (CTCAE), and AKI was classified by Risk, Injury, Failure, Loss, and End-stage kidney disease (RIFLE) and Acute Kidney Injury Network (AKIN). A total of 81 participants were included, of whom only 32 did not have AKI. Almost 90% of participants had a decreased estimated glomerular filtration rate five (D5) days after chemotherapy. The AKI estimate differs between AKIN and RIFLE; more participants were diagnosed by the RIFLE at D5, 19.5% versus 2.4% by AKIN, and fifteen had a discordance between these classifications. All laboratory markers showed significant changes on D5. KIM-1 appeared a possible biomarker when considering CTCAE or AKIN classifications (p < 0.05 on D5), but not when RIFLE classification was used (p = 0.0780). Further studies may seek to understand the profiles of different biomarkers together.     

Kidney Injury in COVID-19: Epidemiology,Molecular Mechanisms and Potential Therapeutic Targets

As of December 2021, SARS-CoV-2 had caused over 250 million infections and 5 million deaths worldwide. Furthermore, despite the development of highly effective vaccines, novel variants of SARS-CoV-2 continue to sustain the pandemic, and the search for effective therapies for COVID-19 remains as urgent as ever. Though the primary manifestation of COVID-19 is pneumonia, the disease can affect multiple organs, including the kidneys, with acute kidney injury (AKI) being among the most common extrapulmonary manifestations of severe COVID-19. In this article, we start by reflecting on the epidemiology of kidney disease in COVID-19, which overwhelmingly demonstrates that AKI is common in COVID-19 and is strongly associated with poor outcomes. We also present emerging data showing that COVID-19 may result in long-term renal impairment and delve into the ongoing debate about whether AKI in COVID-19 is mediated by direct viral injury. Next, we focus on the molecular pathogenesis of SARS-CoV-2 infection by both reviewing previously published data and presenting some novel data on the mechanisms of cellular viral entry. Finally, we relate these molecular mechanisms to a series of therapies currently under investigation and propose additional novel therapeutic targets for COVID-19.     

Disruption of Kidney–Immune System Crosstalk in Sepsis with Acute Kidney Injury: Lessons Learned from Animal Models and Their Application to Human Health

In addition to being a leading cause of morbidity and mortality worldwide, sepsis is also the most common cause of acute kidney injury (AKI). When sepsis leads to the development of AKI, mortality increases dramatically. Since the cardinal feature of sepsis is a dysregulated host response to infection, a disruption of kidney–immune crosstalk is likely to be contributing to worsening prognosis in sepsis with acute kidney injury. Since immune-mediated injury to the kidney could disrupt its protein manufacturing capacity, an investigation of molecules mediating this crosstalk not only helps us understand the sepsis immune response, but also suggests that their supplementation could have a therapeutic effect. Erythropoietin, vitamin D and uromodulin are known to mediate kidney–immune crosstalk and their disrupted production could impact morbidity and mortality in sepsis with acute kidney injury.     

Update on Innate Immunity in Acute Kidney Injury—Lessons Taken from COVID-19

The serious clinical course of SARS-CoV-2 infection is usually accompanied by acute kidney injury (AKI), worsening prognosis and increasing mortality. AKI in COVID-19 is above all a consequence of systemic dysregulations leading to inflammation, thrombosis, vascular endothelial damage and necrosis. All these processes rely on the interactions between innate immunity elements, including circulating blood cells, resident renal cells, their cytokine products, complement systems, coagulation cascades and contact systems. Numerous simultaneous pathways of innate immunity should secure an effective host defense. Since they all form a network of cross-linked auto-amplification loops, uncontrolled activation is possible. When the actions of selected pathways amplify, cascade activation evades control and the propagation of inflammation and necrosis worsens, accompanied by complement overactivity and immunothrombosis. The systemic activation of innate immunity reaches the kidney, where the damage affecting single tubular cells spreads through tissue collateral damage and triggers AKI. This review is an attempt to synthetize the connections between innate immunity components engaged in COVID-19-related AKI and to summarize the knowledge on the pathophysiological background of processes responsible for renal damage.     

Cytokine Profiling in Different SARS-CoV-2 Genetic Variants

This study is a successor of our previous work concerning changes in the chemokine profile in infection that are associated with different SARS-CoV-2 genetic variants. The goal of our study was to take into account both the virus and the host immune system by assessing concentrations of cytokines in patients infected with different SARS-CoV-2 variants (ancestral Wuhan strain, Alpha, Delta and Omicron). Our study was performed on 340 biological samples taken from COVID-19 patients and healthy donors in the timespan between May 2020 and April 2022. We performed genotyping of the virus in nasopharyngeal swabs, which was followed by assessment of cytokines’ concentration in blood plasma. We noted that out of nearly 30 cytokines, only four showed stable elevation independently of the variant (IL-6, IL-10, IL-18 and IL-27), and we believe them to be ‘constant’ markers for COVID-19 infection. Cytokines that were studied as potential biomarkers lose their diagnostic value as the virus evolves, and the specter of potential targets for predictive models is narrowing. So far, only four cytokines (IL-6, IL-10, IL-18, and IL-27) showed a consistent rise in concentrations independently of the genetic variant of the virus. Although we believe our findings to be of scientific interest, we still consider them inconclusive; further investigation and comparison of immune responses to different variants of SARS-CoV-2 is required.     

Inhibition of Toll-Like Receptor 4 Signaling Mitigates Microvascular Loss but Not Fibrosis in a Model of Ischemic Acute Kidney Injury

The development of chronic kidney disease (CKD) following an episode of acute kidney injury (AKI) is an increasingly recognized clinical problem. Inhibition of toll-like receptor 4 (TLR4) protects renal function in animal models of AKI and has become a viable therapeutic strategy in AKI. However, the impact of TLR4 inhibition on the chronic sequelae of AKI is unknown. Consequently, we examined the chronic effects of TLR4 inhibition in a model of ischemic AKI. Mice with a TLR4-deletion on a C57BL/6 background and wild-type (WT) background control mice (C57BL/6) were subjected to bilateral renal artery clamping for 19 min and reperfusion for up to 6 weeks. Despite the acute protective effect of TLR4 inhibition on renal function (serum creatinine 1.6 ± 0.4 mg/dL TLR4-deletion vs. 2.8 ± 0.3 mg/dL·WT) and rates of tubular apoptosis following ischemic AKI, we found no difference in neutrophil or macrophage infiltration. Furthermore, we observed significant protection from microvascular rarefaction at six weeks following injury with TLR4-deletion, but this did not alter development of fibrosis. In conclusion, we validate the acute protective effect of TLR4 signal inhibition in AKI but demonstrate that this protective effect does not mitigate the sequential fibrogenic response in this model of ischemic AKI.