Part Ⅰ：Controversies in Acute Kidney Injury: Conclusions From A Kidney Disease: Improving Global Outcomes (KDIGO) Conference

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Marlies Ostemann, et al

In 2012, Kidney Disease: Improving Global Outcomes (KDIGO)published a guideline on the classification and management of acute kidney injury(AKI).' 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,' the 0by25 Initiative, the Southeast Asia-AKI(SEA AKI) study, 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)" studies. The effectiveness of the KDIGO recommendations in preventing Acute Kidney Injury has been confirmed in small single-center randomized controlled trials (RCTs), such as the Prevention of AKI (PrevAKI)' and the Biomarker Guided Intervention for Prevention of Acute Kidney Injury (BigpAK)" studies. In addition, results of RCTs have provided new data relevant to several facets of preventing and managing AKI, including early resuscitation, fluid therapy, prevention of contrast-associated AKI, and timing of acute renal replacement therapy (RRT)."-13 Finally, there is now evidence from large studies in different countries that the use of KDIGOcriteria for Acute Kidney Injury, as part of computer decision-support systems, can improve clinical outcomes. However, there has also been important progress in the development of new tools to diagnose and manage Acute Kidney Injury, including biomarkers, decision-support programs, and electronic alerts, that go beyond the current KDIGO definition/staging criteria, and these warrant consideration for inclusion in Acute Kidney Injury guidelines.

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These advances are not without controversy. Adoption of new biomarkers has been heterogeneous, and there are calls to revise KDIGO Acute Kidney Injury staging based on creatinine and urine output, and even calls to discard the KDIGO staging completely.7Thus, in April 2019, KDIGO held a controversial conference entitled Acute Kidney Injury, in Rome, Italy. Participants examined and summarized evidence published since 2012 as it relates to the risk assessment, diagnosis, and management of patients with AKI and provided commentary on areas of controversy and agreement. The ultimate goals were to provide the clinical and research communities with a snapshot of the current state of the art for diagnosis and management of Acute Kidney Injury and to prepare for a future revision of the 2012 guideline.

NOMENCLATURE AND DIAGNOSTIC CRITERIA

Acute Kidney Injury related definitions

Acute Kidney Injury and chronic kidney disease(CKD) are increasingly recognized as related entities representing a continuum of diseases. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative(NKF-KDOQI)2002 guideline and the 2012 KDIGO AKI guideline defined CKD as measured or estimated glomerular filtration rate(GFR)<60 ml/min per 173 m²， or the presence of markers of kidney damage (e.g, albuminuria) for >90 days. The 2012 KDIGO guideline defined AKI as an abrupt decrease in kidney function occurring over 7 days or fewer(Table 1). To complete the continuum, the 2012 guideline proposed the term acute kidney diseases and disorders (AKD) to define conditions of impaired kidney function not meeting the criteria for either AKI or CKD but having adverse outcomes and requiring clinical care. However, consensus on the exact criteria and indicators of severity is urgently needed.

Because the diagnosis of Acute Kidney Injury should be tied to management decisions, and because changing disease definitions may have major implications for disease epidemiology, the case for revising the 2012 KDIGO definition of AKI should be strong before changes are proposed. Furthermore, in the context of an AKI guideline revision, several classification systems in addition to the stages of AKI should be rigorously defined. These relate to the distinctions among persistent, transient, relapsing, and recovered AKI; various etiologies of AKI; and community-onset versus hospital-onset AKI. In addition, there is emerging evidence that markers of structural kidney damage may be associated with clinically relevant outcomes and therefore identify potentially actionable entities. For an AKI guideline revision, the evidence base should be reviewed to determine whether markers of kidney damage constitute risk factors for AKI, define a new entity(such as subclinical or preclinical AKI), or should be incorporated into the AKI definition. Finally, the future guideline should use nomenclature that is precise and patient-centered.

The clinical importance of Acute kidney disease needs to be further assessed. Retrospective cohort data based only on changes in serum creatinine values and with limited clinical context sug-gest a relevance for Acute kidney disease: the population of patients who meet laboratory criteria for AKD but not CKD or AKI is relatively large, and these individuals have increased risks of the incident and progressive CKD, kidney failure (formally referred to as"end-stage kidney disease"), and death," confirming the need to better define and classify AKD. Furthermore, a revised definition and classification of Acute kidney disease could be better harmonized with both the definitions and classifications of AKI and CKD and tie to clinical management. As in adults, the AKI/AKD/CKD spectrum should be unified in children, and definitions should be the same for children and adults. Special consideration in children, as well as in adults with low muscle mass, is a reduced serum creatinine concentration, which may impact AKI diagnosis.

The assessment of renal recovery is still controversial, and its definition is essential given the implications for patients and clinicians. Issues related to assessment of recovery include changes in creatinine generation due to reduction in muscle mass, among others.

Advances in the Diagnosis of Acute Kidney Injury

Serum creatinine and urine output continue to be the foundational measures for Acute Kidney Injury diagnosis even though their limitations are well known. In the future, kidney damage biomarkers, biopsy, and imaging may be useful for staging AKI, classification of cause, prognosis, and treatment. However, currently, there is insufficient information about any of these measures to warrant addition to the AKI definition. Given that the global availability of novel biomarkers is limited, incorporating them into definitions will be challenging. Measurements of real-time or kinetic GFR are research tools at present, and more evidence is needed regarding their clinical applicability(Table 2).

Both urine output and serum creatinine level should continue to be used; ideally, the new Acute Kidney Injury guideline would provide further clarification as to the role of these measurements. If possible, both should be ascertained. However, if serum creatinine measurements are not immediately available, urine output criteria should be used.

It remains unclear how to best determine baseline kidney function. What constitutes a baseline serum creatinine level is controversial and inconsistently defined. It would be ideal to have prior serum creatinine or GFR measurements widely available through electronic medical records, but this is not current practice in many parts of the world. Prior serum creatinine or GFR measures may also further elucidate the risk of Acute Kidney Injury in patients considered at high risk on the basis of either comorbidity or an intervention. There is controversy about whether an acute decrease in serum creatinine level

indicates Acute Kidney Injury that has already occurred, and more research is needed in this area. For example, small declines in serum creatinine levels need to be interpreted with caution because they may be the result of acute changes in creatinine production or volume of distribution. After a timed insult(e.g, coronary angiography, elective surgery, nephrotoxic drug exposure), serum creatinine level should be measured at an appropriate time, allowing for AKI to manifest. After Acute Kidney Injury onset, serum creatinine level should be measured during follow-up as necessary for clinical management and care transitions(e.g, transfer to and from intensive care)and for determining changes in AKI staging and classification (AKI vs. AKD), including the onset of chronic kidney disease at 90 days.

How urine output should be evaluated is also an area that needs further investigation to avoid variability in reporting of Acute Kidney Injury incidence(i.e., use of actual or ideal body weight, strict time period vs. time-averaged values). Future guidelines should address how differences in body composition(overweight, fluid overload) affect the interpretation of urine output, and whether these differences need to be considered in regard to the thresholds for AKI. Similarly, fluid status should be considered when evaluating for AKI. Fluid overload is associated with increased mortality and Acute Kidney Injury, and it may impact the diagnosis of AK through its impact on the volume of distribution of serum creatinine. Although there is a research method to define fluid overload, these are not routinely used in clinical practice, and it is unclear whether there is sufficient evidence to define a clinical threshold for fluid overload. In the next Acute Kidney Injury guideline, fluid overload should be defined operationally through a rigorous literature review.

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