Transition from acute kidney injury to chronic kidney disease in liver cirrhosis patients: Current perspective

Abstract

In liver cirrhosis patients, acute kidney injury (AKI) is a common and severe complication associated with significant morbidity and mortality, often leading to chronic kidney disease (CKD). This progression reflects a complex interplay of renal and hepatic pathophysiology, with AKI acting as an initiator through maladaptive repair mechanisms. These mechanisms—such as tubular cell cycle arrest, inflammatory cascades, and fibrotic processes—are exacerbated by the hemodynamic and neurohormonal disturbances characteristic of cirrhosis. Following AKI episodes, persistent kidney dysfunction or acute kidney disease (AKD) often serves as a bridge to CKD. AKD represents a critical phase in renal deterioration, characterized by prolonged kidney injury that does not fully meet CKD criteria but exceeds the temporal scope of AKI. The progression from AKD to CKD is further influenced by recurrent AKI episodes, impaired renal autoregulation, and systemic comorbidities such as diabetes and metabolic dysfunction-associated steatotic liver disease, which compound kidney damage. The clinical management of AKI and CKD in cirrhotic patients requires a multidimensional approach that includes early identification of kidney injury, the application of novel biomarkers, and precision interventions. Recent evidence underscores the inadequacy of traditional biomarkers in predicting the AKI-to-CKD progression, necessitating novel biomarkers for early detection and intervention.

Key Words: Renal dysfunction; Acute kidney injury; Chronic kidney disease; Cirrhosis; Hepatorenal syndrome

Core Tip: In liver cirrhosis patients, acute kidney injury (AKI) frequently progresses to chronic kidney disease (CKD) through an intermediary stage known as acute kidney disease. This progression is driven by maladaptive repair processes, such as tubular cell cycle arrest and fibrosis, and exacerbated by cirrhosis-related hemodynamic and neurohormonal changes. Early detection of this AKI-to-CKD transition is crucial, and novel biomarkers and innovative imaging techniques, such as renal elastography, may present promising avenues for risk assessment and diagnosis. Integrating these tools into clinical practice, alongside targeted antifibrotic therapies and oxidative stress modulation, presents a promising strategy for managing renal complications in cirrhosis patients.

INTRODUCTION

Acute kidney injury (AKI) frequently occurs during the natural course of liver cirrhosis. The negative impact of AKI on cirrhosis patients is well-established and includes longer hospital stays, increased morbidity, and significantly higher rates of both in-hospital, short-term, and long-term mortality[1]. The prevalence of acute renal dysfunction in patients with cirrhosis ranges from 14% to 50%[1]. As the severity of liver disease increases, the incidence and risk of developing repeated episodes of AKI also rise. Moreover, patients who are discharged after an AKI episode have a higher risk of experiencing multiple AKI episodes and developing chronic kidney disease (CKD)[2,3]. Each AKI episode results in a reduction of renal reserve due to the loss of functional nephrons. Further, during the recovery phase, maladaptive repair mechanisms may trigger an inflammatory cascade, leading to interstitial fibrosis and eventually progressing to CKD[2]. The number of cirrhosis patients with CKD had increased from about 1% in 2005 to as high as 46.8% in 2019, reflecting the increasing incidence and prevalence of chronic liver disease (CLD) worldwide[4]. This paradigm shift signifies the convergence of important epidemiological factors common to both CLD and CKD, such as obesity, diabetes mellitus, hypertension, and metabolic dysfunction-associated steatotic liver disease (MASLD), besides the heightened risk of AKI-to-CKD progression in cirrhosis patients[5,6]. The transition from AKI to CKD in cirrhosis patients poses a significant clinical challenge, highlighting the urgent need for early detection, prompt intervention, and comprehensive management strategies. Figure 1 depicts factors associated with development of CKD in cirrhosis patients, with AKI playing and important role as initiator. CKD in cirrhosis patients has significant clinical implications, including an increased risk of recurrent AKI, refractory ascites, higher mortality, increased hospitalization rates, bacterial infections, higher liver transplantation (LT) rates, and reduced post-transplant survival[3,6]. However, data on CKD in CLD patients remains scarce. Hence, the present article will briefly discuss the AKI-to-CKD transition, the factors responsible for it, novel biomarkers for early identification, clinical impacts, and future therapies aimed at halting this progression from AKI to CKD.

Figure 1 Diagrammatic representation of factors associated with chronic kidney disease in liver cirrhosis patients. Acute kidney disease due to various causes can progressed to chronic kidney disease (CKD) in a significant proportion of cirrhosis patients. In addition, diabetes mellitus, hypertension and fatty liver disease, and certain etiological factors also increase the risk of CKD. AKI: Acute kidney injury; AKD: Acute kidney disease; CKD: Chronic kidney disease; DM: Diabetes mellitus; GI: Gastrointestinal; HBV: Hepatis B virus; HCV: Hepatitis C virus; HTN: Hypertension; HRS: Hepatorenal syndrome; MASLD: Metabolic dysfunction-associated steatotic liver disease.

AKI: THE INITIATOR

Among patients with cirrhosis and ascites, the overall prevalence of AKI is estimated to be around 14% to 50%, with many developing renal impairment upon hospital admission[1]. In a meta-analysis of 30 studies involving 18474 patients with cirrhosis, 5648 developed AKI, resulting in a pooled AKI incidence of 0.29 (95%CI: 0.28-0.30)[7]. In a meta-analysis focused on the incidence of AKI in acute-on chronic liver failure (ACLF) patients, Jiang et al[8] found it to be 0.41 (95%CI: 0.32-0.50). Another meta-analysis by Bai et al[9] found the incidence of AKI in cirrhosis patients admitted with acute gastrointestinal bleeding to be 0.21 (95%CI: 0.16-0.25). This broad variation in numbers occurs possibly because of heterogeneity in study populations and the use of diverse criteria to define renal dysfunction. Due to challenges in assessing renal function with accurate and less reliable creatinine-based assays, the International Club of Ascites revised its diagnostic approach in 2015, adopting the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 criteria to define AKI in the context of cirrhosis, although some limitations persist[10]. Another recent meta-analysis by Lekakis et al[11], the largest to date on AKI incidence in cirrhotic patients, analyzed 5202232 participants from 73 studies, reporting an overall AKI incidence of 0.33 (95%CI: 0.29–0.38) and confirming that AKI is a common complication. Intensive care unit (ICU) patients had the highest AKI incidence at 0.61, while ACLF patients also showed significantly higher rates than general inpatients (0.43 vs 0.29). Studies using international classification of diseases-10 code reported lower AKI rates (0.16), while those employing KDIGO criteria showed higher rates (0.71)[11].

As cirrhosis progresses, renal and circulatory abnormalities not only predispose the kidneys to injury but also actively induce damage, a phenomenon known as hepatorenal physiology, potentially leading to conditions such as prerenal azotemia and acute tubular necrosis (ATN). Prerenal azotemia, driven by reduced blood flow, is reversible, while ATN involves structural damage to the kidney tubules. The combination of hemodynamic changes, nephrotoxins, and inflammation drives a continuum of renal dysfunction, where AKI may begin as a functional disorder but can progress to irreversible structural injury with sustained hypoperfusion. This underscores the importance of early diagnosis and intervention to prevent permanent renal damage[12]. A meta-analysis of 13 cohort studies found that patients with AKI have a substantially increased risk of developing CKD and end-stage renal disease (ESRD), with incidence rates of 25.8 and 8.6 per 100 person-years, respectively. Compared to those without AKI, these patients faced higher risks of CKD [hazard ratio (HR) = 8.8], ESRD (HR = 3.1), and mortality (HR = 2.0), indicating that AKI significantly impacts both renal and overall long-term outcomes[13]. This risk appears to be much higher in cirrhosis patients due to underlying hemodynamic impairments and neurohormonal changes, which lead to increased renal vasoconstriction, reduced renal perfusion, and decreased glomerular filtration, predisposing these individuals to recurrent AKI episodes and subsequent CKD. Cirrhosis patients discharged following an episode of AKI are at an increased risk of recurrent episodes of AKI, progression to CKD, dialysis dependency and mortality[3]. Bassegoda et al[6] determined the frequency of CKD in 409 patients with cirrhosis (168 with AKI and 241 without AKI). At three months, 25% of AKI survivors (24 of 97) had CKD, compared to only 1% (2 of 188) of patients without AKI (P < 0.0001). Both the severity and recovery patterns of AKI affect long-term kidney health and the progression from AKI to CKD. A study on AKI recovery patterns in 22000 patients revealed that most of them (91%) had stage 1 AKI, with 71% recovering within 2 days (fast recovery). By one year, 18.2% of all patients developed CKD, with AKI patients showing a higher incidence (31.8%) than non-AKI patients (15.5%, P < 0.001). For stage 1 AKI, the adjusted relative risk of progressing to CKD stage 3 or higher was 1.43 for fast recovery, 2.00 for intermediate recovery (3–10 days), and 2.65 for slow (> 10 days) or unknown recovery[14]. In a recent study on a nationwide United States cohort of hospitalised cirrhosis patients AKI stage 1B patients had a significantly higher risk of AKI progression [OR = 1.42 (95%CI: 1.14-1.72)] and 90-day mortality (27.2% vs 19.7%, P < 0.001) than AKI stage 1A patients[15]. A longer time to AKI-recovery appears to increase the risk of adverse renal outcomes. Patidar et al[16] found that the cumulative incidence of subsequent major adverse kidney events, including development of de-novo CKD stage ≥ 3, was 15%, 20%, and 29% for 0-2 days, 3-7 days, and > 7 days recovery groups in a large cohort of patients with cirrhosis and AKI (n = 5937), with 75% achieving AKI-recovery. However, AKI no-recovery occurs in more than half (57%) of critically ill cirrhosis patients. These patients are more likely to have grade 3 ACLF and significantly higher mortality risk (sub HR = 3.55)[17].

The progression from AKI to CKD through an intermediary stage called acute kidney disease (AKD) represents a continuum of renal dysfunction (Figure 2). AKI often initiates this cascade with an acute renal insult that, if unresolved, leads to persistent kidney injury. Persistent AKI, defined by kidney dysfunction lasting beyond 48 hours, is an important precursor to AKD and is associated with higher rates of progression to CKD[18,19]. Conversely, those with CKD experience higher rates of AKI. This dynamic nature of renal function is evident in how AKI, AKD, and CKD overlap, leading to the consideration of AKI and CKD as interconnected syndromes[20,21]. Both AKI and CKD share common risk factors and independent risk factors for increased morbidity, mortality, negative clinical impacts, and reduced life expectancy in cirrhosis patients. In summary, patients with cirrhosis are at risk of developing AKI, which is associated with increased risk of morbidity, mortality and a risk of progressing to CKD. Early detection of AKI is essential since prompt therapy can reverse the condition and improve the outcome.

Figure 2 Transition of acute kidney injury to chronic kidney disease in cirrhosis patients: Natural history and management strategies. The progression from acute kidney injury to chronic kidney disease represents a continuum of renal dysfunction that occurs through an intermediary stage called acute kidney disease. AKD: Acute kidney disease; AKI: Acute kidney injury; CKD: Chronic kidney disease; NAKI: Non-acute kidney injury; SLKT: Simultaneous liver and kidney transplantation.

AKD: THE PROGRESSOR

The concept of AKD is introduced as a key intermediary phase in the progression from AKI to CKD. Unlike AKI, which is defined by a rapid decline in kidney function over a brief period (typically 7 days), AKD encompasses a broader range of kidney injuries lasting up to three months, bridging the gap between AKI and CKD. This concept is essential because many patients do not fully recover from AKI, where the renal pathophysiologic processes remain functional, but also do not meet the criteria for CKD or AKI, necessitating a more comprehensive classification[22]. According to KDIGO 2012 guidelines, AKD is broadly classified to include patients with an estimated glomerular filtration rate (eGFR) below 60 mL/minute per 1.73 m², a glomerular filtration rate (GFR) decrease of 35% or more, or a serum creatinine increase greater than 50%, all lasting for less than three months[23]. However, for cirrhosis patients, the criteria differ slightly. The International Club of Ascites expert committee permits the use of baseline creatinine levels from up to three months earlier when diagnosing AKI. For AKD in cirrhosis, the definition includes either an eGFR below 60 mL/minute per 1.73 m² for less than three months or a serum creatinine increase of less than 50% in the same duration[24]. This tailored approach accounts for the unique renal diagnostic challenges presented by cirrhosis. AKD can develop either as an extension of AKI (AKI-AKD) or independently, even without an initial rapid onset of kidney impairment (non-acute kidney injury-AKD). In simple terms, AKD reflects scenarios where kidney function deteriorates over a period too prolonged for AKI but too short to be classified as CKD.

In a prospective study involving 272 cirrhosis patients, 80 patients (29.4%) developed AKD during follow-up. Of these, 42 patients (52.5%) recovered from their first episode of AKD, 16 (20%) experienced a second episode of AKD, and 36 (45.0%) died while experiencing AKD. Additionally, AKD progressed to CKD in 11 patients (13.8%), as compared to 2.1% in patients who did not develop AKD (P < 0.001). The 5-year survival rate was significantly lower in patients who developed AKD than in those who did not (34.8% vs 88.8%, P < 0.001). The significant negative impact of AKD on transplant-free survival was demonstrated regardless of the severity of cirrhosis at the time of inclusion. Besides age, GFR and mean arterial pressure (MAP) were identified as independent predictors of AKD in patients with cirrhosis. Therefore, these factors should be closely monitored in this patient population[25]. This study highlights the potentially reversible nature of AKD, suggesting that the continuum from AKI to CKD is neither obvious nor linear if appropriate intervention is implemented.

The clinical significance of AKD has been demonstrated in non-cirrhotic patients too[26,27]. James et al[26] indicated that the presence of AKD without AKI increased the risk of mortality and progression to CKD. A five-year observational study found that 47% of 232 patients who developed AKI during their ICU admission progressed to AKD by day 7. The cumulative incidence of CKD at the five-year follow-up was 30%. Multivariate analysis revealed that the risk of CKD in AKD patients was significantly higher in the first six months post-AKI, decreasing thereafter[28]. These findings emphasize that the trajectory of kidney recovery is crucial, with the lack of recovery being more significant than the presence of AKD itself in predicting the transition to CKD, further signifying the reversible nature of AKD. AKD often goes undetected if not properly recognized, despite its potential long-term impacts. Current management primarily focuses on the initial stages of AKI rather than the post-AKI period. Many patients may still exhibit subtle kidney dysfunction or structural abnormalities after recovery from AKI, qualifying for AKD[29]. Recognizing AKD is critical as it expands our understanding of kidney disease beyond AKI and CKD alone. It enables early identification of patients at elevated risk for CKD, providing a vital window for proactive measures to prevent further progression, as well as integrating structural damage markers into assessment criteria. However, recognition of AKD in clinical practice faces barriers such as unclear definitions, limited awareness, and lack of readily available and reliable biomarkers. Addressing these challenges requires standardized diagnostic criteria, enhanced clinician education, integration of novel biomarkers, and improved electronic health systems for trend analysis. In summary, AKD represents a pivotal transitional phase between AKI and CKD, offering a crucial window for proactive interventions to halt disease progression. Effective management of AKD demands collaborative efforts and targeted research to develop and implement strategies for timely identification and treatment, ultimately improving patient outcomes.

CKD: THE OUTCOME

In cirrhosis patients, CKD is defined as an eGFR of less than 60 mL/minute per 1.73 m² for over three months. Estimating eGFR remains challenging in cirrhosis patients; however, the 6-variable Modification of Diet in Renal Disease (MDRD6) formula, which includes factors such as serum creatinine, age, gender, albumin, blood urea nitrogen, and race, is acceptable. Notably, the MDRD6 can overestimate GFR, especially in patients with GFR below 40 mL/minute, highlighting the need for future studies to refine this estimation method. The diagnosis of CKD in cirrhosis patients does not require imaging as structural damage often precedes imaging changes. Renal biopsy poses risks of bleeding due to coagulopathy and technical difficulties due to large-volume ascites[30]. KDIGO classifies CKD into structural and functional types based on the presence of kidney injury. The former type 2 hepatorenal syndrome (HRS), now termed HRS-CKD, is classified as functional CKD, which could be reversible[31]. However, ongoing renal vasoconstriction in functional CKD can lead to structural changes, evolving into structural CKD. Patients with cirrhosis often face additional risks of structural CKD due to conditions such as diabetes mellitus, hypertension, MASLD, and atherosclerosis[32].

Prevalence of CKD in cirrhosis patients

In a prospective study of 818 cirrhosis patients, 61% and 32.8% developed AKI and CKD, respectively, during follow-up. The median time to the development of CKD was 173 days, and interestingly, 81.7% of those who developed CKD had a prior history of AKI[33]. In a five-year follow-up observational study by Orieux et al[28], the cumulative incidence of CKD at five years was 30%, primarily due to the trajectory of non-recovery from AKI in 70% of patients. Another study evaluating patients with cirrhosis found that 25% of those who survived an episode of AKI developed CKD at three months post-AKI, compared to only 1% of patients without AKI, establishing the key pathogenic role of AKI in the development of CKD[6]. In a large cross-sectional study of 7440 adult cirrhosis patients from Taiwan, CKD was present in approximately 46% of patients[34]. In a prospectively managed North American Consortium for the Study of End-Stage Liver Disease data, the prevalence of CKD was 46.8% in non-electively admitted patients, of which 68% had superimposed AKI[4]. A large retrospective analysis of 78640 patients awaiting LT by Cullaro et al[35] reported the prevalence of CKD at 7.8% in 2002 compared to 14.6% in 2017, suggesting a rising trend over time.

Mechanism of AKI to CKD transition

After AKI, the kidneys initiate repair mechanisms involving renal progenitor cells and de-differentiated mature cells to restore function. During recovery, surviving cells activate protective pathways to help epithelial cells regain their properties. This repair involves processes such as dedifferentiation, metabolic changes, extracellular matrix production, and nephron hypertrophy. If successful, these coordinated actions result in adaptive repair, allowing the kidneys to reach a new equilibrium, as seen in the rapid recovery of kidney function in young patients or after mild injury. However, despite an incomplete understanding of the transition from AKI to CKD, current evidence suggests that maladaptive repair—a process where inappropriate cellular reactions lead to improper healing—is the most likely mechanism driving chronic kidney damage[36]. Maladaptive repair in tubular, vascular, and interstitial compartments after AKI can lead to progressive renal interstitial fibrosis. This occurs through mechanisms such as cell cycle arrest, secretion of profibrotic cytokines, pericyte activation leading to myofibroblast generation, inflammation, loss of peritubular capillaries, and increased production of extracellular matrix. Collectively, these processes contribute to long-term damage and dysfunction of the kidneys[37].

After AKI, the activation of the DNA damage response is essential for initiating repair in renal epithelial cells. When complete repair fails, proximal tubules may enter G2/M cell cycle arrest to maintain genomic stability. Although initially protective, prolonged G2/M arrest can promote a profibrotic state, leading to fibrosis and irreversible damage[38,39]. Cellular senescence, associated with repeated injury and DNA damage, accelerates fibrosis and mimics aging[40]. The role of epigenetic modifications is gaining attention lately, as changes in DNA methylation, histone modifications, and noncoding RNAs are believed to play a crucial role. These changes, often triggered by hypoxia, promote the expression of inflammatory genes and increase collagen secretion, contributing to fibrosis[41]. Both innate and adaptive immune responses, such as macrophages, complements, and T cells, are involved in this transition[37,42]. Mitochondrial dysfunction in proximal tubules, including disrupted homeostasis and mtDNA release, triggers immune responses that activate inflammatory pathways. Hypoxia during AKI exacerbates mitochondrial dysfunction, leading to capillary rarefaction and further kidney injury[43,44].

Risk factors and predictors of AKI to CKD transition

The frequent use of diuretics, nephrotoxic medications, and uncontrolled ascites significantly contribute to the persistence of AKI and increase the risk of progression to CKD[6,45]. Additionally, besides HRS-CKD, other liver-associated renal pathologies such as immunoglobulin A nephropathy, hepatitis B virus or hepatitis C virus-associated glomerulonephritis, and polyarteritis nodosa further predispose cirrhosis patients to CKD[46,47]. Systemic comorbidities known to promote renal injury, including hypertensive nephrosclerosis, diabetic nephropathy, obesity/metabolic syndrome-related nephropathy, and unresolved obstructive uropathy, are risk factors that may further contribute to the progression from AKI to CKD. The presence of concurrent diabetes is one of the most common causes of CKD developing in cirrhosis patients[33]. Diabetes mellitus is highly prevalent in cirrhosis, with rates between 35% and 71%, significantly exceeding those in the general population[48]. A recent study by Maji et al[49] found that apart from type 2 diabetes, cirrhosis itself may lead to a form of diabetes known as hepatogenous diabetes, which is the predominant type in child C cirrhosis patients. Another important risk factor for CKD is MASLD. MASLD and CKD are closely linked, primarily due to shared risk factors such as obesity, insulin resistance, and metabolic syndrome. The prevalence of MASLD among CKD patients is significant, with studies indicating that 30%–40% of individuals with CKD also have MASLD[50]. In a meta-analysis by Musso et al[51], the incidence and prevalence of CKD are approximately twice as high in MASLD patients. Thus, screening for kidney function in MASLD patients is crucial for early interventions. In cirrhotic patients with AKI, baseline elevated serum cystatin C levels and higher model for end-stage liver disease scores also predict poor renal recovery. Additionally, higher initial AKI stages—particularly stages 2 and 3—predict a greater likelihood of CKD development[33]. Each new episode of AKI further impairs the kidney's autoregulation mechanisms, ultimately resulting in interstitial fibrosis rather than regeneration[52].

Clinical implications of CKD in cirrhosis

In cirrhosis patients, CKD is associated with significantly worse outcomes[3]. They experience higher rates of AKI (68% vs 21%), an increased need for dialysis (11% vs 2%), and a higher 30-day mortality rate (16% vs 7%) compared to cirrhosis patients without CKD. Further, CKD is also associated with more frequent occurrences of refractory ascites (25% vs 7%), bacterial infections (58% vs 34%), and a greater likelihood of LT (25% vs 10%), as well as higher rates of hospitalization (70% vs 63%) compared to those without CKD[4]. Similarly, Bassegoda et al[6] also reported that patients with cirrhosis and CKD had a greater frequency of AKI (75% vs 45%), refractory ascites (25% vs 7%), bacterial infections (58% vs 34%), and a higher likelihood of needing LT (25% vs 10%) compared to those without CKD[5]. Cullaro et al[35] highlighted that one-year post-LT mortality was also higher in patients with CKD (12% vs 9%), suggesting that CKD may impact renal outcomes after transplantation too.

Patients with cirrhosis and CKD often experience overlapping symptoms such as ascites, edema, and bleeding tendencies, complicating the determination of disease-specific contributions and the selection of appropriate therapies. CKD can exacerbate other manifestations of cirrhosis, including anemia, immunodepression, and bleeding tendencies. Additionally, CKD raises cardiovascular mortality risk in cirrhosis patients[47]. CKD is also linked to a higher prevalence of hepatocellular carcinoma and other cancers, particularly in patients with MASLD. Shared risk factors such as alcohol use and viral hepatitis further contribute to the complexity of managing these patients[53-55]. Standard therapies like hemodialysis are poorly tolerated by cirrhosis patients with CKD compared to peritoneal dialysis[56]. To summarize, up to 25% of cirrhosis patients who recover from AKI may progress to CKD, potentially due to maladaptive repair processes and ongoing hemodynamic alterations. This risk is heightened by concurrent risk factors, such as diabetes and MASLD. Progression to CKD is associated with various complications and poorer clinical outcomes in cirrhosis patients.

EARLY IDENTIFICATION OF AKI TO CKD TRANSITION

To improve renal outcomes in cirrhosis patients, early identification of persistent AKI, AKD, and CKD is crucial. Traditional tools, such as creatinine-based eGFR equations, often overestimate GFR, leading to delayed diagnosis[57]. Cystatin C-based eGFR calculation may be a better tool for assessing kidney function in cirrhosis, as it is less affected by hepatic function, muscle mass, and serum bilirubin, enabling earlier CKD detection[58]. However, cost, availability, and lack of standardization limit its use[59]. Conventional urine indicators such as albuminuria are less accurate in cirrhosis patients due to hypoalbuminemia and increased capillary permeability[60]. These factors underscore the need for novel biomarkers of kidney damage that may be present before the development of functional abnormalities. Kidney injury molecule 1 (KIM-1), a type 1 transmembrane glycoprotein, is expressed in response to mainly tubular injury and is upregulated in dedifferentiated proximal tubular epithelial cells after ischemic or toxic injury. Urinary KIM-1 is a good predictor of renal injury before detectable changes in eGFR, making it a potential biomarker for early detection of CKD[61]. Neutrophil gelatinase-associated lipocalin (NGAL), produced by renal tubular cells in response to injury, is a highly studied biomarker for renal dysfunction in cirrhosis patients. NGAL is a rapid-response biomarker for kidney damage, detectable within two hours of injury[62]. Its role in inflammation and cell proliferation also links it to CKD progression. Elevated levels of NGAL in plasma and urine correlate inversely with eGFR, reflecting its predictive value for renal function decline[63]. Urinary NGAL has shown a specificity of 83.3% and a sensitivity of 70.6% in predicting microalbuminuria and early kidney damage, suggesting its potential to stratify CKD progression risk post-AKI[64,65]. There are multiple point-of-care test devices available for quick measurement of plasma/urine NGAL, providing results within 15–20 minutes. MicroRNAs (miRNAs), non-coding RNAs that regulate gene expression, are also promising biomarkers for CKD. Circulating miR-21, associated with fibrosis, correlates inversely with renal function, while urinary miRNAs are stable and detectable even in early CKD stages[66-68]. Specific miRNA families, such as miR-29 and miR-200, diminish with kidney damage, indicating disease severity[68]. Other potential biomarkers of CKD include uromodulin, which decreases with reduced nephron mass[69], and dimethylarginine, markers of endothelial dysfunction that increase with CKD progression[70]. Lastly, emerging proteomic and metabolomic panels, like the CKD273 urinary peptide panel, may further improve the early detection of CKD[71,72]. Plasma concentrations of soluble tumor necrosis factor receptors 1 and 2 have been consistently found to be associated with incident CKD in nondiabetic subjects[73]. The CKD Biomarkers Consortium's protocols have yielded important insights into the role and validation of biomarkers. Their research found that elevated plasma and urine NGAL were associated with faster eGFR decline and progression to ESRD. NGAL also predicted the onset of albuminuria and structural kidney damage. These markers are particularly useful when combined with traditional risk factors to CKD, like proteinuria and other clinical parameters. Results of phase II protocols found that higher NGAL levels when combined with KIM-1 and IL-18 predicted adverse outcomes including hospitalisation, rapid CKD progression and mortality[74]. In another prospective study by Wen et al[75], involving 656 patients hospitalised with AKI followed up with 7 different biomarkers, each standard deviation increase in KIM-1 from baseline to 12 months, along with other biomarkers, increases risk of progression to CKD by 2-3 times.

The use of biomarkers in the routine clinical practice is generally constrained by cost, availability, and lack of standardization. The current biomarkers of AKI have limited efficacy in predicting AKD or CKD on their own. There is a pressing need for the development of novel biomarkers that can accurately predict the transition from AKI to CKD. The CKD Biomarker Consortium is actively working toward this goal. Besides KIM-1 and NGAL, other markers such as liver fatty acid-binding protein, interleukin-18, and tissue inhibitor of metalloproteinases (TIMP)-2 × insulin-like growth factor-binding protein-7 (IGFBP7) reflect sustained tubular injury, indicating a higher risk of CKD development[76]. A study of 692 patients found that TIMP-2 × IGFBP7 levels above 2.0 at admission were associated with increased mortality or the need for dialysis within nine months[77]. Given the role of the renin-angiotensin-aldosterone system in CKD progression, urinary angiotensinogen could serve as a useful marker[78]. The acute dialysis quality index has recently proposed a staging system for AKD that incorporates traditional markers like albuminuria, hematuria, and imaging findings, along with newer biomarkers to better stratify AKD patients at high risk of progression[79]. Additionally, the Chronic Renal Insufficiency study identified rapid CKD progressors with specific DNA methylation patterns linked to inflammation and fibrosis, particularly involving transforming growth factor (TGF)-β[80].

Fibrosis onset in the kidney is a key indicator of CKD progression. Although tissue biopsy is the gold standard for assessing renal fibrosis, it is invasive, prone to sampling error and observer variability, and can be problematic for patients with advanced cirrhosis. Non-invasive assessment of renal fibrosis has shown promise because of recent advancements in diagnostic imaging techniques including magnetic resonance imaging (MRI) and ultrasound. These imaging techniques quantify renal fibrosis by evaluating its impact on the molecular, mechanical, and functional properties of the kidney, including water mobility restriction by diffusion MRI, tissue hypoxia by blood-oxygenation-level-dependent MRI, renal stiffness by magnetic resonance (MR) and ultrasound elastography. Moreover, other MR techniques like susceptibility-weighted imaging and T1/T2 mapping have been used to quantify renal fibrosis[81-85]. The renal resistive index (RRI), measured by renal duplex ultrasound, is a marker of renal vascular resistance that has potential in assessing functional CKD. RRI can also predict CKD progression as it correlates with renal histopathological changes such as glomerular sclerosis and interstitial fibrosis[86]. Surya et al[87] studied 200 consecutive cirrhosis patients and found RRI could stratified different AKI phenotypes and predicted AKI mortality. As the severity of AKI is a crucial factor for progression, RRI may identify patients at high risk for AKI to CKD progression. In summary, biomarkers of kidney damage can play a crucial role in identifying the transition from AKI to CKD. While several biomarkers have been developed, existing AKI biomarkers face challenges, including limited ability to predict CKD progression, high costs, poor accessibility, and lack of standardization. Further research is necessary to address these gaps. Furthermore, non-invasive imaging techniques for assessing kidney fibrosis have garnered significant attention due to promising results. However, these methods require further refinement to ensure their clinical utility and practicality.

THERAPEUTIC IMPLICATIONS

Addressing AKI promptly in cirrhosis patients and providing appropriate and timely treatment will lead to early recovery from AKI and reduce the progression to CKD. The primary objective in managing HRS-AKI is to reverse the hemodynamic alterations leading to renal vasoconstriction. Management is also tailored to address the underlying cause and precipitating factors of AKI. In HRS-AKI patients, terlipressin plus albumin has been shown to achieve a significantly higher rate of HRS reversal (27% vs 14%, P = 0.004) compared to albumin alone[88]. Terlipressin plus albumin is also more effective in reversing HRS-AKI than a combination of midodrine and octreotide plus albumin[89]. Early institution of therapy results in a better response rate. In a recent study, AKI reversal was higher and earlier in patients with ACLF when terlipressin was administered after 12 hours of volume expansion, rather than 48 hours (68.6% vs 31.4%, P = 0.03)[90]. Reversal of HRS-AKI also reduces the risk of developing CKD after LT. A study demonstrated that patients who responded to terlipressin and albumin had a significantly lower probability of developing CKD one year post-LT compared to non-responders (31% vs 65%, P = 0.019)[91]. It is essential to note that vasoconstrictors are more effective in treating HRS when initiated at lower serum creatinine levels (< 2.25 mg/dL) and when achieving a significant increase in MAP of 15 mmHg or more[3]. Reversal of HRS is less likely in patients with higher baseline creatinine, lower baseline MAP, underlying cirrhotic cardiomyopathy, or portopulmonary hypertension. Transjugular intrahepatic portosystemic shunt (TIPS) placement has been shown to reverse HRS and improve renal and cardiac function by reducing portal hypertension. In a metanalysis of 9 studies, the pooled rate of renal function improvement after TIPS was 83% in any type of HRS, although with a high incidence of hepatic encephalopathy (49%)[92].

Emerging therapies aimed at preventing the transition from AKI to CKD in cirrhotic patients focus on managing inflammation, oxidative stress, and fibrosis, as well as promoting kidney repair and regeneration. The role of antifibrotic therapy is still evolving and is currently hindered by poor specificity, incomplete fibrosis reversal, off-target effects, and limited clinical trials validating long-term outcomes. Targeted antifibrotic therapies, such as those inhibiting TGF-β signalling, are under investigation to reduce kidney fibrosis and inflammation—key contributors to CKD progression[93,94]. Pirfenidone, an antifibrotic drug, inhibits the expression of TGF-β and exhibits anti-inflammatory activity by suppressing tumor necrosis factor expression. Approved for idiopathic pulmonary fibrosis in 2021, it is currently under investigation for renal fibrosis[95,96]. In a double-blind randomized controlled trial involving 77 participants with diabetic nephropathy, the pirfenidone 1200 mg/day group showed a mean eGFR increase of 3.3 mL/minute/1.73 m² ± 8.5 mL/minute/1.73 m²[97]. The results of the ongoing Phase 2 TOP-CKD trial (ID: NCT04258397), the largest trial on pirfenidone for kidney fibrosis using imaging and urinary biomarkers, are awaited. Another drug, Lademirsen, is a microRNA inhibitor targeting miR-21, which regulates kidney fibrosis. A Phase 2 trial of Lademirsen is underway for Alport's syndrome (HERA; trial ID: NCT02855268)[96]. Hypoxia-inducible factor stabilizers, such as FG-4592 (Roxadustat), have shown promising effects by supporting renal vascular regeneration and reducing oxidative stress. This helps alleviate ischemia-induced renal injury and can decrease the likelihood of fibrosis and long-term CKD development[98]. Similarly, therapies aimed at modulating the renin-angiotensin-aldosterone system have shown potential for slowing fibrosis and improving renal outcomes in cirrhotic AKI patients[99].

Newer interventions targeting endothelial dysfunction and oxidative stress, such as the use of nitric oxide donors and antioxidants, may also offer protective effects for these patients by improving blood flow to the kidneys[100]. Mesenchymal stem cell (MSC) therapies have demonstrated potential in reducing renal fibrosis and encouraging kidney repair by releasing anti-inflammatory exosomes[101]. Currently, the idea of using stem cell therapy for renal fibrosis is based on inhibiting signalling pathways involved in the development of fibrosis, including both TGF-β/Smad-dependent and independent pathways. Most studies involving stem cell therapies are in the preclinical phase. Results have shown no significant adverse events, but their efficacy remains controversial[102]. Lang et al[103] demonstrated that bone marrow-derived MSCs could significantly reduce renal fibrosis in a diabetic nephropathy rat model, potentially by inhibiting the TGF-β1/Smad3 signalling pathway. Nevertheless, stem cell therapy in CKD faces limitations such as high costs, immune rejection, ethical concerns, and inconsistent efficacy. Additionally, antioxidant and anti-inflammatory agents, such as lactoferrin and poricoic acid, have shown efficacy in animal models[104,105]. In combination with melatonin, these agents help reduce oxidative stress and inflammation, attenuating fibrosis, and the transition from AKI to CKD. Particularly, Lactoferrin enhances kidney autophagy while inhibiting apoptosis, promoting a more resilient renal environment less prone to fibrosis[104]. The emerging field of nanotherapeutics is being investigated as a novel treatment strategy for AKI. Recent developments have led to the creation of various nanomaterials, including molybdenum-based polyoxometalate nanoclusters, mitochondria-targeting ceria nanoparticles, and black phosphorus nanosheets. These nanomaterials have been shown to scavenge reactive oxygen species and reduce inflammation in various AKI models[106]. Biomarker-driven therapies are another promising avenue guiding individualized treatment plans[107,108]. Thus, our growing understanding of kidney injury and repair mechanisms is facilitating the creation of targeted treatments, currently being tested in clinical trials. As precision medicine advances, these targeted therapies and early interventions hold promise for reducing the transition from AKI to CKD.

CONCLUSION

The transition from AKI to CKD in cirrhotic patients poses a significant clinical challenge, underscoring the urgent need for early detection, prompt intervention, and comprehensive management strategies. Table 1 summarizes the critical issues involving the transition from AKI to CKD in patients with liver cirrhosis. Clinicians should prioritize the utilization of novel biomarkers and the development of non-invasive imaging techniques, such as renal elastography and MRI-based fibrosis assessment, to enhance monitoring and inform therapeutic decisions. Future research should aim to refine these biomarkers, improving diagnostic accuracy in the AKI-to-CKD continuum, particularly in the unique context of cirrhosis. Additionally, innovative therapeutic strategies targeting maladaptive repair mechanisms, including cellular senescence, fibrotic signalling, and oxidative damage, may offer avenues to mitigate or even prevent CKD progression. Ultimately, a multidisciplinary approach that integrates early detection, advanced monitoring, and targeted interventions is crucial for improving renal outcomes and enhancing the quality of life for cirrhosis patients at risk for CKD.

Table 1 Important issues involving transition of acute kidney injury to chronic kidney disease in patients with liver cirrhosis.

Factors	Description
Risk factors for CKD transition	AKI characteristics: Recurrent AKI, severe AKI, acute kidney disease
	Metabolic factors: Diabetes mellitus, hypertension, metabolic dysfunction-associated steatotic liver disease
	Cirrhosis factors: Higher model for end-stage liver disease scores, neuro-hormonal alterations
	Etiological factors: Alcohol, hepatis B virus and hepatitis C virus (glomerulonephritis)
Putative mechanisms for chronic liver disease transition	Maladaptive repair mechanism: Cell cycle arrest and cellular senescence
	Inflammation and fibrosis: Profibrotic cytokines, myofibroblast generation, and increase in extracellular matrix
Clinical impacts of CKD	Refractory ascites and increased frequency of bacterial infection
	Increased frequency of AKI
	Need for dialysis and need for liver transplantation and simultaneous liver and kidney transplantation
	Higher mortality risk
Novel biomarkers for AKI-CKD	Kidney injury molecule-1
	Neutrophil gelatinase-associated lipocalin
	Tissue inhibitor of metalloproteinases-2
	Uromodulin and dimethylarginine
	Liver type-fatty acid binding protein
Future potential therapies	Targeted transforming growth factor-β inhibition
	Modulation of renin-angiotensin-aldosterone system, endothelial dysfunction and oxidative stress biomarker driven therapy
	Hypoxia inducible factor stabilizers
	Mesenchymal stem cell therapies

AKI: Acute kidney injury; CKD: Chronic kidney disease.