Acute kidney injury, its definition, and treatment in adults: guidelines and reality (2023)

Introduction

Over thepast decades, there has been asignificant increase in theincidence of acute kidney injury (AKI),1 especially in theolder population (>65 years). Thenumber of AKI cases in thehospitalized population have more than doubled; it also concerns AKI requiring dialysis.2 Atthe same time, in high-income countries, we have witnessed aprofound change in thedisease spectrum (Figure 1). It is aconsequence of thespectacular progress in medicine, leading to aconsiderable life extension. In high-income countries, AKI develops in up to 20% of hospitalized patients, which is approximately 50% of adult patients receiving intensive care, and in 1 in 4 pediatric patients receiving intensive care.3,4 In adults, it has become adisease of theolder, who, with many comorbidities and chronic degenerative organ changes, are much more vulnerable to acute insults. Many of them have already had some form of chronic kidney disease (CKD), called “AKI on CKD.” Patients who survive extensive, high-risk cardiovascular or abdominal surgery, extensive trauma, or burns and those after hematopoietic stem cell or solid organ transplant often develop sepsis and other complications. In many of them, AKI occurs as alate event, often as amanifestation of multiorgan dysfunction syndrome. Therefore, in the1970s and 1980s, patients with severe AKI were treated mainly in general wards. Today, most of them are referred to intensive care units (ICUs). Such achange in thespectrum of AKI must have influenced patients’ survival; that is why mortality in severe AKI remains very high, despite several treatment improvements. In patients requiring renal replacement therapy (RRT), theoverall 90-day mortality ranges between 44% and 60%.5-7 Moreover, those who survive thehospitalization period are atrisk of developing long-term complications associated with asubstantial cost burden. Recent studies have consistently shown that, in both adults and children, AKI and its stage is astrong, independent risk factor for CKD development.8,9 Themechanisms of progression from AKI to CKD have been partially elucidated in experimental studies. They include maladaptive repair and endothelial injury, which result in nephron and capillary dropout, interstitial fibrosis, and theprogressive decline of glomerular filtration rate (GFR).10-12 In those with already existing CKD, AKI may significantly accelerate its progression to theend-stage disease. Patients who recover from AKI also remain athigher risk of developing hypertension and cardiovascular events.10,13,14

Acute kidney injury, its definition, and treatment in adults: guidelines and reality (1)

In thelast decades, much research has been conducted to improve our understanding of AKI as well to standardize its definition and diagnostic criteria. It was necessary, since there had been more than 35 definitions in use, based on various serum creatinine levels or its clearances obtained using different methods, precluding any data or study comparisons in thefield. Thefirst consensus definition of AKI, theRisk, Injury, Failure, Loss of kidney function, and End-stage kidney disease (RIFLE) criteria, were published in 2003, as ajoint work of intensivists and nephrologists,15 subsequently changed by thesame group to theAcute Kidney Injury Network (AKIN) criteria 3 years later,16 and finally unified by theKidney Disease: Improving Global Outcomes (KDIGO) group and published in 201217 (Table 1). TheKDIGO criteria, or classification, refer to thetime of AKI development and are based on serum creatinine level increase and / or urine output decrease. It is defined as anincrease in serum creatinine levels atleast by 0.3mg/dl within 48 hours or 1.5-fold thebaseline, which is known or presumed to have occurred within the preceding 7 days, or—according to theurine output criterion—as urine volume below 0.5ml/kg/hour for atleast 6 hours.

Acute kidney injury, its definition, and treatment in adults: guidelines and reality (2)

Table1. Acute kidney disease staging according to theKidney Disease: Improving Global Outcomes classification8

Stage

Serum creatinine levels

Urine output

1

1.5–1.9-fold higher than baseline or increase≥0.3mg/dl

<0.5ml/kg/hr for 6–12 hrs

2

2–2.9-fold higher than baseline

<0.5ml/kg/hr for≥12 hrs

3

3-fold higher than baseline or increase≥4mg/dl, or initiation of RRT

<0.3ml/kg/hr for≥24 hrs or anuria for≥12 hrs

Abbreviations: RRT, renal replacement therapy

TheKDIGO definition has been developed to achieve several objectives: to unify terminology, to facilitate research and comparability among studies, to raise theawareness of AKI among general practitioners and non-nephrologists, to enable its earlier detection and, possibly, prevention, and, ultimately, to improve patient outcomes. Let us have aquick look athow it has fulfilled these goals.

Question 1: is theKDIGO definition of acute kidney injury valuable in clinical research and global epidemiology?

Theanswer is equivocal. From 2012, when it was introduced, theclassification has been evaluated and validated in several studies and claimed by many as useful in comparing outcomes between AKI studies and interventions.18-22 Theadoption of theKDIGO staging system also allowed for thestandardization of entry criteria and endpoints in theclinical trials of AKI, although there have been numerous studies that used classification systems other than theKDIGO criteria.23-28

However, thequestion remains as to whether it is areliable tool for theestimation of AKI global epidemiology? This issue has been amatter of aheated debate. Probably, thehighest controversy is related to thepossibility of diagnosing AKI based on theincrease in serum creatinine levels≥0.3mg/dl within 48 hours. It was criticized by many as atoo small alteration to eliminate laboratory errors or physiologic fluctuations, which may misclassify healthy patients as well as patients with CKD and baseline serum creatinine levels≥1.5mg/dl,29 in whom such small increases may represent normal daily variations. Another limitation of theKDIGO definition is thedetermination of abaseline creatinine level when thetrue value is unknown. None of theproposed methods seems to be reliable, and all of them may be thesource of substantial errors. Theincorporation of RRT initiation as apossible definition of stage 3 disease is maybe even more unfavorable, since this criterion is subjective.

Thediuresis criterion, although reported to increase early AKI detection rates, has raised many doubts. Urine output is easy and inexpensive to determine, but it can be significantly changed by theuse of diuretics, fluid therapy, and hemodynamic status. Therefore, it may increase diagnostic false-positive rates. Of note, in patients who have undergone major surgical procedures, oliguria may be anappropriate physiological response to stress related to surgery. Also, theproposed threshold is controversial. As rightly pointed out by Erdbruegger and Okusa,30 in a70-kg adult man, diuresis≤0.5ml/kg/hour for 6 hours would represent aurine volume as high as 840ml/d, which seems to be anadequate response to limited fluid intake. Last but not least, what about nonoliguric AKI?

However, in our opinion, thegreatest uncertainty about thevalue of theKDIGO classification in clinical research is thefact that thedefinition does not differentiate between 2 extreme forms of AKI: thefunctional one, formerly called prerenal azotemia, and structural tubular injury. Prerenal kidney injury is not clearly defined by theKDIGO classification and seems often to be aneglected issue. Unfortunately, this may be aserious obstacle in theaccurate estimation of AKI global epidemiology and should be overcome.

Many shortcomings of theKDIGO definition result from thefact that it is based on serum creatinine levels, which are imperfect biomarkers of AKI, being affected by numerous factors. In their excellent review, Thomas et al31 delineated as many as 14 various acute or chronic factors that may alter serum creatinine levels, making it difficult to establish anaccurate diagnosis. The serum creatinine level is afunctional marker, and its rise does not necessarily represent kidney injury. There are numerous examples of hemodynamically driven, transient serum creatinine elevations, like in patients with prerenal azotemia and hepatorenal or cardiorenal syndrome. In anumber of these clinical situations, thekidney is not injured, and its response to reduced intravascular volume is homeostatic, thus, absolutely normal and can be life-saving. However, tubular damage can occur in some situations, but it is insufficient to considerably change serum creatinine levels in thevolume-overloaded patient. Theincorporation of structural biomarkers that directly indicate tubular damage could improve thediagnostic value of theAKI definition.

Several recent cardiologic studies have advocated theneed to redefine AKI, which is often replaced in cardiology with theterm “worsening renal function (WRF)” in patients with acute heart failure (HF), linking biochemical changes with clinical status.32-36 Worsening renal function that has occurred in thesetting of acute HF is classified into 2 categories, ie, true and pseudo-worsening renal function, by theextension of theRIFLE / AKIN criteria and combining them with thepresence or absence of worsening HF.13,14,33,36 True WRF is diagnosed in patients with thesimultaneous presence of worsening HF, defined as thedeterioration or no improvement of HF that requires intensified therapy during thefirst 3 days of hospitalization. Those who demonstrate only isolated alterations in creatinine levels or eGFR are classified as having pseudo-WRF. Therationale behind this distinction is that not every increase in serum creatinine levels in acute HF indicates kidney injury or dysfunction with unfavorable consequences, and anincrease in creatinine levels with simultaneous effective decongestion and hemoconcentration is often related to better outcomes.33-35 Recently, Sokolski et al36 investigated thedefinition of true WRF in relation to clinical characteristics and outcomes in patients with acute HF. They found that while 14% of patients developed WRF during hospitalization, achange in creatinine or eGFR was associated with unfavorable clinical settings only in 4%. In theremaining 10%, theclinical course was uneventful and did not differ from that observed in patients without WRF. It may be of interest to compare WRF with theAKI definition proposed by theKDIGO group.

Unfortunately, despite extensive research, the uphill battle to find reliable structural biomarkers of AKI may last longer than we expect, provided they can ever be found. Therefore, we agree that the AKI definition endorsed by the KDIGO guidelines, with serum creatinine levels as themain parameter, remains thebest option for clinical research. However, we should be aware of its weakness in theestimation of AKI global epidemiology, since it may be apotent source of mainly false-positive results.

Considering epidemiological studies, one cannot forget that many of them use large administrative databases based on theInternational Classification of Diseases, Tenth Revision (ICD-10) coding, which neither accounts for thecurrent AKI definition nor distinguishes between various AKI stages. Moreover, as stressed by several researchers, changes in discharge coding practices, driven by reimbursement systems, may, in part, explain thedramatic rises in theincidence of AKI observed in some countries over thepast 2 decades.37-39 TheInternational Classification of Diseases, Eleventh Revision is on its way and is expected to replace ICD-10 on January 1, 2022. It will be integrated with theKDIGO classification, including thecurrent definition and differentiation between AKI stages. If and to what extent it will improve AKI identification remains unclear.

Question 2: is theKDIGO definition of acute kidney injury helpful in everyday clinical practice?

We do not think so. There are atleast 3 crucial questions, which aclinician facing apatient with anabrupt worsening of kidney function should ask. Is thepatient in alife-threatening condition? What is (are) themost probable cause(s) of AKI? How should they manage thepatient? TheKDIGO definition leaves us without any answer to these issues. Thereason for that is its complete lack of theclinical context, which can vary alot, with entirely different forms of worsened kidney function such as hemodynamic AKI, blockage of urine flow, and adecrease in renal secretion due to tubular damage.

For this reason, in our practice, we prefer to use theold pathophysiological classification, which categorizes thecauses of AKI into 3 groups: prerenal (renal hypoperfusion), postrenal (obstruction of theurinary tract), and intrinsic (structural damage to thekidney), which can be related to ischemia, nephrotoxins, or inflammatory processes. Thestrengths of this old approach lie in what remains theweakness of theRIFLE, AKIN, and KDIGO classifications, namely, limited complexity, memorability, and therelation to theetiology and pathophysiology of thecondition. It determines theappropriate diagnostic steps and provides us with vital therapeutic suggestions. Therefore, when keeping in mind that this old classification simplifies ahighly complex clinical syndrome and, in many cases, thepathogenesis of AKI is multifactorial, we still recommend its use to our students and trainees.

Although we do not find theKDIGO criteria much helpful in theeveryday care of patients with AKI, we do recognize that there are some positive consequences of introducing them to clinical practice. Most importantly, it raised theawareness of AKI among physicians. Theadoption of theconsensus definition has enabled us to build electronic AKI alerts, similar to other healthcare information technology systems, coupled with hospital-wide AKI guidelines and educational programs, warning clinicians of possible AKI and supporting them in implementing appropriate nephroprotective measures. These include thediscontinuation of nephrotoxic agents, avoidance of diuretics and radiocontrast media, ensuring anadequate volume status, hemodynamic management in patients with hypotension, monitoring urine output and serum creatinine levels, as well as additional diagnostic workup (ie, urinalysis, kidney ultrasound). In numerous alert systems, when thepatient is diagnosed with AKI, arequest for nephrology consultation is automatically generated. Finally, these systems may identify candidates for appropriate outpatient follow-up and monitoring for long-term renal recovery after AKI. It remains unclear whether these systems will meet theexpectations. Theresults of somestudies, mostly from theUnited Kingdom, are inconsistent, with some of them showing animprovement in thecare of patients with AKI, and others demonstrating no substantial benefit, theincreased use of resources, and higher hospitalization rates.40-42

Question 3: is theKDIGO definition of acute kidney injury helpful in thetreatment of critically ill patients with acute kidney injury?

In thetreatment of critically ill patients, theclinical context matters most. Thepresence of sepsis, failure of other organs, and malnutrition may dramatically influence theoutcome. Thesequence of clinical events is also essential. In thecase when AKI develops late, after ICU admission, as a manifestation of multiple organ failure, theprognosis seems to be much worse. Since these patients are often in ahighly catabolic state, thedevelopment of metabolic disorders may rapidly progress and be accompanied by severe acidosis and hyperkalemia, while extensive fluid resuscitation and parenteral nutrition pose arisk of severe fluid overload. Of note, in critically ill patients, theseverity of AKI can be underestimated due to dilution of serum creatinine by fluid accumulation, increased or decreased creatinine production, and loss of muscle mass, and may delay therapeutic decisions.

In ICU practice, theseverity of renal failure is often evaluated by combining thefunctional parameters of thekidneys and other organs. In their recently published systematic review, daHora Passos et al24 evaluated thecriteria used to determine theseverity and progression of kidney injury in multicenter randomized clinical trials conducted in ICUs, with mortality regarded as aprimary outcome. Out of 46 studies, only 7 (15.2%) included mean or median serum creatinine levels. TheSequential Organ Failure Assessment (SOFA) renal score was themost commonly used system to define and quantify thefrequency of AKI (43.5% of studies), while the RIFLE / AKIN / KDIGO criteria were used only in 5trials (10.9%). Theauthors stated that their findings may raise concerns about theevidence-based use of these classification systems in theclinical management of critically ill patients.

Initiation of renal replacement therapy

Classic indications for dialysis in AKI are well known; they are based mainly on thedevelopment of refractory to diuretics, life-threatening fluid overload and severe solute imbalances, accompanied by hyperkalemia and acidosis. However, in theabsence of these clearly urgent indications, thedecision when to initiate RRT in critically ill patients with AKI is often much more difficult and—despite aremarkable progress in intensive care medicine during thelast decades—remains asubject of controversy. Notably, although RRT is inevitable and life-saving in many cases of severe AKI, it may also negatively impact theoutcomes of these patients. Dialysis exposes them to (or aggravates thealready present) hemodynamic instability with deleterious intradialytic hypotension, anticoagulation-induced bleeding, vascular access–related bacteremia, and inflammatory stress due to bioincompatibility of anextracorporeal circuit. One of thekey untoward effects of RRT is anot entirely predictable change in thepharmacokinetics of various therapeutic agents, especially antibiotics, posing asubstantial risk of underdosing them.

Theongoing discussion entitled “early versus late”43-49 seems to be as passionate as abit pointless, since what is early for one patient may be too late for another one. Recently, as aresult of theAcute Disease Quality Initiative (ADQI) 17th Conference on Continuous RRT, anindividualized approach based on the demand–capacity balance was proposed.50 According to theconsensus, acute RRT should be considered when metabolic and fluid demands exceed thepatient’s total kidney capacity. This “watchful waiting” strategy requires acareful ongoing recognition of theclinical context (causes, theclinical course, theAKI trajectory, nonrenal organ dysfunction, thedegree of fluid overload, chronic comorbidities, accommodation of nutritional and medication needs and other organ support therapies) by theexperienced, optimally multidisciplinary, treatment team.

Recently, theidea of rapid response teams composed of different healthcare professionals (physicians, nurses, and paramedics) was conceived to bring ICU-level skills such as theintensification of fluid resuscitation, anappropriate antimicrobial therapy in previously unrecognized septic shock, and care outside of theICU.51 It also appears that this approach may not only reduce theincidence of AKI but also decrease in-hospital and long-term mortality. However, anincreased workload of active team members has been themajor concern about implementing this system in Polish hospitals.51

Key messages for everyday practice

Thecurrent approach to AKI includes: 1) identification and treatment of theunderlying causes such as volume depletion, hypotension, use of selected drugs, or urinary tract obstruction; 2) removal of any potential insults to minimize additional injury; and 3) supportive measures to maintain optimal fluid, acid–base, and electrolyte balances. In patients with severe AKI, RRT is initiated when these measures fail to provide an adequate and safe control of homeostasis. Astepwise approach for therecognition and management of AKI is presented in Figure2. Thetiming of dialysis initiation as well as its optimal dose remains controversial. It should be related to thegeneral condition of thepatient, capacity of thecardiovascular system and other organs, as well as observed or predicted dynamics of serum potassium and acid–base alterations. In recent years, aconcept of thedifferentiated and individualized approach has been increasingly appreciated,50 according to which RRT should be considered when metabolic and fluid demands exceed the total kidney capacity.

Acute kidney injury, its definition, and treatment in adults: guidelines and reality (3)

Theprognosis in hospital-acquired AKI is generally poor and is associated with high in-hospital and long-term mortality. However, since AKI is not asingle disease yet acomplex, heterogeneous syndrome being acollection of entirely different entities, ranging from those relatively benign such as pre- and postrenal AKI to multiorgan failure, theprognosis widely varies among patients. In addition to thecause, therisk of poor outcomes is determined by avariety of clinical factors including patients’ age, underlying CKD, baseline renal function, failure of other organs, sepsis, chronic comorbidities, stage and length of anAKI episode, and thedegree of renal recovery.

It is suggested that AKI survivors, especially those who develop AKI in thehospital, should be closely followed up, since they are atsubstantial risk of relapse and thesubsequent development of end-stage CKD as well as other adverse outcomes including hypertension and cardiovascular disease. According to the2012 KDIGO guidelines, patients discharged from thehospital with adiagnosis of AKI should be evaluated within 90 days for resolution and new onset or worsening of pre-existing CKD.17 However, data from multiple healthcare systems have indicated that, despite these recommendations, most patients who survive AKI do not see anephrologist and many of them do not receive any follow-up.52-54 Harel et al55 demonstrated that early postdischarge outpatient follow-up with anephrologist in patients after AKI requiring RRT was associated with a24% reduction in mortality during 2 years. Whether postdischarge AKI care will confer areal net benefit needs to be addressed in large clinical trials. Recently, theexperience of 2clinical programs for the care of post-AKI patients were presented: theAcute Kidney Injury Follow-up Clinic for adults in Toronto and theAKI Survivor Clinic for children in Cincinnati.56 Theauthors planned arandomized controlled trial atmultiple centers in Toronto to compare AKI Follow-up Clinic interventions and standard care. Theprimary outcome of this ongoing trial (ClinicalTrials.gov identifier, NCT02483039) includes major adverse kidney events at1 year following anAKI episode; theestimated study completion date is December2022. As thepopulation of AKI survivors is growing, theextension of care on all AKI survivors may be impossible. However, this population is very heterogeneous and it could be reasonable to stratify patients by therisk of AKI development to target those who would most likely benefit from various specific transitional strategies.

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