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I n 2012, Kidney Disease: Improving Global Outcomes (KDIGO) published a guideline on the classification and management of acute kidney injury (AKI). 1 Since then, new evidence has emerged that has important implications for clinical practice. Large epidemiology studies and risk profiles for AKI have become available in adults and children, such as the AKI-Epidemiologic Prospective Investigation (AKI-EPI) study, 2 the 0by25 Initiative, 3 the Southeast Asia-AKI (SEA-AKI) study, 4 and the Assessment of Worldwide Acute Kidney Injury, Renal Angina, and Epidemiology (AWARE) 5 and Assessment of Worldwide Acute Kidney Injury Epidemiology in Neonates (AWAKEN) 6 studies. The effectiveness of the KDIGO recommendations in preventing AKI has been confirmed in small single-center randomized controlled trials (RCTs), such as the Prevention of AKI (PrevAKI) 7 and the

1 Fibrosis leads to chronic impairment of cardiac and renal function and thus reversal of existing ®brosis may improve function and survival. This project has determined whether pirfenidone, a new anti®brotic compound, and spironolactone, an aldosterone antagonist, reverse both deposition of the major extracellular matrix proteins, collagen and ®bronectin, and functional changes in the streptozotocin(STZ)-diabetic rat. 2 Streptozotocin (65 mg kg 71 i.v.)-treated rats given pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone; approximately 200 mg kg 71 day 71 as 0.2 ± 2g 1 71 drinking water) or spironolactone (50 mg kg 71 day 71 s.c.) for 4 weeks starting 4 weeks after STZ showed no attenuation of the increased blood glucose concentrations and increased food and water intakes which characterize diabetes in this model. 3 STZ-treatment increased perivascular and interstitial collagen deposition in the left ventricle and kidney, and surrounding the aorta. Cardiac, renal and plasma ®bronectin concentrations increased in STZ-diabetic rats. Passive diastolic sti ness increased in isolated hearts from STZ-diabetic rats. Both pirfenidone and spironolactone treatment attenuated these increases without normalizing the decreased +dP/dt max of STZ-diabetic hearts. 4 Left ventricular papillary muscles from STZ-treated rats showed decreased maximal positive inotropic responses to noradrenaline, EMD 57033 (calcium sensitizer) and calcium chloride; this was not reversed by pirfenidone or spironolactone treatment. STZ-treatment transiently decreased GFR and urine¯ow rates in isolated perfused kidneys; pirfenidone but not spironolactone prevented the return to control values. 5 Thus, short-term pirfenidone and spironolactone treatment reversed cardiac and renal ®brosis and attenuated the increased diastolic sti ness without normalizing cardiac contractility or renal function in STZ-diabetic rats.

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Acute kidney injury (AKI) is a common but complex clinical syndrome with multiple etiologies. These etiologies target different sites and pathways within the kidney. Novel biomarkers of 'kidney damage' (which can be tubular or glomerular) can be used to diagnose AKI, even in the absence of an increase in serum creatinine or oliguria. These biomarkers of kidney damage can be combined with biomarkers of kidney function to facilitate classification of AKI. A comprehensive review of the literature was performed using the published methodology of the Acute Dialysis Quality Initiative (ADQI) working group and used to establish consensus statements regarding the use of biomarkers in the differential diagnosis of AKI. We recommend that the pathophysiological terms 'functional change' and 'kidney damage' be used in preference to the anatomical classification using the terms pre-renal, renal and post-renal AKI. We further recommend the use of both renal and non-renal biomarkers in establishing the specific cause of AKI as soon as possible after diagnosis. The presence of underlying CKD or of sepsis poses additional challenges in differential diagnosis, since these conditions alter both baseline biomarker excretion and biomarker performance. We recommend that biomarkers be validated within the clinical context in which they are to be used. Within that context, combinations of biomarkers may, in the future, allow differentiation of the site, mechanism and phase of injury.

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1. The distribution of morphological injury was assessed qualitatively and quantitatively in the perfused rat kidney in vitro at controlled rates of oxygen delivery in the presence of low concentrations of erythrocytes. 2. In control kidneys (total oxygen delivery approximately 32 μmol/min per kidney) no injury was seen in the medullary thick ascending limb of Henle's loop (MTAL) whilst 11 ± 5 (sd)% of proximal tubules sustained damage. 3. Mild hypoxia (total oxygen delivery approximately 28 μmol/min per kidney) produced little or no injury to MTAL, namely 6 ± 4(sd)% and 3 ± 3% of tubules damaged, respectively. In contrast, both groups sustained extensive damage to proximal tubules, averaging 46 ± 13% (P < 0.01 vs control) and 84 ± 14% (P < 0.001 vs control), respectively. This damage was equally distributed between the superficial and deep cortex. 4. Comparison with morphometric data obtained previously from cell-free-perfused rat kidneys [P. J. Ratcliffe, Z. H. Endre, S. J. Scheinman, J. D. Tange, J. G. G. Ledingham & G. K. Radda (1988) Clinical Science74, 437–448] showed that (a) erythrocytes prevent hypoxic damage to the MTAL at mild and moderate levels of hypoxia; (b) when oxygen delivery rates are matched between cell-free- and erythrocyte-perfused kidneys, proximal tubular injury is greater in the presence of erythrocytes; (c) when arterial partial pressure of oxygen is matched between cell-free- and erythrocyte-perfused kidneys, the degree of proximal tubular injury is similar. 5. The data suggest that the proximal tubule and not the MTAL is the nephron segment most at risk of hypoxic injury in vitro.

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