Research Progress Of Creatinine As Biomarkers in Disease Diagnosis And Drug Evaluation

Abstract: As a highly effective biomarker of kidney function, creatinine has been used clinically in the diagnosis of kidney diseaseand the evaluation of kidney-related drugs. It is also useful in the diagnosis of other systemic diseases, the calibration of substances to be tested in urine samples, and the assessment of function. This article reviews the clinical applications of creatinine and highlights the use of creatinine in the diagnosis of kidney disease and in the evaluation of the efficacy and adverse effects of kidney-related drugs, and concludes that creatinine has a promising future in clinical diagnosis and drug evaluation. Key words: creatinine; biomarkers; nephropathy; drug evaluation

Serum creatinine (serum creatinine) has received extensive attention as the most commonly used biomarker of renal function. Human creatinine (creatinine, molecular formula C4H7N3O) is divided into endogenous and exogenous creatinine. The main source of endogenous creatinine is the product of decarboxylation reaction during muscle metabolism, while exogenous creatinine mainly comes from the metabolites of meat [1]. Creatinine is not reabsorbed by the renal tubules after glomerular filtration, so it is a better biomarker than urea to quantitatively measure the glomerular filtration rate, or renal excretion function.

Click here to know how to use cistanche 

as an herbal formulation for reducing creatinine

Zhou Biyan et al[2] summarized the serum creatinine detection methods including alkaline picric acid method and enzymatic method, as well as the normal range values of serum creatinine in different methods and genders; Pavlakou et al[3] summarized some existing acute renal failure In addition to creatinine, the biomarkers of injury include neutrophil gelatinase-related lipocalin, kidney injury molecule-1, tissue inhibitor of metalloproteinase-2, etc. At present, the diseases and other clinical applications that can use creatinine as a biomarker are rarely summarized. Therefore, this paper summarizes the diagnosis of diseases that can use creatinine as a biomarker, and summarizes the application of creatinine in other systemic diseases and drug evaluation. The purpose is to sort out the research progress of creatinine in disease diagnosis and drug evaluation, contribute to the correct clinical diagnosis of creatinine-related diseases, reduce drug renal injury, and effectively reduce the burden on patients, and reduce related misdiagnosis and adverse drug reactions to patients. troubled.

1 The application of creatinine in disease diagnosis

Biomarkers generally refer to biochemical indicators that can be used as objective measurements or to evaluate the characteristics of ordinary physiology or pathology or in the treatment process.

Cheng [4]. In recent years, the detection of specific biomarkers for specific types of diseases has become an extremely important part of the process of disease identification, early diagnosis, prevention and treatment. At present, the research hotspots of biomarkers mainly focus on finding and discovering valuable biomarkers.

1.1 Kidney-related diseases

Serum creatinine level can more accurately reflect the glomerular filtration function, so it has become a common clinical indicator of renal function [5]. The diagnostic criteria for serotonin is one of the following: within 48 hours, serum creatinine rises more than 0.3 mg/dL; serum creatinine rises more than 1.5 times the baseline within 7 days; urine output lasts for more than 6 hours and less than 0.5 mL/(kg·h ), while excluding urinary tract obstruction and other diseases that can lead to decreased urine output [6]

. At the same time, it is recommended that chronic kidney disease should detect urine albumin and serum creatinine at least once a year [7]

. It can be seen that creatinine plays a crucial role in the diagnosis of acute kidney injury, chronic kidney injury and other kidney diseases.

Clinically, nephropathy can be roughly divided into primary nephropathy and secondary nephropathy according to the etiology. Primary nephropathy refers to diseases caused by the kidney itself, such as idiopathic membranous nephropathy, IgA nephropathy, acute glomerulonephritis, chronic glomerulonephritis, etc. Idiopathic membranous nephropathy is a common cause of nephrotic syndrome in adults, and it is the most common glomerular disease associated with malignant tumors. Some researchers found that the serum creatinine in patients with membranous nephropathy accompanied by cancer was significantly higher than that in patients with primary membranous nephropathy [8], which could identify potential malignant tumors to a certain extent. IgA nephropathy refers to the occurrence of IgA in the mesangial region of the glomerulus

Or accompanied by other immunoglobulin deposition diseases, the serum creatinine value of patients with IgA nephropathy increases with the grade of the pathological type, showing an upward trend [9], that is, the creatinine value can reflect the severity of IgA nephropathy. Secondary nephropathy mainly refers to kidney damage indirectly caused by other diseases, such as diabetic nephropathy, lupus nephritis, and heart failure kidney damage. Diabetic nephropathy is one of the most serious complications of diabetic patients, because it can cause complex metabolic disorders, making treatment extremely difficult. Therefore, early diagnosis is of great significance for delaying the disease. Zhu Qinghong et al[10] found that serum creatinine, blood urea, serum Cystatin C, neutrophil gelatinase-related lipocalin and serum complement C1q are helpful for early diagnosis of diabetic nephropathy. Lupus nephritis refers to kidney damage caused by systemic lupus erythematosus, and its pathogenesis is related to immune system abnormalities such as immune complexes, immune cells, and cytokines of patients with lupus nephritis have a poor prognosis and low renal survival.

Urinary creatinine is widely used for the calibration of other biomarkers in urine. Since creatinine will not be reabsorbed again after glomerular filtration, it can be used as a quantitative measure of glomerular filtration rate, i.e. renal excretion function.

24-hour urine retention can accurately reflect the number of biomarkers in urine, but in practice, it is sometimes difficult to collect urine samples for a long time, and there are many factors affecting storage, so it can be used The ratio of biomarkers to creatinine in random urine samples is used as the detection index, which can more conveniently and effectively reflect the real situation of patients and the sampling is more convenient. The most common of these is the urinary microalbumin/creatinine ratio, which can better reflect early kidney damage such as early diabetic nephropathy than testing creatinine alone. The reported biomarkers that can be corrected by creatinine include blood urea nitrogen [12] and uric acid [13].

It can be seen that creatinine can be used as an effective detection index for many different types of kidney-related diseases and other diseases accompanied by kidney damage, and can be used as a calibration index for substances in urine. This is because the generation rate of creatinine in the body is relatively stable, and its clearance rate is highly correlated with renal function. When renal function is affected, it can be quickly reflected by creatinine.

1.2 Other diseases

In addition to kidney-related diseases, many studies in recent years have pointed out that some diseases not related to kidneys can also use creatinine as a biomarker.

1.2.1 Cancer

 Cancer is a kind of disease that seriously endangers human health. It has been reported that creatinine can be used as a biomarker for renal cancer. The combination of miR-27b with serum creatinine and cystatin C has a sensitivity of 85.7% and a specificity of 87.5% for the diagnosis of renal cancer. [14]. For some other cancers, creatinine also has an indicative role. Wei et al. [15] found that serum creatinine and uric acid were reduced in samples of pancreatic cancer patients. However, neither of them could diagnose pancreatic cancer alone, but the ratio of the two could reflect pancreatic cancer patients. The antioxidant capacity in the body can be diagnosed from the side; Sun Haiyan et al. [16] found that creatinine was negatively correlated with gastric cancer-related fatigue through multiple stepwise regression analysis, presumably due to the relationship between creatinine and protein metabolism and energy metabolism. .

1.2.2 Mental illness

With the development of society, mental health has been paid more and more attention by people. In the past, people thought that mental illness was caused entirely by psychological factors, but with the deepening of research, it has been found that genetic factors and environmental damage can affect the structure or function of the brain, thereby causing mental illness. Therefore, biomarkers can also be used to diagnose psychiatric disorders. Creatinine has been reported as a biomarker for psychiatric disorders such as autism spectrum disorder [17] and bipolar disorder [18].

1.2.3 Nervous system diseases Nervous system diseases refer to the occurrence of

Diseases of the central nervous system, peripheral nervous system, and autonomic nervous system are characterized by sensory, motor, consciousness, and autonomic dysfunction. Yang Guang et al. [19] found that the levels of blood urea nitrogen, creatinine and urine protein were positively correlated with the Parkinson's rating scale scores, which could effectively predict the onset and progression of Parkinson's disease.

1.2.4 Inflammation

Inflammation is an immune response of the body to external stimuli. Chronic inflammation is mostly developed from acute inflammation, which can lead to long-term chronic pain and reduced quality of life in patients. Some studies have pointed out that some chronic inflammation may induce cancer. Wu Weihong et al [20] found that when serum creatinine and serum uric acid decreased in rheumatoid arthritis patients, the level of inflammation was higher. Wang Yu et al [21] found that creatinine was positively correlated with the severity of neonatal necrotizing enterocolitis, but negatively correlated with its prognosis.

1.2.5 Cardiovascular disease

Cardiovascular disease has become a global public health problem. Due to the improvement of living standards, the prevalence of cardiovascular disease in China is on the rise, and the mortality rate of cardiovascular disease ranks first among various causes of death [22]. Most cardiovascular diseases eventually lead to heart failure, which in turn leads to adverse cardiovascular events such as patient death. Chen Jiying et al[23] concluded that adiponectin, serum creatinine, and serum cystatin C were one of the independent risk factors for cardiovascular events in hemodialysis patients through Logistic multivariate analysis.

1.2.6 Liver disease

The pathogen of hepatitis B is hepatitis B virus, and the clinical symptoms include nausea, fatigue, abdominal distension, pain in the liver area, etc., and it is contagious to a certain extent. Ni Wen et al. [24] found that hepatic blood flow and serum creatinine level were negatively correlated in patients with hepatitis B fibrosis, which was speculated to be due to the mutual promotion and damage of liver and kidney functions in the course of hepatitis B disease.

1.2.7 Heavy metal poisoning

Heavy metal poisoning refers to a kind of poisoning caused by irreversible changes in protein structure caused by heavy metal elements or their compounds, which can be detected by blood or urine. As mentioned above, creatinine can correct other renal biomarkers in urine, and creatinine can also calibrate the detection of many heavy metals in urine, such as urinary cadmium [25], urinary mercury [26] and so on.

2 Drug Evaluation for Kidney Disease

As a biomarker, creatinine has been used in the evaluation of drug efficacy and adverse drug reactions.

2.1 Evaluation of drug efficacy

Since the creatinine clearance rate can directly reflect the glomerular filtration function, it can reflect the renal injury to a certain extent, so creatinine is also used clinically for the treatment of renal disease and the renal function.

Determination of the degree of adverse drug reactions. When the kidney is damaged, the creatinine value will rise rapidly. On the contrary, when the creatinine value decreases, it means that the drug has played a role in treating kidney disease or improving the disease. Chen Li et al[27] evaluated the efficacy of tacrolimus in the treatment of membranous nephropathy by comparing the levels of serum creatinine, serum albumin, and 24-hour urine protein before and 3 months after treatment. Serum creatinine and 24-h urine protein levels decreased significantly, while serum albumin increased significantly, proving that tacrolimus is effective in treating idiopathic membranous nephropathy. Heng Hongjun et al[28] used serum potassium and serum creatinine as biomarkers to measure the effect of treating hypertension, and concluded that levamlodipine besylate combined with valsartan can reduce serum creatinine concentration more than the former alone, and the curative effect is better.

2.2 Evaluation of adverse drug reactions

Many drugs such as gentamicin, indomethacin [29] and some herbs such as aristolochia [30]

and so on can cause renal damage, so specific indicators are needed to evaluate renal damage to avoid harm to patients, and creatinine can also indicate renal damage caused by drugs. Some studies have established a serum creatinine kinetic model [31] to simulate the impact and recovery of renal function in very low birth weight neonates exposed to ibuprofen. Another researcher used pembrolizumab to treat tumors. The patient's serum creatinine increased during treatment. Renal biopsy showed IgA nephropathy. After 2 months of stopping treatment, renal function did not improve. After restarting treatment, serum creatinine fluctuated about is 1.4 times the original baseline [32].

It can be seen that the serum creatinine value should be monitored at any time when using drugs that may damage the kidneys to ensure the safety of patients. Contrast media nephropathy is an adverse reaction caused by the high iodine content of contrast media and its original metabolism in the body, which increases its concentration in the kidney during dehydration, which in turn leads to renal damage and even acute renal failure. Studies have found that serum cystatin C and serum creatinine can be used to evaluate renal injury in patients after surgery using contrast media [33].

Cilostazol is an antiplatelet drug, and its adverse reactions include bleeding, liver damage, etc., but little is known about its kidney damage. Hisato et al. [34] found that a patient hospitalized with acute kidney injury had elevated serum creatinine, and urine showed hematuria, proteinuria, and β-2 microglobulin.

It was diagnosed as acute tubulointerstitial nephritis induced by cilostazol, and the serum creatinine, urine protein and other indicators returned to normal after drug withdrawal and treatment. It can be seen that when it is uncertain whether the drug has a damaging effect on the kidneys, creatinine can be used for timely and rapid judgment.

3 Conclusion

As a commonly used biomarker, creatinine has been widely used in the diagnosis of renal function and other related diseases. By summarizing the literature on creatinine as a biomarker, it can be seen that creatinine has the potential to become a biomarker other than renal disease. At the same time, creatinine also plays a certain role in the clinical evaluation of nephropathy drugs. In addition, since creatinine is metabolized from creatine and phosphocreatine, it is closely related to cell function and muscle mass, so it can also be used clinically to reflect the physical condition of patients with lack of skeletal muscle mass [35] or to the physical function of athletes. Evaluate.

3.1 Other biomarkers of renal function

Molecules such as cystatin C and renal injury molecule-1 are co-expressed with creatinine in various types of kidney-related diseases [36-38]. Cystatin C metabolism is similar to creatinine, its production is relatively stable, and it is only cleared by glomerular filtration, so it can also accurately reflect renal function [39]; There is a trace amount of expression in the spleen, and its expression is significantly enhanced in the regenerated renal proximal tubule epithelial cells after injury, which makes it sensitive and specific to reflect renal injury [40]. It can be seen that biomarkers such as cystatin C and renal injury molecule-1 may be able to detect other diseases related to renal injury and other systemic diseases that can be detected by creatinine, or can be used as one of the future research directions.

3.2 The application prospect of creatinine as a biomarker in diseases other than kidney disease

Creatinine also has the function of diagnosing or detecting treatment, recovery or critical condition of diseases of different systems other than kidney diseases. There are other biomarkers for these diseases as well, and creatinine also has potential as a biomarker-detectable biomarker for diseases other than kidney disease. Therefore, when the creatinine index increases clinically, the possibility of other diseases other than the kidney should also be considered. In some diseases, the serum creatinine value decreases, which may interfere with the doctor's judgment of the patient's renal function. In addition, some drugs and endogenous substances have a considerable degree of interference with the main clinical methods of creatinine detection, namely the picric acid method and the enzymatic method. For example, pyruvate and bilirubin in the blood have positive interference with the picric acid method [41] ], calcium dobesilate will negatively interfere with the sarcosine oxidase method in the enzymatic method [42]. At the same time, some drugs such as trimethoprim and sorafenib can increase serum creatinine through competitive inhibition. Therefore, when using creatinine as a biomarker, it should not be judged only by the creatinine value, but should be comprehensively judged by contacting other pathophysiological indicators. In addition, the pathogenic mechanism of some diseases is not completely clear, maybe a new idea can be opened from the perspective of creatinine metabolism-energy metabolism.

3.3 The role of creatinine in drug evaluation

Creatinine has a certain indication effect on the efficacy of some drugs, especially kidney disease drugs. This is because after the drug improves renal function, the creatinine clearance rate increases, so that the serum creatinine rapidly decreases to the normal level. Creatinine also has a certain role in the diagnosis of other systemic diseases, so creatinine may be able to make certain inferences about the efficacy of drugs related to these diseases, and current research in this area is relatively rare and can be used as a future research direction. Drug-induced kidney injury has become a serious medical problem, especially for many elderly patients with poor kidneys and concurrent use of multiple renal metabolizing drugs to increase the burden on the kidneys.

The doctor or pharmacist should adjust the patient's medication in time to avoid irreversible consequences on the kidneys. For some drugs with unknown kidney-related side effects, elevated serum creatinine can also prompt doctors that they may cause kidney damage.

3.4 Research prospects of creatinine as a biomarker

The current research on creatinine mainly focuses on the detection of biomarkers of kidney disease, and the replacement of creatinine with other more effective or earlier biomarkers that can reflect the corresponding kidney disease status. but few

There are literature on the indicator role of creatinine in other systemic diseases and research on drug evaluation with creatinine, so the application of creatinine in other systemic diseases and drug evaluation has quite broad research prospects. This study can serve as a guide for clinical efficacy, early diagnosis of creatinine-related diseases, and follow-up studies.

If you are interested in Chinese herbs for treating CKD problems, please send us an email at: wallence.suen@wecistanche.com