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Organ transplantation is often a recommended way out for many end-stage diseases. It is a very complex medical procedure wherein an organ is removed from the donor’s body and placed in the recipient’s body in order to replace the dysfunctional organ.
The main hurdle associated with the success rate of organ transplantation is rejection of the transplanted organ by the recipient’s immune system. Thus, to ensure successful organ transplantation, it is important to regularly monitor immunological reactions between the transplant and the recipient’s immune system, functional recovery of the transplant, and chances of infection. Current strategies used to monitor these conditions are either non-specific or invasive in nature, indicating the need for good follow-up strategies.
Metabolomics is the comprehensive study of the metabolome, a group characterized by a complete set of metabolites present in the cells, tissues, or body. Since metabolomics measures downstream products of metabolic activities, it can rapidly and significantly reflect stress-induced cellular phenotypes, and could serve as a great platform for the timely and accurate monitoring of the pathophysiological aspects of organ transplantation. In addition, metabolomics could rapidly measure a large number of metabolites in a single measurement, which makes it even more advantageous in terms of gaining detailed information on the organ transplantation outcome.
With the discovery of effective immunosuppressants, the rejection rate of organ transplantation has reduced considerably; however, in case of renal allograft transplantation, a condition wherein kidney is received from a genetical non-identical recipient of the same species, the rejection rate is still high. Presently, the monitoring of renal allograft rejection is mainly performed by measuring serum creatinine level, a non-specific biomarker noticed in the serum long after the initiation of rejection. To overcome problems associated with traditional biomarkers and measurement techniques, many studies have been done to authenticate the importance of metabolomics.
Metabolomics is considered as a powerful alternative in comparison to the measurement of traditional biomarkers. Using metabolomics, a large number of metabolites associated with allograft rejection, such as amino acids, carbohydrates, lipids, catabolic compounds, and metabolites related to gut microorganisms, are identified. One such metabolite is kynurenine, a tryptophan degradation product produced by immunomodulatory enzyme, indoleamine 2, 3-dioxygenase, which promotes immune tolerance. Similarly, one study employing metabolomics has identified four unknown metabolites that have 100% specificity for predicting allograft rejection.
Ischemia/reperfusion injury is a type of damage that may occur in the kidney due to lack of oxygen supply during its preservation period before transplantation. Such injury can significantly increase the risk of organ dysfunction and rate of rejection. Studies have found that metabolomics has the potential to detect such injury.
For instance, metabolomics has identified elevated levels of several metabolites in the blood, such as trimethylamine-N-oxide (TMAO), allantoin, inosine, and hypoxanthine, which significantly correlate with the degree of renal ischemia/reperfusion injury.
As most of the detoxification reactions occur in the liver, changes in metabolites that reflect pathophysiological conditions are very high during liver transplantation. Metabolomics serves as an excellent platform for profiling these metabolic alterations. Similar to renal transplantation, liver transplantation also requires continuous monitoring to avoid immune rejection and to evaluate functional recovery.
In case of liver ischemia/reperfusion injuries, metabolomics studies have identified altered levels of several important metabolites, including urea cycle metabolites (urea, glutamate), energy-related metabolites (formate, orthophosphate, ADP, lactate, pyruvate, glycerol, fatty acids, and carbohydrates), metabolites of oxidative phosphorylation (fumarate and succinate), oxidative stress-related metabolites (homovanillic acid, methionine, reduced glutathione), and several bile acids metabolites.
As identified by many metabolomics studies, the most important and frequently observed biomarker of liver ischemia/reperfusion injury is asymmetric dimethylarginine. Regarding immune rejection markers, metabolomic studies have identified taurine-conjugated bile acid as a good predictor of immune rejection in case of liver transplantation.
Similar to other organ transplantation, heart transplantation also needs regular fellow-up. Nuclear magnetic resonance-based metabolomics studies in heart transplantation patients have identified high plasma levels of lipoproteins and lipids as possible indicators of heart immune rejection. In addition, a metabolomics study in rats has revealed that metabolites such as D-tagatose, choline, C16 sphinganine, and D-glutamine are highly sensitive and specific biomarkers to predict auto rejection after heart transplantation. These results, however, need to be extrapolated in human applications in order to make them viable in clinical settings.