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New Pathogenetic Mechanisms and Therapeutic Challenges in Acute Kidney Injury

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Nephrology & Urology".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 41540

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Dr. Giuseppe Regolisti

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Nephrology Unit, Department of Medicine and Surgery, University of Parma, Via Gramsci 14, I-43100 Parma, Italy
Interests: electrolyte disorders; acid-base disorders; acute kidney injury; secondary hypertension

Special Issue Information

Dear Colleagues,

As acute kidney injury (AKI) complicates the clinical course of approximately 20% of hospitalized patients, is responsible for about 1.7 million deaths yearly, and confers an 8-fold greater risk of developing chronic kidney disease (CKD) with a 3-fold greater risk of end-stage kidney disease, it represents a formidable challenge for the healthcare system worldwide.

While no effective treatment is available at present, new data have emerged concerning prevention of AKI by reducing the risk associated with drugs, and immunomodulatory mechanisms associated with both the regeneration of tubular cells and the progression from AKI to CKD. In clinical research, big efforts have been devoted to improving strategies of renal replacement therapy (RRT) in patients with severe AKI. Among further fields of growing clinical interest, energy and protein deficits and malnutrition risk in the setting of AKI pose new challenges in the clinical management of these patients.

Thus, it is an exciting time for research in the field of AKI. This Special Issue of the Journal of Clinical Medicine will be devoted to providing a focused perspective in specific areas of investigation, with topics including but not limited to:

Risk of death and hospital readmission in patients surviving an AKI episode;
Pathophysiology of sepsis-induced AKI;
Pathogenetic mechanisms in the progression from AKI to CKD;
Biomarkers in AKI: do they have a clinical impact in early diagnosis and prognostic judgment?
Clinical outcomes of kidney transplantation from donors with AKI;
Timing of renal replacement therapy in critically ill patients with AKI: where are we now?
Renal replacement therapy in patients with septic AKI: is endotoxin/cytokine removal clinically effective?
Clinical impact of phosphate and magnesium depletion during sustained low-efficiency dialysis and continuous renal replacement therapies: do we have preventative tools?
Intermittent renal replacement therapies in critically ill patients with AKI;
Nutritional status evaluation in patients with AKI;
Nephrotoxicity of new oncologic drugs;
Electrolyte disorders in AKI;
Renal toxicity of radiocontrast media;
Pharmacokinetics of antibiotics in critically ill patients on prolonged intermittent renal replacement therapies.

Dr. Giuseppe Regolisti
Guest Editor

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Keywords

AKI
Biomarkers
Continuous renal replacement therapy
Chronic kidney disease
Clinical nutrition
Cytokines
Electrolyte disorders
Endotoxin
Extracellular vesicles
Immune system
Onconephrology
Prolonged intermittent renal replacement therapies

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Published Papers (11 papers)

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Research

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13 pages, 584 KiB

Open AccessArticle

SARS-CoV-2 Renal Impairment in Critical Care: An Observational Study of 42 Cases (Kidney COVID)

by Antoine-Marie Molina Barragan, Emmanuel Pardo, Pierre Galichon, Nicolas Hantala, Anne-Charlotte Gianinazzi, Lucie Darrivere, Eileen S. Tsai, Marc Garnier, Francis Bonnet, Fabienne Fieux and Franck Verdonk

J. Clin. Med. 2021, 10(8), 1571; https://doi.org/10.3390/jcm10081571 - 8 Apr 2021

Cited by 10 | Viewed by 2331

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to 5% to 16% hospitalization in intensive care units (ICU) and is associated with 23% to 75% of kidney impairments, including acute kidney injury (AKI). The current work aims to precisely characterize the renal impairment associated to SARS-CoV-2 in ICU patients. Forty-two patients consecutively admitted to the ICU of a French university hospital who tested positive for SARS-CoV-2 between 25 March 2020, and 29 April 2020, were included and classified in categories according to their renal function. Complete renal profiles and evolution during ICU stay were fully characterized in 34 patients. Univariate analyses were performed to determine risk factors associated with AKI. In a second step, we conducted a logistic regression model with inverse probability of treatment weighting (IPTW) analyses to assess major comorbidities as predictors of AKI. Thirty-two patients (94.1%) met diagnostic criteria for intrinsic renal injury with a mixed pattern of tubular and glomerular injuries within the first week of ICU admission, which lasted upon discharge. During their ICU stay, 24 patients (57.1%) presented AKI which was associated with increased mortality (p = 0.007), hemodynamic failure (p = 0.022), and more altered clearance at hospital discharge (p = 0.001). AKI occurrence was associated with lower pH (p = 0.024), higher PaCO₂ (CO₂ partial pressure in the arterial blood) (p = 0.027), PEEP (positive end-expiratory pressure) (p = 0.027), procalcitonin (p = 0.015), and CRP (C-reactive protein) (p = 0.045) on ICU admission. AKI was found to be independently associated with chronic kidney disease (adjusted OR (odd ratio) 5.97 (2.1–19.69), p = 0.00149). Critical SARS-CoV-2 infection is associated with persistent intrinsic renal injury and AKI, which is a risk factor of mortality. Mechanical ventilation settings seem to be a critical factor of kidney impairment. Full article

(This article belongs to the Special Issue New Pathogenetic Mechanisms and Therapeutic Challenges in Acute Kidney Injury)

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10 pages, 234 KiB

Open AccessArticle

The Impact of Allogeneic Hematopoietic Stem Cell Transplantation on Kidney Function in Children—A Single Center Experience

by Kinga Musiał, Krzysztof Kałwak and Danuta Zwolińska

J. Clin. Med. 2021, 10(5), 1113; https://doi.org/10.3390/jcm10051113 - 7 Mar 2021

Cited by 6 | Viewed by 1942

Abstract

Background: Knowledge about the impact of allogeneic hematopoietic stem cell transplantation (alloHSCT) on renal function in children is still limited. Objectives: The aim of the study was to evaluate kidney function in children undergoing alloHSCT, with special focus on differences between patients transplanted due to oncological and non-oncological indications. Materials and Methods: The data of 135 children undergoing alloHSCT were analyzed retrospectively. The serum creatinine and estimated glomerular filtration rate (eGFR) values were estimated before transplantation at 24 h; 1, 2, 3, 4 and 8 weeks; and 3 and 6 months after alloHSCT. Then, acute kidney injury (AKI) incidence was assessed. Results: Oncological children presented with higher eGFR values and more frequent hyperfiltration rates than non-oncological children before alloHSCT and until the 4th week after transplantation. The eGFR levels rose significantly after alloHSCT, returned to pre-transplant records after 2–3 weeks, and decreased gradually until the 6th month. AKI incidence was comparable in oncological and non-oncological patients. Conclusions: Children undergoing alloHSCT due to oncological and non-oncological reasons demonstrate the same risk of AKI, but oncological patients may be more prone to sustained renal injury. Serum creatinine and eGFR seem to be insufficient tools to assess kidney function in the early post-alloHSCT period, when hyperfiltration prevails, yet they reveal significant differences in long-term observation. Full article

(This article belongs to the Special Issue New Pathogenetic Mechanisms and Therapeutic Challenges in Acute Kidney Injury)

12 pages, 3596 KiB

Open AccessArticle

Role of C5aR1 and C5L2 Receptors in Ischemia-Reperfusion Injury

by Carlos Arias-Cabrales, Eva Rodriguez-Garcia, Javier Gimeno, David Benito, María José Pérez-Sáez, Dolores Redondo-Pachón, Anna Buxeda, Carla Burballa, Marta Crespo, Marta Riera and Julio Pascual

J. Clin. Med. 2021, 10(5), 974; https://doi.org/10.3390/jcm10050974 - 2 Mar 2021

Cited by 5 | Viewed by 2421

Abstract

The role of C5a receptors (C5aR1 and C5L2) in renal ischemia-reperfusion injury (IRI) is uncertain. We generated an in vitro model of hypoxia/reoxygenation with human proximal tubule epithelial cells to mimic some IRI events. C5aR1, membrane attack complex (MAC) and factor H (FH) deposits were evaluated with immunofluorescence. Quantitative polymerase chain reaction evaluated the expression of C5aR1, C5L2 genes as well as genes related to tubular injury, inflammation, and profibrotic pathways. Additionally, C5aR1 and C5L2 deposits were evaluated in kidney graft biopsies (KB) from transplant patients with delayed graft function (DGF, n = 12) and compared with a control group (n = 8). We observed higher immunofluorescence expression of C5aR1, MAC and FH as higher expression of genes related to tubular injury, inflammatory and profibrotic pathways and of C5aR1 in the hypoxic cells; whereas, C5L2 gene expression was unaffected by the hypoxic stimulus. Regarding KB, C5aR1 was detected in the apical and basal membrane of tubular epithelial cells, whereas C5L2 deposits were observed in endothelial cells of peritubular capillaries (PTC). DGF-KB showed more frequently diffuse C5aR1 staining and C5L2 compared to controls. In conclusion, C5aR1 expression is increased by hypoxia and IRI, both in vitro and in human biopsies with an acute injury. C5L2 expression in PTC could be related to endothelial cell damage during IRI. Full article

(This article belongs to the Special Issue New Pathogenetic Mechanisms and Therapeutic Challenges in Acute Kidney Injury)

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13 pages, 1349 KiB

Open AccessArticle

Independent Predictive Ability of Procalcitonin of Acute Kidney Injury among Critically Ill Patients

by Ya-Ting Huang, Min-Yu Lai, Wei-Chih Kan and Chih-Chung Shiao

J. Clin. Med. 2020, 9(6), 1939; https://doi.org/10.3390/jcm9061939 - 21 Jun 2020

Cited by 12 | Viewed by 2701

Abstract

It is unclear whether serum procalcitonin (PCT) levels rise in patients with acute kidney injury (AKI), and it is also unclear whether the elevation of PCT levels in this setting is independent of the existence of infection and impaired renal clearance. We conducted a retrospective study in a regional teaching hospital in Taiwan to evaluate the AKI-predictive ability of serum PCT among critically ill patients. We enrolled 330 patients (mean age, 70.5 ± 16.4 years; 57.0% men) who were admitted to the intensive care unit (ICU) from 1 July 2016, to 31 December 2016, and who had serum PCT measurement performed within 24 h after ICU admission. We used the generalized additive model and generalized linear model to evaluate the association of serum PCT levels and renal function variables. In addition, we used the multivariate logistic regression method to demonstrate serum PCT level as an independent predictor of AKI in both the non-infected patients (odds ratio (OR) = 1.38, 95% confidence interval (CI) = 1.12–1.71, p = 0.003) and the infected patients (OR = 1.23, 95% CI = 1.03–1.46, p = 0.020). In conclusion, serum PCT level at ICU admission is an independent predictor of developing AKI irrespective of infection among critically ill patients. Full article

(This article belongs to the Special Issue New Pathogenetic Mechanisms and Therapeutic Challenges in Acute Kidney Injury)

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12 pages, 810 KiB

Open AccessArticle

Liver Transplant Patients with High Levels of Preoperative Serum Ammonia Are at Increased Risk for Postoperative Acute Kidney Injury: A Retrospective Study

by Yoon Sook Lee, Yoon Ji Choi, Kyu Hee Park, Byeong Seon Park, Jung-Min Son, Ju Yeon Park, Hyun-Su Ri and Je Ho Ryu

J. Clin. Med. 2020, 9(6), 1629; https://doi.org/10.3390/jcm9061629 - 28 May 2020

Cited by 8 | Viewed by 2352

Abstract

Acute kidney injury (AKI) is one of the most frequent postoperative complications after liver transplantation (LT). Increased serum ammonia levels due to the liver disease itself may affect postoperative renal function. This study aimed to compare the incidence of postoperative AKI according to preoperative serum ammonia levels in patients after LT. Medical records from 436 patients who underwent LT from January 2010 to February 2020 in a single university hospital were retrospectively reviewed. The patients were then categorized according to changes in plasma creatinine concentrations within 48 h of LT using the Acute Kidney Injury Network criteria. A preoperative serum ammonia level above 45 mg/dL was associated with postoperative AKI (p < 0.0001). Even in patients with a normal preoperative creatinine level, when the ammonia level was greater than 45 μg/dL, the incidence of postoperative AKI was significantly higher (p < 0.0001); the AKI stage was also higher in this group than in the group with preoperative ammonia levels less than or equal to 45 μg/dL (p < 0.0001). Based on the results of our research, an elevation in preoperative serum ammonia levels above 45 μg/dL is related to postoperative AKI after LT. Full article

(This article belongs to the Special Issue New Pathogenetic Mechanisms and Therapeutic Challenges in Acute Kidney Injury)

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Review

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13 pages, 303 KiB

Open AccessReview

Acute Kidney Injury (AKI) before and after Kidney Transplantation: Causes, Medical Approach, and Implications for the Long-Term Outcomes

by Alessandra Palmisano, Ilaria Gandolfini, Marco Delsante, Chiara Cantarelli, Enrico Fiaccadori, Paolo Cravedi and Umberto Maggiore

J. Clin. Med. 2021, 10(7), 1484; https://doi.org/10.3390/jcm10071484 - 2 Apr 2021

Cited by 25 | Viewed by 5138

Abstract

Acute kidney injury (AKI) is a common finding in kidney donors and recipients. AKI in kidney donor, which increases the risk of delayed graft function (DGF), may not by itself jeopardize the short- and long-term outcome of transplantation. However, some forms of AKI may induce graft rejection, fibrosis, and eventually graft dysfunction. Therefore, various strategies have been proposed to identify conditions at highest risk of AKI-induced DGF, that can be treated by targeting the donor, the recipient, or even the graft itself with the use of perfusion machines. AKI that occurs early post-transplant after a period of initial recovery of graft function may reflect serious and often occult systemic complications that may require prompt intervention to prevent graft loss. AKI that develops long after transplantation is often related to nephrotoxic drug reactions. In symptomatic patients, AKI is usually associated with various systemic medical complications and could represent a risk of mortality. Electronic systems have been developed to alert transplant physicians that AKI has occurred in a transplant recipient during long-term outpatient follow-up. Herein, we will review most recent understandings of pathophysiology, diagnosis, therapeutic approach, and short- and long-term consequences of AKI occurring in both the donor and in the kidney transplant recipient. Full article

(This article belongs to the Special Issue New Pathogenetic Mechanisms and Therapeutic Challenges in Acute Kidney Injury)

15 pages, 314 KiB

Open AccessReview

Determinants of Outcomes of Acute Kidney Injury: Clinical Predictors and Beyond

by Emaad M. Abdel-Rahman, Faruk Turgut, Jitendra K. Gautam and Samir C. Gautam

J. Clin. Med. 2021, 10(6), 1175; https://doi.org/10.3390/jcm10061175 - 11 Mar 2021

Cited by 13 | Viewed by 2959

Abstract

Acute kidney injury (AKI) is a common clinical syndrome characterized by rapid impairment of kidney function. The incidence of AKI and its severe form AKI requiring dialysis (AKI-D) has been increasing over the years. AKI etiology may be multifactorial and is substantially associated with increased morbidity and mortality. The outcome of AKI-D can vary from partial or complete recovery to transitioning to chronic kidney disease, end stage kidney disease, or even death. Predicting outcomes of patients with AKI is crucial as it may allow clinicians to guide policy regarding adequate management of this problem and offer the best long-term options to their patients in advance. In this manuscript, we will review the current evidence regarding the determinants of AKI outcomes, focusing on AKI-D. Full article

(This article belongs to the Special Issue New Pathogenetic Mechanisms and Therapeutic Challenges in Acute Kidney Injury)

18 pages, 337 KiB

Open AccessReview

COVID-19 and the Kidney: A Worrisome Scenario of Acute and Chronic Consequences

by Luis Sanchez-Russo, Marzuq Billah, Jorge Chancay, Judy Hindi and Paolo Cravedi

J. Clin. Med. 2021, 10(5), 900; https://doi.org/10.3390/jcm10050900 - 25 Feb 2021

Cited by 7 | Viewed by 2950

Abstract

Acute kidney injury (AKI) is a common finding in patients with coronavirus disease 2019 (COVID-19) and has been associated with higher rates of death when compared to COVID-19 patients without kidney injury. Whereas the definitive pathogenesis of COVID-19-related AKI (CoV-AKI) is not clear, histopathologic evidence seems to point at multiple etiologies for the disease, including indirect and direct viral kidney injury. The high incidence of CoV-AKI, along with the aggressive clinical presentation of this entity, have increased the demands for kidney replacement therapies, rapidly overwhelming the supplies of healthcare systems even in major tertiary care centers. As a result, nephrologists have come up with alternatives to maximize the efficiency of treatments and have developed non-conventional therapeutic alternatives such as the implementation of acute peritoneal dialysis for critically ill patients. The long-term implications of CoV-AKI are yet unknown, though early studies suggest that around one third of the patients who survive will remain dependent on kidney replacement therapy. Nephrologists and healthcare workers need to be familiar with the clinical presentation and therapeutic challenges of CoV-AKI in order to develop strategies to mitigate the burden of the disease for patients, and for services providing kidney replacement therapies. Full article

(This article belongs to the Special Issue New Pathogenetic Mechanisms and Therapeutic Challenges in Acute Kidney Injury)

23 pages, 2091 KiB

Open AccessReview

SARS-CoV-2 and Viral Sepsis: Immune Dysfunction and Implications in Kidney Failure

by Alessandra Stasi, Giuseppe Castellano, Elena Ranieri, Barbara Infante, Giovanni Stallone, Loreto Gesualdo and Giuseppe Stefano Netti

J. Clin. Med. 2020, 9(12), 4057; https://doi.org/10.3390/jcm9124057 - 15 Dec 2020

Cited by 31 | Viewed by 6273

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causal agent of coronavirus disease 2019 (COVID-19), first emerged in Wuhan, China. The clinical manifestations of patients infected with COVID-19 include fever, cough, and dyspnea, up to acute respiratory distress syndrome (ARDS) and acute cardiac injury. Thus, a lot of severe patients had to be admitted to intensive care units (ICU). The pathogenic mechanisms of SARS-CoV-2 infection are mediated by the binding of SARS-CoV-2 spikes to the human angiotensin-converting enzyme 2 (ACE-2) receptor. The overexpression of human ACE-2 is associated with the disease severity in SARS-CoV-2 infection, demonstrating that viral entry into cells is a pivotal step. Although the lung is the organ that is most commonly affected by SARS-CoV-2 infection, acute kidney injury (AKI), heart dysfunction and abdominal pain are the most commonly reported co-morbidities of COVID-19. The occurrence of AKI in COVID-19 patients might be explained by several mechanisms that include viral cytopathic effects in renal cells and the host hyperinflammatory response. In addition, kidney dysfunction could exacerbate the inflammatory response started in the lungs and might cause further renal impairment and multi-organ failure. Mounting recent evidence supports the involvement of cardiovascular complications and endothelial dysfunction in COVID-19 syndrome, in addition to respiratory disease. To date, there is no vaccine, and no specific antiviral medicine has been shown to be effective in preventing or treating COVID-19. The removal of pro-inflammatory cytokines and the shutdown of the cytokine storm could ameliorate the clinical outcome in severe COVID-19 cases. Therefore, several interventions that inhibit viral replication and the systemic inflammatory response could modulate the severity of the renal dysfunction and increase the probability of a favorable outcome. Full article

(This article belongs to the Special Issue New Pathogenetic Mechanisms and Therapeutic Challenges in Acute Kidney Injury)

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23 pages, 908 KiB

Open AccessReview

Molecular Mechanisms of AKI in the Elderly: From Animal Models to Therapeutic Intervention

by Barbara Infante, Rossana Franzin, Desirèe Madio, Martina Calvaruso, Annamaria Maiorano, Fabio Sangregorio, Giuseppe Stefano Netti, Elena Ranieri, Loreto Gesualdo, Giuseppe Castellano and Giovanni Stallone

J. Clin. Med. 2020, 9(8), 2574; https://doi.org/10.3390/jcm9082574 - 8 Aug 2020

Cited by 24 | Viewed by 5949

Abstract

Acute kidney injury (AKI), a critical syndrome characterized by a sudden reduction of renal function, is a common disorder among elderly patients particularly in Intensive Care Unit (ICU). AKI is closely associated with both short- and long-term mortality and length of hospital stay and is considered a predictor of chronic kidney disease (CKD). Specific hemodynamic, metabolic, and molecular changes lead to increased susceptibility to injury in the aged kidney; therefore, certain causes of AKI such as the prerenal reduction in renal perfusion or vascular obstructive conditions are more common in the elderly; moreover, AKI is often multifactorial and iatrogenic. Older patients present several comorbidities (diabetes, hypertension, heart failure) and are exposed to multiple medical interventions such as the use of nephrotoxic contrasts media and medications, which can also trigger AKI. Considering the emerging relevance of this condition, prevention and treatment of AKI in the elderly should be crucial in the internist and emergency setting. This review article summarizes the incidence, the risk factors, the pathophysiology, the molecular mechanisms and the strategies of prevention and treatment of AKI in elderly patients. Full article

(This article belongs to the Special Issue New Pathogenetic Mechanisms and Therapeutic Challenges in Acute Kidney Injury)

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43 pages, 1336 KiB

Open AccessReview

Current Concepts on the Reno-Protective Effects of Phosphodiesterase 5 Inhibitors in Acute Kidney Injury: Systematic Search and Review

by Georgios Georgiadis, Ioannis-Erineos Zisis, Anca Oana Docea, Konstantinos Tsarouhas, Irene Fragkiadoulaki, Charalampos Mavridis, Markos Karavitakis, Stavros Stratakis, Kostas Stylianou, Christina Tsitsimpikou, Daniela Calina, Nikolaos Sofikitis, Aristidis Tsatsakis and Charalampos Mamoulakis

J. Clin. Med. 2020, 9(5), 1284; https://doi.org/10.3390/jcm9051284 - 29 Apr 2020

Cited by 33 | Viewed by 5241

Abstract

Acute kidney injury (AKI) is associated with increased morbidity, prolonged hospitalization, and mortality, especially in high risk patients. Phosphodiesterase 5 inhibitors (PDE5Is), currently available as first-line therapy of erectile dysfunction in humans, have shown a beneficial potential of reno-protection through various reno-protective mechanisms. The aim of this work is to provide a comprehensive overview of the available literature on the reno-protective properties of PDE5Is in the various forms of AKI. Medline was systematically searched from 1946 to November 2019 to detect all relevant animal and human studies in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. In total, 83 studies were included for qualitative synthesis. Sildenafil is the most widely investigated compound (42 studies), followed by tadalafil (20 studies), icariin (10 studies), vardenafil (7 studies), zaprinast (4 studies), and udenafil (2 studies). Even though data are limited, especially in humans with inconclusive or negative results of only two clinically relevant studies available at present, the results of animal studies are promising. The reno-protective action of PDE5Is was evident in the vast majority of studies, independently of the AKI type and the agent applied. PDE5Is appear to improve the renal functional/histopathological alternations of AKI through various mechanisms, mainly by affecting regional hemodynamics, cell expression, and mitochondrial response to oxidative stress and inflammation. Full article

(This article belongs to the Special Issue New Pathogenetic Mechanisms and Therapeutic Challenges in Acute Kidney Injury)

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