Evaluation Of Renal Fibrosis In Chronic Kidney Diseases With Functional Magnetic Resonance Imaging

Chronic kidney disease(CKD)is a global public health problem.The prevalence of CKD was 8-16%in 2013.China is a big country of CKD.According to the statistics in2012,the prevalence of CKD is about 10.8%,about 130 million patients;among them,chronic glomerular disease is the most common.The diagnosis of CKD indicates a state of disease,and its significance is to stage the slow decline of renal function.The evaluation of glomerular filter rate(GFR)is a key link in the diagnosis and treatment of kidney disease.It is an important indicator to reflect the severity and progression of CKD.It is of great significance for guiding clinical medication and judging the disease progression and prognosis.At present,the clinical methods of GFR measurement are mainly based on single photon emission computed tomography(SPECT)and GFR estimation.The level of renal function is closely related to the changes of renal histology,especially chronic diseases such as fibrosis.Tissue fibrosis is the final common pathological change of CKD.Renal fibrosis is an important risk factor in CKD development.Although the histomorphology can reflect the severity of CKD,the clinical access to histologic material renal biopsy is limited,which is difficult to reflect the overall appearance of renal tissue changes,and is an invasive operation,which is not conducive to repeated observation and follow-up of the changes of the disease.The main diagnostic basis of the present day,namely gold standard,is still percutaneous renal biopsy.Renal fibrosis is an important pathological marker of CKD progress,which is accompanied by changes of renal microcirculation,hypoxia and damage of nephron.It is very important to evaluate the degree of renal fibrosis in order to understand the condition of renal disease,to judge prognosis and to develop treatment plan.However,there is no noninvasive examination of renal fibrosis in clinical.The main diagnostic basis,namely gold standard,is still percutaneous renal biopsy.However,the shortcomings of biopsy are not only in the trauma,but also in the limitations of material acquisition.Recently,some new magnetic resonance imaging(MRI)techniques have been developed and successfully applied in clinical application to evaluate the degree of tissue fibrosis.MRI has no ionizing radiation,high resolution of soft tissue,multi-plane imaging,and can evaluate the physiological function and pathophysiological changes of tissue and organs without injection of contrast agent.With the emergence of new functional sequences,the research of abdominal functional MRI has gradually recognized its safety and practicability.Because MRI not only provides complex anatomical information of the solid organs,but also reveals the characteristics of the lesions in the aspects of water molecular movement and cell function.In the field of nephrology,magnetic resonance elastography(MRE)was performed in renal transplantation patients.It was found that allograft elastic value can predict the prognosis of renal transplantation.The results showed that there was a negative correlation between serum creatinine and DWI ADC value.However,in CKD patients,especially chronic glomerulonephritis,there are chronic fibrosis.Currently,there is little research on renal fibrosis imaging in China.Moreover,in clinical work,there is no good correlation between functional imaging data and renal function and renal tissue fibrosis.Therefore,the study focuses on the analysis of three histopathological indexes related to renal fibrosis–peritubular capillary density,the content of extracellular matrix and the density of renal tubular epithelial cells.The new MRI technology includes the internal motion diffusion weighted imaging(IVIM DWI),including DWI standard ADC sequence,DWI fraction sequence and AQP sequence,and MRE technology.The study is divided into three parts.From the evaluation of renal function status of CKD patients by functional image,the mapping correlation of renal tissue fibrosis index in CKD patients,and into the multi-modal model is constructed based on the parameters of MRI sequence and renal function.The degree of renal fibrosis in CKD patients is predicted.These three parts are gradually developed from the aspects of CKD renal function,functional imaging and histology.Part one:Evaluation of renal function in patients with chronic kidney disease by functional magnetic resonance imagingBackground and objective:China is a large country of CKD,and GFR is an important index for the assessment and staging of CKD.At present,the main clinical evaluation methods of CKD are e GFR and SPECT-GFR.Functional magnetic resonance imaging(f MRI)has high diagnostic value in abdominal organ function,especially in blood flow and water molecule diffusion,because of its unique advantage in reflecting organ physiological function.This part of the study aims to observe the correlation between f MRI sequences and GFR in patients with CKD,and determine the relevant MRI sequences that can evaluate GFR.Methods:Based on the data of retrospective cohort study,CKD patients hospitalized in the National Clinical Research Center of Kidney Disease from April 2016 to December 2016were selected as the research objects.All patients underwent IVIM-DWI,DKI,DTI and MRE sequence scanning on GE MR 750 3.0 Tesla MRI system.The post-processing software of functool software package in ADW 4.6 workstation was used to generate the corresponding f MRI pseudo color images and obtain the corresponding f MRI sequence parameters.GFR was calculated by CKD-EPI formula,and SPECT-GFR was performed at the same time.Pearson or Spearman correlation test was used to detect the correlation between f MRI sequence parameters and renal function indexes.Results:(1)DWI standard ADC,DWI fraction sequence parameters cortical area data in different stages of CKD were significantly different,with the progress of CKD,the parameter values gradually decreased.DWI standard ADC value of renal cortex in CKD stage 1 was significantly higher than that in CKD stage 4(1.91±0.11mm~2/s*10~4vs.1.61±0.15mm~2/s*10~4,P<0.01);DWI fraction value of renal cortex in CKD stage 1 was significantly higher than that in CKD stage 4(0.46±0.02mm~2/s*10~4vs.0.36±0.04mm~2/s*10~4,P<0.01).The cortical parameters of DWI standard ADC were positively correlated with e GFR(rho=0.660,P<0.01),and the cortical parameters of DWI fraction were positively correlated with e GFR(rho=0.673,P=0.001).The data of medullary region obtained by DWI sequence had similar statistical results.(2)DWI-AQP sequence parameters were significantly different in different stages of CKD,and gradually increased with the progression of CKD.The DWI-AQP value of renal cortex in CKD stage 1 was significantly lower than that in CKD stage 4(0.24±0.06mm~2/s*10~4vs.0.32±0.05mm~2/s*10~4,P<0.05).There was a significant negative correlation between DWI-AQP parameters and e GFR(rho=-0.506,P=0.006).The parameters of AQP in medullary region had similar statistical results.(3)At 60Hz,MRE sequence parameters were significantly different between different stages of CKD,and gradually decreased as CKD progressed.MRE of renal cortex in CKD stage 1 was significantly lower than that in CKD stage 4(4.565±0.575 k Pa vs.3.728±0.575 k Pa,P<0.05).There was a significant positive correlation between MRE cortical parameters and e GFR(rho=0.411,P=0.03).The parameters of MRE in medullary region had similar statistical results.At 45Hz,the correlation between MRE and GFR was not significant.The correlation between DKI,DTI and GFR was not significant.Conclusion:There is a good correlation between DWI,MRE sequence and GFR,which may be used as a candidate index to evaluate renal function injury in CKD patients.This part of the results also provides basic data for further research on the relationship between f MRI sequence and specific morphological indicators of renal fibrosis.Part two:Evaluation of renal fibrosis in patients with chronic kidney disease by functional magnetic resonance imagingBackground and objective:Research content 1 has provided DWI,MRE and other f MRI sequences,which are correlated with the GFR level of CKD patients,with significant differences in different CKD stages.However,as a f MRI sequence,its practical significance should be to reflect the pathophysiological changes of organs and tissues.Based on the basic principles of DWI standard ADC,DWI fraction,DWI-AQP and MRE sequences,and the common characteristics of the pathophysiological state of human tissues and organs,this paper puts forward the scientific hypothesis,and verifies the actual reflection and correlation characteristics of the new MRI technology in the evaluation of renal fibrosis in CKD patients by mapping and associating the fibrosis tissue characteristics of CKD patients with f MRI sequences.Methods:Based on the cohort study database,CKD patients admitted to the national clinical research center of kidney disease from January 2016 to December 2017 and included in Nanjing Glomerulonephritis Registry were collected.The content of extracellular matrix in cortical interstitium and the density of capillaries around the tubules in renal pathology were observed,and the correlation analysis was carried out according to the parameters of f MRI scanning sequence.The content of extracellular matrix was analyzed by analyzing Masson's trichrome sections with the system of Aperio Scan Scope.The number of peritubular capillaries was calculated and the distribution density of peritubular capillaries was analyzed by CD34 immunohistochemical staining.According to the conventional pathological calculation,the proportion of glomerulosclerosis and the semi quantitative score of interstitial fibrosis were divided into 0(fibrosis<10%),1(fibrosis 10-30%),2(fibrosis 30-50%)and 3(fibrosis>50%).AQP1 staining was used to calculate the proportion of AQP1 positive renal tubules.Pearson or Spearman correlation test was used to detect the correlation between MRE sequence parameters and extracellular matrix content,DWI sequence parameters and peritubular capillary density,AQP sequence parameters and the proportion of AQP1 protein positive renal tubules.Result:(1)97 patients with CKD were included in this study.With the progress of CKD,the density of peritubular capillaries and the number of AQP1 positive renal tubules decreased significantly,and the content of extracellular matrix in cortex increased significantly.(2)According to CKD staging,DWI standard ADC sequence parameters,DWI fraction parameters and MRE parameters were significantly decreased.There was no significant difference in AQP parameters between different stages of CDK,and similar results were obtained by grouping according to the severity of glomerulosclerosis and chronic renal interstitial score.(3)There was a negative correlation between DWI standard ADC sequence parameters and the proportion of spherical sclerosis(rho=-0.428,P<0.001),DWI fraction sequence parameters and the proportion of spherical sclerosis(rho=-0.272,P=0.007),and MRE sequence parameters and the proportion of spherical sclerosis(rho=-0.519,P<0.001).(4)DWI standard ADC sequence parameters were positively correlated with peritubular capillary density(rho=0.244,P=0.016);DWI fraction sequence parameters were positively correlated with peritubular capillary density(rho=0.472,P=0.001).(4)MRE sequence parameters were negatively correlated with extracellular matrix content in cortex(rho=-0.397,P<0.001).(5)There was no significant correlation between AQP-ADC parameters and AQP1protein expression(rho=-0.089,P=0.385).Conclusion:This part of the study provides histopathological evidence for functional MRI sequence to effectively evaluate renal fibrosis in CKD patients,and explores the mapping relationship between MRI and histopathology.DWI standard ADC sequence,DWI fraction sequence and MRE sequence,no matter from the theoretical point of view or the actual data results,all suggest that there are advantages in the evaluation of glomerular fibrosis and renal cortical interstitial fibrosis in the future.Based on the data results of this study,external validation of a larger sample and longer-term follow-up study are needed.Objective to compare the traditional pathological chronicity index with these new f MRI sequence indexes,so as to clarify the evaluation of fibrosis and the prognosis of CKD.Part three:Establishment of multimodal model based on functional magnetic resonance imaging,renal function and renal histology parameters in patients with chronic kidney diseaseBackground and objective:Based on the first and second studies,this part constructs the model of specific pathological indexes of renal fibrosis based on functional magnetic resonance parameters and renal function parameters.Methods:The study population and basic data were the same as the second part.The histopathological indexes of severe renal fibrosis included capillary density and extracellular matrix content.Functional MRI included IVIM-DWI and MRE.A multiple linear regression model was established to predict renal fibrosis based on f MRI sequence parameters and e GFR,and the best fitting line was constructed according to the principle of minimizing the sum of squares in the multiple regression model.Result:(1)Based on MRE sequence parameters and e GFR,the most suitable equation to reflect the extracellular matrix content in cortex was constructed as follows:Interstitial Extracellular Matrix Volume=218.504-14.651×ln(MRE)-18.499×ln(eGFR)There was a linear relationship between extracellular matrix content and MRE sequence parameters and natural logarithm of e GFR in renal cortical interstitial fibrosis of CKD patients,both P values were less than 0.05(6.16e-05,0.0326 and 3.88e-10).(2)Based on DWI fraction and e GFR,the most suitable equation of capillary density in cortical area was constructed as follow:Peritubular Capillaries Density=17.914+9.403×(DWI-fraction)+0.112×(eGFR)There was a linear correlation between the distribution density of peripapillary capillaries and the sequence parameters of DWI fraction and e GFR.Compared with e GFR,the relationship between DWI fraction and the distribution density of peripapillary capillaries was relatively weak,and the P value was larger.(3)Based on DWI standard ADC and EGFR,the most suitable equation to reflect the distribution density of peritubular capillaries in cortex was constructed as follow:Peritubular Capillaries Density=22.136-0.809×(DWI-Standard ADC)+0.130×(eGFR)The correlation between DWI standard ADC sequence parameters and perivascular capillary density was weak compared with e GFR,and similar results were obtained compared with DWI fraction.Conclusion:On the basis of previous studies and based on the mapping relationship between MRI and histology,this part of the study constructs a mathematical model to obtain the important histological characteristics of fibrosis kidney by functional imaging parameters and renal function indexes,which is of great significance to promote the clinical application of functional imaging in CKD.