Diagnosis,evaluation, and management of acute kidney injury: a KDIGO summary (Part 1)

Acute kidney injury (AKI) is a common and serious problem affecting millions and causing death and disability for many. In 2012, Kidney Disease: Improving Global Outcomes completed the first ever, international, multidisciplinary, clinical practice guideline for AKI. The guideline is based on evidence review and appraisal, and covers AKI definition, risk assessment, evaluation, prevention, and treatment. In this review we summarize key aspects of the guideline including definition and staging of AKI, as well as evaluation and nondialytic management. Contrast-induced AKI and management of renal replacement therapy will be addressed in a separate review. Treatment recommendations are based on systematic reviews of relevant trials. Appraisal of the quality of the evidence and the strength of recommendations followed the Grading of Recommendations Assessment, Development and Evaluation approach. Limitations of the evidence are discussed and a detailed rationale for each recommendation is provided.     

Renal recovery after acute kidney injury

Acute kidney injury (AKI) is a frequent complication of critical illness and carries a significant risk of short- and long-term mortality, chronic kidney disease (CKD) and cardiovascular events. The degree of renal recovery from AKI may substantially affect these long-term endpoints. Therefore maximising recovery of renal function should be the goal of any AKI prevention and treatment strategy. Defining renal recovery is far from straightforward due in part to the limitations of the tests available to assess renal function. Here, we discuss common pitfalls in the evaluation of renal recovery and provide suggestions for improved assessment in the future. We review the epidemiology of renal recovery and of the association between AKI and the development of CKD. Finally, we stress the importance of post-discharge follow-up of AKI patients and make suggestions for its incorporation into clinical practice. Summary key points are that risk factors for non-recovery of AKI are age, CKD, comorbidity, higher severity of AKI and acute disease scores. Second, AKI and CKD are mutually related and seem to have a common denominator. Third, despite its limitations full recovery of AKI may best be defined as the absence of AKI criteria, and partial recovery as a fall in AKI stage. Fourth, after an episode of AKI, serial follow-up measurements of serum creatinine and proteinuria are warranted to diagnose renal impairment and prevent further progression. Measures to promote recovery are similar to those preventing renal harm. Specific interventions promoting repair are still experimental.     

Clinical review: Drug metabolism and nonrenal clearance in acute kidney injury

Decreased renal drug clearance is an obvious consequence of acute kidney injury (AKI). However, there is growing evidence to suggest that nonrenal drug clearance is also affected. Data derived from human and animal studies suggest that hepatic drug metabolism and transporter function are components of nonrenal clearance affected by AKI. Acute kidney injury may also impair the clearance of formed metabolites. The fact that AKI does not solely influence kidney function may have important implications for drug dosing, not only of renally eliminated drugs but also of those that are hepatically cleared. A review of the literature addressing the topic of drug metabolism and clearance alterations in AKI reveals that changes in nonrenal clearance are highly complicated and poorly studied, but they may be quite common. At present, our understanding of how AKI affects drug metabolism and nonrenal clearance is limited. However, based on the available evidence, clinicians should be cognizant that even hepatically eliminated drugs and formed drug metabolites may accumulate during AKI, and renal replacement therapy may affect nonrenal clearance as well as drug metabolite clearance.     

急性肾损伤的流行病学研究现状

急性肾损伤（AKI）是由不同原因引起肾脏滤过功能短期内急性减退或丧失导致的临床综合征，是影响人类健康的重要疾病。近年来，AKI的发病率和死亡率都持续上升。国内外学者对AKI的流行病学做了很多研究，但由于各研究采用的诊断标准、诊断指标、患者人群、地域和观察时点等的不同，导致统计数据的差异较大。在早期，中国的AKI流行病学调查研究较少，且多为单中心、小样本研究数据，报道的发病率明显低于发达国家。近几年来，我国在住院患者和重症监护治疗病房重症患者AKI流行病学研究方面均取得了较大进展。本文对国内外各个临床背景下的AKI流行病学研究现状进行综述，旨在介绍AKI的发病情况和严重程度，以及近几年来我国学者对AKI流行病学的研究成果。     

Fluid management in acute kidney injury

Acute kidney injury (AKI) and fluids are closely linked through oliguria, which is a marker of the former and a trigger for administration of the latter. Recent progress in this field has challenged the physiological and clinical rational of using oliguria as a trigger for the administration of fluid and brought attention to the delicate balance between benefits and harms of different aspects of fluid management in critically ill patients, in particular those with AKI. This narrative review addresses various aspects of fluid management in AKI outlining physiological aspects, the effects of crystalloids and colloids on kidney function and the effect of various resuscitation and de-resuscitation strategies on the course and outcome of AKI.     

New insights on intravenous fluids, diuretics and acute kidney injury

Acute kidney injury (AKI) is commonly and increasingly encountered in patients with critical illness. Fluid therapy is the cornerstone for the prevention and management of critically ill patients with AKI. New data have emerged that have raised concern that specific types of fluid (i.e. hydroxyethylstarch) may either contribute to or exacerbate AKI. Additional data have accumulated to indicate that the unnecessary accumulation of fluid and volume overload can negatively impact clinical outcomes. This finding may be further compounded in patients with oliguric AKI where solute and free water elimination are impaired. Diuretic therapy in AKI remains controversial. However, diuretic use is common, despite a paucity of evidence to show improved clinical outcomes. There are few therapeutic interventions proven to impact the clinical course and outcome of critically ill patients with established AKI. Current management strategies center largely on supportive care, with rapid resuscitation, removal of the stimulus contributing to AKI, judicious avoidance of complications, and allowing time for recovery. In this review, we explore recent insights on intravenous fluid therapy, volume overload, and diuretic therapy in the context of the critically ill patients with AKI.     

Inflammation in acute kidney injury

Ischemia-reperfusion injury (IRI) is one of the major causes of acute kidney injury (AKI) and evidence supporting the involvement of both innate and adaptive immunity in renal IRI has accumulated in recent years. In addition to leukocytes, kidney endothelial cells promote inflammation after IRI by increasing adhesion molecule expression and vascular permeability. Kidney tubular epithelial cells increase complement binding and upregulate toll-like receptors, both of which lead to cytokine/chemokine production in IRI. Activation of kidney resident dendritic cells, interferon-gamma-producing neutrophils, infiltrating macrophages, CD4+ T cells, B cells and invariant natural killer T cells are all implicated in the pathogenesis of AKI. The complex interplay between innate and adaptive immunity in renal IRI is still not completely understood, but major advances have been made. This review summarizes these recent advances to further our understanding of the immune mechanisms of acute kidney injury.     

Urinary biomarkers in septic acute kidney injury

Objective To appraise the literature on the value of urinary biomarkers in septic acute kidney injury (AKI). Design Systematic review. Setting Academic medical centre. Patients and participants Human studies of urinary biomarkers. Interventions None. Measurements and results Fourteen articles fulfilled inclusion criteria. Most studies were small, single-centre, and included mixed medical/surgical adult populations. Few focused solely on septic AKI and all had notable limitations. Retrieved articles included data on low-molecular-weight proteins (β₂-microglobulin, α₁-microglobulin, adenosine deaminase binding protein, retinol binding protein, cystatin C, renal tubular epithelial antigen-1), enzymes (N-acetyl-β-glucosaminidase, alanine-aminopeptidase, alkaline phosphatase; lactate dehydrogenase, α/π-glutathione-S-transferase, γ-glutamyl transpeptidase), cytokines [platelet activating factor (PAF), interleukin-18 (IL-18)] and other biomarkers [kidney injury molecule-1, Na/H exchanger isoform-3 (NHE3)]. Increased PAF, IL-18, and NHE3 were detected early in septic AKI and preceded overt kidney failure. Several additional biomarkers were evident early in AKI; however, their diagnostic value in sepsis remains unknown. In one study, IL-18 excretion was higher in septic than in non-septic AKI. IL-18 also predicted deterioration in kidney function, with increased values preceding clinically significant kidney failure by 24–48 h. Detection of cystatin C, α₁-microglobulin, and IL-18 predicted need for renal replacement therapy (RRT). Conclusions Few clinical studies of urinary biomarkers in AKI have included septic patients. However, there is promising evidence that selected biomarkers may aid in the early detection of AKI in sepsis and may have value for predicting subsequent deterioration in kidney function. Additional prospective studies are needed to accurately describe their diagnostic and prognostic value in septic AKI.     

脓毒症诱导急性肾损伤的研究进展

脓毒症是一种发病急、病情进展迅速、病死率高的危重疾病,急性肾损伤(AKI)被认为是预测脓毒症患者死亡的独立危险因素,但脓毒症诱导AKI的机制并不十分清楚.另外,RIFLE 标准中的血清肌酐增加和尿量减少已经使我们能够在相对早的阶段诊断AKI,中性粒细胞明胶酶相关载脂蛋白(NGAL)作为肾损伤的一种早期标志物,在诊断及早期治疗干预中可能发挥潜在的作用.本文在此对脓毒症诱导的AKI发病机制、早期诊断及生物学标志物的研究进展做一探讨.     

Radiocontrast-induced acute kidney injury

Many radiographic studies and procedures use iodinated contrast media and consequently pose the risk of contrast-induced acute kidney injury (AKI). This is an important complication, which accounts for a significant number of cases of hospital-acquired renal failure associated increased hospital length of stay and increased mortality. Sustained reductions in renal blood flow, hypoxic injury, direct cellular toxicity by the contrast media, and superimposed organ injury are all believed to play a role in this form of AKI. Avoidance of dehydration and multimodality prevention measures may reduce rates of this problem in patients at risk. Contrast-induced AKI is likely to remain a significant challenge for specialists in the future since the patient population is aging, chronic kidney disease and diabetes are coming more common, and use of iodinated contrast is growing.     

Distant-organ changes after acute kidney injury

Acute kidney injury (AKI) contributes significantly to morbidity and mortality in both adults and children. While clinical data suggest that AKI contributes to and exacerbates multiorgan failure, the physiologic and molecular mechanisms responsible for these interactions were previously unknown. New data linking AKI with distant-organ dysfunction includes evidence that inflammatory cascades are abnormal after organ injury. Leukocyte trafficking, cytokine expression, cell adhesion-molecule expression and membrane ion and water-channel expression in distant organs are deranged after kidney injury. The responses to oxidative stress after AKI are also altered, suggesting complex mechanisms of crosstalk between the injured kidney and distant organs. Novel methodologies, including genomics and proteomics, are now being employed to unravel interorgan communication to accelerate clinically meaningful discovery for this serious disease.     

Acute kidney injury in sepsis

Acute kidney injury (AKI) and sepsis carry consensus definitions. The simultaneous presence of both identifies septic AKI. Septic AKI is the most common AKI syndrome in ICU and accounts for approximately half of all such AKI. Its pathophysiology remains poorly understood, but animal models and lack of histological changes suggest that, at least initially, septic AKI may be a functional phenomenon with combined microvascular shunting and tubular cell stress. The diagnosis remains based on clinical assessment and measurement of urinary output and serum creatinine. However, multiple biomarkers and especially cell cycle arrest biomarkers are gaining acceptance. Prevention of septic AKI remains based on the treatment of sepsis and on early resuscitation. Such resuscitation relies on the judicious use of both fluids and vasoactive drugs. In particular, there is strong evidence that starch-containing fluids are nephrotoxic and decrease renal function and suggestive evidence that chloride-rich fluid may also adversely affect renal function. Vasoactive drugs have variable effects on renal function in septic AKI. At this time, norepinephrine is the dominant agent, but vasopressin may also have a role. Despite supportive therapies, renal function may be temporarily or completely lost. In such patients, renal replacement therapy (RRT) becomes necessary. The optimal intensity of this therapy has been established, while the timing of when to commence RRT is now a focus of investigation. If sepsis resolves, the majority of patients recover renal function. Yet, even a single episode of septic AKI is associated with increased subsequent risk of chronic kidney disease.     

The intensive care medicine agenda on acute kidney injury

Acute kidney injury (AKI) is a common complication in the critically ill. Current standard of care mainly relies on identification of patients at risk, haemodynamic optimization, avoidance of nephrotoxicity and the use of renal replacement therapy (RRT) in established AKI. The detection of early biomarkers of renal tissue damage is a recent development that allows amending the late and insensitive diagnosis with current AKI criteria. Increasing evidence suggests that the consequences of an episode of AKI extend long beyond the acute hospitalization. Citrate has been established as the anticoagulant of choice for continuous RRT. Conflicting results have been published on the optimal timing of RRT and on the renoprotective effect of remote ischaemic preconditioning. Recent research has contradicted that acute tubular necrosis is the common pathology in AKI, that septic AKI is due to global kidney hypoperfusion, that aggressive fluid therapy benefits the kidney, that vasopressor therapy harms the kidney and that high doses of RRT improve outcome. Remaining uncertainties include the impact of aetiology and clinical context on pathophysiology, therapy and prognosis, the clinical benefit of biomarker-driven interventions, the optimal mode of RRT to improve short- and long-term patient and kidney outcomes, the contribution of AKI to failure of other organs and the optimal approach for assessing and promoting renal recovery. Based on the established gaps in current knowledge the trials that must have priority in the coming 10 years are proposed together with the definition of appropriate clinical endpoints.     

The promise of immune cell therapy for acute kidney injury

Acute kidney injury (AKI) often results from ischemia reperfusion, sepsis, or exposure to nephrotoxins and is associated with a high rate of mortality and morbidity. Advances in understanding the pathophysiology of AKI may lead to the development of specific therapies. Although there is evidence of an important role for immune cells in AKI, the specific relevant populations and the mechanisms of their actions are unclear. In this issue of the JCI, Li et al. demonstrate that adenosine manipulates DC responses to kidney injury, raising hope that immunotherapy could be a tangible approach to AKI.     

Conflict between guideline methodologic quality and recommendation validity: a potential problem for practitioners

BACKGROUND: It is not clear if good methodologic quality in current practice guidelines necessarily leads to more valid recommendations, i.e., those that are supported with consistent research evidence or, when evidence is conflicting or lacking, with sufficient consensus among the guideline development team. To help clarify this issue, we assessed whether there is a link between methodologic quality and recommendation validity in practice guidelines for the use of laboratory tests in the management of patients with non-small cell lung cancer (NSCLC). METHODS: We conducted a systematic review of data on laboratory tests in NSCLC published in English or in French within the last 10 years and retrieved 11 practice guidelines for the use of these tests. The guidelines were critically appraised and scored for methodologic quality and recommendation validity based on the Appraisal of Guidelines Research and Evaluation (AGREE) criteria and on the systematic review. RESULTS: Overall, these 11 guidelines had considerable shortcomings in methodologic quality and, to a lesser extent, in recommendation validity. Practice guidelines with the best methodologic quality were not necessarily the most valid in their recommendations, and conversely. CONCLUSIONS: Poor methodologic quality and lack of recommendation validity in laboratory medicine call for methodologic standards of guideline development and for international collaboration of guideline development agencies. We advise readers of guidelines to critically evaluate the methods used as well as the content of the recommendations before adopting them for use in practice.     

Plasma neutrophil gelatinase-associated lipocalin in acute kidney injury superimposed on chronic kidney disease after cardiac surgery: a multicenter prospective study

Introduction

Plasma neutrophil gelatinase-associated lipocalin (NGAL) is reportedly useful for post-cardiac surgery acute kidney injury (AKI). Although chronic kidney disease (CKD) is a strong risk factor for AKI development, no clinical evaluation of plasma NGAL has specifically examined AKI occurring in patients with CKD. This study evaluated plasma NGAL in AKI superimposed on CKD after cardiac surgery.

Methods

This study prospectively evaluated 146 adult patients with scheduled cardiac surgery at 2 general hospitals. Plasma NGAL was measured before surgery, at ICU arrival after surgery (0 hours), and 2, 4, 12, 24, 36, and 60 hours after ICU arrival.

Results

Based on the Kidney Disease Improving Global Outcomes (KDIGO) CKD guideline, 72 (49.3%) were diagnosed as having CKD. Of 146 patients, 53 (36.3%) developed AKI after surgery. Multiple logistic regression analysis revealed that preoperative plasma NGAL, estimated glomerular filtration rate (eGFR), and operation time are significantly associated with AKI occurrence after surgery. Plasma NGAL in AKI measured after surgery was significantly higher than in non-AKI irrespective of CKD complication. However, transient decrease of plasma NGAL at 0 to 4 hours was observed especially in AKI superimposed on CKD. Plasma NGAL peaked earlier than serum creatinine and at the same time in mild AKI and AKI superimposed on CKD with increased preoperative plasma NGAL (>300 ng/ml). Although AKI superimposed on CKD showed the highest plasma NGAL levels after surgery, plasma NGAL alone was insufficient to discriminate de novo AKI from CKD without AKI after surgery. Receiver operating characteristics analysis revealed different cutoff values of AKI for CKD and non-CKD patients.

Conclusions

Results show the distinct features of plasma NGAL in AKI superimposed on CKD after cardiac surgery: 1) increased preoperative plasma NGAL is an independent risk factor for post-cardiac surgery AKI; 2) plasma NGAL showed an earlier peak than serum creatinine did, indicating that plasma NGAL can predict the recovery of AKI earlier; 3) different cutoff values of post-operative plasma NGAL are necessary to detect AKI superimposed on CKD distinctly from de novo AKI. Further investigation is necessary to confirm these findings because this study examined a small number of patients.     

Management of acute kidney injury in gastrointestinal tumor: An overview

Gastrointestinal tumors remain a global health problem. Acute kidney injury (AKI) is a common complication during the treatment of gastrointestinal tumors. AKI can cause a decrease in the remission rate and an increase in mortality. In this review, we analyzed the causes and risk factors for AKI in gastrointestinal tumor patients. The possible mechanisms of AKI were divided into three groups: pretreatment, intrafraction and post-treatment causes. Treatment and prevention measures were proposed according to various factors to provide guidance to clinicians and oncologists that can reduce the incidence of AKI and improve the quality of life and survival rate of gastrointestinal tumor patients.     

Diagnostic work-up and specific causes of acute kidney injury

Acute kidney injury (AKI) is common in critically ill patients and associated with grim short- and long-term outcome. Although in the vast majority of cases AKI is multifactorial, with sepsis, shock and nephrotoxicity accounting for most episodes, specific causes of AKI are not uncommon. Despite remaining uncertainties regarding their prevalence in the ICU, prompt recognition of specific aetiologies of AKI is likely to ensure timely management, limit worsening of renal dysfunction, and ultimately limit renal and systemic consequences of AKI. The ability to recognize conditions that may be associated with specific aetiologies and the appropriate use of clinical imaging, biological and immunological tests, along with optimal assessment of the need for renal biopsies, should be part of routine ICU care. In this review, we summarize uncertainties, current knowledge and recent advances regarding specific types of AKI. We describe the most common specific causes as well as rare aetiologies requiring urgent management, and outline available tools that may be used during the diagnostic work-up along with their limitations.     

Urinalysis and pre-renal acute kidney injury: time to move on

Urinary indices are classically believed to allow differentiation of transient (or pre-renal) acute kidney injury (AKI) from persistent (or acute tubular necrosis) AKI. However, the data validating urinalysis in critically ill patients are weak. In the previous issue of Critical Care, Pons and colleagues demonstrate in a multicenter observational study that sodium and urea excretion fractions as well as urinary over plasma ratios performed poorly as diagnostic tests to separate such entities. This study confirms the limited diagnostic and prognostic ability of urine testing. Together with other studies, this study raises more fundamental questions about the value, meaning and pathophysiologic validity of the pre-renal AKI paradigm and suggests that AKI (like all other forms of organ injury) is a continuum of injury that cannot be neatly divided into functional (pre-renal or transient) or structural (acute tubular necrosis or persistent).In textbook medicine, pre-renal acute kidney injury (AKI) is classically differentiated from other subtypes of AKI such as acute tubular necrosis (ATN) by means of urinary indices such as fractional excretion of sodium or urea. However, this approach has never been validated in critically ill patients.In the previous issue of Critical Care, Pons and colleagues examine the diagnostic accuracy of early changes in several urinary indices to differentiate transient AKI from persistent AKI [1]. In a study in six centers and 244 critically ill patients, they assessed urinalysis against an objective, time-based definition for pre-renal (transient) AKI. In addition, the authors examined dynamic changes in such indices by repeating measurements every 6 hours after ICU admission. Their results confirm the poor performance of urinary indices as diagnostic tools to separate transient AKI from persistent AKI in critical illness. This performance remained low even after exclusion of patients who received diuretics in the previous 6 hours and those with sepsis. The authors correctly conclude that urinary indices remain insufficiently reliable to be clinically relevant.Numerous studies had observed the limited diagnostic or prognostic ability of urinary biochemistry [2-6]. Pons and colleagues confirmed these limits even when objective and verifiable criteria are used to define pre-renal AKI. Beyond the lack of utility of urinary diagnostic tests, this work highlights the absence of a universally accepted gold standard to define pre-renal AKI or transient AKI [7]. Without a gold standard for diagnosing a syndrome in a given patient, the performance of any diagnostic test is likely to be controversial. Indeed, the performance of early biomarkers of renal injury (such as urinary or plasma neutrophil gelatinase-associated lipocalin) to discriminate transient AKI from persisting AKI is also poor [8].Altogether, the results presented by Pons and colleagues should make us question the whole paradigm of pre-renal AKI. Indeed, classically, pre-renal AKI is thought to represent situations of oliguria and azotemia associated with histologically intact nephrons. However, in the absence of a renal biopsy this concept remains purely theoretical. Similarly, there is no evidence that ATN is the histopathological substrate of nonresolving AKI. Early postmortem series in patients with sepsis with or without AKI revealed that renal tubular injury was common in all patients but presented focally and that most renal tubular cells appeared normal [9]. The actual existence of a histopathological lesion-free AKI can therefore be challenged as unrealistic and nonevidence based, at least in septic patients.If histology and urinary biochemistry are unable to discriminate between these two entities, one possible logical explanation may be that they simply do not exist except in the mind of some physicians. A more pragmatic definition based on the duration of AKI is similarly problematic because determining the correct cutoff point to separate any two entities is impossible. Why choose 72 hours, not 24 or 48 hours? In a large epidemiological study (more than 3,000 AKI patients), Uchino and colleagues found that, compared with no AKI, the odds of dying in hospital increased by a factor of two in patients with transient (<3 days) AKI and by a factor of six in those with persistent (>3 days) AKI [10]. However, the mortality increased with the duration of AKI without any particular cutoff point. Hence, like every other disease known to man, AKI seems to be a continuum and its duration, consequences and reversibility are more probably related to the severity and duration of the injury than to different pathophysiological mechanisms. Now is the time to let go of outdated and invalid concepts such as pre-renal AKI, transient AKI, or ATN that, in critically ill patients, have no supportive evidence.In conclusion, Pons and colleagues'' study is important because it confirms the limited diagnostic or prognostic ability of urinary biochemistry in critical care and also because it challenges the pre-renal AKI paradigm. Pre-renal AKI and ATN probably do not exist in the way we classically conceptualize them. It is time to move on.