Abstract

Kidney disease is an important public health problem. Both acute kidney injury (AKI) and chronic kidney disease have been well-defined and classified, which has led to improved research efforts and subsequent management strategies and recommendations. Gaps in research, care, and guidance remain for patients with abnormal renal function and/or structure that meet neither the definition of AKI nor the definition of chronic kidney disease. The term acute kidney disease and disorders, abbreviated as acute kidney disease (AKD), has been introduced as an important construct to address this issue. In an effort to expand and harmonize existing definitions and ultimately better inform research and clinical care, Kidney Disease: Improving Global Outcomes (KDIGO) organized a consensus workshop. Multiple invitees from around the globe, representing acute and chronic kidney disease researchers and experts, met virtually to review existing data and discuss key concepts related to AKD. Despite some unresolved issues, participants reached general consensus on the definition and classification of AKD, management strategies, and research priorities.AKD is defined as an abnormality of renal function and/or structure that affects health and lasts for 3 months.AKD may include AKI, but more importantly, also includes an abnormal renal function that is not as severe as AKI or that progresses beyond 7 days. The cause of AKD should be sought and the classification includes both functional and structural parameters. management of AKD is currently based on empirical considerations. A strong research agenda is proposed to improve and validate the definition and classification system in order to test interventions and strategies.

Keywords

acute kidney disease; acute kidney injury; chronic kidney disease; classification; evaluation; management; Cistanche extract.

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In August 2020, Kidney Disease: Improving Global Outcomes (KDIGO) convened a consensus meeting to address the need to harmonize existing definitions of acute kidney disease (AKD) and chronic kidney disease (CKD), recognizing that the concepts of acute kidney disease and illness (abbreviated AKD) as distinct from acute kidney injury (AKI) are not well recognized or understood. Conference participants conducted virtual sessions in a series of plenary sessions, discussions, and closing sessions. Data were presented, interpretations were discussed, and discussion groups focused on 3 related goals of the meeting: (i) to revisit and refine the definition and classification of AKD to improve understanding and describe the relationship between AKD, AKI, and CKD; (ii) to develop and propose management strategies for AKD; and (iii) to identify key research areas for AKD to improve understanding and improve clinical practice and public health. Here, we describe the background, rationale, and results of these discussions.

Background

Over the past 20 years, we have defined and classified CKD and AKI and established standard definitions and staging systems for both. This has enabled reliable estimates of their incidence and prevalence, standardized their management, and stimulated research and funding in the field of human kidney disease (KD). The KDIGO guidelines define KD as functional and/or structural abnormalities of the kidney that affect health and classify KD according to the cause of the structural and functional abnormalities, their severity, and the duration of these abnormalities. The key phrase to distinguish patients with KD from those without kidney disease (NKD) is "health impact" (e.g., simple renal cysts do not have a health impact). AKI was defined and staged according to serum creatinine (SCr) and/or urine output (UO) criteria; however, this did not mention the duration of AKI, recovery criteria, or markers of renal damage (e.g., urinalysis, proteinuria, more recent biomarkers, and imaging abnormalities), GFR and proteinuria criteria (CGA classification). More importantly, patients may have severe functional and structural abnormalities that affect health and last for 3 months, and do not meet the definition of AKI or CKD. The term AKD should be used to define this time and status (Figure 1). AKI is specifically included in AKD and therefore covers all patients with functional and/or structural abnormalities that affect health and last for 3 months.

Therefore, it is possible to develop models of care that are correlated with severity and to investigate interventions for specific stages of AKD. This requires a clear and standardized description of methods to assess functional and structural abnormalities, the establishment of methods to measure baseline renal function for any changes, and methods to assess changes in the absence of prior values. Assessment of changes in renal function after AKD should include loss or reduction of functional reserve in addition to renal function itself4 (Figure 2). Descriptions need to include both adult and pediatric KD and apply to all jurisdictions.

AKD may occur in the absence of known prior KD or may be associated with CKD. Recent data suggest that AKD unrelated to AKI is common, almost three times more common than AKI, and, like AKI, is associated with an increased risk of death and the development or progression of CKD.5 Conceptually, AKD, AKI, and CKD are interrelated by their relationship to each other and their criteria, complications, and outcomes (Figure 3). The terms AKI, AKD, and CKD describe functional and/or structural abnormalities of the kidney and do not constitute a "diagnosis. It is important to determine the cause of each disease, recognizing that in some cases, AKI, AKD, and CKD may be caused by the same conditions. Clearly, there is wide heterogeneity in the etiology of AKD, ranging from etiologies that directly affect function, such as volume depletion or reduced perfusion after heart failure, to parenchymal diseases that affect structure and function, such as glomerulonephritis or interstitial nephritis, to obstructive etiologies. All of these occur in the absence or in the absence of function or in the time it takes to meet the criteria for AKI or to meet the criteria for CKD.

Published data support these concepts. using a large administrative population database, James et al. classified their cohort as having no KD (NKD) or both CKD and AKD, CKD and AKI, and CKD, AKI, and AKD (where AKD refers to AKD without AKI). AKD combined with CKD had the highest risk of CKD progression and renal failure, and CKD combined with AKI has the highest risk of death. In a retrospective cohort study including 36,118 hospitalized adult patients with a median follow-up of 2.6 years (interquartile range 0.8-4.4 years), See et al. examined the outcomes of AKD patients without AKI and AKD patients after AKI. The primary outcome was a composite of CKD, renal failure, or death. The corrected hazard ratio (HR) for the primary outcome was 2.51 (95% confidence interval, 2.16-2.91) in patients with AKD after AKI compared with those without AKD and 2.26 (95% confidence interval, 1.89-2.7) in patients with AKD without AKI.

Other published data to date have focused on clinically enriched populations with AKD combined with AKI, mainly related to cardiovascular disease, but also including all hospitalized patients and patients from different clinical areas (intensive care, postoperative, liver disease, etc.). The studies were mandatory retrospective studies and reported outcomes were mainly limited to mortality and CKD events with follow-up from 90 days to 10 years. These studies confirmed the increased risk of death and sudden CKD associated with AKD.

Both AKI and AKD can occur in the hospital or community setting. A growing body of literature describes community-acquired AKI, some of which may be AKD without AKI. community-acquired AKD may often go undetected and have long-term health consequences.

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Definition and staging for AKD

Defining AKD

We propose a broader term "kidney diseases and disorders" (KD) to describe functional and/or structural abnormalities of the kidney that are associated with health. Thus, AKD and CKD can be distinguished based on duration and coordinated under one term KD. The term "acute" defines a transient and reversible condition with recent or sudden onset; in contrast, "chronic" refers to a long-term and persistent condition. The definition of AKI does not include markers of kidney damage, such as abnormal urine deposits or proteinuria, nor does it include conditions in which the increase in SCr or decrease in UO is less severe or more rapid than AKI, nor does it include conditions in which the presence of markers of kidney damage without functional abnormalities. To address these gaps and harmonize definitions across time, the AKD definition criteria incorporate a number of AKI criteria and are aligned with those for CKD. The rationale for these criteria is based on modeling the relationship between decreasing GFR and increasing SCr, which is described in detail in the appendix of the KDIGO AKI guidelines.

Classification and severity staging

The current classification of both AKI and CKD is based on the cause of the disease and the severity of the functional abnormality or structural abnormality. Determining the cause allows for the implementation of cause-specific therapy. the AKI guidelines recommend the classification of specific causes when possible, but recognize that AKI is often multifactorial. the CKD guidelines also recommend a cause-specific classification that incorporates the severity staging of GFR and proteinuria levels (cause, GFR, and proteinuria criteria, CGA classification). We believe that the causes of AKD may include many of the causes of AKI and CKD, but we have not further specified a classification system at this time.

Therefore, we propose a classification system that distinguishes AKD without AKI from AKD with AKI (before or after AKI). As with AKI, AKD without AKI and AKD with AKI can occur in combination with CKD. Recognition of the different entities is necessary because management considerations may differ (figure 2) The severity staging of AKI and CKD, regardless of cause, drives prognosis and management recommendations. A more severe stage predicts a worse outcome.

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Unresolved questions and future directions in defining and classifying AKD.

Defining AKD according to SCr criteria requires knowledge of baseline SCr. In AKI studies lacking baseline SCr values, several methods have been used: using admission SCr, using the lowest hospital SCr, or calculating back values from an assumed eGFR of 75 ml/min / 1.73 m2. As described by Siew and Matheney, these methods have a bidirectional effect on the incidence of AKI and also affect the reported outcomes. In a post hoc analysis of data from the Simple Intensive Care Study II (SICS-II) study, the incidence of AKI varied by up to 15% in AKD studies without AKI using 4 different methods This variation would be even greater in AKD studies without AKI, especially in community studies, suggesting the need for standardized methods for comparison whenever possible. All reports must clearly describe the methods used as well as potential biases and possible directions.

Finally, although we tend to assume reduced GFR when discussing the loss of functional reserve, we should also consider the loss of tubular and endocrine function. Sensitive and prognostic markers of various forms of renal function loss are clearly needed, especially when they remain clinically silent.

Evaluation and management of ambulatory AKD patients

Participants recognized the lack of data to guide the assessment and management of AKD. A consensus was reached on the approach to the evaluation and management of patients with AKD based on supporting evidence, clinical experience, and data regarding prognosis.

AKD without AKI often occurs in community or primary care settings: Data are needed to inform clinicians and researchers to better understand this. However, in some cases, a trend toward a slow increase in SCr can also be identified at admission. The assessment and management of AKD depend on the clinical situation, local resources, and the local healthcare system. AKD without AKI may be appropriately treated as AKI when driven by clinically relevant factors. patients with AKD may have signs directly related to the kidney (e.g., abnormal urine deposits) or associated non-renal manifestations (e.g., edema or hypertension). Others may have incidentally elevated SCr, abnormal urine test results, or abnormal renal imaging as part of routine monitoring or after investigation for concurrent disease.

Recent hypovolemia occurring during a concurrent illness (e.g., upper or lower respiratory tract infection, urinary tract infection, or gastrointestinal illness and/or recent exposure to potentially nephrotoxic substances) may indicate that the current AKD likely occurred after an "undiagnosed" episode of AKI.

Evaluation of the urine in AKD

Test paper results for blood, protein, white blood cells, and glucose are usually sensitive, but not necessarily specific, and AKD can occur in normal test paper urinalysis. Test availability will be resource driven. Test paper analysis and a careful knowledgeable examination of urine deposits may help determine the cause of AKD and guide further diagnostic testing; therefore, these are essential elements of patient evaluation.

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Research and future directions in AKD

Little is known about the epidemiology, etiology, pathophysiologic subtypes, prevention, and treatment of AKD without AKI. It is likely that these are not just extensions of AKD after known AKI. The continuum from AKI and AKD to CKD is an area of increasing research intensity that would benefit from an organized approach. Accuracy and clarity are needed to inform future work, consistently identify patients (for clinical practice and research purposes), and design studies to test appropriate interventions. Significant gaps in the evidence to support clinical decision-making and care remain; therefore, there is a need for the medical and public health communities to conduct research in this area and to address the methodological issues that complicate research in this entity.

Studies of AKD should include large clinical datasets supplemented by administrative data (e.g., diagnosis codes). Large clinical datasets are available in most resource-rich regions but are almost non-existent in resource-poor regions. However, there is evidence that prospective epidemiological data on AKD and CKD are available in low-income countries with the support of the international nephrology community However, even in resource-rich settings, integration between care transitions or across providers is often poor (i.e., inadequate communication between primary care and specialists and vice versa). Because AKD occurs in a variety of settings (community and hospital), we need comprehensive datasets that can provide information on (i) population incidence and prevalence; (ii) prognosis across the entire disease spectrum, not just the most obvious selected subset; and (iii) the degree of variation present.

To achieve this goal, prospective studies are also needed, especially in countries without well-established electronic medical record systems. To go beyond the basic prognostic questions, we must better understand the specific time windows and causes of health deterioration; therefore, we need to collect detailed clinical data through a series of data collection points, regardless of clinical status, to avoid the inherent bias (indication confounding) that arises from examining and treating patients, which occurs when data collection is dependent on clinical causes. Without continuous monitoring, we will not be able to determine whether individuals are experiencing adverse outcomes, and deterioration in renal or cardiovascular function (or other events) gradually or abruptly in the community.

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Norbert H. Lameire¹, Adeera Levin², John A. Kellum³, Michael Cheung⁴ , Michel Jadoul⁵ , Wolfgang C. Winkelmayer⁶ and Paul E. Stevens⁷

1. Renal Division, Department of Medicine, University Hospital Ghent, Ghent, Belgium;

2. Division of Nephrology, The University of British Columbia, Vancouver, British Columbia, Canada;

3. Department of Critical Care Medicine, Center for Critical Care Nephrology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA;

4. KDIGO, Brussels, Belgium;

5. Cliniques Universitaires Saint Luc, Université Catholique deLouvain, Brussels, Belgium;

6. Selzman Institute for Kidney Health, Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA;

7. Kent Kidney Care Centre, East Kent Hospitals University NHS Foundation Trust, Canterbury, UK