Exploring The Promise Of Biomarkers For Acute Kidney InjuryⅢ

3. Biomarker breakthroughs: exploring clinical applications

AKI biomarkers are gradually finding their place in precise clinical applications to assist clinicians in identifying specific risk groups, guiding treatment, and predicting prognosis and progression to CKD. Although they have not yet been included in the definition of AKI, several detection methods are currently available and significant progress has been made in various fields. In this section, we explore how the implementation of biomarkers can shift clinical practice toward a more personalized approach. Biomarkers have the potential to identify patients before any loss of function occurs, opening the door to preventive and customized treatments for AKI. Risk models can also play a vital role in predicting in-hospital and long-term complications and mortality, guide the development of short-term personalized follow-up plans after hospital discharge, and contribute to long-term risk management. Here, we provide a comprehensive summary of clinical applications and ongoing randomized clinical trials.

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3.1. Acute kidney injury after cardiac surgery

The incidence of AKI in cardiac surgery inpatients is 14% to 30%, worsening the overall prognosis, increasing the risk of death, prolonging the length of stay, and increasing the medical burden. Therefore, the need for early damage detection is critical. An increase in SCr or a decrease in urine output indicates that the injury has entered an advanced stage. Translational Research in Biomarker Endpoint Consortium (TRIBE-AKI) aims to explore the role of postoperative biomarkers in predicting short-term outcomes, such as acute kidney injury, need for dialysis, and increased risk, in the context of cardiac surgery. length of hospital stay, and long-term outcomes such as overall mortality and progression to CKD.

In 2013, 1199 patients from 6 different centers were tested for 5 urinary biomarkers (NGAL, IL-18, KIM-1, L-FABP, and albumin) within 3 days after cardiac surgery, with a median follow-up of The time is 3 years. These biomarkers were found to be independently associated with a 2-3.2-fold increased risk of death in patients with clinical AKI and were measured at the highest percentile of the combination. IL-18 and KIM-1 were also independently associated with mortality in patients without clinical AKI. Concentrations of the five urinary biomarkers were also associated with longer AKI duration, duration greater than 7 days, and a 5-fold increase in 3-year mortality. It should be emphasized that hematuria, proteinuria, leukocyte esterase, and nitrite can affect the concentration of urinary biomarkers in dipstick testing. This effect was evident in post hoc analyses involving four specific biomarkers (NGAL, IL-8, KIM-1, and L-FABP), where the factors mentioned contributed to false negative results. In this case, these biomarkers do not accurately reflect tubular damage.

In the same cohort, plasma NGAL was measured preoperatively and 3 days postoperatively in 1191 patients undergoing cardiac surgery, with a median follow-up of 3 years. Preoperative plasma NGAL levels have also been found to predict mortality 3 years after cardiac surgery, suggesting prognostic value. At the same time, postoperative NGAL loses this correlation when correlated with SCr, highlighting the distinct pathophysiology of urinary and plasma NGAL as discussed previously.

Subsequently, the association investigated perioperative plasma MCP-1 levels in 972 patients undergoing cardiac surgery. Patients with higher preoperative MCP-1 levels have a higher risk of developing AKI, longer duration of AKI, and higher in-hospital mortality. In this case, preoperative levels can predict which patients are at risk of developing AKI, thereby guiding physicians to stratify high-risk patients who require earlier preventive measures and interventions. Preoperative urinary α1-M was also added to the list of biomarkers found to be associated with a higher risk of postoperative AKI as well as CKD progression and overall mortality.

In the same TRIBE-AKI cohort, 1444 adults undergoing cardiac surgery had plasma VEGF and PGF and the anti-angiogenic marker VEGFR1 measured before and within 6 hours of surgery. The evaluation showed that higher pro-angiogenic markers after surgery were associated with lower incidence and duration of AKI and reduced 1-year mortality. In contrast, elevated VEGFR1 levels after surgery are associated with an increased risk of AKI. Notably, combined angiogenesis-related markers, including the combination of three of these biomarkers, exceeded the power of the individual results. These findings may not be extrapolated to patients with chronic kidney disease (CKD), where higher levels of VEGF and PGF are associated with adverse outcomes in diabetic nephropathy and cardiovascular events, respectively. This difference reflects the different physiological responses to angiogenesis in acute injury, and the resulting repair response, compared with CKD, often results in fibrosis.

3.2. Occurrence of cardiorenal syndrome and hepatorenal syndrome during acute hospitalization

Identifying the cause of AKI is a significant challenge in patients with cirrhosis, who often have multiple comorbidities and are susceptible to infectious complications and potential adverse effects of treatments such as diuretics. The causes of AKI include prerenal azotemia, acute tubular injury (ATI), and hepatorenal syndrome (HRS). Prompt and accurate diagnosis is critical because AKI significantly increases the risk of death in these patients and management approaches vary.

Although treatment guidelines recommend two consecutive days of intravenous albumin testing starting at a daily dose of 1 g/kg body weight to restore effective arterial blood volume in cirrhotic patients with AKI, the administration of large amounts of albumin may not always be beneficial and may induce pulmonary edema. Furthermore, current definitions of hepatorenal syndrome rely in part on plasma creatinine, whose interpretation in cirrhosis is limited by liver damage and reduced muscle mass and protein intake. Furthermore, urinary excretion of sodium is ineffective in this condition.

At the therapeutic level, in the CONFIRM study, hepatorenal syndrome patients with higher creatinine levels were less responsive to vasoconstrictors such as terlipressin, emphasizing the need for early initiation of this treatment.

For all these reasons, there is an urgent need to identify valid biomarkers to help differentiate the diagnosis of hepatorenal syndrome, tubular injury, or prerenal azotemia. Early research on biomarkers focused on their use as tools to identify patients with renal tubular injury and, therefore, should be excluded from vasocompression therapy. Clinicians can refine their diagnosis by incorporating biomarkers, combined with clinical judgment and other arguments. One study combining uNGAL, IL-18, L-FABP, and albumin, defining specific cutoffs for each biomarker, showed that the proportion of patients with all biomarkers above the cutoffs who developed ATN was 91%; The number of patients without any positive markers was 7%. Later, the focus shifted more to the ability to identify patients with HRS who would benefit from specific therapies and even predict which patients might further benefit from such therapies. In this context, a study included 162 patients with cirrhosis and acute kidney injury and followed them until death, liver transplantation, or 90 days after inclusion; 39.5% of patients had hepatorenal syndrome. Of note, uNGAL was measured exclusively in patients diagnosed according to The International Club of Ascites criteria who did not improve after 48 hours of initial treatment. Although uNGAL levels were higher in patients with more severe AKI, uNGAL levels remained significantly elevated in ATN patients compared with HRS patients regardless of AKI stage. The uNGAL level of 220 ng/mL was the optimal threshold, with a sensitivity of 89% and a specificity of 78%. More interestingly, in the subgroup of patients who developed HRS, patients who had a complete response to terlipressin and albumin treatment had lower uNGAL levels compared with patients who had a partial or no response. Furthermore, uNGAL was an independent predictor of in-hospital and 90-day mortality.

IL-18 has also been studied in this context but was found to be less accurate in predicting ATN. However, HRS is associated with higher in-hospital mortality. The use of these biomarkers may also provide an additional argument in the decision-making between kidney-liver combination alone or liver transplantation.

Cardiorenal syndrome is another clinical condition in which decision-making is not as straightforward, and cardiologists and nephrologists often lack specific arguments to balance the need for diuretics against elevated creatinine. Current treatments include diuretics to restore effective renal perfusion pressure and increase hemoconcentration, which are associated with reduced mortality and heart failure rehospitalization, even in the setting of worsening renal function during hospitalization. Since clinical parameters alone may not be sufficient to identify response to treatment, biomarkers could serve as an additional factor in this setting and address the heterogeneity of pathophysiological mechanisms of cardiorenal syndrome. Urinary NGAL and IL-18 were found to be independently associated with the progression of AKI in patients with acute decompensated heart failure. Adding these biomarkers along with urinary angiotensinogen to clinical models improved risk stratification and identified adverse kidney disease Populations at the highest risk for outcomes. Baseline urinary L-FABP levels in hospitalized patients with acute decompensated heart failure were also found to be an independent predictor of the development of AKI in these patients. Parikh et al proposed a paradigm in which low levels of urinary NGAL, N-acetyl-B-D-glucosidase, and KIM-1 support the continuation of diuretic therapy despite elevated SCr. Although many biomarkers have been studied in this context and have been shown to correlate well with the risk of heart failure hospitalization, AKI, and death, there is little need to compare these biomarkers and derive direct results to promote their use in routine Much work remains to be done about its application in clinical decision-making.

3.3 Diagnosis of acute interstitial nephritis

Diagnosis of acute interstitial nephritis (AIN) and differentiation from acute tubular necrosis and other acute kidney diseases can be challenging. As effective treatments exist, timely establishment of the diagnosis of AIN is crucial, which requires stopping the causative factor or treating the underlying disease. The use of biomarkers would also benefit this setting, providing an alternative to renal biopsy in cases where the diagnosis is unclear. To identify potential biomarkers, a study included 218 patients from two different centers who underwent renal biopsy for acute kidney injury. The histological diagnosis of AIN is found in 15% of biopsies, reflecting its actual proportion as a cause of acute kidney injury. Of the 12 urine and 10 plasma biomarkers tested, urinary TNF-α and IL-9 were independently associated with AIN, and their levels were higher in biopsies showing more severe AIN histological lesions (such as microvasculitis or lymphadenitis). cells and eosinophilic infiltration) were higher in patients. Of note, two models were created: one comparing these biomarkers to clinician judgment and another comparing them to a model consisting of clinical variables commonly associated with AIN. Adding these biomarkers to both models significantly improved their ability to predict diagnosis, improving the clinician AUC from 0.62 to 0.84 and the clinical model from 0.69 to 0.84. This is an example of how biomarkers can be incorporated into clinical or other biological models, thereby increasing their utility. Furthermore, CXCL9 was recently identified as a biomarker for AIN. In a urinary proteomic analysis of 88 AKI patients, it was the highest protein biomarker among 180 urinary proteins associated with AIN, 35% of which were confirmed by renal biopsy. Urinary CXCL9 also correlates with the severity of histological lesions. This is consistent with CXCL9 being a chemokine that, by binding to CXCR-3, whose expression is induced by IFN-γ, guides activated T lymphocytes to sites of inflammation, mainly in the renal tubular region. Adding CXCL9 to the above model further enhances the performance of the model. Finally, the combination of CXCL9 with TNF-α and IL-9 was found to have the highest diagnostic accuracy. Tubulointerstitial nephritis with uveitis syndrome is another example of a tubulointerstitial disease that perfectly exemplifies a clinical setting where a biomarker is included in the classification criteria and may even help clinicians avoid Kidney biopsy. Evidence of tubulointerstitial nephritis can be demonstrated by renal biopsy elevated urinary beta2-microglobulin, abnormal urinalysis, or elevated serum creatinine.

3.4 Contrast agent-related AKI

Many studies have suggested the potential use of biomarkers, such as NGAL and IL-18, in predicting contrast agent-related AKI. However, most are single-center studies with low event rates. Identification of high-risk patients can guide nephrologists in endorsing the use of contrastive testing, especially in non-emergency settings. It can also help determine which patients require hospitalization and close follow-up. In this regard, a larger study based on the PRESERVE trial cohort was conducted, measuring a plasma biomarker in 916 patients and a urinary biomarker in 797 patients with chronic kidney disease at 19 different centers: MCP-1, KIM-1, NGAL, IL-18, UMOD, and YKL-40. These markers are measured 1 to 2 hours before imaging. Patients with higher pre-angioplasty plasma KIM-1, NGAL, and YKL-40 were at higher risk for major adverse renal events, such as the need for dialysis or a persistent decline in renal function (defined as an increase in serum creatinine >50%) and within 90 days Death(MAKE-D). Urinary creatinine-corrected IL-18, MCP-1, and YKL-40 were also associated with higher MAKE-D. In addition, plasma KIM-1 was significantly elevated in patients with contrast agent-related AKI, defined as an increase in serum creatinine of ≥25% or ≥0.5 mg/dL from baseline 3 to 5 days after contrast agent injection.

3.5 Biomarkers of Aki after renal transplantation

Biomarkers also play a role in the field of kidney transplantation, where they can assist in decisions about donor selection and kidney transplant monitoring. They also have the potential to improve graft survival risk prediction, as shown in a recent study of 709 stable kidney transplant recipients. Urinary and plasma NGAL and calprotectin levels were measured at least 2 months postoperatively, and follow-up was extended to 58 months. Studies have shown that plasma NGAL independently predicts kidney allograft loss.

In the post-transplant setting, another valuable tool for evaluating kidney transplants is donor-derived cell-free DNA (dd-cfDNA), as its half-life of release into the blood in the event of graft injury ranges from 30 to 120 Minutes. What appears clinically relevant is its high negative predictive value, helping clinicians avoid invasive biopsies in high-risk patients. In a retrospective observational study of 317 kidney transplant recipients with preserved allograft function, patients with high dd-cf DNA (≥1%) compared with those with low dd-cf DNA (<0.5%) Rejection reactions are more likely to occur. Furthermore, elevated dd-cfDNA precedes other clinical manifestations of rejection and the detection of emerging donor-specific antibodies by several weeks, and dd-cfDNA is strongly associated with antibody- and T-cell-mediated rejection, but it is not completely Specific to transplant rejection, elevated dd-cfDNA has also been observed in conditions such as acute tubular necrosis, pyelonephritis, and BK virus nephropathy.

Furthermore, urinary CXCL9 and CXCL10 were integrated with eGFR, donor-specific antibodies, and polyoma viremia into clinical models, and found that urinary CXCL9 and CXCL10 could effectively predict transplant rejection. This integration resulted in a significant reduction in the number of protocol biopsies, particularly when the predicted risk of rejection was less than 10%, with 59 protocol biopsies avoided per 100 patients. What differentiates these biomarkers from other non-invasive markers, such as cell-free DNA or mRNA markers, is the accessibility and simplicity of the measurement technology. On the other hand, a recent meta-analysis showed that biomarker studies in kidney transplantation lack validation, rigorous design, and comparison with standard graft monitoring, thus highlighting the need for more efforts in this area.

How Does Cistanche Treat Kidney Disease?

Cistanche is a traditional Chinese herbal medicine used for centuries to treat various health conditions, including kidney disease. It is derived from the dried stems of Cistanche deserticola, a plant native to the deserts of China and Mongolia. The main active components of cistanche are phenylethanoid glycosides, echinacoside, and acteoside, which have been found to have beneficial effects on kidney health.

Kidney disease, also known as renal disease, refers to a condition in which the kidneys are not functioning properly. This can result in a buildup of waste products and toxins in the body, leading to various symptoms and complications. Cistanche may help treat kidney disease ase through several mechanisms.

Firstly, cistanche has been found to have diuretic properties, meaning it can increase urine production and help eliminate waste products from the body. This can help relieve the burden on the kidneys and prevent the buildup of toxins. By promoting diuresis, cistanche may also help Reduce high blood pressure, a common complication of kidney disease.

Moreover, cistanche has been shown to have antioxidant effects. Oxidative stress, caused by an imbalance between the production of free radicals and the body's antioxidant defenses, plays a key role in the progression of kidney disease. ies help neutralize free radicals and reduce Oxidative stress, thereby protecting the kidneys from damage. The phenylethanoid glycosides found in cistanche have been particularly effective in scavenging free radicals and inhibiting lipid peroxidation.

Additionally, cistanche has been found to have anti-inflammatory effects. Inflammation is another key factor in the development and progression of kidney disease. Cistanche's anti-inflammatory properties help reduce the production of pro-inflammatory cytokines and inhibit the activation of inflammation mandatory pathways, thus alleviating inflammation in the kidneys.

Furthermore, cistanche has been shown to have immunomodulatory effects. In kidney disease, the immune system can be dysregulated, leading to excessive inflammation and tissue damage. Cistanche helps regulate the immune response by modulating the production and activity of immune cells, such as T cells and macrophages. This immune regulation helps reduce inflammation and prevent further damage to the kidneys.

Moreover, cistanche has been found to improve renal function by promoting the regeneration of renal tubes with cells. Renal tubular epithelial cells play a crucial role in the filtration and reabsorption of waste products and electrolytes. In kidney disease, these cells can be damaged, leading to damaged renal function. Cistanche's ability to promote the regeneration of these cells helps restore proper renal function and improve overall kidney health.

In addition to these direct effects on the kidneys, cistanche has been found to have beneficial effects on other organs and systems in the body. This holistic approach to health is particularly important in kidney disease, as the condition often affects multiple organs and systems. che has been shown to have protective effects on the liver, heart, and blood vessels, which are commonly affected by kidney disease. By promoting the health of these organs, cistanche helps improve overall kidney function and prevent further complications.

In conclusion, cistanche is a traditional Chinese herbal medicine used for centuries to treat kidney disease. Its active components have diuretic, antioxidant, anti-inflammatory, immunomodulatory, and regenerative effects, which help improve renal function and protect the kidneys from further damage. , cistanche has beneficial effects on other organs and systems, making it a holistic approach to treating kidney disease.