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  • Review Article
  • Published:

Paradigms of acute kidney injury in the intensive care setting

Nature Reviews Nephrology volume 14, pages 217–230 (2018)Cite this article

Subjects

Key Points

  • Acute kidney injury (AKI) is not a single disease but a loose collection of syndromes characterized by an abrupt decrease in glomerular filtration rate

  • Broad classifications of AKI — according to the dominant aetiology (such as sepsis or nephrotoxicity) as opposed to pseudo-anatomical categories (for example, prerenal or intrarenal) — demonstrate more consistent relationships with pathophysiology and can improve therapeutic approaches

  • Broad aetiology-based classification may still be insufficient, as heterogeneity could exist at the molecular level; however, whether this heterogeneity leads to differences in response to therapy is not yet known

  • Protein biomarkers and other in vitro diagnostics are likely to have a role in both characterizing clinical phenotypes of AKI and aiding the discovery of new endophenotypes, with the ultimate goal of matching subsets of patients to effective therapeutic approaches

Abstract

Acute kidney injury (AKI) is a heterogeneous clinical syndrome that has multiple aetiologies, variable pathogenesis and diverse outcomes. However, these heterogeneities are not reflected in current approaches to the diagnosis and, to some degree, treatment of AKI. For example, congestive heart failure and dehydration can produce identical changes in serum creatinine level and urine output (parameters that are used to define AKI); however, they differ vastly in their physiological contexts and demand completely opposite treatments. AKI is often still considered to be a homogeneous clinical entity, which implies a uniform pathogenesis and a well-defined prognosis. As a consequence, efforts to find effective AKI treatments have been hampered by a lack of clear clinical classifications for various types of AKI. In addition, subclassification of AKI into subclinical phenotypes — for example, on the basis of protein biomarkers and other in vitro diagnostics that take into account disease aetiology and underlying pathogenesis — might be necessary to develop therapeutic approaches that effectively target the widely differing pathomechanisms of AKI. In this Review, we discuss the major subtypes of AKI that are associated with sepsis, major surgery, renal hypoperfusion and nephrotoxin exposure —situations that are typically seen in the intensive care setting. We consider differences and similarities in their phenotype, pathogenesis and outcomes and how this information might be used to guide treatment.

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Figure 1: Principal pathogenic mechanisms of acute kidney injury in the context of sepsis or major surgery.
Figure 2: Principal pathogenic mechanisms of acute kidney injury in the context of global hypoperfusion.
Figure 3: Principal pathogenic mechanisms of acute kidney injury in the context of exogenous and endogenous nephrotoxins, including typical examples.
Figure 4: Potential patient outcomes following acute kidney injury.

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Authors and Affiliations

  1. Department of Critical Care Medicine, Center for Critical Care Nephrology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, 3347 Forbes Avenue, Suite 220, Pittsburgh, 15213, Pennsylvania, USA

    John A. Kellum

  2. Department of Renal and Transplant Medicine, Adult Critical Care Unit, The Royal London Hospital, Whitechapel Road, London, E1 1BB, UK

    John R. Prowle

  3. William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK

    John R. Prowle

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Contributions

J.A.K. and J.R.P. researched the data, discussed the article's content, wrote the text and reviewed or edited the article before submission.

Corresponding author

Correspondence to John A. Kellum.

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Competing interests

J.A.K. has received consulting fees and grant support from Astute Medical and Bioporto. J.R.P. declares no competing interests.

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Glossary

Inflammatory mediators

A wide array of substances that mediate and modulate various aspects of inflammation. These substances include vasoactive proteins (for example, bradykinin, histamine), complement and molecules involved in coagulation (for example, plasmin, thrombin). Cytokines (for example, TNF, IL-6, IL-10), chemokines (for example, IL-8) and eicosanoids (for example, leukotrienes, prostaglandins) are the major mediators of inflammation during infection. Although some molecules are often labelled pro-inflammatory (for example, IL-6) and others anti-inflammatory (for example, IL-10), the actions of each mediator may be complex and context-dependent, making simple classification difficult.

Damage-associated molecular patterns

(DAMPs; also known as danger-associated molecular patterns). Endogenous molecules often released from damaged tissues or dying cells. They can be detected by various receptors on cells, including TLRs and receptor for advanced glycosylation end products (RAGE; also known as AGER). Typical DAMPs include high mobility group protein B1 (HMGB1), RNA, DNA and myoglobin.

Pathogen-associated molecular patterns

(PAMPs). Similar to DAMPs, PAMPs are molecules released from pathogens. Many of the same receptors that recognize DAMPs also recognize PAMPs, leading to similar cellular responses when either are encountered. Typical PAMPs include lipopolysaccharide (LPS; also known as endotoxin), lipoteichoic acid from Gram-positive bacteria, peptidoglycan and nucleic acid variants normally associated with viruses.

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Kellum, J., Prowle, J. Paradigms of acute kidney injury in the intensive care setting. Nat Rev Nephrol 14, 217–230 (2018). https://doi.org/10.1038/nrneph.2017.184

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