Basic And Clinical Studies Of Functional Magnetic Resonance Imaging In Diagnosing Renal Transplant Rejection

Introduction:Kidney transplantation is the best treatment for most patients with end-stage renal disease (ESRD). Although major advances in the skill of surgery and transplant immunology and pharmacotherapy have led to improvement of the first-year renal graft survival, late graft loss is still a significant problem in renal transplantation. Allograft rejection (AR) and acute tubular necrosis (ATN) are two important causes of early kidney allograft dysfunction, and it is difficult to discriminate between them by regular clinical tests.Magnetic resonance imaging (MRI) provides good contrast between the different soft tissue of the body and multi-imaging capabilities, which make it especially useful in imaging the organ function such as organ perfusion and metabolic imaging features. Diffusion weighted imaging (DWI) is a MR modality using strong bipolar gradients to create a sensitivity of the signal to the thermally induced Brownian (or random walk) motion of water molecules and in vivo measurement of molecular diffusion. The apparent diffusion coefficient (ADC) as a quantitative parameter calculated from diffusion-weighted images, which is used as a measure of diffusion.Since the ADC is also dependent on capillary perfusion and water diffusion in the extravascular space, alteration of the ADC provides information concerning microstructure changes. The ADC of the kidney is higher than the ADC of other abdominal organs, most likely due to the high water content and the high blood supply of the kidney and possible contributions of the flow in the tubular system. Therefore, DWI MRI can provide information on perfusion and diffusion of microcirculation. In renal transplant patients, DWI MRI can detect renal cortex and medulla microcirculation blood flow changes of transplant. Some study found that in situ renal microcirculation in the renal cortex is better than medulla, but in the transplanted kidney cortex and medulla microcirculation perfusion no significant difference, suggesting the existence of blood flow abnormal distribution between transplanted renal cortex and medulla. Blood oxygen level-dependent magnetic resonance imaging (BOLD MRI) is based on the paramagnetic moments by its unpaired electrons in a magnetic field. The increased R2* level implies an increased deoxyhaemoglobin level and decreased oxygen bioavailability in the tissue. Djamali et al using BOLD MRI studied the MR images of allograft underwent renal AR and ATN. They found that allograft underwent renal AR shown characteristic BOLD MRI changes, which was related with the pathologic changes of allograft renal.Thus, functional MRI provides a large clinical application in the non-invasive diagnosis and differential diagnosis of transplanted kidney with AR. Therefore, on the one hand, in this study we used BOLD MRI, DWI MRI imaging in high field MR machine to establish the characteristic MRI imaging of AR, and carried out dynamic observation of renal function from clinical cases. On the other hand, since these MRI images were more affected by imaging time, blood pressure, capacity, age etc., we established AR, ATN, and a control group of mice kidney transplantation model. In order to determine the value of DWI MRI and BOLD MRI for the diagnosis and differential diagnosis we used DWI MRI and BOLD MRI to study diffusion and oxygenation parameters of AR or ATN renal cortex and medulla; we also studied the molecular mechanism of the renal hemodynamic and oxygenation changes.Experimental procedures: 1. In this study 158 allograft kidney transplant recipients of our center were selected, including 124 patients with normal renal function,25 patients with, and 9 patients with ATN. The diagnosis of AR, ATN was confirmed by biopsy. We obtained cortical R2* (CR2*), medullary R2* (MR2*), medullary/cortical R2* ratios (MCR) from BOLD MRI image of all patients. We analyzed the dynamic changes of the parameters, influencing factors, the diagnosis, differential diagnosis and predictive value to AR.2. We selected 50 allograft kidney transplant recipients of our center, including 35 patients with normal renal function,10 patients with AR, and 5 patients with ATN. The diagnosis of AR, ATN was confirmed by biopsy. We obtained cortical ADC (CADC), medullary ADC (MADC), medullary/cortical ADC ratios (MCA) from DWI MRI image of all patients. We analyzed the dynamic changes of the parameters, influencing factors, the diagnosis, differential diagnosis and predictive value to AR, and the correlation of R2 and ADC.3. We established renal transplantation AR, ATN and control groups mice models. We also analyzed the relation between functional MR imaging parameters and expression level of transplant renal microcirculation adjustment factors, like inducible nitric oxide synthase (iNOS), angiotensin type 1 receptor (AT1R), prostaglandin E receptor 4 (EP4), and sodium-potassium ATP enzyme (Na+-K+-ATPase, NKA), sodium hydrogen exchanger (Na+/H+exchanger, NHE).Results:1. BOLD MRI can reflect the oxygenation of transplanted kidney. The R2* value of the tissues did not significantly correlate with age and gender of recipients, the source of donor, post-transplantation time, and serum creatinine level, hemoglobin, mean arterial pressure, volume of urine, and blood trough concentration when imaging. The MR2* and CR2* value of the transplanted kidneys decreased during post-transplantation period, but not statistically significant. BOLD MRI can effectively separate transplanted kidneys underwent AR from that with ATN, but cannot tell between different types of AR. The MR2*, CR2*, MCR of transplanted kidney can all be the diagnostic indexes of AR of transplanted kidney. And MR2* is more efficient than CR2* or MCR since the incidence of AR within a short time can be predicted according to MR2*.2. The CADC and MADC value of DWI MRI of transplanted kidney was close, and the ADC value was different when imaged at low B value or high B value. ADC value did not significantly correlate with age and gender of recipients, the source of donor, post-transplantation time, and serum creatinine level, hemoglobin, mean arterial pressure, volume of urine, and blood trough concentration when imaging. The ADC value did not change significantly during post-transplantation period. The CADC and MADC can effectively separate transplanted kidney underwent AR from that with normal function. But the CADC and MADC of transplanted kidneys underwent AR and ATN were not significantly different. CADC and MADC can be the diagnostic indexes of AR, and the diagnostic efficiency of ADC got with high B value was better than that of ADC got with low B value.3. The R2* value of cortex and medulla of transplanted kidney showed no significant correlation with the ADC value under neither low B value nor high B value. The R2* value of cortex and medulla of transplanted kidney showed no significant correlation with the ADC value obtained at neither low B value nor high B value. For medulla of transplant, the area under ROC curve of R2* was between that of ADC at high B value and that of ADC at low B value, but the difference was not significant.4. We established the mice model for renal transplantation with AR, ATN and normal kidney function.5. BOLD MRI image of the transplanted kidney of the mice model showed that CR2* of ATN mice was significantly higher than AR and control mice. MR2* of AR mice was significantly lower than control and ATN mice, indicating the elevated oxygen concentration in renal medulla. DWI MRI image showed the average ADC of renal parenchyma of AR mice was lower than that of ATN mice which was lower than that of control mice, but the difference was not statistically significant. CR2*, MR2* and ADC were not significantly correlated.6. We found that expression of iNOS and AT1R in transplanted kidney of AR mice was significantly higher than that in control or ATN mice by both immunohistochemistry and western blotting, indicating that during the process of AR, factors upregulating and downregulating blood supply in transplanted kidney are co-existed. Expression of NKA and NHE decreased in renal tubular epithelial cells in AR and ATN mice, indicating the transportation function was inhibited in renal tubule, which may lead to reduced oxygen consumption and elevated local oxygen concentration in kidney.Conclusions:1. BOLD MRI can effectively discriminate AR and ATN in the early post-renal-transplantation stage. The R2* value can be a diagnostic index of AR, and MR2* may have certain value in predicting incidence of AR.2. DWI MRI can effectively discriminate AR and normally functioned transplant in the early post-renal-transplantation stage. ADC can be a diagnostic index of AR.3. BOLD MRI can detect the change of oxygenation in transplant and increase of oxygen concentration during the process of AR. DWI MRI can reflect the change of perfusion of microcirculation and diffusion of water in transplant. Both perfusion of microcirculation and diffusion of water are reduced when AR occurs.4. Expression of renal tubular transport protein is reduced in AR mice, indicating the tubular transportation capability is inhibited, which may lead to reduced oxygen consumption and elevated oxygen concentration.