Part Ⅱ：Biomarkers Of Acute And Chronic Kidney Disease
Mar 13, 2022
Contact: Audrey Hu Whatsapp/hp: 0086 13880143964 Email: audrey.hu@wecistanche.com
The advances in the identification of these serum and urinary biomarkers representing
tubular health have been investigated widely in AKI and can complement serum creatinine
to improve patient management. Biomarkers can complement and provide mechanistic
context to the rise in serum creatinine and improve clinical management of kidney disease
in different settings (Figure 4).
Early detection of subclinical AKI following cardiac surgery.—Cardiac surgery is a leading cause of ischemic AKI in hospitalized patients and is strongly associated with significant morbidity and mortality. However, serum creatinine rises late in the disease course at 48–72 h postsurgery and limits the ability for early detection and intervention of these cases of AKI. The futility of attempting to treat patients following recognition of kidney injury based on serum creatinine has been compared to initiating treatment of myocardial infarction or stroke 48 h after the onset of ischemia. Preclinical models have demonstrated global changes in renal gene expression during early ischemic injury (79, 80), including the production of proteins that have since been identified as biomarkers of AKI (81). The use of these biomarkers can augment the clinical ability to detect cases of kidney injury, improve risk stratification, and provide insight into therapeutic targets (82). Biomarkers of renal tubular injury, including IL-18, NGAL, and KIM-1, measured within 6 h following cardiac surgery, have been demonstrated to predict the risk of AKI well before the rise in serum creatinine. For example, the highest quintiles of serum IL-18 within 6 h postsurgery were associated with a sevenfold increased risk of AKI in both adults and children, compared to the respective lowest quintiles (83, 84). Similarly, the highest quintiles of plasma NGAL and urinary KIM-1 were associated with increased risk of developing AKI, compared with the first quintile (adjusted OR 5.0, 95% CI: 1.6–15.3; adjusted OR 4.8, 95% CI: 1.6–14.6, respectively) (40, 83).
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Although serum creatinine returns to normal levels in many of these cases of AKI, the
burden on the kidneys may not be completely benign. For example, preclinical studies have
demonstrated the development and persistence of inflammation, renal fibrosis, abnormal
kidney gene expression profiles, and functional deficits after ischemic kidney injury, despite a
return of serum creatinine concentrations to normal values (85, 86). Accordingly, these
biomarkers of tubular injury were also associated with the severity and progression of AKI in
the postcardiac surgery setting. The highest quintile of urinary IL-18 predicted those who
progressed from early AKI (Acute Kidney Injury Network [AKIN] Stage 1) to more severe
stages of AKI (AKIN Stage 2 or 3) (adjusted OR 3.00, 95% CI: 1.25–7.25) and was
associated with duration of AKI >7 days (adjusted OR 2.90, 95% CI: 1.80–4.68) (87, 88).
Similarly, those with the highest quintile of plasma NGAL were nearly eight times more
likely to develop progressive AKI (OR 7.72, 95% CI: 2.65–22.49) compared with those in
the first two quintiles. The highest quintile of urinary KIM-1 was also associated with a longer
duration of AKI (adjusted OR 2.3, 95% CI: 1.51–3.53) (88). L-FABP was associated with the duration of AKI, and both the fourth and fifth quintiles were associated with a longer
duration of AKI (adjusted OR 1.77, 95% CI: 1.17–2.67; adjusted OR 1.92, 95% CI: 1.26–
2.93, respectively) (88).
Moreover, these biomarkers of tubular injury have even demonstrated the potential to portend long-term mortality following cardiac surgery. Even in patients without AKI, the highest tertile of IL-18 was associated with increased risk of mortality over a median follow-up time of 3.0 years [interquartile range (IQR) 2.2 to 3.6] compared with the first tertile [adjusted hazard ratio (HR) 1.23, 95% CI: 1.02–1.48]. This effect was magnified in those subjects with perioperative AKI (adjusted HR 3.16, 95% CI: 1.53–6.53) (89). Similarly, the highest tertile of perioperative urinary KIM-1 was associated with increased mortality (adjusted HR 1.83, 95% CI: 1.44–2.33) in those who did not develop AKI as well as in those who developed AKI (adjusted HR 2.01, 95% CI: 1.31–3.1) (89). These findings may be especially critical because the association of troponin with mortality, in conjunction with its tissue specificity, was an important component of its incorporation into the diagnosis of myocardial infarction (90). However, given the long latency between an episode of kidney injury and mortality, in contrast to myocardial infarction, it may be difficult to determine causality. Nonetheless, these data suggest that recovery of serum creatinine levels may not capture the residual injury and fibrosis within the kidney that predisposes to increased morbidity and mortality. Recent evidence has demonstrated that elevated urinary kidney biomarkers of tubular damage, including α1M, PIIINP, and NGAL, are independent risk factors for both CVD and mortality over a median follow-up period of 12.4 years among elderly individuals with preserved baseline kidney function in a case-cohort study of the Health, Aging, and Body Composition (ABC) Study (91).
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Distinguishing distinct etiologies of AKI in cardiorenal and hepatorenal
syndromes.—Kidney injury in the settings of cardiorenal and hepatorenal syndromes
(CRS, HRS) may have diverse underlying pathophysiology. Both cardiac dysfunction and
cirrhosis can reduce renal perfusion through decreased forward flow and increased venous
congestion, predisposing patients to kidney injury of prerenal physiology and intrinsic
tubular injury. A wide variety of comorbidities and treatments may further complicate
interpreting the meaning of rising serum creatinine concentrations. Biomarkers of tubular
injury have demonstrated utility in distinguishing these distinct pathological processes.
For example, in the setting of CRS, aggressive diuresis is the mainstay of treatment to relieve congestion and restore cardiovascular hemodynamics but is also associated with elevations in serum creatinine, a phenomenon known as worsening renal function in the cardiology literature and often considered to be AKI (92, 93). Due to this perceived kidney damage, which is thought to be associated with adverse events (94, 95), diuresis and additional treatment are often halted (96). However, a rise in serum creatinine may not necessarily be uniformly associated with intrinsic kidney damage and adverse outcomes. For example, in a prospective cohort study of patients with acute decompensated heart failure, those who developed AKI following diuretic therapy did not have a significant rise in urinary NGAL levels (97). Furthermore, a recent ancillary study of the Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE-AHF) clinical trial using biomarkers of tubular health among 283 participants undergoing aggressive diuresis demonstrated that worsening renal function was not associated with elevations in biomarkers of kidney tubular injury, including NGAL and KIM-1, nor with adverse outcomes (98). The results demonstrated that the rise in creatinine may reflect clinically benign changes infiltration and suggest that such increases in creatinine may not warrant withdrawal of beneficial therapies.
Similarly, biomarkers have the ability to help narrow the differential diagnosis in the setting of cirrhosis between the two common etiologies of HRS and acute tubular necrosis. The ability to make the distinction between hepatorenal physiology and intrinsic tubular injury is critical because treatments differ considerably. HRS may be reversed with the restoration of renal perfusion through systemic vasoconstrictor therapy in addition to intravenous albumin treatment and subsequent liver transplantation. In contrast, patients with intrinsic tubular injury should be treated with dialysis and considered for combined liver-kidney transplantation (99–102). However, the current clinical paradigm to diagnose HRS is largely based on serum creatinine. Biomarkers of tubular health may distinguish causes of AKI and enable more rapid diagnoses and appropriate treatments. In a study of patients with cirrhosis who developed AKI, urinary levels of NGAL, IL-18, and L-FABP were elevated in patients with clinically adjudicated acute tubular necrosis but not in those with HRS or prerenal etiologies (103). In addition, the highest biomarker levels were found in patients with acute tubular injury, followed by HRS and prerenal azotemia, respectively, concordant with the physiology of the extent of tubular injury (100, 104). The combination of several biomarkers, including NGAL, L-FABP, and IL-18, was also assessed in diagnosing the type of AKI in patients with cirrhosis, with the likelihood of being diagnosed with acute tubular injury increasing in a stepwise fashion with the number of biomarkers that were above the optimal diagnostic cutoffs. For example, patients with cirrhosis who had at least one biomarker above the cutoff level were five times as likely to have an acute tubular injury and those with all markers positive were 13 times as likely to have an acute tubular injury (105).
Delineating prognosis of AKI in deceased donor kidney transplantation.—Ischemia-reperfusion injury-mediated AKI is often seen in deceased donor kidneys, which subsequently have higher discard rates. Given the significant shortage of kidneys for transplantation, salvaging every viable kidney is imperative. However, serum creatinine may not accurately capture kidney injury and provide information about performance posttransplantation. In fact, an analysis of a biopsy series found that more than 20% of cases of biopsy-proven acute tubular injury did not meet the Kidney Disease: Improving Global Outcomes (KDIGO) serum creatinine-based AKI definition (106). Biomarkers of tubular injury can provide insight into the quality of deceased donor kidneys. For example, a study of deceased kidney donors demonstrated that serum creatinine had limited accuracy for diagnosing acute tubular necrosis, whereas urinary NGAL levels outperformed the diagnosis of acute tubular injury (107). In addition, these biomarkers of tubular health may provide prognostic information. A large study of deceased donors of kidney injury demonstrated that increased urinary levels of NGAL, KIM-1, IL-18, and L-FABP were strongly associated with donor AKI but not with delayed graft function (107). Interestingly, the study reported that higher levels of kidney injury biomarkers were associated with higher 6-month eGFRs in recipients with delayed graft function. The protective effects of the intrinsic kidney injury from AKI are believed to be due to ischemic preconditioning, which involves the upregulation of anti-ischemic mediators. Consistent with these findings, ischemic preconditioning has been demonstrated to provide both acute and delayed protection against renal ischemia-reperfusion injury in mouse models via distinct signaling pathways (108).
In addition, YKL-40, a biomarker of adaptive repair after kidney injury, has been shown to be cytoprotective in the setting of kidney transplantation. Deceased kidney donors who had the highest YKL-40 levels had higher eGFRs at 6 months compared with patients whose donors had the lowest YKL-40 levels, after adjusting for donor and recipient factors, as well as the degree of kidney injury. Moreover, recipients with the highest donor YKL-40 levels also had 50% lower hazards of graft failure (adjusted HR 0.50, 95% CI: 0.27–0.94) (109).
Chronic Kidney Disease
In CKD, the timing and nature of the insult may be more difficult to estimate, as an accrual of kidney insults and injury over many years leads to the development of this condition. Thus, the early search for biomarkers of CKD lagged behind the research of AKI. However, because AKI and CKD share similar underlying mechanisms of functional and structural injury and exist on the same pathophysiologic continuum, biomarkers of AKI have also been applied to CKD. The biomarkers have been especially promising in identifying susceptibility to and predicting the development of incident CKD; however, they have not been as robust in predicting CKD progression after adjustment for serum creatinine, and studies in different settings may be biased based on the etiology of underlying CKD and enrollment criteria. In participants without CKD at baseline, the “renal filtration reserve” (4, 5) is able to compensate for filtration deficits and, in effect, absorbs the insult (Figure 4). Biomarkers of tubular injury are critical to providing information about kidney tubular injury in these situations in which serum creatinine does not change appreciably. Accordingly, these biomarkers of tubular injury have been shown to be especially promising in prognosticating the development of incident CKD. For example, in a nested-case control study of 686 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), in which cases were defined as those with a baseline eGFR >60 ml/min who subsequently developed CKD Stage 3 and/or had a rapid drop in kidney function over the five-year study period, higher levels of KIM-1 were associated with increased odds of developing CKD stage 3 or a rapid decline in eGFR (adjusted OR 1.15, 95% CI: 1.02–1.29). Similarly, at study entry, those in the highest decile of KIM-1 had a twofold increased risk of this same endpoint compared with the lower 90%. This ability to predict the development and progression of CKD was independent of the presence of albuminuria (110). Similarly, when investigated in a cohort of 149 persons with chronic congestive heart failure during 5 years of follow-up, urinary KIM-1 levels were strongly associated with the progression of CKD, defined as a >25% drop in eGFR from baseline (111).
However, when renal filtration reserve is lost, each insult to the kidney will correspond with an added decrease in glomerular filtration and, thus, serum creatinine may provide as much information as tubular injury biomarkers. For example, a recent study of participants in the Chronic Renal Insufficiency Cohort (CRIC) with baseline CKD demonstrated that urinary KIM-1, NGAL, and L-FABP levels were significantly associated with CKD progression in unadjusted analyses; however, once controlling for serum creatinine-based eGFR and urinary albumin/creatinine ratio, two traditional markers of kidney function, these biomarkers were no longer independently associated with CKD progression. In addition, none of the biomarkers improved risk stratification of the clinical model for CKD progression, suggesting that tubular injury biomarkers may have limited utility in patients who have diminished renal reserve (112). Additional studies of individuals with CKD have also demonstrated that tubular injury markers do not add to risk prediction of disease progression after accounting for traditional markers of kidney function (113–115).
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Diabetic nephropathy.—Diabetes is a major risk factor and the leading cause of CKD and ESRD. However, 20–30% of individuals with diabetes have rapidly declining kidney function even when on optimal therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. Kidney disease progression in diabetes is multifactorial and may be driven by ongoing inflammation, intrinsic tubular injury, or maladaptive repair, among other pathways (116, 117), and biomarkers may help to discern the dominant underlying etiologies (Figure 5). Addressing this key clinical question with biomarkers of tubular health may improve risk stratification and enable effective treatment of progressive diabetic kidney disease.
For example, biomarkers of tubular injury have been found to be associated with kidney disease in diabetic patients, indicating underlying intrinsic tubular injury. Plasma KIM-1 was measured in subjects from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and US Veterans Administration Nephropathy in Diabetes (VA-NEPHRON-D) cohorts. In the ACCORD cohort, those who went on to develop incident CKD had higher baseline KIM-1 levels. Similarly, in the VA-NEPHRON-D study, those who went on to develop progressive CKD had higher baseline levels (118). In both of these studies, those with the highest quartile of KIM-1 concentrations were more likely to experience adverse renal outcomes, compared with those in the lowest quartiles of KIM-1 concentrations (119, 120).
In these two cohorts, plasma TNFR1 and TNFR2 were also found to be higher among those with advanced diabetic kidney disease, compared with those with the early-stage disease at baseline, and higher levels of these two cytokine receptors predicted eGFR decline, even after adjustment for baseline eGFR and albuminuria (118). These biomarkers have been implicated in an inflammatory pathway representing ongoing endothelial inflammation, a known etiology of diabetic kidney disease (121). Consistent with this notion, the TNF pathway has been linked to diabetic kidney disease: Genome-wide association studies have demonstrated that transcripts inversely correlated with GFR clustered around TNF-α, which directly acts on podocytes to propagate the inflammatory cascade via TNFRs (122). In addition, several studies have found that plasma TNFR1 and TNFR2 are associated with incident diabetic kidney disease and ESRD in diabetic patients (59, 60, 123, 124). Interestingly, TNFR1 and TNFR2 may represent distinct pathways, but the nuances are still being elucidated (125).
Furthermore, urinary MCP-1 has also been found to be significantly elevated in patients with diabetic nephropathy, and these levels correlate significantly with albuminuria in humans as well as in experimental diabetic nephropathy (126–129). In a prospective observational study of patients with diabetic nephropathy, urinary MCP-1 levels were associated with macroalbuminuria and correlated with the subsequent rate of eGFR decline over a median follow-up of six years. These findings suggest that MCP-1 is associated with later-stage disease and potentially represents a pathway of maladaptive repair (130).
HIV-associated chronic kidney disease.—HIV-infected individuals are at substantial risk of kidney disease, as the virus is known to take host in and damage renal tubular cells, even in those with controlled viremia (131). In addition, the HIV-infected population has numerous metabolic and vascular comorbidities and treatment-related risk factors that increase the risk of kidney disease. Serum creatinine cannot distinguish between the many potential etiologies of kidney disease, which impedes clinical management. Biomarkers of tubular dysfunction and injury have been especially promising in this setting in detecting early injury attributable to the virus. For example, α1M levels in women infected with HIV were associated with both kidney function decline and mortality (132). Compared to those with the lowest α1M levels, those with the highest levels had an increased risk of developing CKD (adjusted OR 2.1, 95% CI: 1.3–3.4) and a 2.7-fold risk of a 10% decline in eGFR. This correlation in CKD development and progression was separate from the 1.6-fold adjusted risk of mortality, which accounted for baseline kidney function as well as the presence of albuminuria (132). In addition, urine IL-18 was associated with worsening renal function over time in a cohort of the Women’s Interagency HIV Study. IL-18 was higher in HIV-infected women compared to those who were not infected, as well as significantly associated with higher HIV RNA levels and lower CD4 counts, a lower proportion of hepatitis C infection, and lower HDL cholesterol levels (133, 134). Similar findings with IL-18 were also reported in a cross-sectional study of 1,144 men of the Multicenter AIDS Cohort Study (MACS), which found substantial elevations of IL-18, KIM-1, PIIINP, and albumin/ creatinine ratio in HIV-infected men, compared with uninfected men (135).
These biomarkers can also identify kidney damage from tenofovir disoproxil fumarate (TDF), a widely used, first-line antiretroviral that is known to cause kidney disease via proximal tubular pathology (136, 137). Cross-sectional studies have demonstrated that cumulative TDF exposure in HIV-infected men enrolled in MACS was independently associated with elevations in concentrations of urinary α1M, IL-18, KIM-1, and PIIINP, but not with albuminuria, consistent with the notion that TDF is a proximal tubular toxin (138, 139). These tubular injury biomarkers may identify subclinical injury before the onset of overt, irreversible disease and distinguish kidney injury attributable to TDF use. Ongoing work is investigating the ability of biomarker patterns and signatures to discern diverse etiologies of kidney injury among HIV-infected individuals.
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FUTURE DIRECTIONS
The use of biomarkers in nephrology has gained considerable traction; however, there are still strides to be made before they can cross the threshold of clinical application. As a variety of biomarkers of kidney health have demonstrated robust associations with adverse outcomes in diverse clinical settings, they have begun to shed light on unique biological pathways that mediate injury and repair. Studying biomarkers in clinical models has also highlighted the limitations of animal models that do not simulate the complexities of overlapping comorbidities, such as diabetes, hypertension, and aging. Future studies will need to develop animal models that can capture such complexity. This deeper understanding may lead to the identification and individualization of effective therapeutic windows and targets that can maximally limit injury, promote repair, and prevent fibrosis without hindering an appropriate host defense.
These biomarkers may be applied as tools in clinical trials for the evaluation of novel therapeutics (Figure 6). Biomarkers of tubular injury can be used in clinical trials to enrich the population for true cases of intrinsic injury versus hemodynamic injury (as diagnostic biomarkers), select for participants at high risk for associated outcomes (as prognostic biomarkers), and identify those who may be more likely to respond to a particular intervention (as predictive biomarkers). These more sensitive and specific metrics for trial enrollment can increase statistical power, decrease the required sample size, and reduce trial costs. In a series of simulated clinical trials using diagnostic biomarkers to enroll patients at high risk for AKI following cardiac surgery in the TRIBE-AKI cohort, investigators demonstrated that trial costs could be substantially decreased from 29% to 64%, with the trade-off requiring a larger screening group of participants and limited generalizability (140). In addition, when IL-18 and NGAL were used as the outcomes for a simulated trial of statin use during the perioperative period, AKI defined by elevations in biomarkers could discern significant differences in the outcome and renoprotective effects of statins, whereas AKI defined by serum creatinine could not (141). These findings question whether the previously failed trials in nephrology were perhaps using the wrong target or suboptimal designs.
In addition, these biomarkers can be utilized as safety biomarkers for the monitoring of toxicity or harm in clinical trials. In fact, the FDA, along with its European and Japanese counterparts, has collaboratively approved a panel of urinary biomarkers of kidney injury that includes KIM-1, albumin, total protein, cystatin C, clusterin, trefoil factor 3, and α1M for use in preclinical models of nephrotoxicity (142–144).
Similar to the predictive biomarkers that have advanced the field of therapeutics in oncology, such as with the use of Herceptin in human epidermal growth factor receptor 2 (HER2)- positive breast cancers, targeted interventions may play an important role in the effective treatment of kidney disease. For example, a drug acting on the apoptosis pathway via the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome complex may be effective in patients in whom this AKI pathway is active. A biomarker, such as urinary IL-18, that is released upon activation of the NLRP3 inflammasome pathway could be a predictive biomarker to select patients for enrollment in a trial of such a drug. In addition, individuals with diabetic nephropathy driven by high levels of TNFR1 and TNFR2 may indicate that anti-inflammatory agents could be repurposed to treat these conditions.
To achieve these goals, more work is needed to further phenotype these kidney disease syndromes with biomarkers of tubular injury and other biological data. In order to fully capture the diverse manifestations and apply them reliably to clinical trial design, new strategies that rely on a panel of several novel biomarkers will be necessary, perhaps as a composite biomarker score. Ongoing research is working toward contending with this complexity by using methods such as metabolomics profiling (145) and by investigating circulating microRNAs, which have been shown to specifically change in various kidney diseases (146). In addition, large-scale efforts are underway to elucidate and trace these very pathways of kidney disease. The ongoing National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)-funded Kidney Precision Medicine Project (147) aims to obtain kidney biopsies of AKI and CKD and construct a kidney tissue atlas to define disease subgroups with genetics, transcriptomics, and corresponding plasma and urine biomarkers. The availability of these tissue-based atlantes will allow for comparisons of biomarkers to the true gold standard of kidney biopsies and the discovery of novel biomarkers. These future studies may unmask the more robust utility of biomarkers, which may have appeared to be suboptimal due to comparisons with the imperfect standard of serum creatinine. Similar to the field of oncology, molecular phenotyping from this resource may lead to personalized treatments for kidney disease patients based on distinct disease signatures. Along with these developments, novel statistical approaches will be needed to evaluate the accuracy of biomarkers in risk prediction, especially as these markers are compared to the imperfect gold standard of serum creatinine. In addition, with the large number of biomarkers that are now available, biomarkers may need to be combined into composite scores to enhance predictive abilities and improve the feasibility of implementation into clinical practice (148–150).
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CONCLUSIONS
In conclusion, several promising biomarkers of kidney health that are involved in the pathophysiologic mechanism of kidney damage have demonstrated the potential to improve the clinical treatment of kidney diseases. These biomarkers have demonstrated the ability to detect early damage, localize injury, and predict disease progression, severity, and associated long-term mortality. Future work is underway to characterize biological pathways that promote kidney repair and long-term survival, which may inform the development of novel therapeutics in the field of nephrology.
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