Assessment of cognitive functioning after living kidney donation: A cross-sectional pilot study.

BACKGROUND: Chronic kidney disease (CKD) has emerged as a risk factor for cognitive impairment. Living kidney donation results in reduction of the donors' renal function. This is considered acceptable in general but possible associations with cognitive function have not yet been studied. METHODS: Sixty living kidney donors (LKD), who had donated between 2003 and 2012 at Hannover Medical School, underwent neurocognitive testing including attentional and memory testing. In a cross-sectional design results were compared with data of healthy controls (n = 40) and with norm data given in the respective test manuals adjusted for age, sex, and education. RESULTS: The median age of the LKD was 58 (range 39-70) years and the median time since donation was 7 (range 4-14) years. The LKD did not differ from controls in most of the cognitive test results and a composite attention test sum score. However, LKD did worse than controls in tests of working memory, parallel processing of stimuli, and sustained attention. No differences were found regarding quality of life. In LKD cognitive test results correlated significantly only with educational level but not with time since transplantation, eGFR, somatic comorbidity, quality of life and levels of fatigue, distress, depression, and anxiety. CONCLUSIONS: Our data show a fairly normal performance of LKD in most attentional and memory tests. However, our pilot study also suggests some cognitive impairment in attention tests in LKD which would need to be confirmed in longitudinal prospective studies.

Application of MR diffusion imaging for non-invasive assessment of acute kidney injury after lung transplantation.

To assess whether MR diffusion imaging may be applied for non-invasive detection of renal changes correlating with clinical diagnosis of acute kidney injury (AKI) in patients after lung transplantation (lutx).Fifty-four patients (mean age 49.6, range 26-64 years) after lutx were enrolled in a prospective clinical study and underwent functional MR imaging of the kidneys in the early postoperative period. Baseline s-creatinine ranged from 39 to 112 µmol/L. For comparison, 14 healthy volunteers (mean age 42.1, range 24-59 years) underwent magnetic resonance imaging (MRI) using the same protocol. Renal tissue injury was evaluated using quantification of diffusion and diffusion anisotropy with diffusion-weighted (DWI) and diffusion-tensor imaging (DTI). Renal function was monitored and AKI was defined according to Acute-Kidney-Injury-Network criteria. Statistical analysis comprised one-way ANOVA and Pearson correlation.67% of lutx patients (36/54) developed AKI, 47% (17/36) had AKI stage 1, 42% (15/36) AKI stage 2, and 8% (3/36) severe AKI stage 3. Renal apparent diffusion coefficients (ADCs) were reduced in patients with AKI, but preserved in transplant patients without AKI and healthy volunteers (2.07 ±â€Š0.02 vs 2.18 ±â€Š0.05 vs 2.21 ±â€Š0.03 × 10 mm/s, P < .05). Diffusion anisotropy was reduced in all lutx recipients compared with healthy volunteers (AKI: 0.27 ±â€Š0.01 vs no AKI: 0.28 ±â€Š0.01 vs healthy: 0.33 ±â€Š0.02; P < .01). Reduction of renal ADC correlated significantly with acute loss of renal function after lutx (decrease of renal function in the postoperative period and glomerular filtration rate on the day of MRI).MR diffusion imaging enables non-invasive assessment of renal changes correlating with AKI early after lutx. Reduction of diffusion anisotropy was present in all patients after lutx, whereas marked reduction of renal ADC was observed only in the group of lutx recipients with AKI and correlated with renal function impairment.

Gd-EOB-DTPA-enhanced MRI for quantitative assessment of liver organ damage after partial hepatic ischaemia reperfusion injury: correlation with histology and serum biomarkers of liver cell injury.

OBJECTIVE: To evaluate Gd-EOB-DTPA-enhanced MRI for quantitative assessment of liver organ damage after hepatic ischaemia reperfusion injury (IRI) in mice. METHODS: Partial hepatic IRI was induced in C57Bl/6 mice (n = 31) for 35, 45, 60 and 90 min. Gd-EOB-DTPA-enhanced MRI was performed 1 day after surgery using a 3D-FLASH sequence. A subgroup of n = 9 animals with 60 min IRI underwent follow-up with MRI and histology 7 days after IRI. The total liver volume was determined by manual segmentation of the entire liver. The volume of functional, contrast-enhanced liver parenchyma was quantified by a region growing algorithm (visual threshold) and an automated segmentation (Otsu's method). The percentages of functional, contrast-enhanced and damaged non-enhanced parenchyma were calculated according to these volumes. MRI data was correlated with serum liver enzyme concentrations and histologically quantified organ damage using periodic acid-Schiff (PAS) staining. RESULTS: The percentage of functional (contrasted) liver parenchyma decreased significantly with increasing ischaemia times (control, 94.4 ± 3.3%; 35 min IRI, 89.3 ± 4.1%; 45 min IRI, 87.9 ± 3.3%; 60 min IRI, 68 ± 10.5%, p < 0.001 vs. control; 90 min IRI, 55.9 ± 11.5%, p < 0.001 vs. control). The percentage of non-contrasted liver parenchyma correlated with histologically quantified liver organ damage (r = 0.637, p < 0.01) and serum liver enzyme elevations (AST r = 0.577, p < 0.01; ALT r = 0.536, p < 0.05). Follow-up MRI visualized recovery of functional liver parenchyma (71.5 ± 8.7% vs. 84 ± 2.1%, p < 0.05), consistent with less histological organ damage on day 7. CONCLUSION: We demonstrated the feasibility of Gd-EOB-DTPA-enhanced MRI for non-invasive quantification of damaged liver parenchyma following IRI in mice. This novel methodology may refine the characterization of liver disease and could have application in future studies targeting liver organ damage. KEY POINTS: • Prolonged ischaemia times in partial liver IRI increase liver organ damage. • Gd-EOB-DTPA-enhanced MRI at hepatobiliary phase identifies damaged liver volume after hepatic IRI. • Damaged liver parenchyma quantified with MRI correlates with histological liver damage. • Hepatobiliary phase Gd-EOB-DTPA-enhanced MRI enables non-invasive assessment of recovery from liver injury.

Assessment of liver ischemia reperfusion injury in mice using hepatic T2 mapping: Comparison with histopathology.

BACKGROUND: Liver ischemia reperfusion injury (IRI) occurs during liver surgery or transplantation resulting in an inflammatory response, tissue damage, and functional impairment of the organ. PURPOSE: To assess the feasibility of T2 mapping for noninvasive quantification of liver edema after partial liver IRI in mice. STUDY TYPE: Prospective, experimental study. ANIMAL MODEL: Partial liver IRI was induced in C57BL/6-mice by transient clamping of the left lateral and median liver lobes for 35 (n = 8), 45 (n = 6), 60 (n = 17), or 90 minutes (n = 5). For comparison, healthy C57BL/6-mice were examined as controls (n = 9). FIELD STRENGTH/SEQUENCE: Functional liver MRI was performed on a 7T scanner using a respiratory-triggered multiecho spin-echo sequence. ASSESSMENT: Healthy control mice and mice with partial liver IRI on day 1 after surgery, and additionally on day 7 in a subgroup with 60 minutes IRI (n = 8) were examined. Maps of T2 relaxation time of liver tissue were used to assess distribution, severity of tissue edema (mean T2 time), and the percentage of edematous liver tissue. STATISTICAL TEST: One-way analysis of variance (ANOVA) with Tukey's honest significant difference (HSD), paired t-tests, Pearson's test for correlation of MRI parameters with levels of liver enzymes, and histopathology, receiver operating characteristic (ROC) analysis. RESULTS: Significant tissue edema induced by liver IRI as compared to the control group was detected by increased mean T2 times in groups with 60 minutes (P < 0.001) and 90 minutes IRI (P < 0.001). The percentage of edematous liver tissue significantly increased with longer ischemia times (controls 3.4 ± 0.4%, 35 minutes 5.3 ± 0.6%, 45 minutes 23.3 ± 7.6%, 60 minutes 39.7 ± 3.6%, 90 minutes 51.3 ± 4.5%). Mean T2 times and the percentage of edematous liver tissue significantly correlated with elevation of liver enzymes (P < 0.001), histological evidence of liver injury (r = 0.80 and r = 0.82, P < 0.001), and neutrophil infiltration (r = 0.70 and r = 0.74, P < 0.001). In the subgroup with follow-up, the severity (P < 0.01) and extent of liver edema decreased significantly over time (P < 0.01). DATA CONCLUSION: T2 mapping allows quantification and follow-up of liver injury in mice. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:1586-1594.

T2 Mapping for Noninvasive Assessment of Interstitial Edema in Acute Cardiac Allograft Rejection in a Mouse Model of Heterotopic Heart Transplantation.

OBJECTIVES: Heart transplantation (HTX) in mice is used to characterize gene-deficient mice and to test new treatment strategies. The purpose was to establish noninvasive magnetic resonance imaging techniques in mice to monitor pathophysiological changes of the allograft during rejection. MATERIALS AND METHODS: Magnetic resonance imaging was performed at baseline and days 1 and 6 after isogenic (n = 10, C57BL/6) and allogenic (n = 12, C57BL/6 to BALB/c) heterotopic HTX on a 7 T small animal scanner. Respiratory- and electrocardiogram-gated multislice multi-echo spin echo sequences were acquired, and parameter maps of T2 relaxation time were generated. T2 times in septal, anterior, lateral, and posterior myocardial segments as well as global T2 times were calculated and compared between groups. At day 7 animals were sacrificed and graft pathology was assessed by semiquantitative regional analysis and correlated with magnetic resonance imaging results. RESULTS: Myocardial T2 relaxation time was significantly increased in allogenic (33.4 ± 0.1 ms) and isogenic cardiac grafts (31.8 ± 1.8 ms) on day 1 after HTX compared with healthy donor hearts at baseline (23.1 ± 0.3 ms, P < 0.001). Until day 6 after HTX, myocardial T2 further increased markedly in allografts but not in isografts (43.4 ± 1.9 vs 31.2 ± 1.1 ms, P < 0.001). Mean segmental T2 values as well as mean global T2 values in allogenic compared with isogenic cardiac grafts on day 6 were significantly higher (P < 0.01). Histologically, isogenic grafts were almost normal besides small focal leukocyte infiltrates and signs of interstitial edema, most likely due to ischemia reperfusion injury (histological sum score, 0.9 ± 0.4). In allogenic HTX, histology revealed severe inflammation and tissue edema representing allograft rejection with increased histological scores (5.3 ± 0.7, P < 0.001). Higher histological scores of rejection were significantly associated with increased T2 times on a segmental and a global level. CONCLUSIONS: We could show that T2 mapping is a suitable noninvasive imaging method to monitor global and regional HTX pathologies in experimental heart transplantation in mice. Progressive prolongation of T2 time was significantly associated with pathological signs of rejection.

Assessment of acute kidney injury with T1 mapping MRI following solid organ transplantation.

OBJECTIVES: To evaluate T1 mapping as a non-invasive, functional MRI biomarker in patients shortly after solid organ transplantation to detect acute postsurgical kidney damage and to correlate T1 times with renal function. METHODS: 101 patients within 2 weeks after solid organ transplantation (49 kidney transplantation, 52 lung transplantation) and 14 healthy volunteers were examined by MRI between July 2012 and April 2015 using the modified Look-Locker inversion recovery (MOLLI) sequence. T1 times in renal cortex and medulla and the corticomedullary difference were compared between groups using one-way ANOVA adjusted for multiple comparison with the Tukey test, and T1 times were correlated with renal function using Pearson's correlation. RESULTS: Compared to healthy volunteers T1 times were significantly increased after solid organ transplantation in the renal cortex (healthy volunteers 987 ± 102 ms; kidney transplantation 1299 ± 101 ms, p < 0.001; lung transplantation 1058 ± 96 ms, p < 0.05) and to a lesser extent in the renal medulla. Accordingly, the corticomedullary difference was diminished shortly after solid organ transplantation. T1 changes were more pronounced following kidney compared to lung transplantation, were associated with the stage of renal impairment and significantly correlated with renal function. CONCLUSIONS: T1 mapping may be helpful for early non-invasive assessment of acute kidney injury and renal pathology following major surgery such as solid organ transplantation. KEY POINTS: • Renal cortical T1 relaxation times are prolonged after solid organ transplantation. • Cortical T1 values increase with higher stages of renal function impairment. • Corticomedullary difference decreases with higher stages of renal function impairment. • Renal cortical T1 relaxation time and corticomedullary difference correlate with renal function. • T1 mapping may be helpful for non-invasive assessment of post-operative renal pathology.

Kidney Transplantation: Multiparametric Functional Magnetic Resonance Imaging for Assessment of Renal Allograft Pathophysiology in Mice.

OBJECTIVES: The aims of this experimental study were to investigate renal allograft pathophysiology by multiparametric functional magnetic resonance imaging (MRI) and to directly correlate MRI parameters with renal histopathology in mouse models of allogenic and isogenic kidney transplantation (ktx). MATERIALS AND METHODS: Allograft rejection was induced by transplantation of C57BL/6 (B6) donor kidneys into BALB/c recipients (allogenic ktx). B6 mice that received B6 kidneys served as controls (isogenic ktx). Three weeks after ktx, MRI was performed using a 7-T small-animal scanner. Flow sensitive alternating inversion recovery echoplanar imaging arterial spin labeling, multiecho turbo spin echo, and diffusion-weighted imaging sequences were acquired. Maps of renal perfusion, T2 and T1 relaxation times, and apparent diffusion coefficients were calculated. Histological changes in the kidney were evaluated according to Banff criteria. Renal cell infiltrates and fibrosis were quantified by immunohistochemistry. Differences between groups were assessed using the Mann-Whitney U test, and the correlation of MRI parameters with renal histopathology was determined by Spearman correlation analysis. RESULTS: After allogenic, but not isogenic, ktx, animals developed acute allograft rejection. Allogenic grafts were infiltrated by macrophages and T-lymphocytes and exhibited marked renal fibrosis. Magnetic resonance imaging revealed stronger impairment of renal perfusion (56 ± 7 vs 293 ± 44 mL/[min × 100 g]; P < 0.01) and more pronounced increases in T2 (60.1 ± 2.0 vs 45.7 ± 1.2 milliseconds, P < 0.01) and T1 relaxation times (1938 ± 53 vs 1350 ± 27 milliseconds, P < 0.01) in allogenic than in isogenic kidneys. Apparent diffusion coefficient was reduced to 1.39 ± 0.14 × 10(-3) mm2/s in kidneys with an acute rejection and was 1.83 ± 0.05 × 10(-3) mm2/s in isogenic kidneys without rejection (P < 0.05). Magnetic resonance imaging parameters significantly correlated with the amount of cellular infiltration and renal fibrosis observed histologically. CONCLUSIONS: Functional MRI allows detection of acute renal allograft rejection after allogenic ktx in mice. Functional MRI parameters correlate with cell infiltrates and fibrosis. Thus, MRI may be used noninvasively and longitudinally to investigate mechanisms of renal allograft rejection and evaluate novel therapeutic strategies in experimental studies.

T1-mapping for assessment of ischemia-induced acute kidney injury and prediction of chronic kidney disease in mice.

OBJECTIVES: To investigate whether T1-mapping allows assessment of acute kidney injury (AKI) and prediction of chronic kidney disease (CKD) in mice. METHODS: AKI was induced in C57Bl/6N mice by clamping of the right renal pedicle for 35 min (moderate AKI, n = 26) or 45 min (severe AKI, n = 23). Sham animals served as controls (n = 9). Renal histology was assessed in the acute (day 1 + day 7; d1 + d7) and chronic phase (d28) after AKI. Furthermore, longitudinal MRI-examinations (prior to until d28 after surgery) were performed using a 7-Tesla magnet. T1-maps were calculated from a fat-saturated echoplanar inversion recovery sequence, and mean and relative T1-relaxation times were determined. RESULTS: Renal histology showed severe tubular injury at d1 + d7 in both AKI groups, whereas, at d28, only animals with prolonged 45-min ischemia showed persistent signs of AKI. Following both AKI severities T1-values significantly increased and peaked at d7. T1-times in the contralateral kidney without AKI remained stable. At d7 relative T1-values in the outer stripe of the outer medulla were significantly higher after severe than after moderate AKI (138 ± 2% vs. 121 ± 3%, p = 0.001). T1-elevation persisted until d28 only after severe AKI. Already at d7 T1 in the outer stripe of the outer medulla correlated with kidney volume loss indicating CKD (r = 0.83). CONCLUSION: T1-mapping non-invasively detects AKI severity in mice and predicts further outcome. KEY POINTS: Renal T1-relaxation times are increased after ischemia-induced acute kidney injury. Renal T1-values correlate with subsequent kidney volume loss. T1-mapping detects the severity of acute kidney injury and predicts further outcome.

Assessment of impaired vascular reactivity in a rat model of diabetic nephropathy: effect of nitric oxide synthesis inhibition on intrarenal diffusion and oxygenation measured by magnetic resonance imaging.

Diabetes is associated with impaired vascular reactivity and the development of diabetic nephropathy. In a rat model of streptozotocin-induced diabetic nephropathy, the effects of systemic nitric oxide (NO) synthesis inhibition on intrarenal diffusion and oxygenation were determined by noninvasive magnetic resonance diffusion tensor imaging and blood O2 level-dependent (BOLD) imaging, respectively. Eight weeks after the induction of diabetes, 21 rats [n = 7 rats each in the untreated control group, diabetes mellitus (DM) group, and DM with uninephrectomy (DM UNX) group] were examined by MRI. Diffusion tensor imaging and BOLD sequences were acquired before and after NO synthesis inhibition with N-nitro-L-arginine methyl ester (L-NAME). In the same rats, mean arterial pressure and vascular conductance were determined with and without the influence of L-NAME. In control animals, NO synthesis inhibition was associated with a significant increase of mean arterial pressure of 33.8 ± 4.3 mmHg (P < 0.001) and a decrease of vascular conductance of -17.8 ± 2.0 µl·min(-1)·100 mmHg(-1) (P < 0.001). These changes were attenuated in both DM and DM UNX groups with no significant difference between before and after L-NAME measurements in DM UNX animals. Similarly, L-NAME challenge induced a significant reduction of renal transverse relaxation time (T2*) at MRI in control animals, indicating reduced renal oxygenation after L-NAME injection compared with baseline. DM UNX animals did not show a significant T2* reduction after NO synthesis inhibition in the renal cortex and attenuated T2* reduction in the outer medulla. MRI parameters of tissue diffusion were not affected by L-NAME in all groups. In conclusion, BOLD imaging proved valuable to noninvasively measure renal vascular reactivity upon NO synthesis inhibition in control animals and to detect impaired vascular reactivity in animals with diabetic nephropathy.

T2 relaxation time and apparent diffusion coefficient for noninvasive assessment of renal pathology after acute kidney injury in mice: comparison with histopathology.

INTRODUCTION: Renal ischemia reperfusion injury leads to acute kidney injury (AKI) and is associated with tissue edema, inflammatory cell infiltration, and subsequent development of interstitial renal fibrosis and tubular atrophy. The purpose of this study was to investigate the value of the functional magnetic resonance imaging (MRI) techniques, T2 mapping, and diffusion-weighted imaging (DWI) in characterizing acute and chronic pathology after unilateral AKI in mice. MATERIALS AND METHODS: Moderate or severe AKIs were induced in C57Bl/6 mice through transient unilateral clamping of the renal pedicle for 35 minutes (moderate AKI) or 45 minutes (severe AKI), respectively. Magnetic resonance imaging was performed in 10 animals with moderate AKI and 7 animals with severe AKI before surgery and at 5 time points thereafter (days 1, 7, 14, 21, 28) using a 7-T magnet. Fat-saturated T2-weighted images, multiecho turbo spin echo, and diffusion-weighed sequences (7 b values) were acquired in matching coronal planes. Parameter maps of T2 relaxation time and apparent diffusion coefficient (ADC) were calculated, and mean values were determined for the renal cortex, the outer medulla, and the inner medulla. Inflammatory cell infiltration with monocytes/macrophages (F4/80), T-lymphocytes (CD4, CD8), and dendritic cells (CD11c) as well as the degree of interstitial fibrosis 4 weeks after AKI were determined through renal histology and immunohistochemistry. Statistical analysis comprised unpaired t tests for group comparisons and correlation analysis between MRI parameters and kidney volume loss. RESULTS: Increase of T2 relaxation time, indicating tissue edema, was most pronounced in the outer medulla and reached maximum values at d7 after AKI. At this time point, T2 values in the outer medulla were significantly increased to 53.8 ± 2.5 milliseconds after the severe AKI and to 46.3 ± 2.3 milliseconds after the moderate AKI when compared with the respective contralateral normal kidneys (40.9 ± 0.9 and 36.4 ± 1.2 milliseconds, respectively; P < 0.01). The T2 values reached baseline by d28. Medullary ADC was significantly reduced at all time points after AKI; restriction of diffusion was significantly more pronounced after the severe AKI than after the moderate AKI at d14 and d28. Changes of renal T2 and ADC values were associated with the severity of AKI as well as the degree of inflammatory cell infiltration and interstitial renal fibrosis 4 weeks after AKI. Furthermore, relative changes of both MRI parameters significantly correlated with kidney volume loss 4 weeks after AKI. DISCUSSION: Measuring T2 and ADC values through MRI is a noninvasive way to determine the presence and severity of acute and chronic renal changes after AKI in mice. Thus, the method should prove useful in animal and human clinical studies.