Molecular nephrology: types of acute tubular injury

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Abstract

The acute loss of kidney function has been diagnosed for many decades using the serum concentration of creatinine — a muscle metabolite that is an insensitive and non-specific marker of kidney function, but is now used for the very definition of acute kidney injury (AKI). Fortunately, myriad new tools have now been developed to better understand the relationship between acute tubular injury and elevation in serum creatinine (SCr). These tools include unbiased gene and protein expression analyses in kidney, urine and blood, the localization of specific gene transcripts in pathological biopsy samples by rapid in-situ RNA technology and single-cell RNA-sequencing analyses. However, this molecular approach to AKI has produced a series of unexpected problems, because the expression of specific kidney-derived molecules that are indicative of injury often do not correlate with SCr levels. This discrepancy between kidney injury markers and SCr level can be reconciled by the recognition that many separate subtypes of AKI exist, each with distinct patterning of molecular markers of tubular injury and SCr data. In this Review, we describe the weaknesses of isolated SCr-based diagnoses, the clinical and molecular subtyping of acute tubular injury, and the role of non-invasive biomarkers in clinical phenotyping. We propose a conceptual model that synthesizes molecular and physiological data along a time course spanning from acute cellular injury to organ failure.

Key points

  • Current definitions of acute kidney injury (AKI), based on serum creatinine (SCr) level, focus on loss of kidney function rather than kidney injury.

  • AKI definitions cannot provide an acute measurement of loss of function, however, because SCr is a quantitative functional marker only at the steady state.

  • Current AKI metrics can neither detect kidney injury in real time nor distinguish dramatically different types of kidney injury.

  • Molecular analyses of acutely damaged kidneys have detected cellular and segment-specific responses to injurious stimuli, prior to and distinct from the loss of function as measured by SCr.

  • As a result, molecular analyses have detected different types of acute tubular injury and have re-characterized the concept of the kidney response to noxious stimuli into biomarker-positive ʻinjury’ and biomarker-negative ʻno injury’.

  • A conceptual model places ʻtubular injury’ (biomarkers) upstream of ʻloss of function’ (AKI metrics), providing a unifying ʻinjury’ and ʻloss of function’ sequence consistent with biological pathways.

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Fig. 1: Rapid resolution of serum creatinine in most patients with AKI.
Fig. 2: Renal expression of NGAL mRNA.
Fig. 3: Sources of AKI biomarker mRNA and protein.
Fig. 4: Biomarkers change the definition of AKI.
Fig. 5: Combined analysis of biomarker, serum creatinine and urine output for the assessment of kidney injury.

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Acknowledgements

J.B. is supported by NIH 1U54DK104309, NIH 2R01DK073462, UG3 DK114926, T32-DK108741 and a Columbia Precision Medicine Pilot Award. P.D. is funded by NIH P50 DK096418, NIH R01HL133695, NIH 1R01HL132551.

Author information

B.D.D.O., K.X., T.H.S., K.K., V.D.D., N.P.T., J.B. and P.D. researched data for the article. All authors contributed equally to discussion of the article’s content, writing the article and review/editing the manuscript before submission.

Correspondence to Prasad Devarajan.

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Competing interests

J.B. and P.D. are co-inventors on patents (US57766204P; US8592170; US797710; EP1766395B1; EP1616184) for the use of NGAL in kidney disease.

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Peer review information

Nature Reviews Nephrology thanks M. Ostermann, J. Prowle and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Thiouracil tagging

Tagging of newly synthesized RNA. The Uprt gene is activated in the Rosa locus by segment-specific Cre drivers. 4-Thiouracil is then introduced at the time of choosing and 4 h later, thiouracil-labelled RNA is extracted from the whole organ without the need for cell dissociation.

Warm IRI

Arterial ischaemia–reperfusion injury of the kidney in the setting of normal body temperature (37 oC).

Sterile inflammation

The presence of inflammatory cells (neutrophils, macrophages and lymphocytes) in the absence of overt infection with bacteria or virus.

RNA pulldown

A process of extraction and purification of labelled RNA from an organ.

Partial pressure of oxygen

(pO2). The percentage of atmosphere occupied by oxygen gas, multiplied by the total atmospheric pressure.

Fine mapping

The use of high-resolution microscopy, whereby single cells and cellular details are microscopically discernible.

Siderophore

An organic chemical that binds with high affinity to iron. Bacteria create many different types of complex siderophores (catecholates, hydroxamates, carboxylates) to capture host iron from serum, urine and cells. Metabolic fragments, such as catecholates, can serve as siderophores in mammals. NGAL protein binds catechols and catecholate siderophores enterochelin with high affinity.

Nutritional immunity

A process of sequestering critical nutrients needed for bacterial growth. This includes the capture of iron-bound siderophores by NGAL and more generally the capture of iron by transferrin and lactoferrin.

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