Sepsis-Associated Acute Kidney Injury

doi:10.1016/j.semnephrol.2015.01.002

Seminars in Nephrology

Volume 35, Issue 1, January 2015, Pages 2-11

https://doi.org/10.1016/j.semnephrol.2015.01.002 Get rights and content

Summary

Acute kidney injury (AKI) is an epidemic problem. Sepsis has long been recognized as a foremost precipitant of AKI. Sepsis-associated AKI (SA-AKI) portends a high burden of morbidity and mortality in both children and adults with critical illness. Although our understanding of its pathophysiology is incomplete, SA-AKI likely represents a distinct subset of AKI contributed to by a unique constellation of hemodynamic, inflammatory, and immune mechanisms. SA-AKI poses significant clinical challenges for clinicians. To date, no singular effective therapy has been developed to alter the natural history of SA-AKI. Rather, current strategies to alleviate poor outcomes focus on clinical risk identification, early detection of injury, modifying clinician behavior to avoid harm, early appropriate antimicrobial therapy, and surveillance among survivors for the longer-term sequelae of kidney damage. Recent evidence has confirmed that patients no longer die with AKI, but from AKI. To improve the care and outcomes for sufferers of SA-AKI, clinicians need a robust appreciation for its epidemiology and current best-evidence strategies for prevention and treatment.

Section snippets

General Epidemiology

Sepsis-associated AKI occurs at a high incidence rate in critically ill patients (Table 1). A large study from 57 adult ICUs in Australia and New Zealand identified SA-AKI in 11.7% of 120,123 patients.²⁴ The Beginning, Ending Supportive Therapy for the Kidney, a large prospective observational study of more than 29,000 patients, reported an AKI incidence of 5.7%, with SA-AKI being the highest associated etiology (47.5%).²⁵ Analysis of 276,731 admissions to 170 adult critical care units of the

Severity of Illness

Compared with nonseptic AKI, SA-AKI is associated with a higher acuity of illness. Patients with more severe AKI by RIFLE criteria were more likely to have Acute Physiology and Chronic Health Evaluation II (APACHE II) scores higher than 45 (Risk, 45%; Failure, 70%).²⁹ Similarly, sequential organ failure assessment scores were found to be higher in patients with SA-AKI compared with nonseptic AKI.²⁵ Compared with nonseptic AKI, SA-AKI patients have more abnormalities in markers of inflammation

Timing of SA-AKI

Observational data suggest that injury during SA-AKI occurs early in the course of critical illness and after ICU admission. Separate studies have reported that AKI occurred within 24 hours of ICU admission for adult patients with sepsis.29, 45 In a large recent cohort, 68% of 5,443 patients with septic shock had evidence of AKI within 6 hours after presentation.⁴⁶

Patients who showed evidence of kidney function recovery or improvement in their RIFLE category within 24 hours after presentation

General Pathophysiology

Our current understanding of the pathophysiology driving AKI mediated by sepsis is incomplete47, 48 (Fig. 1). Sepsis-mediated hypoperfusion leading to tubular necrosis traditionally has been cited as the primary pathophysiology for SA-AKI, however, mounting evidence has challenged this paradigm.49, 50 Numerous drivers for injury now are recognized as playing a role in SA-AKI, including ischemia-reperfusion injury to the glomerulus, inflammation of specific parts of the nephron, hypoxic and/or

Risk Recognition and Early Diagnosis

The severity of injury and poor outcomes associated with SA-AKI worsen with delayed recognition of injury. Because no singular effective therapy has been uncovered, early initiation of supportive care targeting the drivers of injury are the mainstays of therapy. The activation of such support relies on risk recognition and early diagnosis of injury. Urinary indices and urine biochemistry, traditionally used to classify AKI, are inadequate to delineate subtypes of AKI during sepsis. In a study

Conclusions

AKI is a significant clinical challenge for clinicians. Although SA-AKI is likely a unique subset of all AKI, our capability to effectively intervene therapeutically has been paralyzed largely by an incomplete understanding of its complex pathophysiology. The preponderance of evidence imply that SA-AKI contributes to a high burden of morbidity and mortality in both children and adults with critical illness. To date, no singular effective therapy has been developed to alter its natural history.

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Cited by (253)

The effects of antibiotic therapy on neonatal sepsis-associated acute kidney injury
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Neonatal sepsis remains one of the most dangerous conditions in the neonatal intensive care units. One of the organs affected by sepsis is the kidney, making acute kidney injury (AKI) a common complication of sepsis. Treatment of sepsis almost always involves antibiotic therapy, which by itself may cause some adverse effects, including nephrotoxicity. We analyzed the mutual effect of antibiotic therapy and sepsis on AKI in an experimental and clinical study in infants and neonatal rats.
We evaluated the influence of therapy with different antibiotics on the appearance of AKI markers (blood urea nitrogen (BUN), neutrophil gelatinase-associated lipocalin (NGAL), clusterin, interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), monocyte chemoattractant protein 1 (MCP-1), calbindin, glutation-S-transferase subtype π (GST-π)) and liver injury markers in newborns with or without clinical signs of sepsis in the intensive care unit. In parallel, we analyzed the development of AKI in experimental lipopolysaccharide (LPS)-induced systemic inflammation in newborn rats accompanied by antibiotic therapy.
We showed that therapy with metronidazole or ampicillin in combination with sulbactam had a beneficial effect in children with suspected sepsis, resulting in a decrease in AKI markers levels. However, treatment of newborns with netilmicin, cefepime, linezolid, or imipenem in combination with cilastatin worsened kidney function in these patients.
This prospective study indicates which antibiotics are preferable in neonatal sepsis and which should be used with caution in view of the risk of AKI development.
Polygonum cuspidatum Sieb. et Zucc. Extracts improve sepsis-associated acute kidney injury by inhibiting NF-κB-mediated inflammation and pyroptosis
2024, Journal of Ethnopharmacology
Polygonum cuspidatum Sieb. et Zucc. (Polygonum cuspidatum) is a herbaceous perennial plant in the Polygonaceae family that produces biofunctional stilbenes and quinones. The dried rhizome and root of P. cuspidatum in traditional oriental medicine have been used for ameliorating inflammatory illnesses, diabetes, gout, cancer, and other ailments.
This work aimed to investigate the protective effects of P. cuspidatum extracts (PCE) on sepsis-associated acute kidney injury (SA-AKI) and its underlying mechanism.
The potential mechanisms by which PCE improved SA-AKI were preliminarily predicted by network pharmacology. The dry powders of PCE were obtained using the freeze-drying method. A mouse model of SA-AKI was established by intraperitoneal injection of lipopolysaccharide (LPS). The protective effects of PCE on SA-AKI in vivo were studied using pathological and biochemical methods. LPS-stimulated HK-2 cells were prepared for in vitro evaluation. The qPCR and immunoblotting assays were performed to confirm the mechanism involved.
The network pharmacology results indicate that emodin (Emo) and polydatin (PD) are potential active components of P. cuspidatum ameliorating SA-AKI. The experimental results showed that PCE improved renal function indices (creatinine, urea nitrogen, and urinary protein) in SA-AKI mice. Mechanistically, PCE mitigated oxidative stress, regulated the expression levels of pyroptosis-related proteins, and repressed the production of inflammatory cytokines by inactivating nuclear factor-kappa B (NF-κB) signaling in vivo. Similar results were observed in LPS-stimulated HK-2 cells in the presence of Emo or PD.
Our results demonstrated that PCE and active ingredients (Emo and PD) in PCE ameliorated SA-AKI by suppressing oxidative stress, inflammation, and pyroptosis.
Infections and Acute Kidney Injury: A Global Perspective
2023, Seminars in Nephrology
Globally, there are an estimated 13.3 million cases of acute kidney injury (AKI) annually. Although infections are a common cause of AKI globally, most infection-associated AKI occurs in low- and lower-middle-income countries. There are marked differences in the etiology of infection-associated AKI across age groups, populations at risk, and geographic location. This article provides a global overview of different infections that are associated commonly with AKI, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human immunodeficiency virus, malaria, dengue, leptospirosis, tick-borne illnesses, and viral hemorrhagic fevers. Further discussion focuses on infectious conditions associated with AKI including sepsis, diarrheal diseases and pregnancy, peripartum and neonatal AKI. This article also discusses the future of infection-associated AKI in the framework of climate change. It explores how increased investment in achieving the sustainable development goals may contribute to the International Society of Nephrology's 0 by 25 objective to curtail avoidable AKI-related fatalities by 2025.
Sepsis-mediated renal dysfunction: Pathophysiology, biomarkers and role of phytoconstituents in its management
2023, Biomedicine and Pharmacotherapy
Sepsis has evolved as an enormous health issue amongst critically ill patients. It is a major risk factor that results in multiple organ failure and shock. Acute kidney injury (AKI) is one of the most frequent complications underlying sepsis, which portends a heavy burden of mortality and morbidity. Thus, the present review is aimed to provide an insight into the recent progression in the molecular mechanisms targeting dysregulated immune response and cellular dysfunction involved in the development of sepsis-associated AKI, accentuating the phytoconstituents as eligible candidates for attenuating the onset and progression of sepsis-associated AKI. The pathogenesis of sepsis-mediated AKI entails a complicated mechanism and is likely to involve a distinct constellation of hemodynamic, inflammatory, and immune mechanisms. Novel biomarkers like neutrophil gelatinase-associated lipocalin, soluble triggering receptor expressed on myeloid cells 1, procalcitonin, alpha-1-microglobulin, and presepsin can help in a more sensitive diagnosis of sepsis-associated AKI. Many bioactive compounds like curcumin, resveratrol, baicalin, quercetin, and polydatin are reported to play an important role in the prevention and management of sepsis-associated AKI by decreasing serum creatinine, blood urea nitrogen, cystatin C, lipid peroxidation, oxidative stress, IL-1β, TNF-α, NF-κB, and increasing the activity of antioxidant enzymes and level of PPARγ. The plant bioactive compounds could be developed into a drug-developing candidate in managing sepsis-mediated acute kidney injury after detailed follow-up studies. Lastly, the gut-kidney axis may be a more promising therapeutic target against the onset of septic AKI, but a deeper understanding of the molecular pathways is still required.
Immunoregulatory mechanism of acute kidney injury in sepsis: A Narrative Review
2023, Biomedicine and Pharmacotherapy
Sepsis acute kidney injury (SAKI) is a common complication of sepsis, accounting for 26–50 % of all acute kidney injury (AKI). AKI is an independent risk factor for increased mortality risk in patients with sepsis. The excessive inflammatory cascade reaction in SAKI is one of the main causes of kidney damage. Both the innate immune system and the adaptive immune system are involved in the inflammation process of SAKI. Under the action of endotoxin, neutrophils, monocytes, macrophages, T cells and other complex immune network reactions occur, and a large number of endogenous inflammatory mediators are released, resulting in the amplification and loss of control of the inflammatory response. The study of immune cells in SAKI will help improve the understanding of the immune mechanisms of SAKI, and will lay a foundation for the development of new diagnostic and therapeutic targets. This article reviews the role of known immune mechanisms in the occurrence and development of SAKI, with a view to finding new targets for SAKI treatment.
Neohesperidin dihydrochalbazone protects against septic acute kidney injury in mice
2023, Phytomedicine
Citation Excerpt :
Acute Kidney Injury (AKI), a common syndrome characterized by a sharp decline of renal function, can be caused by a variety of reasons (Alobaidi et al., 2015).
Neohesperidin dihydrochalbazone (NHDC) shows a range of pharmacological actions, however, in septic acute kidney injury (AKI), the effect of NHDC is little known.
To assess the role of NHDC against AKI and the possible mechanisms.
In vivo, we used different concentration of NHDC (50, 100, and 200 mg/kg) treated septic AKI model of mice. Moreover, in vitro, in HK-2 cells, a lipopolysaccharide (LPS) induced cell model was treated with 10, 20, and 30 μM NHDC. Next, kidney tissue pathologic change, marker of renal injury, apoptosis, and inflammatory factors were assessed using hematoxylin and eosin staining, enzyme-linked immunosorbent assay, terminal deoxynucleotidyl transferase dUTP nick end labeling, and western blot. HK-2 cell apoptosis and viability were assessed via flow cytometry and cell counting kit-8. In HK-2 cells and tissues, NLRP3, caspase 1, ASC, and P38/ERK 1/2/JNK pathway related protein levels were tested using western blot.
NHDC (100 and 200 mg/kg) significantly attenuated kidney injury in caecal ligation and puncture (CLP)-treated mice. In CLP-treated mice, the level of BUN, Scr, KIM-1, and NAGL was reduced by 100 and 200 mg/kg NHDC. Furthermore, 100 and 200 mg/kg NHDC inhibited inflammation by reducing the production of IL-6, TNF-α, and IL-1β, and inhibited oxidative stress by regulating the change of MDA, SOD, GSH, and CAT. NHDC (100 and 200 mg/kg) inhibited renal cell apoptosis by increasing Bcl2 protein expression and inhibiting Bax and cleaved caspase-3 protein expression. Additionally, NHDC (100 and 200 mg/kg) inhibited the protein levels of phosphorylated (p)-P38, p-JNK, p-ERK 1/2, NLRP3, caspase 1, ASC. In vitro, in LPS-stimulated HK-2 cells, NHDC (20 and 30 μM) increased cell viability, reduced cell apoptosis, restrained inflammation by reducing the content of IL-6, TNF-α, and IL-1β, and inhibited the protein expression of caspase 1, NLRP3, ASC, p-P38, p-JNK, and p-ERK1/2. Importantly, the promotive effect of NHDC on HK-2 cell viability was reversed by DHR (an activator of P38 MAPK signaling pathway), and DHR reversed the inhibitive effects of NHDC on HK-2 cell apoptosis and inflammation.
For the first time, NHDC was found to inhibit oxidative stress, inflammation, and apoptosis in AKI model, which was related to the inhibition of P38 MAPK pathways. Our findings provided the theoretical basis for NHDC on the prevention of AKI.

View all citing articles on Scopus

^☆: Financial support: Supported in part by a grant from the National Institutes of Health (P50 DK096418 to R.B. and S.G.), and by a Canada Research Chair in Critical Care Nephrology and an Independent Investigator Award from Alberta Innovates–Health Solutions (S.B.).

^☆☆: Conflict of interest statement: none.

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Sepsis-Associated Acute Kidney Injury☆,☆☆

Summary

Section snippets

General Epidemiology

Severity of Illness

Timing of SA-AKI

General Pathophysiology

Risk Recognition and Early Diagnosis

Conclusions

Int J Infect Dis

Am J Kidney Dis

J Crit Care

Am J Med

J Crit Care

Chest

Kidney Int

Biochim Biophys Acta

J Crit Care

Am J Kidney Dis

Clin Biochem

Kidney Int

Am J Kidney Dis

Lancet

Kidney Int

Kidney Int

Acute renal failure in the ICU: risk factors and outcome evaluated by the SOFA score

Intensive Care Med

Beginning, Ending Supportive Therapy for the Kidney (B.E.S.T. Kidney) Investigators. Acute renal failure in critically ill patients: a multinational, multicenter study

JAMA

Changes in the incidence and outcome for early acute kidney injury in a cohort of Australian intensive care units

Crit Care

Acute kidney injury in the intensive care unit according to RIFLE

Crit Care Med

A multi-centre evaluation of the RIFLE criteria for early acute kidney injury in critically ill patients

Nephrol Dial Transplant

Epidemiology of acute renal failure in ICUs: a multi-center prospective study

Blood Purif

Incidence and outcomes of acute kidney injury in intensive care units: a Veterans Administration study

Crit Care Med

Epidemiology of acute kidney injury in Hungarian intensive care units: a multicenter, prospective, observational study

BMC Nephrol

NEFROINT Investigators. Prospective multicenter study on epidemiology of acute kidney injury in the ICU: a critical care nephrology Italian collaborative effort (NEFROINT)

Minerva Anestesiol

Incidence, risk factors and 90-day mortality of patients with acute kidney injury in Finnish intensive care units: the FINNAKI study

Intensive Care Med

Acute kidney injury in patients with severe sepsis in Finnish intensive care units

Acta Anaesthesiol Scand

Risk factors of acute renal failure in critically ill children: a prospective descriptive epidemiological study

Pediatr Crit Care Med

Serum creatinine as stratified in the RIFLE score for acute kidney injury is associated with mortality and length of stay for children in the pediatric intensive care unit

Crit Care Med

Childhood acute renal failure: 22-year experience in a university hospital in southern Thailand

Pediatrics

Patients are dying of acute renal failure

Crit Care Med

The epidemiology of sepsis in the United States from 1979 through 2000

N Engl J Med

Benchmarking the incidence and mortality of severe sepsis in the United States

Crit Care Med

Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012

JAMA

CUB-Réa Network. Current epidemiology of septic shock: the CUB-Réa Network

Am J Respir Crit Care Med

Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care

Crit Care Med

A prospective, observational registry of patients with severe sepsis: the Canadian Sepsis Treatment and Response Registry

Crit Care Med

Incidence, treatment, and outcome of severe sepsis in ICU-treated adults in Finland: the Finnsepsis study

Intensive Care Med

Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008

Intensive Care Med

Early acute kidney injury and sepsis: a multicentre evaluation

Crit Care

Beginning, Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators. Septic acute kidney injury in critically ill patients: clinical characteristics and outcomes

Clin J Am Soc Nephrol

Sepsis Occurrence in Acutely Ill Patients Investigators. Sepsis in European intensive care units: results of the SOAP study

Crit Care Med

North East Italian Prospective Hospital Renal Outcome Survey on Acute Kidney Injury I. North East Italian Prospective Hospital Renal Outcome Survey on Acute Kidney Injury (NEiPHROS-AKI): targeting the problem with the RIFLE criteria

Clin J Am Soc Nephrol

Acute kidney injury in septic shock: clinical outcomes and impact of duration of hypotension prior to initiation of antimicrobial therapy