Renal ischemia-reperfusion injury causes hypertension and renal perfusion impairment in the CD1 mice which promotes progressive renal fibrosis.

Renal ischemia-reperfusion injury (IRI) is a severe complication of major surgery and a risk factor for increased morbidity and mortality. Here, we investigated mechanisms that might contribute to IRI-induced progression to chronic kidney disease (CKD). Acute kidney injury (AKI) was induced by unilateral IRI for 35 min in CD1 and C57BL/6 (B6) mice. Unilateral IRI was used to overcome early mortality. Renal morphology, NGAL upregulation, and neutrophil infiltration as well as peritubular capillary density were studied by immunohistochemistry. The composition of leukocyte infiltrates in the kidney after IRI was investigated by flow cytometry. Systemic blood pressure was measured with a tail cuff, and renal perfusion was quantified by functional magnetic resonance imaging (fMRI). Mesangial matrix expansion was assessed by silver staining. Following IRI, CD1 and B6 mice developed similar morphological signs of AKI and increases in NGAL expression, but neutrophil infiltration was greater in CD1 than B6 mice. IRI induced an increase in systemic blood pressure of 20 mmHg in CD1, but not in B6 mice; and CD1 mice also had a greater loss of renal perfusion and kidney volume than B6 mice ( P < 0.05). CD1 mice developed substantial interstitial fibrosis and decreased peritubular capillary (PTC) density by day 14 while B6 mice showed only mild renal scarring and almost normal PTC. Our results show that after IRI, CD1 mice develop more inflammation, hypertension, and later mesangial matrix expansion than B6 mice do. Subsequently, CD1 animals suffer from CKD due to impaired renal perfusion and pronounced permanent loss of peritubular capillaries.

Patterns of relapse as determined by 68Ga-PSMA ligand PET/CT after radical prostatectomy : Importance for tailoring and individualizing treatment.

PURPOSE: To evaluate the patterns of relapse and impact on the intended treatment when using 68Ga-prostate-specific membrane antigen (PSMA) ligand positron emission tomography/computed tomography (PET/CT) imaging for restaging of disease in patients with biochemical relapse after radical prostatectomy (RP) before salvage radiotherapy (sRT). METHODS: In all, 39 patients with biochemical recurrence after RP who had no primary indication for adjuvant RT due to the absence of biologically unfavorable disease (e.g., extracapsular extension, seminal vesicle invasion, positive margins, or lymph node involvement) underwent a 68Ga-PSMA ligand PET/CT for planning of sRT. RESULTS: PET/CT was positive in 84.6% (33/39) of patients. A total of 61 lesions were observed in these patients (on average 1.8 lesions per patient); 30.3% (10/33) of patients had locally recurrent disease in the prostatic bed. The clinical TNM stage (TNM: tumour-lymph nodes-metastasis-classification) was altered in 69.7% (23/33) of patients following PET, resulting in individualized treatment concepts. A prostate-specific antigen (PSA) >1.0 ng/mL was significantly associated with an increased risk of extrapelvic metastatic disease (p = 0.048). The PSA level at the time of PSMA ligand PET/CT correlated with the peak standardized uptake value (SUVpeak; p = 0.002). According to current clinical guidelines, the remaining 15.4% (6/39) of patients without evidence of disease on PET received sRT with a dose of 66.0 Gy. CONCLUSION: Our results suggest that in patients with biochemical recurrence who did not receive early sRT, a 68Ga-PSMA ligand PET/CT for restaging of disease allows for tailoring and individualizing treatment. Particularly in patients with PSA levels above 1.0 ng/mL, a 68Ga-PSMA ligand PET/CT should be performed for therapy planning, since patients often have metastases not confined to the pelvis.

PSA-stratified detection rates for [68Ga]THP-PSMA, a novel probe for rapid kit-based 68Ga-labeling and PET imaging, in patients with biochemical recurrence after primary therapy for prostate cancer.

PURPOSE: [68Ga]Tris(hydroxypyridinone)(THP)-PSMA is a novel radiopharmaceutical for one-step kit-based radiolabelling, based on direct chelation of 68Ga3+ at low concentration, room temperature and over a wide pH range, using direct elution from a 68Ge/68Ga-generator. We evaluated the clinical detection rates of [68Ga]THP-PSMA PET/CT in patients with biochemically recurrent prostate cancer after prostatectomy. METHODS: Consecutive patients (n=99) referred for evaluation of biochemical relapse of prostate cancer by [68Ga]THP-PSMA PET/CT were analyzed retrospectively. Patients underwent a standard whole-body PET/CT (1 h p.i.), followed by delayed (3 h p.i.) imaging of the abdomen. PSA-stratified cohorts of positive PET/CT results, standardized uptake values (SUVs) and target-to-background ratios (TBRs) were analyzed, and compared between standard and delayed imaging. RESULTS: At least one lesion suggestive of recurrent or metastatic prostate cancer was identified on PET images in 52 patients (52.5%). Detection rates of [68Ga]THP-PSMA PET/CT increased with increasing PSA level: 94.1% for a PSA value of ≥10 ng/mL, 77.3% for a PSA value of 2 to <10 ng/mL, 54.5% for a PSA value of 1 to <2 ng/mL, 14.3% for a PSA value of 0.5 to <1 ng/mL, 20.0% for a PSA value of >0.2 to <0.5, and 22.2% for a PSA value of 0.01 to 0.2 ng/mL. [68Ga]THP-PSMA uptake (SUVs) in metastases decreased over time, whereas TBRs improved. Delayed imaging at 3 h p.i. exclusively identified pathologic findings in 2% of [68Ga]THP-PSMA PET/CT scans. Detection rate was higher in patients with a Gleason score ≥8 (P=0.02) and in patients receiving androgen deprivation therapy (P=0.003). CONCLUSIONS: In this study, [68Ga]THP-PSMA PET/CT showed suitable detection rates in patients with biochemical recurrence of prostate cancer and PSA levels ≥ 2 ng /mL. Detections rates were lower than in previous studies evaluating other PSMA ligands, though prospective direct radiotracer comparison studies are mandatory particularly in patients with low PSA levels to evaluate the relative performance of different PSMA ligands.

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.

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 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.

Longitudinal evaluation of perfusion changes in acute and chronic renal allograft rejection using arterial spin labeling in translational mouse models.

PURPOSE: To examine the longitudinal changes of renal perfusion due to acute and chronic renal allograft rejection by using arterial spin labeling (ASL) MRI in translational mouse models of isogenic and allogenic kidney transplantation (ktx). MATERIALS AND METHODS: Acute rejection was induced by allogenic ktx of C57BL/6 (B6)-kidney grafts to BALB/c-recipients with prolonged cold ischemia (CIT) of 60 minutes (n = 13). To induce chronic rejection BALB/c-kidneys were transplanted into B6-recipients with short CIT of 30 minutes (n = 22). Isogenic grafts without rejection (n = 14 with prolonged, n = 9 with short CIT) and normal kidneys (n = 22) were used for comparison. Perfusion was measured on a 7T small-animal magnetic resonance imaging (MRI) scanner using flow-sensitive alternating inversion recovery (FAIR) ASL-sequences at day 1 and 6 (acute) or at week 3 and 6 (chronic) after surgery. Histological analyses of grafts included inflammation, vascular changes, and fibrosis. RESULTS: In the acute ktx model, ASL showed perfusion impairment in isogenic and allogenic kidney grafts. Perfusion of allografts further decreased until day 6 and remained stable in isografts without rejection (allogenic ktx 62 ± 21 vs. isogenic ktx 181 ± 39 ml/min/100g, P < 0.01). In the chronic ktx model, perfusion in isografts was similar to normal kidneys over the entire observation period. Perfusion was severely reduced in allografts compared to isografts (week 3: 28 ± 7 vs. 310 ± 46 ml/min/100g, P < 0.001, week 6: 32 ± 5 vs. 367 ± 72 ml/min/100g, P < 0.001). Histological analysis revealed severe inflammation, vascular occlusion, and rejection in allografts. Chronic rejection grafts showed endothelialitis, peritubular capillaritis, interstitial fibrosis, and tubular atrophy. CONCLUSION: ASL allows longitudinal assessment of renal perfusion impairment due to acute and chronic renal allograft rejection in translational mouse models. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017;46:1664-1672.

Diffusion-Weighted imaging and diffusion tensor imaging detect delayed graft function and correlate with allograft fibrosis in patients early after kidney transplantation.

PURPOSE: To combine diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI) for detection of allograft dysfunction in patients early after kidney transplantation and to correlate diffusion parameters with renal function and renal histology of allograft biopsies. MATERIALS AND METHODS: Between day 4 and 11 after kidney transplantation 33 patients with initial graft function and 31 patients with delayed graft function (DGF) were examined with a 1.5T magnetic resonance imaging (MRI) scanner. DTI and DWI sequences were acquired and fractional anisotropy (FA), apparent diffusion coefficient (ADCmono), pure diffusion (ADCdiff ), and the perfusion fraction (Fp) were calculated. Kidney biopsies in 26 patients were analyzed for allograft pathology, ie, acute tubular injury, inflammation, edema, renal fibrosis, and rejection. Histological results were correlated with MRI parameters. RESULTS: In the renal medulla FA (0.25 ± 0.06 vs. 0.29 ± 0.06, P < 0.01) and ADCmono (1.73 ± 0.13*10(-3) vs. 1.93 ± 0.16*10(-3) mm(2) /s, P < 0.001) were significantly reduced in DGF patients compared with patients with initial function. For ADCdiff and Fp similar reductions were observed. FA and ADCmono significantly correlated with renal function (r = 0.53 and r = 0.57, P < 0.001) and were inversely correlated with the amount of renal fibrosis (r = -0.63 and r = -0.65, P < 0.05). CONCLUSION: Combined DTI and DWI detected allograft dysfunction early after kidney transplantation and correlated with allograft fibrosis. J. Magn. Reson. Imaging 2016;44:112-121.

Radiotherapy for isolated lymph node metastases in patients with locally advanced prostate cancer after primary therapy.

PURPOSE: To evaluate the outcome of radiotherapy for isolated lymph node metastases in patients with progression towards castration-resistant prostate cancer (CRPC) after definitive therapy. METHODS: Between 11/2009 and 06/2014, 18 patients with isolated lymph node metastases after definitive prostate cancer therapy received radiotherapy to the affected lymph nodes with a total dose of 50.4 or 54.0 Gray (Gy). All patients had continuously rising levels of PSA despite androgen deprivation therapy (ADT). Biochemical progression-free survival (BPFS), clinical failure-free survival (CFFS) and freedom from local failure were assessed, as was the toxicity profile. RESULTS: Of the 18 patients, 17 had high-risk prostate cancer. Radiotherapy was performed at a median interval of 64.55 [interquartile range (IQR) 23.2-153.8] months after definitive therapy. ADT was administered for a median (IQR) time of 3.8 (3.2-24.7) months prior to irradiation. The median (IQR) follow-up was 15.59 (5.3-28.5) months with 94.1 % freedom from local failure. The median BPFS and CFFS were 5.85 (IQR 3.0-20.3) and 9.60 months (IQR 5.9-28.8), respectively. No grade III acute or grade II late toxicity was observed. Only two patients developed local relapse. No patients exhibited deterioration of urinary or faecal continence. CONCLUSION: Radiotherapy of isolated lymph node metastases in patients who develop CRPC provides effective local control, is not associated with clinically important acute or long-term side effects, improves PSA kinetics and may delay the necessity of chemotherapy.

Pulmonary Microvascular Blood Flow in Mild Chronic Obstructive Pulmonary Disease and Emphysema. The MESA COPD Study.

RATIONALE: Smoking-related microvascular loss causes end-organ damage in the kidneys, heart, and brain. Basic research suggests a similar process in the lungs, but no large studies have assessed pulmonary microvascular blood flow (PMBF) in early chronic lung disease. OBJECTIVES: To investigate whether PMBF is reduced in mild as well as more severe chronic obstructive pulmonary disease (COPD) and emphysema. METHODS: PMBF was measured using gadolinium-enhanced magnetic resonance imaging (MRI) among smokers with COPD and control subjects age 50 to 79 years without clinical cardiovascular disease. COPD severity was defined by standard criteria. Emphysema on computed tomography (CT) was defined by the percentage of lung regions below -950 Hounsfield units (-950 HU) and by radiologists using a standard protocol. We adjusted for potential confounders, including smoking, oxygenation, and left ventricular cardiac output. MEASUREMENTS AND MAIN RESULTS: Among 144 participants, PMBF was reduced by 30% in mild COPD, by 29% in moderate COPD, and by 52% in severe COPD (all P < 0.01 vs. control subjects). PMBF was reduced with greater percentage emphysema-950HU and radiologist-defined emphysema, particularly panlobular and centrilobular emphysema (all P ≤ 0.01). Registration of MRI and CT images revealed that PMBF was reduced in mild COPD in both nonemphysematous and emphysematous lung regions. Associations for PMBF were independent of measures of small airways disease on CT and gas trapping largely because emphysema and small airways disease occurred in different smokers. CONCLUSIONS: PMBF was reduced in mild COPD, including in regions of lung without frank emphysema, and may represent a distinct pathological process from small airways disease. PMBF may provide an imaging biomarker for therapeutic strategies targeting the pulmonary microvasculature.

Functional MRI detects perfusion impairment in renal allografts with delayed graft function.

Delayed graft function (DGF) after kidney transplantation is not uncommon, and it is associated with long-term allograft impairment. Our aim was to compare renal perfusion changes measured with noninvasive functional MRI in patients early after kidney transplantation to renal function and allograft histology in biopsy samples. Forty-six patients underwent MRI 4-11 days after transplantation. Contrast-free MRI renal perfusion images were acquired using an arterial spin labeling technique. Renal function was assessed by estimated glomerular filtration rate (eGFR), and renal biopsies were performed when indicated within 5 days of MRI. Twenty-six of 46 patients had DGF. Of these, nine patients had acute rejection (including borderline), and eight had other changes (e.g., tubular injury or glomerulosclerosis). Renal perfusion was significantly lower in the DGF group compared with the group with good allograft function (231 ± 15 vs. 331 ± 15 ml·min(-1)·100 g(-1), P < 0.001). Living donor allografts exhibited significantly higher perfusion values compared with deceased donor allografts (P < 0.001). Renal perfusion significantly correlated with eGFR (r = 0.64, P < 0.001), resistance index (r = -0.57, P < 0.001), and cold ischemia time (r = -0.48, P < 0.01). Furthermore, renal perfusion impairment early after transplantation predicted inferior renal outcome and graft loss. In conclusion, noninvasive functional MRI detects renal perfusion impairment early after kidney transplantation in patients with DGF.

Targeted MRI/TRUS fusion-guided biopsy in men with previous prostate biopsies using a novel registration software and multiparametric MRI PI-RADS scores: first results.

PURPOSE: To evaluate a novel system for MRI/TRUS fusion-guided biopsy for detection of prostate cancer (PCa) in patients with previous negative prostate biopsy and determine diagnostic accuracy when using the Prostate Imaging Reporting and Data System (PI-RADS) for multiparametric magnetic resonance imaging (mpMRI) as proposed by the European Society of Urogenital Radiology. METHODS: Thirty-nine men with clinical suspicion of PCa and history of previous prostate biopsy underwent mpMRI on a 3-T MRI. In total, 72 lesions were evaluated by the consensus of two radiologists. PI-RADS scores for each MRI sequence, the sum of the PI-RADS scores and the global PI-RADS were determined. MRI/TRUS fusion-guided targeted biopsy was performed using the BioJet™ software combined with a transrectal ultrasound system. Image fusion was based on rigid registration. PI-RADS scores of the dominant lesion were compared with histopathological results. Diagnostic accuracy was determined using receiver operating characteristic curve analysis. RESULTS: MRI/TRUS fusion-guided biopsy was reliable and successful for 71 out of 72 lesions. The global PI-RADS score of the dominant lesion was significantly higher in patients with PCa (4.0 ± 1.3) compared to patients with negative histopathology (2.6 ± 0.8; p = 0.0006). Using a global PI-RADS score cut-off ≥4, a sensitivity of 85 %, a specificity of 82 % and a negative predictive value of 92 % were achieved. CONCLUSIONS: The described fusion system is dependable and efficient for targeted MRI/TRUS fusion-guided biopsy. mpMRI PI-RADS scores combined with a novel real-time MRI/TRUS fusion system facilitate sufficient diagnosis of PCa with high sensitivity and specificity.

Renal PKC-ε deficiency attenuates acute kidney injury and ischemic allograft injury via TNF-α-dependent inhibition of apoptosis and inflammation.

Acute kidney injury (AKI) increases the risk of morbidity and mortality after major surgery and transplantation. We investigated the effect of PKC-ε deficiency on AKI and ischemic allograft damage after kidney transplantation. PKC-ε-deficient and wild type (WT) control mice were subjected to 35 min of renal pedicle clamping to induce AKI. PKC-ε deficiency was associated with a marked improvement in survival and an attenuated loss of kidney function. Furthermore, functional MRI experiments revealed better renal perfusion in PKC-ε-deficient mice than in WT mice one day after IRI. Acute tubular necrosis and neutrophil infiltration were markedly reduced in PKC-ε-deficient mice. To determine whether this resistance to ischemia-reperfusion injury resulted from changes in local renal cells or infiltrating leukocytes, we studied a life-supporting renal transplant model of ischemic graft injury. We transplanted kidneys from H(2b) PKC-ε-deficient mice (129/SV) and their corresponding WT littermates into major histocompatibility complex-incompatible H(2d) recipients (BALB/c) and induced ischemic graft injury by prolonged cold ischemia time. Recipients of WT allografts developed severe renal failure and died within 10 days of transplantation. Recipients of PKC-ε-deficient allografts had better renal function and survival; they had less generation of ROS and upregulation of proinflammatory proteins (i.e., ICAM-1, inducible nitric oxide synthase, and TNF-α) and showed less tubular epithelial cell apoptosis and inflammation in their allografts. These data suggest that local renal PKC-ε expression mediates proapoptotic and proinflammatory signaling and that an inhibitor of PKC-ε signaling could be used to prevent hypoxia-induced AKI.

Acute kidney injury: arterial spin labeling to monitor renal perfusion impairment in mice-comparison with histopathologic results and renal function.

PURPOSE: To determine if arterial spin-labeling (ASL) magnetic resonance (MR) imaging can show serial changes in renal perfusion in mice with ischemia-induced acute kidney injury (AKI) and to compare imaging results with those of renal histologic examination and inulin and para-aminohippuric acid (PAH) clearance. MATERIALS AND METHODS: In this animal care committee-approved study, AKI was induced in C57Bl/6 mice (n = 26) by clamping the right renal pedicle for 35 minutes for moderate (n = 16) or 45 minutes (n = 11) for severe AKI. Renal perfusion was measured in 10 animals with moderate and seven animals with severe AKI before and at five time points 1-28 days after surgery by using ASL with a 7-T MR imaging unit. Kidney volume loss and histologic evidence of acute tubular injury were assessed. Inulin and PAH clearance was determined in four animals with moderate and six animals with severe AKI to evaluate renal function and plasma flow for statistical analysis. Repeated measures analysis of variance, unpaired t tests, and correlation analysis were used. RESULTS: Renal perfusion values at day 7 were significantly reduced after moderate (56% ± 8; P < .01) and severe (33% ± 6; P < .001) AKI compared with presurgery values. Renal perfusion had returned to baseline levels at day 21 after moderate (96% ± 14) and remained compromised until day 28 after severe (46 % ± 9; P < .05) AKI. At day 28, for moderate versus severe AKI, kidney volume (84% ± 6 vs 60% ± 5; P < .05), degree of tubular injury (5.6% ± 1.8 vs 15.8% ± 2.4; P < .01), and inulin and para-aminohippuric acid clearance (47.5 µL/min ± 5.6 vs 7.3 µL/min ± 2.7; P < .001 and 100.8 µL/min ± 24.3 vs 4.8 µL/min ± 1.0; P < .001, respectively) were significantly different. Relative renal perfusion at days 7-28 significantly correlated with kidney volume loss (P < .01) and tubular injury (P < .05) 4 weeks after AKI. CONCLUSION: ASL allows evaluation of renal perfusion impairment associated with kidney volume loss and histologic changes after AKI in mice and may serve as a noninvasive biomarker for AKI.

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.

Endothelial microparticles in mild chronic obstructive pulmonary disease and emphysema. The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease study.

RATIONALE: Basic research implicates alveolar endothelial cell apoptosis in the pathogenesis of chronic obstructive pulmonary disease (COPD) and emphysema. However, information on endothelial microparticles (EMPs) in mild COPD and emphysema is lacking. OBJECTIVES: We hypothesized that levels of CD31(+) EMPs phenotypic for endothelial cell apoptosis would be elevated in COPD and associated with percent emphysema on computed tomography (CT). Associations with pulmonary microvascular blood flow (PMBF), diffusing capacity, and hyperinflation were also examined. METHODS: The Multi-Ethnic Study of Atherosclerosis COPD Study recruited participants with COPD and control subjects age 50-79 years with greater than or equal to 10 pack-years without clinical cardiovascular disease. CD31(+) EMPs were measured using flow cytometry in 180 participants who also underwent CTs and spirometry. CD62E(+) EMPs phenotypic for endothelial cell activation were also measured. COPD was defined by standard criteria. Percent emphysema was defined as regions less than -950 Hounsfield units on full-lung scans. PMBF was assessed on gadolinium-enhanced magnetic resonance imaging. Hyperinflation was defined as residual volume/total lung capacity. Linear regression was used to adjust for potential confounding factors. MEASUREMENTS AND MAIN RESULTS: CD31(+) EMPs were elevated in COPD compared with control subjects (P = 0.03) and were notably increased in mild COPD (P = 0.03). CD31(+) EMPs were positively related to percent emphysema (P = 0.045) and were inversely associated with PMBF (P = 0.047) and diffusing capacity (P = 0.01). In contrast, CD62E(+) EMPs were elevated in severe COPD (P = 0.003) and hyperinflation (P = 0.001). CONCLUSIONS: CD31(+) EMPs, suggestive of endothelial cell apoptosis, were elevated in mild COPD and emphysema. In contrast, CD62E(+) EMPs indicative of endothelial activation were elevated in severe COPD and hyperinflation.

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.

Whole-body diffusion-weighted MRI in a case of Rosai-Dorfman disease with exclusive multifocal skeletal involvement.

Rosai-Dorfman disease (RDD) is a rare disorder and usually presents with painless bilateral cervical lymphadenopathy. About 43% of RDD patients show extranodal involvement, including bones (8%). As RDD is a systemic disease, which can involve lymph nodes, bones, skin, kidneys, respiratory tract, parotid gland, orbital cavity and the central nervous system, whole-body imaging may be useful for the assessment of extent, distribution and follow-up of disease. Whole-body diffusion-weighted MRI is able to demonstrate lesions and to assess therapy response without the need for radiation or intravenous contrast agent. Here, we report a case of a 15-year-old boy with primary skeletal RDD without lymphadenopathy, who was staged and followed by whole-body diffusion-weighted MRI.

Diffusion tensor imaging and tractography for assessment of renal allograft dysfunction-initial results.

OBJECTIVES: To evaluate MR diffusion tensor imaging (DTI) as non-invasive diagnostic tool for detection of acute and chronic allograft dysfunction and changes of organ microstructure. METHODS: 15 kidney transplanted patients with allograft dysfunction and 14 healthy volunteers were examined using a fat-saturated echo-planar DTI-sequence at 1.5 T (6 diffusion directions, b = 0, 600 s/mm²). Mean apparent diffusion coefficient (ADC) and mean fractional anisotropy (FA) were calculated separately for the cortex and for the medulla and compared between healthy and transplanted kidneys. Furthermore, the correlation between diffusion parameters and estimated GFR was determined. RESULTS: The ADC in the cortex and in the medulla were lower in transplanted than in healthy kidneys (p < 0.01). Differences were more distinct for FA, especially in the renal medulla, with a significant reduction in allografts (p < 0.001). Furthermore, in transplanted patients a correlation between mean FA in the medulla and estimated GFR was observed (r = 0.72, p < 0.01). Tractography visualized changes in renal microstructure in patients with impaired allograft function. CONCLUSIONS: Changes in allograft function and microstructure can be detected and quantified using DTI. However, to prove the value of DTI for standard clinical application especially correlation of imaging findings and biopsy results is necessary.