Biomarkers for Kidney-Transplant Rejection: Comparison
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Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by Ayman El-Baz.

Kidney transplantation is the preferred treatment for end-stage renal failure, but the limited availability of donors and the risk of immune rejection pose significant challenges. Early detection of acute renal rejection is a critical step to increasing the lifespan of the transplanted kidney. Investigating the clinical, genetic, and histopathological markers correlated to acute renal rejection, as well as finding noninvasive markers for early detection, is urgently needed. It is also crucial to identify which markers are associated with different types of acute renal rejection to manage treatment effectively. 

  • biomarkers
  • kidney-transplant rejection
  • renal rejection

1. Introduction

Kidney transplantation is a superior treatment to dialysis for individuals with chronic kidney disease or end-stage renal failure, boasting up to 97% survival rates for transplanted kidneys within one year [1]. Nevertheless, a significant hurdle is the limited availability of donors, mainly due to the risk of immune rejection. When genetically dissimilar donor tissue is transplanted, the recipient’s immune system may perceive it as foreign, leading to potential graft rejection [2].
Lymphocytes, essential white blood cells, are vital components of the adaptive immune response, with B-cells producing pathogen-specific antibodies and T-cells capable of killing infected cells or seeking support from other cells [3]. The interaction between the innate and adaptive immune systems defends the body against foreign pathogens and abnormal cells [2][3]. Recent advancements in technology have enabled personalized immunosuppressive therapies based on recipient-specific biomarkers related to immune response activation [3]. Toll-like receptors (TLRs) are extensively studied pattern-recognition receptors (PRRs) that play a critical role in initiating innate responses and guiding adaptive immunity [4]. They are expressed in various hemopoietic cells, including DCs, B-cells, mast cells, T-cells, and endothelial cells. Their stimulation leads to the activation of transcription factors NF-KB and AP-1, which subsequently induce the transcription of inflammation-related genes. This results in the production of proinflammatory cytokines, chemokines, antimicrobial peptides, adhesion molecules, enhanced antigen presentation, and increased expression of costimulatory molecules in APCs. The intricate interplay among these components significantly influences the immune response against transplanted organs and tissues, ultimately impacting the rejection outcome [4].
Acute renal rejection, classified based on histopathological and immunological characteristics, has distinct forms [2]. Hyperacute rejection is a severe type that occurs suddenly within minutes of transplant [5], but it is rare due to successful prevention through tissue cross-matching. Acute rejection can happen at any time after transplantation and includes antibody-mediated rejection (ABMR) and T-cell-mediated rejection (TCMR). ABMR involves immunological damage caused by antibodies and donor-specific alloantibodies in circulation, while TCMR results in lymphocytic infiltration affecting the interstitium, tubules, and sometimes the artery intima. Tubular injury markers differentiate between ABMR and TCMR based on specific histological features. For instance, TCMR is characterized by mononuclear tubulitis and interstitial inflammation, while ABMR exhibits microvascular inflammation, arteritis, acute tubular injury, or thrombotic microangiopathy. Additionally, the presence of complement component C4d in peritubular capillaries indicates the antibody–endothelium interaction in ABMR, although its reproducibility is poor and staining results may vary [2].
The prohibitive expense of postsurgical maintenance, amounting to thousands of dollars per month for antirejection medications, presents a significant challenge for some patients [6]. Untreated rejection can lead to major health problems [7]. To address this issue and enhance transplant outcomes, early detection of renal rejection through innovative biomarkers is essential [8]. These markers include histological, clinical, and genetic indicators. While biopsy remains the gold standard, from these markers, clinical biomarkers such as KIM-1 and CXCL-10 show potential for early diagnosis and prognosis prediction of renal rejection [9].

2. Extraction of RNA and Clinical Markers from Histological Samples

Histopathological markers refer to changes in tissue structure that are observed through a microscope, and they aid in identifying and monitoring renal-transplant rejection. These markers offer valuable insights into the cellular and molecular changes that occur during rejection and can be challenging to detect with clinical markers alone [10]. The presence of infiltrating lymphocytes, which can be detected through a biopsy sample taken from the transplanted kidney, is one of the most commonly used histopathological markers of renal rejection. It indicates an active immune reaction against the grafted tissue. The severity of rejection can be graded based on the number and distribution of infiltrating lymphocytes, with higher numbers indicating more severe rejection [10][11]. Other histopathological markers of renal rejection include changes in the capillary basement membrane, alterations in the glomerular filtration barrier, and modifications in the tubulointerstitium. These changes may indicate acute tissue injury and early lesions of endothelial injury and can be visualized using light microscopy or electron microscopy [12].

3. Clinical Markers

Clinical markers play a critical role in identifying and monitoring the progression of renal rejection, allowing for timely intervention to prevent further damage to the transplanted kidney. Common clinical markers used to detect renal rejection include serum creatinine levels, blood urea nitrogen (BUN) levels, urine output, and proteinuria [13]. An increase in serum creatinine levels may suggest a decrease in kidney function, potentially indicating the onset of rejection. Elevated BUN levels can also indicate a reduction in kidney function. Decreased urine output may be a sign of decreased kidney function or possible obstruction of the urinary tract, both of which can be linked to rejection [14]. Proteinuria, which refers to an excessive amount of protein in the urine, may indicate damage to the glomeruli, the small filtration units within the kidney. Despite having a critical role in identifying rejection, these markers have some limitations detecting renal rejection. They are influenced by nonrenal factors, making early detection of rejection challenging [15]. To address these limitations, researchers have explored other biomarkers, such as interleukin-18 (IL-18) and neutrophil-gelatinase-associated lipocalin (NGAL), released by injured kidneys, which show promise in providing early and sensitive detection of kidney-transplant rejection [15]. It is essential to note that these clinical markers are usually used in combination with other tests, such as biopsy or imaging, to confirm a rejection type and diagnosis, in addition to allowing real-time monitoring of the transplanted kidney. With early detection and prompt treatment, the prognosis for most cases of renal rejection is favorable, and the transplanted kidney can often be salvaged [16]. Additional markers include: urinary β2-microglobulin, N-acetyl-β-glucosaminidase (NAG), and L-FABP, which are markers of rejection in urine tests used in real clinical practice, with β2-microglobulin assessing proximal tubule injury [17], NAG serving as a sensitive marker of tubular injury [13], and L-FABP being a valuable biomarker for diagnosing acute kidney injury and predicting long-term graft outcomes in kidney-transplant patients [18].

4. Genetic Markers

Genetic markers have become increasingly important in identifying and managing renal rejection. They provide valuable information about the genetic factors that influence the likelihood of rejection and the response to treatment. Potential confounding factors influencing the association between genetic markers and renal rejection include different gene-expression-analysis technologies (microarray vs. RNAseq), obtaining extra biopsy cores for profiling, and variability in blood tacrolimus concentrations affecting transplant outcomes and AR risk [19]. One of the most critical genetic markers for renal rejection is the HLA mismatch, which refers to differences in human leukocyte antigen between the donor and recipient [20][21]. The HLA system plays a crucial role in presenting antigens to the immune system and is involved in the recognition and rejection of foreign tissues. In addition to the HLA mismatch, single nucleotide polymorphisms (SNPs) in certain genes related to the immune response have been implicated in renal rejection [21]. The presence of specific SNPs in genes involved in immune response can increase the probability of rejection and affect the response to therapy. Gene-expression patterns are another type of genetic marker that has been investigated as a potential indicator of renal rejection [22]. These markers can provide valuable information about the molecular changes that occur during rejection and could be used to develop more targeted treatments. Overall, genetic markers offer significant insights into the mechanisms of renal rejection and provide opportunities for developing personalized treatments [20][21][22].

References

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