The feasibility of using SERS to monitor the kidney transplant function
Mar 26, 2022
Contact: Audrey Hu Whatsapp/hp: 0086 13880143964 Email: audrey.hu@wecistanche.com
PART Ⅱ: Correlation of surface‑enhanced Raman spectroscopic fingerprints of kidney transplant recipient urine with kidney function parameters
Zhongli Huang, Shijian Feng & et al.
CLICK HERE TO PART Ⅰ & PART Ⅲ
Routine monitoring of kidney transplant function is required for standard care in post-transplantation management, including frequent measurements of serum creatinine with or without kidney biopsy. However, the invasiveness of these methods with the potential for clinically significant complications makes them less than ideal. The objective of this study was to develop a non-invasive tool to monitor kidney transplant function by using Surface-Enhanced Raman Spectroscopy (SERS). Urine and blood samples were collected from kidney transplant recipients after surgery. Silver nanoparticle-based SERS spectra of the urine were measured and evaluated using partial least squares (PLS) analysis. The SERS spectra were compared with conventional chemical markers of kidney transplant function to assess its predictive ability. A total of 110 kidney transplant recipients were included in this study.PLS results showed significant correlation with urine protein(R2=0.4660, p<0.01),creatinine(R2=0.8106,p<0.01), and urea(R2=0.7808,p<0.01).Furthermore, the prediction of the blood markers of kidney transplant function using the urine SERS spectra was indicated by R2=0.7628(p<0.01)for serum creatinine and R2=0.6539 for (p<0.01)for blood urea nitrogen. This preliminary study suggested that the urine SERS spectral analysis could be used as a convenient method for the rapid assessment of kidney transplant function.
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DISCUSSION
In clinics, post-kidney transplant function is mainly determined by monitoring the level of SCr and calculating the eGFR.This involves needle-obtained blood specimens, which can be bothersome and even traumatize some patients. There are other methods to evaluate the renal function, such as 24-h UCR clearance and nuclear medicine scans. However, these methods are rarely performed for post-transplant care secondary to multiple factors, including logistics, expense, and concerns regarding the inaccuracy when the kidney transplant function is poor. Therefore, a rapid and non-invasive tool to monitor the kidney transplant function would be a desirable alternative to these conventional means. Nowadays, non-invasive imaging methods including ultrasonography (US), computed tomography(CT), magnetic resonance imaging (MRI), and renal scintigraphy (RSG) are commonly used in clinics; however, these imaging methods have disadvantages over one or the other, the US has a high inter-observer variability that makes difficulties in imaging interpretation. CT and MRI can provide the details of renal transplant anatomy and the surrounding tissue, but it is hard to measure kidney function using these techniques. RSG, on the other hand, can show the excretion patterns, leakage, and morphology of the kidney, it, however, cannot provide necessary information to differentiate between AR and ATN. Furthermore, the most concern about the nuclide seriation is the low discharge rate due to the poor kidney transplant function.
Urine, a product of the kidney, contains thousands of molecules that reflect the body's homeostasis and metabolic state at any given time. Also, it represents a specimen that is readily available via non-invasive means. Of most significance for renal function and kidney health can be determined by the urine protein, UCR, and urine urea measurements. For example, healthy kidneys do not allow much protein to pass through the glomerular filters, but a damaged or diseased kidney may leak a large amount of the proteins, such as albumin, from the blood into the urine. Thus, it is reasonable to assess the kidney transplant function through urine chemical measurement.
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In the present study, we used SERS as a non-invasive tool to assess kidney transplant function after surgery. Our data potentially demonstrated the feasibility of using SERS to monitor the kidney transplant function in the early postoperative period. We found a strong correlation between SERS spectra and biochemical substances in both the urine and the blood (urine protein/UCR/urea, SCr/BUN)(p<0.01). Previously, we demonstrated that SERS spectra are able to detect or predict renal damage in a rat model24. It has been acknowledged that the chemical composition of the urine from kidney transplant recipients is more complicated than those from the rat models and non-kidney transplant patients(e.g. kidney disease patients), as transplant patients have some remnant kidney function and take immunosuppressants routinely (e.g.tacrolimus, mycophenolate mofetil, etc.). The different therapeutic drugs and the activity of the remnant kidney might result in different urine compositions from one patient to the other. In the present study, we successfully showed that the urine SERS spectra of a small cohort of kidney transplant recipients are capable of predicting essential kidney biomarkers in the presence of interference from these uncertain (remnant kidney function and therapeutic drugs) and other unknown factors. There are other studies in the literature that have also have assessed the abilities of RS to detect the biochemical constituent concentrations in the urine. For example, the creatinine in unaltered human urine from a calibration dataset using RS is indicated by a Root Mean Square Error(RMSE) of 0.4332 mmol/L30. In the measurement of 61 human urine samples(excluding 12 outliers)using liquid-core optical fiber-based RS and multivariate statistical analysis, the statistical error for creatinine quantification is 0.4508 mmol/L31. In Dou et al's study, the correlation coefficients between the concentrations of the urea and creatinine in the urine samples are presented by the intensity of the Raman peaks at 1013 and 692 cm-1 in RS, which show an R2=0.991 and R2=0.998, respectively. And the detection limits in this study are 174.93 and 13.2603 mmol/L, respectively. Wang et al.have also investigated the SERS for the measurement of the concentration of creatinine in both artificial and human urine samples, demonstrating a correlation coefficient of r=0.99 in the artificial urine samples over the range of 3.3946-13.6139 mmol/L, and r=0.96 in the human urine samples over the range of 0.2263-10.1662 mmol/L35. In a follow-up study, these authors have reported R=0.968 in a linear correlation of creatinine concentrations with the range from 0.442 to 15.1167 mmol/L34. Saatkamp et al. report the partially selected RS spectra to predict the urine urea and UCR concentrations with the correlation coefficient of r=0.90 and r=0.91, respectively35.In a separate study, they have identified the peaks specifically for the creatinine with R2=0.968 by using creatinine spiked in three different solutions: creatinine in water, a mixture of creatinine and urea in water, and creatinine in artificial urine within physiologically relevant concentrations. All these results may support the concept that SERS may be considered to be a reliable technique for monitoring the functions of transplanted kidneys non-invasively and rapidly.
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As compared to conventional methods, SERS has many advantages. First, it is non-invasive. By using an optical instrument, it does not cause any damage to the patient's body and the specimens can be non-invasively and conveniently obtained. In the clinic, one of the severe complications after surgery is infection37. This is especially true for those transplant patients who regularly take immunosuppressant drugs, to whom the rate of infection and mortality are higher than the surgical patients without transplants8. To minimize the infection rates, a non-invasive method is required and should be the best choice. Moreover, for kidney transplant patients, routine monitoring of the transplant function after the surgery is very critical for prolonging the survival of the transplants. The results from the present study indicate that SERS may provide a convenient, non-invasive, and pain-free option for routine check-ups of those patients. Second, SERS can detect the change of multiple substances in one sample quickly. Conventional biochemical methods such as the enzyme-linked immunoreactivity method only examine one substance at a time, which is time-consuming. In technology, SERS is designed to detect the covalent bond inside the molecules which is different among different molecules. Thus, it is capable of differentiating multiple substances at the same time. Third, potentially SERS is a more convenient, cheaper(cost-effective), and faster tool than conventional techniques in clinical biochemical laboratories. The SERS procedure can be completed as short as 1s in the instrument, and the data can be calculated and reported immediately. Last but the least, it has great potential in other fields, such as rapid assessment of the deceased kidney donors where the baseline renal function can sometimes be in question.
One has to acknowledge the limitation of this preliminary study, which was mainly related to the limited number of patients(110 patients) from a single transplant center. In this small cohort, the distribution of some variables such as urine protein was not such large, the ability of Ag NP-based SERS was low in the prediction of the urine protein and perhaps the SCR.
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CONCLUSION
In this study. we have demonstrated the high feasibility of using non-invasive Ag NP-based SERS of the urine to predict the kidney transplant function, indicated by the fact that the urine spectra of SERS are predictive of both the urine and blood biochemical constituents(e.g. urine protein, UCR, and urine urea, and SCr and BUN)that conventionally reflect the health of the kidney. Further research is warranted, ideally in a larger cohort, to validate the findings from this study and to build more precise models for monitoring the kidney transplant function in patients in the future.
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