Due to the inherent limitations of SCr, special interest has been focused on new biomarkers that allow for earlier detection of AKI with improved sensitivity and specificity.

Various biomarkers in both blood and urine have been identified that could be useful for early AKI detection, severity stratification, and prognostic assessment. The most promising biomarkers to date include: Kidney Injury Molecule 1 (KIM-1), Neutrophil Gelatinase-Associated Lipocalin (NGAL), Liver-Fatty Acid Binding Protein (L-FABP), Cystatin C, hemojuvelin, N-Acetyl-Glucosaminidase (NAG), netrin-1, gamma-glutamyl transferase (GGT), glutathione S-transferase (GST), Tissue inhibitor of metalloproteinases-2 (TIMP-2), and Insulin-like growth factor-binding protein 7 (IGFBP-7), among others. These molecules participate in different physiological processes altered during AKI, such as renal parenchyma cell death, inflammatory processes, and increased oxidative stress.

Most of these biomarkers are not currently used for AKI diagnosis in routine clinical practice. These biomarkers denote kidney injury, unlike SCr, which denotes a reduction in kidney function. In at-risk patients, the elevation of biomarkers usually occurs before the increase in SCr. Furthermore, cases may occur where biomarkers increase without a corresponding rise in SCr. This situation defines what is known as subclinical AKI. The importance of subclinical AKI is that it may be associated with a worse prognosis.6 Although KDIGO guidelines have suggested that biomarkers could provide added value to SCr determination—thereby improving early AKI diagnosis and prognosis—they have not yet been implemented in clinical practice. Numerous studies indicate these biomarkers could be used in combination with clinical markers to improve risk prediction. In this regard, since 2012, the U.S. Food and Drug Administration (FDA) has approved the use of the TIMP-2/IGFBP-7 ratio as a biomarker for AKI risk stratification, and it has been recommended in clinical guidelines for cardiac surgery.7 In addition to TIMP-2 and IGFBP-7, other biomarkers such as Cystatin C, hemojuvelin, NGAL, and KIM-18,9 might also be useful in estimating the risk of AKI progression. However, this association is not as clear, as contradictory studies exist or suggest that the relevance of these other biomarkers is limited.10 This disparity in results is related to the high heterogeneity of AKI types, the specific AKI definition used, and the sample size of the studies. Therefore, while great progress has been made in validating and applying new biomarkers for AKI diagnosis and prognosis, further research is needed to improve AKI diagnostics. Because current diagnosis remains based on SCr and not on biomarkers, the term AKI is used rather than “Acute Kidney Lesion”.

AKI is one of the most serious and frequent complications in hospitalized patients, entailing high costs and poor global outcomes. Despite its prevalence, impact, and the fact that it is potentially preventable, the onset of AKI often goes unnoticed and is frequently not even recorded in clinical histories or discharge reports. Recognizing the importance of early diagnosis to implement actions aimed at minimizing kidney injury, the introduction of electronic alert systems (e-alerts) within medical record systems has been evaluated in recent years as part of routine clinical practice. The actual effectiveness of these alerts depends on a combination of patient-specific factors, the underlying disease and type of kidney injury developed, the clinical setting, and, above all, the intervention triggered by this early diagnosis.

Perhaps the most representative reports on the utility of these e-alerts are those from the United Kingdom. At the beginning of the last decade, an AKI electronic alert system was mandatorily implemented in inpatient care within the National Health Service (NHS)-UK, which was subsequently extended to Primary Care in a planned manner. These e-alerts are based on the algorithm described in the National Institute for Health and Care Excellence (NICE) guidelines and define the severity of AKI using the KDIGO classification. Laboratory systems automatically calculate the AKI stage based on SCr levels, using the patient's results from the previous year as the baseline creatinine.

The e-alert itself, in addition to identifying the patient, directs the physician toward a decision-support manual. Under this philosophy, each institution opted for different design and implementation modalities for their e-alerts, resulting in significant variability in both the reporting method (email, pop-up windows in the patient's electronic health record, mobile text messages, etc.) and the various clinical action algorithms. Numerous publications have analyzed the impact following their implementation in the United Kingdom, yielding contradictory results. Consequently, in the absence of careful studies regarding both their efficacy and potential adverse effects, various opinions have emerged suggesting the need to moderate the enthusiasm for this type of e-alert.11

In most published studies, no significant impact has been demonstrated regarding short-term mortality or the requirement for dialysis. Nonetheless, positive results have been found concerning a decrease in the prevalence of hospital-acquired AKI, improvements in clinical management, and a reduction in the mean length of hospital stay.12 Results from recent meta-analyses show a high degree of variability in the design of e-alert systems and indicate that the e-alertper se does not improve outcomes unless it is associated with complementary care measures. In such cases, improvements translate into a shorter time for the modification of nephrotoxic drugs, a more rational application of fluid therapy, diuretics, or vasopressors, and more frequent nephrology consultations; this reduces the rate of severe AKI and increases the proportion of patients who achieve renal function recovery.13,14 Recently, results from a large hospital in Birmingham (UK) have demonstrated that, after two years of follow-up post-implementation of e-alerts, the progression of AKI has decreased, and therefore, it is likely that long-term survival will improve. Readmissions to emergency departments following hospital discharge also decreased, a fact the authors attribute to the reduced use of nephrotoxic agents in these patients. The authors emphasize that even minimal changes in patient management can have significant repercussions on long-term outcomes.15

More recently, the NHS has implemented AKI alerts in Primary Care. These experiences have reported an increase in community AKI detection, improvements in follow-up, shorter times to hospital admission, and higher rates of renal injury recovery. The pros and cons of using e-alerts are summarized in Table 1.12,13,15–19

At the consensus conference of the Acute Disease Quality Initiative (ADQI) in 2015, AKI was recognized as an ideal disease state for the application of machine learning and big data. Since then, artificial intelligence has been used to develop AKI risk scales that allow for the implementation of measures in patients at risk of AKI or with early-stage kidney injury. These Machine Learning (ML) models automatically include many variables and allow for the identification of patients at higher risk of adverse outcomes and the discrimination of different kidney injury subgroups. Models published in different AKI settings lack external validation; therefore, the results are not generalizable to other populations. Furthermore, they predict the risk of AKI at a single point in time rather than continuously. On the other hand, there is significant variability among the analyzed cohorts, which, in most cases, are retrospective. Consequently, while the predictive potential of machine learning algorithms is recognized, they still require improvement. Additionally, these models have demonstrated the ability to predict AKI, but not to prevent its occurrence.18,19

One of the key points in AKI management is maintaining an appropriate hydration status. Currently, a wide variety of solutions are available for volume replacement. However, few studies exist, most of them conducted in the critically ill patient setting, that allow for an evaluation of which of these solutions is the most suitable.

The objective of fluid therapy in critically ill patients, and especially in those with septic shock, is to increase preload in order to augment cardiac output. The challenge lies in maintaining adequate tissue perfusion without leading to overhydration. A weight gain exceeding 10% from baseline has been shown to increase mortality in critically ill patients and could have a deleterious effect on renal function.20

In AKI, whether hospital-acquired or community-acquired, one of the main therapeutic pillars is to optimize correct volumetric resuscitation. Resuscitation likely requires individualization in each case, guided by point-of-care ultrasonography (POCUS), capillary refill assessment, or lactate levels.21 Its use should be continuously reassessed to avoid unnecessary fluid overload.

It must be taken into account that fluid therapy is a pharmacological therapy and, as such, can have deleterious effects. There is no ideal composition among the different types of intravenous fluids used.

Three types of fluids are available: colloids, crystalloids, and blood products. The latter are indicated for hemorrhagic shock and will not be discussed in this document.

Within this category, we distinguish between semisynthetic colloids and albumin. The use of semisynthetic colloids was based on maintaining volumetric expansion for a longer duration with a lower volume load. However, in reality, this effect is lost in septic patients due to an increase in endothelial permeability and a higher probability of acute kidney injury (AKI). For this reason, the Surviving Sepsis Campaign guidelines discourage their use, a position endorsed by regulatory agencies such as the FDA and the European Medicines Agency (EMA).22,23 Although the evidence is not as clear, the use of gelatins or dextrans is likewise discouraged.

Regarding the use of albumin as a colloid, it has been shown to be safe in septic patients with respect to the development of AKI, both in the SAFE study and the ALBIOS study, although it should be avoided in patients with traumatic brain injury.24,25

Within this category, we find 0.9% saline and balanced solutions. The use of large volumes of 0.9% saline (>2 L) is associated with the development of hyperchloremic acidosis, which negatively impacts the glomerular filtration rate. It is linked to vasoconstriction and a decrease in renal blood flow that could predispose to the onset of AKI.26 In an effort to avoid this effect, balanced solutions have lower chloride concentrations and lower osmolarity. Additionally, they utilize lactate or acetate as a buffer. Although the evidence is weak, there appears to be a benefit to using balanced solutions.27,28 The vast majority of studies provide contradictory results; only the SMART trial showed a positive outcome in renal events at 30 days in favor of balanced solutions.21

Diuretic treatment is indicated in patients with hypervolemia. This clinical situation is common in various pathologies where, in addition, a certain degree of AKI often coexists, such as in heart failure (HF), hepatic failure, nephrotic syndrome, or in septic patients. The use of diuretics in the context of critically ill patients remains a subject of debate. Nevertheless, volume status must be closely monitored. Thus, their use—especially loop diuretics—is particularly indicated in situations involving hypervolemia.25,29

Studies conducted on the effect of loop diuretics as a treatment for AKI have yielded controversial results. Although they do not shorten the duration of AKI or impact mortality, they do decrease the duration of oliguria and the need for renal replacement therapy (RRT).30 There are different classes of diuretics depending on their site of action. The choice of type and dosage will depend on the cause of the AKI, its severity, and the accompanying electrolyte and acid-base disturbances. Since there are few randomized studies on the use of diuretics, treatment must be individualized for each clinical situation.25

When initiating treatment, it is recommended to assess potential causes of resistance to standard doses. The most common causes of resistance are described in Table 2. Increasing the dose, using the intravenous route, and concomitant use with albumin can help increase the availability of the drug at the tubular level.

Diuretic types are classified by their site of action:

Loop diuretics. Probably the most commonly used in different types of AKI. They are the most potent diuretics. By blocking the sodium-potassium-chloride cotransporter, they prevent the reabsorption of 20%–25% of the sodium reabsorbed in the renal tubule. They can induce hypotension, primarily due to hypovolemia, but also via vasodilation. Other effects, such as hypokalemia and metabolic alkalosis, occur through the activation of the renin-angiotensin-aldosterone system (RAAS). In rare cases, ototoxicity can occur at high doses, typically with the concomitant use of aminoglycosides.

Chawla et al. standardized the furosemide stress test in critically ill patients, which allows for the assessment of tubular function and predicts progression to more severe kidney injury requiring renal replacement therapy (RRT). Thus, the use of loop diuretics would be recommended for volume control in overhydrated patients who show an adequate response to the stress test.34

Assessing urinary sodium in a spot sample is recommended. Values below 50 mmol/L indicate diuretic resistance in patients with HF and predict a negative sodium balance deficit. Furthermore, hypochloremia is associated with a worse diuretic response in acute HF.This information can help in adopting strategies such as the concomitant use of albumin, 0.9% saline, or hypertonic saline, or combination with other diuretics for sequential nephron blockade.35

In patients with HF and an ejection fraction below 40%, the use of hypertonic saline together with furosemide is associated with an increase in daily urine output, improvement in renal function, decreased hospital stay, and a lower rate of readmission for HF.36

Thiazides. They act by blocking the sodium-chloride transporter in the distal tubule, where 5%–10% of sodium is reabsorbed. Their diuretic effect alone is poor. Secondary effects include hypokalemia and metabolic alkalosis, with a higher rate of hyponatremia. It should be noted that they increase calcium reabsorption and decrease magnesium levels. Their use can increase urine volume in situations of HF refractory to loop diuretics, as part of sequential nephron blockade.37

Potassium-sparing diuretics. Two types of diuretics are distinguished within this group: epithelial sodium channel blockers (amiloride and triamterene) and mineralocorticoid receptor antagonists (spironolactone, eplerenone, canrenone). Unlike all others, the site of action for the latter is at the basocellular level in the distal tubule. The most limiting effect is hyperkalemia. Regarding the former, another effect is their ability to reabsorb magnesium and calcium. Their use is common in situations involving hypervolemia that are refractory to loop diuretic treatment, forming part of the sequential nephron blockade strategy. Such situations are encountered in nephrotic syndrome, patients with liver failure, or HF. However, the use of high doses of spironolactone (100 mg/day) is not associated with an increase in diuresis in patients with acute HF.38 In this latter group of patients, a recent study showed that finerenone resulted in a lower rate of hospitalizations due to worsening HF.39

Carbonic anhydrase inhibitors. This type of diuretic inhibits sodium reabsorption at the proximal level but lacks potent diuretic power. By acting in the proximal tubule, they inhibit the reabsorption of calcium, magnesium, and bicarbonate. Their use is associated with the risk of calcium phosphate lithiasis formation due to increased hypercalciuria and urine alkalization. The recently published ADVOR study demonstrated a reduction in congestion symptoms as well as a decrease in hospital stay when adding 500 mg of intravenous acetazolamide to furosemide treatment.40 It should be noted that, by inducing bicarbonate loss, they can compensate for the alkalosis produced by loop diuretics. Nevertheless, close monitoring is required, as prolonged use can lead to metabolic acidosis.

Currently, there is no standardized method for dosing medications in AKI, as calculations of creatinine clearance (CrCl) using the Cockcroft-Gault equation or the estimated glomerular filtration rate (eGFR) according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) are not valid when SCr is not stable. During the development of AKI, the estimated CrCl (by Cockcroft-Gault) or eGFR overestimates renal function and can lead to drug accumulation and potential toxicity; during the recovery phase, they underestimate renal function, and adequate therapeutic levels may not be achieved. Therefore, the trend of SCr across multiple measurements must be taken into account to judge the degree of decrease in eGFR.41 Alternatively, clinician guidance can be derived from measured CrCl.

It is important to remember that drug dosing may need to be adjusted several times during the course of AKI based on the eGFR42:

• 1)

  If SCr is increasing rapidly (or if only a single initial value is available), the eGFR should be assumed to be 0 mL/min.

• 2)

  If SCr is decreasing, the eGFR likely underestimates the actual renal function. In this case, drugs should be dosed according to an eGFR higher than the calculated value, with a daily reassessment of the dosage based on the improvement trajectory. It is advisable to measure trough levels of the administered drugs to make appropriate adjustments in conjunction with the estimation of renal function.

• 3)

  If SCr has reached a plateau and remains stable for several days or more, the eGFR can be used to establish the appropriate dose for each drug.

• 4)

  For drugs with a clear physiological response (e.g., vasopressors), the dose should be titrated based on the achieved and desired response.

In patients with newly established AKI, we typically recommend the discontinuation of drugs such as non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), and other nephrotoxic agents such as aminoglycoside antibiotics, acyclovir, amphotericin, tenofovir, or chemotherapeutic agents.

The use of these drugs nearly doubles the risk of developing AKI,43 with its onset attributed to various associated risk factors:

• •

  Total volume depletion in patients with prerenal AKI (dehydration, hypotension, diarrhea, vomiting, etc.) leads to renal hypoperfusion that increases the nephrotoxicity of drugs excreted by the kidney (excessive drug dosing), those reabsorbed in the proximal tubule (increased intracellular concentration), and those that tend to be insoluble in urine (crystal precipitation in the distal tubule).44

• •

  Effective circulating volume depletion (in patients with HF, nephrotic syndrome, cirrhosis, sepsis, etc.) leads—in addition to the previously mentioned effects of hypoperfusion—to a reduction in drug-protein binding due to hypoalbuminemia (increased serum concentrations of free drug).44

• •

  Performance of diagnostic imaging tests involving the use of radiocontrast media.

• •

  Combined use of Diuretics, ACEIs/ARBs, and NSAIDs: The use of dual therapy (ACEIs + ARBs) is not associated with an increased risk of AKI. However, the risk does increase based on the duration of use of a diuretic + NSAID combination. Furthermore, the use of triple therapy (ACEI/ARB + diuretic + NSAID) is associated with a 31% higher risk of developing AKI within the first 30 days of use.43

• •

  Other nephrotoxic agents: NSAIDs can also increase the risk of ischemic acute tubular necrosis (ATN) or other tubular injuries induced by nephrotoxins such as aminoglycosides, amphotericin B, hydroxyethyl starch, and radiocontrast media.44

Metabolic alterations also increase renal vulnerability to certain drugs and potential toxins.45

• •

  Hypokalemia, hypomagnesemia, and hypocalcemia increase renal toxicity associated with aminoglycosides.

• •

  Severe hypercalcemia: Induces afferent arteriolar vasoconstriction and renal sodium/water loss, increasing injury from nephrotoxic drugs.

• •

  Alteration of urinary pH: Increases the risk of intratubular crystal deposition when certain drugs and substances pass through the tubular lumen in the distal nephron

  • none◦

    Acidic urine pH (<5.5) favors crystal deposition of drugs such as sulfadiazine, methotrexate, and triamterene, which are insoluble in low pH environments.

  • none◦

    Alkaline urine pH (pH > 6.0) increases crystal precipitation of drugs such as indinavir, oral sodium phosphate solution, and ciprofloxacin. Furthermore, drugs like topiramate, zonisamide, and acetazolamide alkalize the urine by inhibiting carbonic anhydrase and promote calcium phosphate precipitation within the tubules, increasing kidney stone formation.

• •

  Systemic metabolic acidosis or alkalosis: Can decrease or increase urine pH, whereas proximal and distal renal tubular acidoses are associated with alkaline urine due to impaired renal capacity to excrete H+ ions.

It is crucial to understand the factors that increase the risk of AKI due to drug-induced nephrotoxicity. These include patient-specific characteristics, the renal handling of agents, and the nephrotoxicity of the substance itself; acting on each of these is decisive in preventing the development of AKI and favoring the recovery of baseline renal function.

AKI requires early and precise differential diagnosis of its etiology to evaluate targeted treatment, prognosis, and progression to chronic kidney disease (CKD). Generally, prerenal and postrenal AKI are diagnosed clinically through physical findings, laboratory tests, and/or imaging studies without the need for a renal biopsy (RB). On the other hand, approximately 8% of cases of intrinsic AKI require histological evaluation via RB to diagnose the etiology, with ATN and acute tubulointerstitial nephritis (AIN) being the primary findings.46 Furthermore, these two entities can sometimes be difficult to differentiate, and a definitive diagnosis can only be established through RB.

Another significant proportion of patients with intrinsic AKI present with accompanying systemic symptoms (arthralgia, myalgia, dyspnea, skin involvement, refractory edema, etc.) and/or atypical urinary sediment alterations (hematuria, pathological cylindruria, or proteinuria), indicating an urgent RB to rule out extracapillary proliferative glomerulonephritis, renal vasculitis, or AIN.47 These diseases require immediate aggressive approaches that must be justified by histological data; therefore, RB must be performed urgently to initiate immunosuppressive treatment and halt or delay the development of irreversible fibrosis, even with proteinuria ranges lower than those accepted in primary nephropathies. The determination of anti-glomerular basement membrane (anti-GBM) antibodies and anti-neutrophil cytoplasmic antibodies (ANCA) aids in the diagnosis but does not replace RB in the acute phase, as they lack prognostic value and do not assist in treatment planning.

RB has been frequently used in daily clinical practice for patients with AKI when they present a clinical course and/or characteristics suggesting a specific diagnosis, or when early intervention may improve the resolution of the condition or the potential underlying pathology. Therefore, the indications for RB in this context are based on studies seeking to identify specific factors that influence the decision to biopsy, especially when the clinical diagnosis is unclear.48–50

• 1

  AKI of unknown etiology:

  • none–

    Indications: RB is indicated when the etiological diagnosis of AKI is uncertain and initial studies (laboratory analysis, clinical history) fail to identify a cause.

  • none–

    Justification: Guidelines recommend RB as a diagnostic method in cases where intrinsic causes of renal damage, such as acute tubulointerstitial nephritis (AIN), glomerulonephritis, or vasculitis, are suspected.48

  • none–

    Various studies have shown that 20%–30% of patients with AKI have a diagnosis that can only be confirmed through a renal biopsy.49,50

• 2

  Suspected glomerular disease or vasculitis:

  • none–

    Indications: RB is appropriate for patients presenting with acute deterioration of renal function accompanied by significant proteinuria (>1 g/día), hematuria, arterial hypertension, or laboratory abnormalities suggesting an immune process (e.g., positive ANCA or anti-nuclear antibodies [ANA])

• 3

  Clinical diagnosis of probable ATN with atypical progression:

  • none–

    Indications: If a patient with AKI attributed to ATN does not show improvement in renal function within 3 weeks, an alternative cause should be suspected.

  • none–

    Justification: In these cases, RB may reveal damage not evident in initial laboratory tests, such as AIN or glomerular disease, although it often confirms persistent ATN

  • none–

    It has been documented that in a significant proportion of non-responding AKI patients, RB reveals treatable pathologies—most frequently AIN—thereby improving outcomes.

• 4

  Suspected drug- or toxin-induced acute interstitial nephritis:

  • none–

    Indications: RB is indicated in patients exposed to potentially nephrotoxic drugs who develop acute renal failure.

  • none–

    Justification: The identification of immunoallergic nephritis or tubular damage through RB can lead to treatment modification, such as the withdrawal of the offending drug or the early initiation of specific immunosuppressive treatments (steroids).

  • none–

    RB in patients with suspected drug-induced nephropathy can identify the cause in 40%–50% of cases, allowing for therapeutic management adjustments.49,50

• 5

  Evaluation of AKI in renal transplantation (refer to renal transplant guidelines).

The decision to perform an RB in the context of AKI must be carefully considered, always weighing the risk-benefit ratio of the procedure.

The administration of radiocontrast media can induce AKI, which may occasionally become irreversible. Studies provide evidence of ATN caused by renal vasoconstriction and medullary hypoxia, mediated by alterations in nitric oxide, endothelin, and/or adenosine, in addition to the direct cytotoxic effect of the contrast medium.51 Likewise, prerenal factors and intratubular obstruction may contribute to the pathogenesis, as the fractional excretion of sodium (FeNa) is typically <1% in these patients.

The primary clinical manifestations of contrast-induced AKI include:

• 1

  Early and mild increase in SCr: An elevation in SCr is generally observed within 24–48 hours following exposure to iodinated contrast and is usually mild. SCr typically begins to decrease within 3–7 days thereafter.51,52

• 2

  Oliguria: Most patients do not experience oliguria; if it occurs, it develops immediately after the procedure.52,53 This is more frequent in patients with pre-existing moderate-to-severe CKD.

• 3

  Urinary sediment compatible with ATN: Muddy brown granular and epithelial casts, and tubular epithelial cells.

It is crucial to identify patients at risk of developing AKI following contrast administration, including the following (according to the KDIGO 2012 guidelines51,52:

• 1

  or patients with an eGFR between 30 and 45 mL/min/1.73 m2, the risk of renal injury increases particularly when comorbidities (diabetes, HF, dehydration, etc.) are present.

• 2

  In patients with an eGFR between 45 and 60 mL/min/1.73 m2 without significant comorbidities, the risk is considered low or negligible.

Preventive or nephroprotective measures, with varying levels of scientific evidence, exist for these patients at risk of developing contrast-associated AKI54:

• 1

  Avoid volume depletion, metformin, and NSAIDs: It is crucial to avoid volume depletion. Regarding drug discontinuation, although it was initially recommended to stop NSAIDs and metformin 24–48 h before the contrast procedure, current consensus suggests that no medication needs to be discontinued. Metformin is contraindicated in cases with an eGFR of less than 30 mL/min regardless. There is no evidence supporting the temporary suspension of ACEIs or ARBs; moreover, there are risks associated with the resulting hypertension following their withdrawal.34

• 2

  Dose, type of contrast agent, and route of administration: The lowest possible effective dose of contrast should be used, and repeated studies in close succession (within 48–72 h) should be avoided. The 2012 KDIGO guidelines recommend the use of low-osmolar or iso-osmolar contrast media (Grade 1B), but without significant evidence to favor one over the other. Greater caution is required for intra-arterial contrast compared to intravenous administration.

• 3

  Fluid therapy: If there are no contraindications for volume expansion, the administration of intravenous isotonic saline before and for 4–6 hours after contrast administration is the only adequate measure to prevent contrast-associated AKI in at-risk patients (Grade 1B). It is postulated that fluid intake dilutes the contrast, reducing nephrotoxicity; furthermore, volume expansion inhibits the renin-angiotensin-aldosterone system (RAAS) and maintains renal blood flow, diminishing vasoconstrictive effects and hypoxia³⁵. The following protocols are recommended for patients with an eGFR lower than 45 mL/min/1.73 m2 (although some recommendations apply them only to eGFR below 30 mL/min/1.73 m2)54:

  • a

    Outpatients: 3 mL/kg for 1 h before the procedure and 1–1.5 mL/kg/h for 4–6 h after the procedure, with a total administration of at least 6 mL/kg post-procedure.

  • b

    Inpatients: 1 mL/kg/h for 6–12 hours before and during the procedure, continuing for 6–12 hours after. This is only necessary in cases where patients were not already receiving supportive fluid therapy for their underlying illness.

Isotonic saline seems to be superior to hypotonic fluids according to the results of a randomized clinical trial of 1,620 patients.55 Regarding the use of saline solution vs. bicarbonate, results from another randomized clinical trial involving 4,993 high-risk patients undergoing elective angiography showed that both treatments were associated with similar outcomes. Bicarbonate provides no additional benefit over saline solution, requires preparation, and is more expensive (Grade 1B).56 There is evidence that oral hydration (500 mL 1 h before and 2 L over the following 24 h) is non-inferior to intravenous hydration for patients with an eGFR greater than 30 mL/min.57

• 1

  Acetylcysteine: No benefit has been demonstrated following its administration prior to a contrast procedure (Grade 2B); therefore, its use is not recommended. Furthermore, in a randomized clinical trial, 7% of patients receiving high doses of intravenous acetylcysteine developed anaphylactoid reactions.32,33

• 2

  Prophylactic hemofiltration and hemodialysis: Routine hemofiltration or hemodialysis is not indicated for the prevention of contrast-induced AKI in patients with CKD. A 2012 meta-analysis⁵⁸ that included 8 hemodialysis studies and 3 hemofiltration/hemodiafiltration studies showed no benefit from renal replacement therapy. Similarly, there is no indication for prophylactic dialysis to prevent volume overload from contrast administration in dialysis-dependent patients.58 Moreover, no studies support immediate dialysis after contrast administration to preserve residual renal function or limit the risk of allergic or toxic reactions to contrast media in hemodialysis patients. Nevertheless, to avoid an impact on residual renal function, it is still recommended that these patients follow the same precautions as those with advanced CKD (eGFR <30 mL/min/1.73 m2). This includes preventive measures such as adequate hydration and avoiding nephrotoxic medications before the contrast procedure, as permitted by the patient’s clinical status.

• 3

  Diuretics: Prophylactic diuretics or mannitol should not be routinely administered for the prevention of contrast-induced AKI.

To date, the strategy of continuous volume expansion with intravenous or oral fluids, the use of low- or iso-osmolar contrast media at the lowest possible volume, and the withdrawal of nephrotoxic drugs are the preventive measures that have consistently proven effective for nephroprotection against iodinated contrast. These recommendations are applicable to intravenously administered contrast. In any case, if a contrast-enhanced radiological test is necessary for effective treatment, it should never be withheld, regardless of the stage of CKD.

Patients undergoing cardiac catheterization (arterial administration) show a higher incidence of AKI, especially in emergent procedures. Many of these patients present with congestive HF, where hydrosaline prevention is more limited.59 In recent years, CO2 has been used as an alternative in endovascular procedures to avoid iodinated contrast, particularly in patients at high risk of nephropathy. CO2 is useful for peripheral vessel studies, as it is a soluble gas and less toxic to the kidneys. Despite its advantages, CO2 is not suitable for all procedures; its use is limited in coronary vessels due to the risk of gas embolization and its effects on the cardiovascular system.60

Proper volumetric management, specifically avoiding congestion, is crucial in both CKD and AKI, not only due to its impact on other organs but also because of its role in the progression of AKI itself.

Historically, the therapeutic approach to AKI episodes has focused on ensuring adequate antegrade flow—for example, by prioritizing volume replacement in episodes of hemorrhagic shock or dehydration. However, the outflow pressure of an organ is also a determining factor for its perfusion and is often undervalued. Prioritizing an increase in inflow pressure can lead to fluid overload and vascular congestion, both of which are associated with greater multi-organ dysfunction and poorer renal outcomes.

Renal perfusion is determined by the difference between the inflow blood flow, which depends on the mean arterial pressure (MAP), and the outflow, defined by the central venous pressure (CVP). In cases where CVP is elevated—secondary, for instance, to right ventricular failure and/or fluid overload—a state of congestion can occur that compromises renal function.61

Congestive nephropathy is defined by the triad of: renal function impairment, venous congestion, and renal hypoperfusion. The pathophysiology is explained by the increase in CVP transmitted through low-resistance renal veins, which causes an increase in afterload and intrarenal pressure, leading to decreased perfusion and intratubular flow. Since the kidneys are encapsulated organs, they are particularly sensitive to this effect. Concurrently, there is activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system, leading to increased sodium and water retention, interstitial edema, and endothelial dysfunction. This results in reduced nitric oxide and increased production of inflammatory cytokines (CKs), with a subsequent reduction in the glomerular filtration rate.

Because this is a potentially reversible entity, a diagnostic suspicion would be confirmed by renal improvement following treatment aimed at reducing congestion. However, a lack of response to treatment does not exclude it, as other factors—such as pre-existing kidney disease or a prolonged clinical course—may influence the renal prognosis.62

At a clinical level, diagnosing congestion can be a challenge given that the sensitivity of physical examination is limited. In this context, the need arises to seek other parameters to complement the assessment of congestive status, including imaging tests (PoCUS) and biomarkers.

Point-of-Care UltraSonography (PoCUS) is a non-invasive, real-time, and reproducible bedside test that allows for the integration of venous circulation assessment into a single examination to establish a targeted therapeutic approach. PoCUS is proposed as a complementary tool to physical examination, but it should not replace it.

As it is a non-invasive test, PoCUS can be performed repeatedly, making it useful not only at the time of diagnosis but also for monitoring treatment response.

Beyond hemodynamic status, ultrasound can provide information on the etiology of acute renal dysfunction, for example, by ruling out obstructive uropathy, or on renal prognosis by measuring the renal resistive index.

Different ultrasound phenotypes can be defined through PoCUS based on whether congestion is present and whether it is predominantly tissue, vascular, or mixed. Defining these phenotypes allows for the individualization of therapeutic strategies, such as increasing intravascular refill in cases of tissue congestion or increasing natriuresis in vascular congestion.63

The assessment of congestion via PoCUS is based on three pillars: Lung Ultrasound (LUS), the assessment of vascular congestion using the Venous Excess Ultrasound (VExUS) grading system, and the study of cardiac and valvular morphology and function through Focused Cardiac Ultrasound (FoCUS):

• •

  LUS: Allows for the diagnosis of tissue congestion and is an important indicator of total volume status, as it depends directly on left ventricular (LV) filling pressures. It is performed by exploring the anterior thorax in eight projections. Under normal conditions, horizontal, hyperechoic, equidistant lines parallel to the pleura are observed, defined as A-lines. B-lines are vertical, hyperechoic pleural artifacts reflecting the ultrasound beam on thickened subpleural interlobular septa. The presence of three B-lines in two or more views has been associated with congestion. Additionally, LUS is useful for detecting the presence of pleural effusion.

• •

  VExUS: Allows for the identification and stratification of vascular congestion by exploring the inferior vena cava (IVC), hepatic veins (HV), portal vein (PV), and intrarenal veins (IRV).

  • none◦

    IVC: The assessment begins in its longitudinal axis 2 cm from its entrance into the right atrium. An IVC diameter <2 cm suggests a non-congestive state, whereas if it is >2 cm, assessment of the rest of the venous system is necessary.

  • none◦

    HV: These veins exhibit pulsatility that correlates with the cardiac cycle; therefore, they are assessed using pulsed-wave Doppler (PWD). Under normal conditions, they present an "aSD pattern," with an initial antegrade (positive) "a" wave from atrial contraction, followed by a retrograde (negative) "S" wave from right ventricular (RV) systole—which is larger in magnitude than the retrograde "D" wave from RV diastole. Changes in flow magnitude determine the severity of congestion.

  • none◦

    PV: Due to its distance from the large vessels, it is non-pulsatile under normal conditions, and PWD shows continuous flow. In congestive situations, the flow becomes pulsatile.

  • none◦

    IRVD: This allows for the identification of renal compromise; it is explored via PWD at the corticomedullary junction to capture flow through the interlobular vessels. Under normal conditions, intrarenal venous flow (IRVF) is monophasic and continuous. In mild-to-moderate congestion, a biphasic flow is observed with the appearance of two waves: systolic "S" and diastolic "D." In severe cases of congestion, monophasic flow is observed with a single "D" wave throughout the cardiac cycle. Discontinuous IRVF patterns predict a reduced diuretic response and deterioration of renal function.

The visualization of IVC size and the PWD of the described venous territories are integrated into a congestion severity score (VExUS score): Grade 0: IVC <2 cm; Grade 1: IVC ≥ 2 cm with PWD showing normal patterns or mild alterations; Grade 2: IVC ≥ 2 cm, with at least one severity pattern on PWD; Grade 3: IVC 2 cm, with two or more severity patterns on PWD.64

Patients with low muscle mass index, hepatic parenchyma alterations, severe tricuspid regurgitation, or advanced CKD may show altered PWD patterns in the absence of congestion, limiting the use of this technique in such cases. Table 3 summarizes the ultrasound criteria for the assessment of congestion.

• •

  FoCUS: This allows for a morphological and functional assessment of the RV in different classic echocardiography planes: parasternal long axis, parasternal short axis, apical 4-chamber, and subcostal views.

By comparing the size of the RV with the LV and assessing septal motion, alterations in RV volume and filling pressure can be described. In these same classic planes, the systolic function of both ventricles can be evaluated relatively easily through direct visualization or using tools for estimation. A widely used and simple indirect measure to quantify RV function is measuring the Tricuspid Annular Plane Systolic Excursion (TAPSE) in M-mode. Diastolic function can also be used to evaluate volume status. FoCUS additionally allows for a rapid assessment of the presence of pericardial effusion and valvular alterations such as tricuspid regurgitation.65

The utility of PoCUS lies in the joint interpretation of the various ultrasound parameters, as they present more limitations in clinical practice when assessed in isolation. In this regard, several studies have been published demonstrating the prediction of congestive kidney injury using the different ultrasound components of VExUS, playing an especially relevant role in post-cardiac surgery patients.64 Similarly, an improvement in signs of congestion has been observed in parallel with the recovery of renal function once AKI is already established.

Amino-terminal pro-B-type natriuretic peptide (NT-proBNP) is the most widely used biomarker for the diagnosis and prognosis of HF. It rises due to the stress placed on cardiomyocytes in situations of increased left-sided filling pressures; however, its relationship with the severity of congestion is debatable.

The highest NT-proBNP values are observed in patients with HF due to LV systolic dysfunction, whereas right-sided dysfunction does not translate into a greater increase in the marker. Several studies show a weaker association of this marker with various clinical, radiological, and echocardiographic parameters of right-sided dysfunction.66

Other factors that can influence the increase in NT-proBNP include age and renal function, so its utility for assessing congestion in this patient group is limited.

Carbohydrate antigen 125 (CA-125) is a glycoprotein synthesized by mesothelial cells on serous surfaces and rises in response to elevated hydrostatic pressure, mechanical stress, and inflammatory stimuli. It is widely used for monitoring ovarian cancer, but it has also been observed to rise in other neoplasms and benign conditions related to volume expansion. In recent years, its use has been developed as a useful marker for identifying patients with both tissue and vascular congestion. Multiple studies associate increased CA-125 values with the presence of serous effusions, peripheral edema, increased IVC pressures, and pulmonary capillary wedge pressure.66

In contrast to NT-proBNP, CA-125 levels are not modified by renal function, age, ischemic etiology, atrial fibrillation, or LV ejection fraction. Its use for monitoring response to diuretic treatment is also relevant.67

In routine clinical practice, it is important to consider that there is a time interval between the onset of congestion and the increase in CA-125 production and release, and that it also has a long circulating half-life (7–12 days). Consequently, its utility is limited in more acute onsets with predominantly intravascular redistribution. Similarly, for monitoring the improvement of congestion, it is useful in the first weeks rather than during the first days of decompensation.68 The use of CA-125 in conjunction with other congestion parameters has proven to be an independent predictor of renal congestion measured by PWD (IRVF), which helps identify patients who would benefit from a more aggressive diuretic strategy.69

AKI is a frequent complication in patients with liver cirrhosis (LC) admitted for acute decompensation, with an incidence of up to 50%.76 Its importance stems from the negative impact on patient prognosis.

Definitions of AKI in LC have been adapted by the International Club of Ascites (ICA) based on KDIGO definitions, adding the concepts of progression (to more severe stages), regression (to less severe stages), non-response (no regression), partial response (regression of stage with creatinine ≥0.3 mg/dL above baseline), and total response (regression of stage with creatinine <0.3 mg/dL above baseline). Additionally, the following modifications to KDIGO have been included76,77:

• 1

  Urine output criteria have been removed due to the typical oliguria of cirrhotic patients secondary to avid sodium retention, the influence of diuretic treatment on output, and the limitations of precise monitoring in general wards. However, since oliguria is a sensitive and early marker of AKI and can be associated with a poorer prognosis, close monitoring should be performed whenever possible. Notably, the 2024 joint document from the ICA and the Acute Disease Quality Initiative (ADQI) also considers a urine output of ≤0.5 mL/kg for a period of 6 h as an AKI criterion in cirrhosis.78

• 2

  Subdivision of KDIGO Stage 1 into two: 1A if serum creatinine (SCr) is <1.5 mg/dL (the classic cutoff for AKI in LC) and 1B if SCr is ≥1.5 mg/dL. This is based on evidence that cirrhotic patients with Stage 1 AKI and SCr 1.5 mg/dL have a significantly worse prognosis.76

• 3

  Renal dysfunction may be underestimated using SCr, as hepatic production is compromised, and many patients present with sarcopenia and malnutrition. Furthermore, bilirubin elevation can interfere with colorimetric assays. Despite these limitations, changes in SCr remain a valid clinical tool. In the absence of a baseline value (community-acquired AKI), the recommendation is to use a value from the previous week; if unavailable, the ICA recommends using a value from the last 3 months instead of the 75 mL/min/1.73 m² eGFR estimation suggested by KDIGO.

The most frequent causes of AKI are prerenal (constituting up to 70%), hepatorenal syndrome (HRS), and ATN. Obstructive causes are relatively rare.

HRS is currently classified as:

• 1

  HRS-AKI: When AKI criteria are met in a cirrhotic patient with ascites, there is no response to diuretic withdrawal and 48 h of albumin expansion, and in the absence of shock, nephrotoxins, proteinuria >500 mg/day, hematuria >50 RBCs/hpf, or ultrasound abnormalities

• 2

  HRS-non-AKI: When AKI criteria are not met; this includes HRS-CKD (chronic kidney disease) and HRS-AKD (acute kidney disease, renal dysfunction <3 months).

Diagnostically, since prerenal causes mostly resolve with volume expansion and HRS has specific treatment unlike ATN, the priority is distinguishing these entities. FeNa is difficult to interpret; while it may be artificially elevated by diuretics, most patients, especially those with ascites, retain sodium avidly, showing FeNa <1% even with ATN. A stricter threshold (<0.2−0.5%) may increase specificity for HRS.79

Glomerular etiology should be excluded by the absence of hematuria and proteinuria. However, the cutoff for non-physiological proteinuria in LC is not well established, and serum protein levels are often low due to liver failure or malnutrition. If in doubt, a renal biopsy is required, though this is difficult due to coagulopathy. This has driven research into biomarkers; urinary NGAL can clearly differentiate HRS (normal values) from ATN (elevated values) with an AUC of 0.87 when measured on the second day of albumin expansion. Furthermore, urinary NGAL levels are associated with persistent AKI and higher 28-day mortality.80

The ICA published a sequential practical algorithm for the differential diagnosis and management of AKI in LC.77 First, precipitating factors such as volume depletion (diuretics, hemorrhage, excessive paracentesis), nephrotoxins (especially NSAIDs), beta-blockers, and infections must be corrected. For Stage 1B or higher (de novo or progressed from 1A), diuretics should be discontinued and plasma expanded with albumin (1 g/kg for 2 days). If there is no response and HRS criteria are met, vasoconstrictors (e.g., terlipressin) with albumin should be initiated. ATN or other causes should be treated individually.

By the third day, 14% of AKI cases progress, 37% stabilize, and 49% resolve.80 By hospital discharge, 67% of cases resolve, especially those due to hypovolemia or HRS-AKI.80 Nevertheless, the medium-term prognosis is poor, with a 3-month mortality rate of 60%. RRT has a clear negative impact, with median transplant-free survival reported at 15 days for HRS and 14 days for ATN.81

The development of AKI in the context of acute HF decompensation corresponds to the definition of Type 1 Cardiorenal Syndrome.

According to various series, the incidence of AKI in this context ranges between 25% and 30%, reaching as high as 60% in patients with CKD.82

The onset of AKI has a marked prognostic value, increasing the morbidity and mortality of these patients.

Pathogenesis involves several mechanisms:

• •

  Decreased cardiac output along with venous congestion, which increases renal venous and interstitial pressure, leading to a reduction in intrarenal flow.

• •

  Activation of the sympathetic nervous system and the RAAS, resulting in vasoconstriction and worsening congestion.

• •

  A pro-inflammatory state that induces oxidative stress affecting both renal and myocardial cells.66

Diagnosis continues to be performed through the classic parameters of decreased urine output and increased creatinine. The latter has limitations, as congestive states can decrease its sensitivity through dilution. Some studies suggest cystatin C as more sensitive and having prognostic implications. The use of renal biomarkers for early diagnosis and assessment of structural damage has been investigated, but they are not currently included in general clinical practice.83

Congestion markers NT-proBNP and CA-125 are included in the diagnostic workup (see section 4.2.2).

Management is based on adequate decongestive therapy supported by the use of potent diuretics such as loop diuretics, with the association of other diuretics if an optimal response is not achieved at high doses. Most protocols associate thiazides as a first step and aldosterone antagonists as a second step. Less common is the association of tolvaptan or the use of hypertonic saline boluses in refractory situations, as described in some protocols (see section 3.2).

If targets are not achieved, ultrafiltration techniques—with or without dialysis—would be indicated depending on the stage of AKI and associated metabolic disturbances.

Ultrasound monitoring and the assessment of congestion markers are frequently used to guide decongestive therapy. Throughout this process, the standard trend is to discontinue RAAS blockade, but some experts now suggest the possibility of maintaining treatment in cases of mild AKI, provided the patient is closely monitored.84

An increase in creatinine is relatively common during decongestive therapy. Studies report that up to 50% of patients may experience creatinine increases during therapy; expert recommendations indicate that increases < 0.5 mg/dL might signify hemoconcentration rather than true AKI. An increasing number of studies demonstrate no worsening of prognosis in patients with variable creatinine increases if adequate decongestion targets are met.85 In this regard, a decrease in filtration rate accompanied by data of hemoconcentration (increased hemoglobin and albumin) as well as a decrease in pro-BNP levels are not associated with a poorer prognosis.9,86,87 In any case, it is always appropriate in this situation to rule out other causes of AKI that may overlap in hospitalized patients.

Sepsis is the most frequent underlying cause of AKI in intensive care units, accounting for 45%–70% of cases.88 Furthermore, the association between sepsis and AKI confers a poor prognosis, with higher morbidity and mortality, longer hospital stays, and long-term sequelae such as CKD. Since both conditions are relatively common and the pathophysiology of AKI in sepsis is complex, definitions have been proposed to further study its pathogenesis, epidemiology, and progression. Thus, the **Acute Disease Quality Initiative (ADQI)**89 group has proposed the following definitions: (1) Sepsis-associated AKI (SA-AKI) when sepsis (defined by Sepsis-3)90 and AKI (defined by KDIGO, see section 1.1) coexist and appear within 7 days of the sepsis diagnosis; (2) Sepsis-induced AKI when sepsis is the primary cause of renal injury. Additionally, a distinction is made between early AKI, occurring within the first 48 h following the sepsis diagnosis, and late AKI, occurring between 48 h and 7 days.

The epidemiology of SA-AKI is essentially unknown due to the variety of definitions used across studies for both sepsis and AKI. Moreover, most studies do not differentiate between sepsis and septic shock and fail to define the temporal relationship between the two conditions.88 Identified risk factors for AKI in sepsis include septic shock, mechanical ventilation, vasopressor use, Gram-negative bacteremia, the use of RAAS inhibitors, and pre-existing conditions such as hypertension, CKD, chronic liver disease, and smoking.88

The pathophysiology of SA-AKI is complex for several reasons. First, the expression of sepsis itself depends on individual susceptibility, which is at times determined by genetic and epigenetic factors. Second, organ dysfunction associated with sepsis, including renal dysfunction, is conditioned by various physiological aspects of organs and tissues. These include micro- and macrocirculatory alterations, inflammation, immunomodulation, complement activation, RAAS dysfunction, and metabolic changes such as metabolic reprogramming and mitochondrial dysfunction. All of these factors affect the kidney in uneven and variable ways, shaping what is known as sepsis-induced AKI. Finally, other common situations in the clinical context of sepsis can affect renal function, including nephrotoxins, abdominal compartment syndrome, and congestion. These, along with the aforementioned factors, constitute the more generic term sepsis-associated AKI. In any case, sepsis-induced AKI is a distinct disorder from classic ATN, differing in its pathophysiology, circulatory dysfunction, and progression.

Given that the fundamental treatment for sepsis is the control of the source of infection, the management of SA-AKI or sepsis-induced AKI in the critically ill patient is similar to that of general AKI in the intensive care setting. Fluid administration must be restricted to the restoration of volemia to preserve tissue perfusion and should be guided by both static and dynamic parameters to avoid congestion. Hemodynamic resuscitation should be performed with crystalloid solutions, using either normal saline or balanced solutions, always based on the monitoring of electrolytic parameters. The use of albumin or bicarbonate may be beneficial in certain situations, although their recommendation requires results from ongoing clinical trials. Conversely, the use of synthetic colloids is contraindicated.91 The first-choice vasopressor in sepsis is norepinephrine, which plays a crucial role as a volume-sparing agent. The use of diuretics is restricted to the treatment of congestion.

Hemodynamic monitoring and the calculation of daily fluid balances are essential to avoid under- or over-hydration. Regarding the volume of fluids to be administered, a restrictive volume strategy has been evaluated in recent years due to the deleterious effects of secondary congestion. Various clinical trials have shown that this strategy is safe in sepsis compared to standard care. However, it does not provide significant benefits in terms of mortality, quality of life, or other relevant variables, such as the incidence of AKI, the need for RRT, or its duration.92 At the end of the observation period (90 days), the cumulative balance difference between the two strategies is approximately 0.7 l (median 1,645 mL in the restrictive group vs. 2,420 mL in the liberal group). Thus, the fluid management strategy in sepsis should follow the conceptual framework divided into different phases based on the evolutionary stage of sepsis: Resuscitation, Optimization, Stabilization, and De-escalation (ROSD), with individualization being important in all cases.89

The application of renal injury biomarkers for early diagnosis of AKI, its subclassification, or to predict the need for RRT or patient outcomes faces the same limitations as AKI from other causes.89

Regarding extracorporeal techniques, the indications and modalities for RRT are similar to those for any other type of AKI. Extracorporeal therapies aimed at modulating inflammation and the immune response are numerous (hemoadsorption, high cut-off) and can be coupled with RRT. However, recommendations for their use are very limited as there is currently no solid evidence of the benefit of these techniques on hard outcomes.

Finally, despite multiple studies, no specific treatment has been found to modify the course of AKI or the patient’s outcome in sepsis. A significant number of products have been tested, most notably dexamethasone, alkaline phosphatase, angiotensin II, levosimendan, and mesenchymal stem cell therapy.89

The incidence of AKI in patients undergoing major surgery varies between 12% and 25% in non-cardiac surgery93 and up to 35% in cardiac surgery.94

AKI in postoperative patients results from multiple causes, including hemodynamic alterations that compromise renal perfusion (both ischemia and congestion), the use of nephrotoxins, and sepsis. In most cases, it is classified as ATN. Regarding cardiac surgery with cardiopulmonary bypass, this belongs to a special group where four major factors must be considered: the mismatch between oxygen supply and demand, the activation of the systemic inflammatory response, hemolysis, and the production of microemboli.95

The measures proposed by the 2012 KDIGO guidelines for its prevention include close monitoring of creatinine and urine output, optimization of hemodynamic parameters and volemia—for which they recommend considering dynamic or functional monitoring based on algorithms—glycemic control, and the suspension of RAAS inhibitors (ACEIs, ARBs) and nephrotoxic treatments.96 A study published by Meersch et al. in 2017 demonstrated that applying these measures in cardiac surgery patients at risk of AKI significantly reduced its occurrence.97 In the trial, patients at risk were selected through the determination of TIMP-2 and IGFBP7 biomarkers (Nephrocheck®), demonstrating that it is possible to modify the course of postoperative AKI in at-risk patients if early intervention is carried out using KDIGO recommended measures.

Furthermore, the blood pressure target in these patients is controversial and depends on their comorbidities. Several studies have shown that strict perioperative hemodynamic control is effective in preventing AKI, whether applied before, during, or early after the intervention.98 Notably, the benefit of hemodynamic control in AKI prevention is primarily obtained in high-risk surgical patients (based on clinical comorbidity scales).

Regarding the need for RRT, the initiation criteria do not differ from the classic criteria, although special attention should be paid to positive fluid balance in postoperative cardiac surgery patients.

AKI occurring during pregnancy constitutes a major public health problem due to its impact on maternal-perinatal morbidity and mortality. It is associated with a higher risk of obstetric complications: uterine hemorrhage, HELLP syndrome, abruptio placentae, and cesarean delivery. In the long term, it increases both cardiovascular risk and the risk of developing CKD. It may also increase maternal mortality. Regarding fetal prognosis, it has been associated with a higher risk of prematurity, low weight for gestational age, increased risk of neonatal ICU admission, and higher mortality.99,100

Globally, approximately 1% of AKI cases are related to pregnancy, with this frequency being higher in developing countries than in developed ones: 3.1% vs. 0.3%. In developing countries, uterine hemorrhage, septic abortions, and puerperal sepsis are the most frequent causes of pregnancy-associated AKI. In contrast, in developed countries, hypertensive disorders of pregnancy are responsible for the majority of cases.99

The definition of AKI in pregnancy is controversial, largely due to the absence of standardized diagnostic criteria. For its definition, different serum creatinine cut-off points or classification systems such as RIFLE or AKIN have been used, based on percentage increases in SCr relative to baseline. Hall and Conti-Ramsden proposed using the Kidney Disease: Improving Global Outcomes (KDIGO) definition, considering an absolute increase in SCr ≥0.3 mg/dL, within a 48-h period as the diagnosis of AKI in pregnancy.101 In this document, by consensus of all authors and based on the definition of acute kidney injury provided by the International Society for the Study of Hypertension in Pregnancy (ISSHP) as a diagnostic criterion for preeclampsia, we define AKI in pregnancy when SCr >1 mg/dL in a pregnant woman with previously normal renal function.102

A key aspect complicating the definition of AKI in pregnant women is the physiological changes that occur during pregnancy: increased cardiac output, renal plasma flow, and intrarenal vasodilation. These changes lead to glomerular hyperfiltration and a 40%–60% increase in the glomerular filtration rate (GFR). This results in a physiological reduction of creatinine, such that in most pregnant women, it remains below 0.8 mg/dL, with levels of 0.4–0.6 mg/dL being frequently found.99,103 Accordingly, formulas estimating GFR from creatinine, as well as AKI diagnostic scales (RIFLE, AKIN, KDIGO), are not validated in pregnancy. Despite all limitations, SCr remains the most cost-effective marker for diagnosing AKI. Furthermore, the lack of routine renal function monitoring during pregnancy and the frequent unavailability of a pre-pregnancy baseline creatinine complicate and delay diagnosis. Renal ultrasound can assist in identifying the etiology of AKI, while renal biopsy is rarely indicated in the pregnant woman with AKI.104

As in the general population, AKI in pregnant women is classified into three groups based on the underlying cause: prerenal, renal, and postrenal.104 Any cause of AKI occurring in the general population can happen in a pregnant woman, added to specific pregnancy-associated causes (Table 4).

The timing of AKI onset relative to the gestational week can help establish its etiology.105 In the first trimester, the most frequent causes are hyperemesis gravidarum, septic abortion, acute pyelonephritis (APN), uterine hemorrhage, and various forms of glomerulonephritis. The latter could debut or flare throughout the pregnancy, as is the case with urinary tract infections. Undoubtedly, most causes of AKI occur in the third trimester: uterine hemorrhages associated with abruptio placentae, uterine rupture, urinary obstruction, preeclampsia (which can develop from the 20th gestational week onwards), HELLP syndrome, acute fatty liver of pregnancy, and thrombotic microangiopathies (TMA)—with an earlier onset of thrombotic thrombocytopenic purpura (TTP), which may appear from the second trimester, and a later onset of atypical hemolytic uremic syndrome (aHUS), more frequent in the peripartum and postpartum periods (Table 5). Finally, in the puerperium, AKI associated with uterine hemorrhage (atony, uterine perforation), puerperal sepsis, NSAID nephrotoxicity, and the aforementioned aHUS stands out.105,106

Management of pregnancy-associated AKI includes:

• 1

  General measures: Fluid therapy for volume depletion, antibiotics for sepsis, transfusion for severe hemorrhage, diuretics for HF, blood pressure control, correction of electrolyte and acid-base imbalances, and dialysis when conservative management is insufficient.

The development of an AKI episode, beyond its immediate negative impact during hospitalization, also results in adverse medium- and long-term outcomes: persistent decrease in GFR over time, recurrence of AKI episodes, development or progression of CKD and end-stage renal disease (ESRD), increased cardiovascular risk, higher hospital readmission rates, and long-term mortality.

In the 2017 ADQI consensus document and the 2020 KDIGO review, the term Acute Kidney Disease (AKD) was proposed to define a clinical situation of impaired renal function that does not meet the criteria for AKI or CKD, yet is related to adverse medium- and long-term outcomes.124–126

Currently, a new conceptual framework is proposed for the spectrum of renal disease over time, conceiving AKI, AKD, and CKD as a continuum (sharing risk factors and pathophysiological mechanisms). Criteria for AKI and CKD remain those defined by existing KDIGO guidelines, although it is important to note that these do not yet include criteria for defining AKI resolution. The proposed criteria for AKD (occurring between 7 days and 3 months) include: SCr increase >50%, eGFR <60 mL/min, a drop in eGFR ≥35% from baseline (using CKD-EPI 2009 for SCr or CKD-EPI 2012 for cystatin C), or the presence of structural damage markers (mainly albuminuria or hematuria). By definition, AKD precedes CKD but can also overlap with pre-existing CKD.

The ADQI group suggests grading AKD severity according to KDIGO AKI stages to define severity and provide a framework for kidney-specific outcomes within a 90-day timeline126 (Table 6).

This classification aims to standardize research results and facilitate the determination of incidence and prognosis.

One reason for the increase in CKD after AKI is "lack of recovery", this is a gradual decline in eGFR that does not return to baseline. Ideally, a biomarker would allow for early diagnosis to implement management strategies aimed at preventing progression.

Using SCr has limitations due to muscle mass loss, changes in distribution volume (dilution), and hyperfiltration; it is also a late marker of injury. GFR at discharge is also a poor predictor of CKD progression. Sawhney et al. demonstrated in a cohort of 14,651 patients followed for 10 years that GFR at discharge does not correlate with CKD progression, and this risk persists for up to 10 years post-AKI.127

Regarding proteinuria as a progression marker, the ASSESS-AKI study showed that higher albumin-to-creatinine ratios (uACR) 3 months after discharge were associated with a higher risk of CKD.128 Although baseline proteinuria was unknown, uACR remains an excellent discriminative tool and a modifiable factor in clinical practice.

Although most studies on progression markers focus on identifying markers that imply AKI persistence after 48−72 h, several works have been published identifying different biomarkers (NGAL, KIM-1, CCL14, TIMP-2*IGFBP7, IL-18, MCP-1, bFGF, NT-proBNP, TNRF1, or sTNFR2) associated with longitudinal adverse outcomes following an AKI episode: mortality events, cardiovascular events, and progression to CKD.9 However, despite extensive research and the development of assays for some of them, these biomarkers remain restricted to research use and have not yet been implemented in clinical practice. It remains to be demonstrated, through prospective trials, to what extent these new biomarkers can help improve short- and long-term outcomes.

The definition of renal function recovery following an AKI episode remains controversial due to the absence of standardized criteria. Various approaches have been used in the literature, ranging from the normalization of SCr to the discontinuation of RRT. It is important, due to its prognostic impact, to differentiate whether the recovery of renal function is complete or partial, as well as the time it takes for renal function to recover. To unify criteria, the authors of this document, as representatives of the Acute Kidney Injury (AKI) workgroup of the Spanish Society of Nephrology (FRASEN), propose, in agreement with other researchers,129 to consider an AKI episode recovered when SCr returns to its baseline level, and partial recovery if it does not reach this threshold. However, even if creatinine levels and GFR return to baseline values, it must not be forgotten that a significant reduction in renal functional reserve may have occurred, exposing the patient to a higher susceptibility to future AKI episodes.130

The FRASEN group recommends assessing recovery at the time of hospital discharge by determining the SCr value. It is considered that this should always be accompanied by the determination of the albumin/creatinine ratio, and the performance of CrCl should be assessed on an individual basis as an indicator of structural renal injury.

It is important to determine the timeframe of discharge relative to the AKI episode. We must not lose sight of the fact that apparent "recovery of renal function" at discharge is not always an indicator of a good renal prognosis, as SCr at that moment may be overestimating the GFR. Furthermore, there may later be a progressive loss of renal function conditioned by numerous factors that are currently difficult to predict with the tools available in clinical practice.

Currently, there are no standardized guidelines for the follow-up of patients with AKI, nor treatment strategies to reduce the incidence of sequelae.

During the AKI episode, the main objective should be the recovery of baseline renal function in the shortest possible time to reduce the duration and severity of the injury. After discharge, it is crucial to preserve renal function and prevent further deterioration by controlling hypertension, proteinuria, diabetes mellitus, and cardiovascular diseases.131

The KDIGO 2012 guidelines recommend follow-up at 3 months post-AKI to assess the resolution of AKI or the persistence of CKD.96,132 This point is probably very late, and the renal injury is already established. In the new KDIGO 2020 recommendations, the degree of nephrological follow-up increases as the duration and severity of AKI/AKD increase.124 According to these recommendations, we must be sensitive to those factors identified as risks for progression and focus on them to establish the timing and degree of follow-up. The risk factors for the progression of renal injury to chronic renal failure identified in previous studies are shown in Table 7.

In the opinion of the FRASEN group, the planning of follow-up visits should be organized based on the severity and duration of the AKI, the need or not for RRT during admission, the degree of recovery of the renal injury based on the indicators currently available in clinical practice, the organizational possibilities of each Nephrology Service, and the relationship with Primary Care for shared follow-up. We consider a review of the patient within the first 30 days of discharge to be optimal in the most severe cases or comorbid situations; if this is not possible, we advise planning the review at 3 months.

At the discretion of the nephrologist who treated the AKI, milder cases (with an episode duration of less than 7 days and/or with complete recovery of renal function at discharge) could be referred to primary care for follow-up. In this sense, we should work toward multidisciplinary follow-up for patients who have suffered an AKI (nephrologist, primary care, nursing, pharmacy, among others). The literature demonstrates that this type of follow-up achieves better results.133

Regarding outpatient follow-up and after reviewing the literature, the FRASEN group, taking into account the absence of evidence and the lack of international consensus, recommends the following measures:

• 1

  Monitor renal function and proteinuria. Incorporation of new markers of renal injury based on new evidence generated.

• 2

  Evaluate the introduction of nephroprotective medication. It will be important to assess potential discontinuations of nephroprotective drugs during the episode (ACEI, ARB, antialdosteronics, SGLT2i) for their reintroduction, according to risk/benefit, in a controlled manner.

  • a

    The prescription of RAAS inhibitors is independently associated with a lower risk of CKD development and lower medium/long-term mortality.131,134

  • b

    The use of SGLT2i after an AKI episode has been associated with a lower risk of CKD progression and recurrent AKI.135

• 3

  Education in nephroprotection. The patient and their environment should be informed about nephrotoxic medications that must be avoided. Recommend the temporary discontinuation of certain medications in situations of dehydration risk (gastroenteritis or fever) to prevent new AKI episodes.

• 4

  Patients who continue to require dialysis at the time of hospital discharge must be monitored during the sessions. In these patients, hemodynamic status, intravascular volume, and diuresis during dialysis must be carefully controlled so as not to interfere with the possibility of renal function recovery. Higher ultrafiltration rates and more intradialytic hypotension episodes are associated with a higher risk of non-recovery.124

AKI is the most frequent cause for initiating RRT, both in continuous modalities and intermittent hemodialysis (IHD). Continuous treatment will be used when the patient is hemodynamically unstable or neurocritical, while an intermittent modality will be used in all other cases.136,137

Emergent indications for the initiation of RRT:

• 1

  Oliguria/anuria unresponsive to standard medical treatment: volume expansion, diuretics, vasoactive drugs, inotropic agents.

Acute pulmonary edema with no response to medical treatment.

Hyperkalemia >6.5 mmol/L refractory to medical treatment.

Metabolic acidosis with pH < 7.2 refractory to medical treatment.

Retention of nitrogenous waste products with secondary uremic complications.

There are other non-emergent indications for starting RRT in the critically ill patient, where it could be considered as supportive therapy:

Metabolic control in hypercatabolic situations.

• 1

  Volume control: Volume overload is an independent risk factor for mortality in critically ill patients and, on occasion, is the determining cause for initiating RRT.138 In these cases, continuous ultrafiltration facilitates the management of the critical patient, avoiding volume overload resulting from the continuous administration of intravenous drugs (antibiotics, vasoactive drugs, inotropes) and blood products, while simultaneously allowing the administration of the appropriate volume of enteral/parenteral nutrition (PN) according to their needs.

Finally, there are other situations, in which AKI may or may not be present, that may require the initiation of RRT:

• 1

  Intoxications: In non-critical patients, IHD is the treatment of choice.139 However, in critical patients, there are some drug intoxications, such as lithium or metformin, where continuous RRT may be an option. These drugs tend to show rebound effects after IHD, and a slower elimination rate does not pose a serious risk to the patient. Another therapeutic scheme in these cases would be a mixed treatment: performing IHD first and subsequently continuing with a continuous technique.

• 2

  Lactic acidosis: allows for the simultaneous removal of lactic acid and the provision of bicarbonate. However, in the absence of AKI or associated metformin intoxication, there is little evidence that initiating RRT influences patient prognosis.136

• 3

  Electrolyte disturbances, refractory to medical treatment, in hemodynamically unstable patients or those with severe brain injury.

• 4

  Congestive HF: SCUF (slow continuous ultrafiltration) as the technique of choice.140

• 5

  Refractory hyper- or hypothermia.

• 6

  Rhabdomyolysis: for the management of AKI, electrolyte disorders, or associated volume overload.

• 7

  Major burns: hypercatabolic patients with difficulties in fluid management.

• 8

  Metabolic and volume management in severe traumatic brain injury

• 9

  In liver failure, when accompanied by AKI or for the management of volume overload.