Noninvasive Urine Diagnostic Kit for Kidney Graft

肾移植免疫排斥三联基因尿检试剂盒

【Background】

Kidney transplantation is the treatment of choice for most patients with end-stage renal disease.  In china, there are approximately 1500 kidney transplantation every year with an annual increase rate more than 10%. With well developed surgical techniques, the main challenge facing transplant surgeons and nephrologists today is the control of organ transplant rejection. By recognizing the polymorphic major-histocompatibility complexes (MHC), recipient’s immune system can mount a response with extraordinary strength to reject donor organs. Acute rejection, defined as a sudden deterioration in organ graft function is a major risk factor for renal allograft failure. Despite the extensive usage of immunesuppressive medicines, there remain 20-50% of kidney transplant recipients have an episode of acute rejection in the first year after transplantation. Acute rejection is associated with a 20% reduction in the one-year survival rate of cadaveric grafts, and the projected half-life of the renal grafts is 4 year shorter in patients who have had an episode of acute rejection. 

Although acute allograft rejection is an immunological response, currently there are no diagnostic methods in clinics directly measuring recipient’s anti-graft immune responses. An increase in the serum creatinine level is often the first clinical indicator of acute rejection and is currently the best surrogate marker. However, it lacks sensitivity and specificity. Instead of an indicator of host immune response, serum creatinine increase is actually a mere results of graft damages, which could be caused by many other complications, such as drug toxicity, ureteral complications, infections in the graft, and the onset of the original renal disease in the graft.  It has been observed that 30% of allograft biopsies performed in patients with stable renal function or in patients who were considered to have been successfully treated for rejection reveal histological features of acute rejection. Needle biopsy of allogafts is the standard test for the accurate diagnosis of acute rejection. Repetitive biopsies, although ideal from a diagnostic perspective, are constrained by several practical considerations. Complications associated with the procedure include hematuria, anuria, perirenal hematoma, bleeding and shock, arteriovenous fistulas, and graft loss. Sampling errors pose an additional problem.

Thus, the development and adaptation of an accurate, noninvasive and immunological diagnostic test is an emergent need in clinical practice.

【Technical Principal & Clinical Application】

We take advantage of the most recent development in transplant immunology research, and design a clinical study to test the potentials of measuring urinary cellular IP-10 and granzyme B mRNA levels in diagnosing kidney graft rejection in transplant recipients.

IP-10 (interferon-inducible protein 10) is a member of chemokine CXCR3 ligand family, which are the major chemotactants for activated T cells. Results obtained in animal models have shown clearly that IP-10 plays a critical role in allograft rejection possibly by recruiting alloreactive T cells into the graft. IP-10 is produced by graft paranchymal cells, such as glomerular mesangial cells, renal proximal tubular cells or interstitial fibroblasts, when stimulated by proinflammatory cytokines including interferons and TNF-alpha. On the other hand, perforin and granzyme B are two major cytotoxic molecules utilized by host cytotoxic CD8+ T effector cells (CTL) to destroy target cells Perforin is secreted by CTLs and forms pores in target cell membranes which facilitates the entry of granzyme B into the cells, causing cell death. Thus, the upregulation of intragraft IP-10 may represent an early event of allograft rejection, while the increased expression of perforin and granzyme B represent an ongoing rejection.

【Character Features】

u    High degree of sensitivity, specificity and effectiveness, based on biologic target gene expression level

u    No injury and risk to the kidney transplant patients

u    Systematic monitoring of the immune system reaction to kidney transplant