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14 pages, 9861 KiB

Open AccessArticle

Systemic Human Neutrophil Lipocalin Associates with Severe Acute Kidney Injury in SARS-CoV-2 Pneumonia

by Sara Bülow Anderberg, Miklos Lipcsey, Michael Hultström, Ann-Katrin Eriksson, Per Venge, Robert Frithiof and on behalf of the Uppsala Intensive Care COVID-19 Research Group

J. Clin. Med. 2021, 10(18), 4144; https://doi.org/10.3390/jcm10184144 - 14 Sep 2021

Cited by 5 | Viewed by 2585

Abstract

Neutrophils have been suggested mediators of organ dysfunction in COVID-19. The current study investigated if systemic neutrophil activity, estimated by human neutrophil lipocalin (HNL) concentration in peripheral blood, is associated with acute kidney injury (AKI) development. A total of 103 adult patients admitted [...] Read more.

Neutrophils have been suggested mediators of organ dysfunction in COVID-19. The current study investigated if systemic neutrophil activity, estimated by human neutrophil lipocalin (HNL) concentration in peripheral blood, is associated with acute kidney injury (AKI) development. A total of 103 adult patients admitted to intensive care, with PCR-confirmed SARS-CoV-2 infection, were prospectively included (Clinical Trials ID: NCT04316884). HNL was analyzed in plasma (P-HNL Dimer) and in whole blood (B-HNL). The latter after ex vivo activation with N-formyl-methionine-leucine-phenylalanine. All patients developed respiratory dysfunction and 62 (60%) were treated with invasive ventilation. Sixty-seven patients (65%) developed AKI, 18 (17%) progressed to AKI stage 3, and 14 (14%) were treated with continuous renal replacement therapy (CRRT). P-HNL Dimer was higher in patients with invasive ventilation, vasopressors, AKI, AKI stage 3, dialysis, and 30-day mortality (p < 0.001–0.046). B-HNL performed similarly with the exception of mild AKI and mortality (p < 0.001–0.004). The cohort was dichotomized by ROC estimated cutoff concentrations of 13.2 µg/L and 190 µg/L for P-HNL Dimer and B-HNL respectively. Increased cumulative risks for AKI, AKI stage 3, and death were observed if above the P-HNL cutoff and for AKI stage 3 if above the B-HNL cutoff. The relative risk of developing AKI stage 3 was nine and 39 times greater if above the cutoffs in plasma and whole blood, respectively, for CRRT eight times greater for both. In conclusion, systemically elevated neutrophil lipocalin, interpreted as increased neutrophil activity, was shown to be associated with an increased risk of severe AKI, renal replacement therapy, and mortality in COVID-19 patients with respiratory failure. Full article

(This article belongs to the Special Issue The New Therapeutic Targets in Acute Kidney Injury)

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13 pages, 2186 KiB

Open AccessArticle

Systematic Scoring of Tubular Injury Patterns Reveals Interplay between Distinct Tubular and Glomerular Lesions in ANCA-Associated Glomerulonephritis

by Samy Hakroush, Désirée Tampe, Peter Korsten, Philipp Ströbel and Björn Tampe

J. Clin. Med. 2021, 10(12), 2682; https://doi.org/10.3390/jcm10122682 - 18 Jun 2021

Cited by 12 | Viewed by 2747

Abstract

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small vessel vasculitis, most frequently presenting as microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA). Acute tubular injury with the presence of tubulitis was previously reported to be of prognostic value in ANCA glomerulonephritis [...] Read more.

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small vessel vasculitis, most frequently presenting as microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA). Acute tubular injury with the presence of tubulitis was previously reported to be of prognostic value in ANCA glomerulonephritis (GN). In particular, distinct tubular injury lesions were associated with the deterioration of kidney function at AAV disease onset, as well as renal resistance to treatment, and higher risk of progression to composite outcome in patients with AAV. To expand our knowledge regarding distinct tubular lesions in AAV, we aimed to describe acute tubular injury patterns in association with glomerular lesions in ANCA GN by systematic histological scoring. Methods: A total number of 48 renal biopsies with confirmed renal involvement of AAV admitted to the University Medical Center Göttingen from 2015 to 2020 were retrospectively examined. By systematic scoring of tubular injury lesions, the association between clinical parameters, laboratory markers, and histopathological findings was explored. Results: We have shown that cellular casts in renal biopsies were frequently observed in the majority of cases with ANCA GN. Furthermore, we showed that tubular epithelial simplification with dilatation correlated with MPA and MPO subtypes, C3c hypocomplementemia, severe renal involvement, and uACR. Red blood cell (RBC) casts were associated with increased levels of C-reactive protein (CRP), leukocyturia, and hematuria. Finally, we found that hyaline casts were associated with an increased fraction of glomeruli with global glomerular sclerosis. Conclusions: Acute tubular injury patterns were correlated with active ANCA GN, whereas tubular injury lesions reflecting the later stages of kidney disease correlated with chronic glomerular lesions. These results suggest an interplay between different renal compartments. Full article

(This article belongs to the Special Issue The New Therapeutic Targets in Acute Kidney Injury)

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Review

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30 pages, 1022 KiB

Open AccessReview

Is the Sympathetic System Detrimental in the Setting of Septic Shock, with Antihypertensive Agents as a Counterintuitive Approach? A Clinical Proposition

by Fabrice Petitjeans, Alain Geloen, Cyrille Pichot, Sandrine Leroy, Marco Ghignone and Luc Quintin

J. Clin. Med. 2021, 10(19), 4569; https://doi.org/10.3390/jcm10194569 - 1 Oct 2021

Cited by 6 | Viewed by 3005

Abstract

Mortality in the setting of septic shock varies between 20% and 100%. Refractory septic shock leads to early circulatory failure and carries the worst prognosis. The pathophysiology is poorly understood despite studies of the microcirculatory defects and the immuno-paralysis. The acute circulatory distress [...] Read more.

Mortality in the setting of septic shock varies between 20% and 100%. Refractory septic shock leads to early circulatory failure and carries the worst prognosis. The pathophysiology is poorly understood despite studies of the microcirculatory defects and the immuno-paralysis. The acute circulatory distress is treated with volume expansion, administration of vasopressors (usually noradrenaline: NA), and inotropes. Ventilation and anti-infectious strategy shall not be discussed here. When circulation is considered, the literature is segregated between interventions directed to the systemic circulation vs. interventions directed to the micro-circulation. Our thesis is that, after stabilization of the acute cardioventilatory distress, the prolonged sympathetic hyperactivity is detrimental in the setting of septic shock. Our hypothesis is that the sympathetic hyperactivity observed in septic shock being normalized towards baseline activity will improve the microcirculation by recoupling the capillaries and the systemic circulation. Therefore, counterintuitively, antihypertensive agents such as beta-blockers or alpha-2 adrenergic agonists (clonidine, dexmedetomidine) are useful. They would reduce the noradrenaline requirements. Adjuncts (vitamins, steroids, NO donors/inhibitors, etc.) proposed to normalize the sepsis-evoked vasodilation are not reviewed. This itemized approach (systemic vs. microcirculation) requires physiological and epidemiological studies to look for reduced mortality. Full article

(This article belongs to the Special Issue The New Therapeutic Targets in Acute Kidney Injury)

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16 pages, 1130 KiB

Open AccessReview

Metabolic Reprogramming and Host Tolerance: A Novel Concept to Understand Sepsis-Associated AKI

by Juan Toro, Carlos L. Manrique-Caballero and Hernando Gómez

J. Clin. Med. 2021, 10(18), 4184; https://doi.org/10.3390/jcm10184184 - 16 Sep 2021

Cited by 20 | Viewed by 3341

Abstract

Acute kidney injury (AKI) is a frequent complication of sepsis that increases mortality and the risk of progression to chronic kidney disease. However, the mechanisms leading to sepsis-associated AKI are still poorly understood. The recognition that sepsis induces organ dysfunction in the absence [...] Read more.

Acute kidney injury (AKI) is a frequent complication of sepsis that increases mortality and the risk of progression to chronic kidney disease. However, the mechanisms leading to sepsis-associated AKI are still poorly understood. The recognition that sepsis induces organ dysfunction in the absence of overt necrosis or apoptosis has led to the consideration that tubular epithelial cells (TEC) may deploy defense mechanisms to survive the insult. This concept dovetails well with the notion that the defense against infection does not only depend on the capacity of the immune system to limit the microbial load (known as resistance), but also on the capacity of cells and tissues to limit tissue injury (known as tolerance). In this review, we discuss the importance of TEC metabolic reprogramming as a defense strategy during sepsis, and how this cellular response is likely to operate through a tolerance mechanism. We discuss the fundamental role of specific regulatory nodes and of mitochondria in orchestrating this response, and how this opens avenues for the exploration of targeted therapeutic strategies to prevent or treat sepsis-associated AKI. Full article

(This article belongs to the Special Issue The New Therapeutic Targets in Acute Kidney Injury)

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19 pages, 1866 KiB

Open AccessReview

Kidney Microcirculation as a Target for Innovative Therapies in AKI

by Bülent Ergin, Sakir Akin and Can Ince

J. Clin. Med. 2021, 10(18), 4041; https://doi.org/10.3390/jcm10184041 - 7 Sep 2021

Cited by 9 | Viewed by 4014

Abstract

Acute kidney injury (AKI) is a serious multifactorial conditions accompanied by the loss of function and damage. The renal microcirculation plays a crucial role in maintaining the kidney’s functional and structural integrity for oxygen and nutrient supply and waste product removal. However, alterations [...] Read more.

Acute kidney injury (AKI) is a serious multifactorial conditions accompanied by the loss of function and damage. The renal microcirculation plays a crucial role in maintaining the kidney’s functional and structural integrity for oxygen and nutrient supply and waste product removal. However, alterations in microcirculation and oxygenation due to renal perfusion defects, hypoxia, renal tubular, and endothelial damage can result in AKI and the loss of renal function regardless of systemic hemodynamic changes. The unique structural organization of the renal microvasculature and the presence of autoregulation make it difficult to understand the mechanisms and the occurrence of AKI following disorders such as septic, hemorrhagic, or cardiogenic shock; ischemia/reperfusion; chronic heart failure; cardiorenal syndrome; and hemodilution. In this review, we describe the organization of microcirculation, autoregulation, and pathophysiological alterations leading to AKI. We then suggest innovative therapies focused on the protection of the renal microcirculation and oxygenation to prevent AKI. Full article

(This article belongs to the Special Issue The New Therapeutic Targets in Acute Kidney Injury)

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16 pages, 593 KiB

Open AccessReview

Targeting Mitochondria and Metabolism in Acute Kidney Injury

by Ying Li, Mark Hepokoski, Wanjun Gu, Tatum Simonson and Prabhleen Singh

J. Clin. Med. 2021, 10(17), 3991; https://doi.org/10.3390/jcm10173991 - 3 Sep 2021

Cited by 24 | Viewed by 3973

Abstract

Acute kidney injury (AKI) significantly contributes to morbidity and mortality in critically ill patients. AKI is also an independent risk factor for the development and progression of chronic kidney disease. Effective therapeutic strategies for AKI are limited, but emerging evidence indicates a prominent [...] Read more.

Acute kidney injury (AKI) significantly contributes to morbidity and mortality in critically ill patients. AKI is also an independent risk factor for the development and progression of chronic kidney disease. Effective therapeutic strategies for AKI are limited, but emerging evidence indicates a prominent role of mitochondrial dysfunction and altered tubular metabolism in the pathogenesis of AKI. Therefore, a comprehensive, mechanistic understanding of mitochondrial function and renal metabolism in AKI may lead to the development of novel therapies in AKI. In this review, we provide an overview of current state of research on the role of mitochondria and tubular metabolism in AKI from both pre-clinical and clinical studies. We also highlight current therapeutic strategies which target mitochondrial function and metabolic pathways for the treatment of AKI. Full article

(This article belongs to the Special Issue The New Therapeutic Targets in Acute Kidney Injury)

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18 pages, 507 KiB

Open AccessReview

Acute Kidney Injury in Monoclonal Gammopathies

by Paolo Menè, Alessandra Moioli, Antonella Stoppacciaro, Silvia Lai and Francescaromana Festuccia

J. Clin. Med. 2021, 10(17), 3871; https://doi.org/10.3390/jcm10173871 - 28 Aug 2021

Cited by 5 | Viewed by 3523

Abstract

Monoclonal gammopathies (MG) encompass a variety of disorders related to clonal expansion and/or malignant transformation of B lymphocytes. Deposition of free immunoglobulin (Ig) components (light or heavy chains, LC/HC) within the kidney during MG may result over time in multiple types and degrees [...] Read more.

Monoclonal gammopathies (MG) encompass a variety of disorders related to clonal expansion and/or malignant transformation of B lymphocytes. Deposition of free immunoglobulin (Ig) components (light or heavy chains, LC/HC) within the kidney during MG may result over time in multiple types and degrees of injury, including acute kidney injury (AKI). AKI is generally a consequence of tubular obstruction by luminal aggregates of LC, a pattern known as “cast nephropathy”. Monoclonal Ig LC can also be found as intracellular crystals in glomerular podocytes or proximal tubular cells. Proliferative glomerulonephritis with monoclonal Ig deposits is another, less frequent form of kidney injury with a sizable impact on renal function. Hypercalcemia (in turn related to bone reabsorption triggered by proliferating plasmacytoid B cells) may lead to AKI via functional mechanisms. Pharmacologic treatment of MG may also result in additional renal injury due to local toxicity or the tumor lysis syndrome. The present review focuses on AKI complicating MG, evaluating predictors, risk factors, mechanisms of damage, prognosis, and options for treatment. Full article

(This article belongs to the Special Issue The New Therapeutic Targets in Acute Kidney Injury)

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17 pages, 1831 KiB

Open AccessReview

Targeting Oxidative Stress in Septic Acute Kidney Injury: From Theory to Practice

by Connie P. C. Ow, Anton Trask-Marino, Ashenafi H. Betrie, Roger G. Evans, Clive N. May and Yugeesh R. Lankadeva

J. Clin. Med. 2021, 10(17), 3798; https://doi.org/10.3390/jcm10173798 - 25 Aug 2021

Cited by 41 | Viewed by 5631

Abstract

Sepsis is the leading cause of acute kidney injury (AKI) and leads to increased morbidity and mortality in intensive care units. Current treatments for septic AKI are largely supportive and are not targeted towards its pathophysiology. Sepsis is commonly characterized by systemic inflammation [...] Read more.

Sepsis is the leading cause of acute kidney injury (AKI) and leads to increased morbidity and mortality in intensive care units. Current treatments for septic AKI are largely supportive and are not targeted towards its pathophysiology. Sepsis is commonly characterized by systemic inflammation and increased production of reactive oxygen species (ROS), particularly superoxide. Concomitantly released nitric oxide (NO) then reacts with superoxide, leading to the formation of reactive nitrogen species (RNS), predominantly peroxynitrite. Sepsis-induced ROS and RNS can reduce the bioavailability of NO, mediating renal microcirculatory abnormalities, localized tissue hypoxia and mitochondrial dysfunction, thereby initiating a propagating cycle of cellular injury culminating in AKI. In this review, we discuss the various sources of ROS during sepsis and their pathophysiological interactions with the immune system, microcirculation and mitochondria that can lead to the development of AKI. We also discuss the therapeutic utility of N-acetylcysteine and potential reasons for its efficacy in animal models of sepsis, and its inefficacy in ameliorating oxidative stress-induced organ dysfunction in human sepsis. Finally, we review the pre-clinical studies examining the antioxidant and pleiotropic actions of vitamin C that may be of benefit for mitigating septic AKI, including future implications for clinical sepsis. Full article

(This article belongs to the Special Issue The New Therapeutic Targets in Acute Kidney Injury)

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18 pages, 866 KiB

Open AccessReview

Angiotensin-(1-7)—A Potential Remedy for AKI: Insights Derived from the COVID-19 Pandemic

by Samuel N. Heyman, Thomas Walther and Zaid Abassi

J. Clin. Med. 2021, 10(6), 1200; https://doi.org/10.3390/jcm10061200 - 13 Mar 2021

Cited by 24 | Viewed by 4457

Abstract

Membrane-bound angiotensin converting enzyme (ACE) 2 serves as a receptor for the Sars-CoV-2 spike protein, permitting viral attachment to target host cells. The COVID-19 pandemic brought into light ACE2, its principal product angiotensin (Ang) 1-7, and the G protein-coupled receptor for the heptapeptide [...] Read more.

Membrane-bound angiotensin converting enzyme (ACE) 2 serves as a receptor for the Sars-CoV-2 spike protein, permitting viral attachment to target host cells. The COVID-19 pandemic brought into light ACE2, its principal product angiotensin (Ang) 1-7, and the G protein-coupled receptor for the heptapeptide (MasR), which together form a still under-recognized arm of the renin–angiotensin system (RAS). This axis counteracts vasoconstriction, inflammation and fibrosis, generated by the more familiar deleterious arm of RAS, including ACE, Ang II and the ang II type 1 receptor (AT1R). The COVID-19 disease is characterized by the depletion of ACE2 and Ang-(1-7), conceivably playing a central role in the devastating cytokine storm that characterizes this disorder. ACE2 repletion and the administration of Ang-(1-7) constitute the therapeutic options currently tested in the management of severe COVID-19 disease cases. Based on their beneficial effects, both ACE2 and Ang-(1-7) have also been suggested to slow the progression of experimental diabetic and hypertensive chronic kidney disease (CKD). Herein, we report a further step undertaken recently, utilizing this type of intervention in the management of evolving acute kidney injury (AKI), with the expectation of renal vasodilation and the attenuation of oxidative stress, inflammation, renal parenchymal damage and subsequent fibrosis. Most outcomes indicate that triggering the ACE2/Ang-(1-7)/MasR axis may be renoprotective in the setup of AKI. Yet, there is contradicting evidence that under certain conditions it may accelerate renal damage in CKD and AKI. The nature of these conflicting outcomes requires further elucidation. Full article

(This article belongs to the Special Issue The New Therapeutic Targets in Acute Kidney Injury)

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