Lumacaftor/ivacaftor therapy is associated with reduced hepatic steatosis in cystic fibrosis patients.

BACKGROUND: Hepatic steatosis is a common form of cystic fibrosis associated liver disease (CFLD) seen in an estimated 15%-60% of patients with cystic fibrosis (CF). The pathophysiology and health implications of hepatic steatosis in cystic fibrosis remain largely unknown. In the general population, hepatic steatosis is strongly associated with insulin resistance and type 2 diabetes. Cystic fibrosis related diabetes (CFRD) impacts 40%-50% of CF adults and is characterized by both insulin insufficiency and insulin resistance. We hypothesized that patients with CFRD would have higher levels of hepatic steatosis than cystic fibrosis patients without diabetes. AIM: To determine whether CFRD is associated with hepatic steatosis and to explore the impact of lumacaftor/ivacaftor therapy on hepatic steatosis in CF. METHODS: Thirty patients with CF were recruited from a tertiary care medical center for this cross-sectional study. Only pancreatic insufficient patients with CFRD or normal glucose tolerance (NGT) were included. Patients with established CFLD, end stage lung disease, or persistently elevated liver enzymes were excluded. Mean magnetic resonance imaging (MRI) proton density fat fraction (PDFF) was obtained for all participants. Clinical characteristics [age, sex, body mass index, percent predicted forced expiratory volume at 1 s (FEV1), lumacaftor/ivacaftor use] and blood chemistries were assessed for possible association with hepatic steatosis. Hepatic steatosis was defined as a mean MRI PDFF > 5%. Patients were grouped by diabetes status (CFRD, NGT) and cystic fibrosis transmembrane conductance regulator (CFTR) modulator use (lumacaftor/ivacaftor, no lumacaftor/ivacaftor) to determine between group differences. Continuous variables were analyzed with a Wilcoxon rank sum test and discrete variables with a Chi square test or Fisher's exact test. RESULTS: Twenty subjects were included in the final analysis. The median age was 22.3 years (11.3-39.0) and median FEV1 was 77% (33%-105%). Twelve subjects had CFRD and 8 had NGT. Nine subjects were receiving lumacaftor/ivacaftor. The median PDFF was 3.0% (0.0%-21.0%). Six subjects (30%) had hepatic steatosis defined as PDFF > 5%. Hepatic fat fraction was significantly lower in patients receiving lumacaftor/ivacaftor (median, range) (2.0%, 0.0%-6.4%) than in patients not receiving lumacaftor/ivacaftor (4.1%, 2.7-21.0%), P = 0.002. Though patients with CFRD had lower PDFF (2.2%, 0.0%-14.5%) than patients with NGT (4.9%, 2.4-21.0%) this did not reach statistical significance, P = 0.06. No other clinical characteristic was strongly associated with hepatic steatosis. CONCLUSION: Use of the CFTR modulator lumacaftor/ivacaftor was associated with significantly lower hepatic steatosis. No association between CFRD and hepatic steatosis was found in this cohort.

Diffusion tensor imaging MRI of sickle cell kidney disease: initial results and comparison with iron deposition.

Chronic kidney disease (CKD) occurs in over one-third of patients with sickle cell disease (SCD) and can progress to end-stage renal disease. Unfortunately, current clinical assessments of kidney function are insensitive to early-stage CKD. Previous studies have shown that diffusion magnetic resonance imaging (MRI) can sensitively detect regional renal microstructural changes associated with early-stage CKD. However, previous MRI studies in patients with SCD have been largely limited to the detection of renal iron deposition assessed by T2 * relaxometry. In this pilot imaging study, we compare MRI assessments of renal microstructure (diffusion) and iron deposition (T2 *) in patients with SCD and in non-SCD control subjects. Diffusion tensor imaging (DTI) and T2 * relaxometry MRI data were obtained for pediatric (n = 5) and adult (n = 4) patients with SCD, as well as for non-SCD control subjects (n = 10), on a Siemens Espree 1.5-T MRI scanner. A region-of-interest analysis was used to calculate mean medullary and cortical values for each MRI metric. MRI findings were also compared with clinical assessments of renal function and hemolysis. Patients with SCD showed a significant decrease in medullary fractional anisotropy (FA, p = 0.0001) in comparison with non-SCD subjects, indicative of microstructural alterations in the renal medulla of patients with SCD. Cortical and medullary reductions in T2 * (increased iron deposition, p = ≤0.0001) were also observed. Significant correlations were also observed between kidney T2 * assessments and multiple measures of hemolysis. This is the first DTI MRI study of patients with SCD to demonstrate reductions in medullary FA despite no overt CKD [estimated glomerular filtration rate (eGFR) > 100 mL/min/1.73 m2 ]. These medullary FA changes are consistent with previous studies in patients with CKD, and suggest that DTI MRI can provide a useful measure of kidney injury to complement MRI assessments of iron deposition.

Dual Contrast - Magnetic Resonance Fingerprinting (DC-MRF): A Platform for Simultaneous Quantification of Multiple MRI Contrast Agents.

Injectable Magnetic Resonance Imaging (MRI) contrast agents have been widely used to provide critical assessments of disease for both clinical and basic science imaging research studies. The scope of available MRI contrast agents has expanded over the years with the emergence of molecular imaging contrast agents specifically targeted to biological markers. Unfortunately, synergistic application of more than a single molecular contrast agent has been limited by MRI's ability to only dynamically measure a single agent at a time. In this study, a new Dual Contrast - Magnetic Resonance Fingerprinting (DC - MRF) methodology is described that can detect and independently quantify the local concentration of multiple MRI contrast agents following simultaneous administration. This "multi-color" MRI methodology provides the opportunity to monitor multiple molecular species simultaneously and provides a practical, quantitative imaging framework for the eventual clinical translation of molecular imaging contrast agents.

Intrarenal Injection of Escherichia coli in a Rat Model of Pyelonephritis.

Pyelonephritis is a bacterial infection of the kidney and is most commonly caused by Escherichia coli. Recurrent infections can cause significant renal inflammation and fibrosis ultimately resulting in declining kidney function. Before improved clinical management and prevention of pyelonephritis can be instituted, a reliable animal model must be established in order to study the mechanisms of progression, recurrence, and therapeutic efficacy. The transurethral infection model closely mimics human pyelonephritis but exhibits considerable variation due to its reliance on urethral reflux to transport the bacteria to the kidney. Herein, a detailed surgical protocol for performing bacterial injections into the rat renal pelvis is provided and confirmed by non-invasive Magnetic Resonance Imaging (MRI). Using this protocol, animals receive direct exposure to a desired concentration of E. coli bacteria and can fully recover from the surgical procedure with adequate post-operative care. This facilitates subsequent longitudinal MRI assessments of the experimental animal models for comparison with saline (sham) controls. Using this direct delivery approach, the severity of infection is controllable and applicable for mechanistic studies of progression as well as development of novel treatment strategies.

Preliminary comparison of normalized T1 and non-contrast perfusion MRI assessments of regional lung disease in cystic fibrosis patients.

BACKGROUND: Previous studies have shown that Magnetic Resonance Imaging (MRI) techniques can be used to non-invasively assess lung disease in CF patients. In this study, we compare the sensitivity of normalized T1 (nT1) and non-contrast perfusion MRI techniques to detect regional lung disease in CF patients. MATERIALS AND METHODS: MRI data were obtained for eight adult CF patients without overt pulmonary exacerbation (FEV1=45-127%) and six healthy volunteers on a Siemens Espree 1.5T MRI scanner. Sagittal nT1 and perfusion data were acquired for each subject's left and right lungs. A region-of-interest analysis was used to calculate mean nT1 and perfusion values in the individual lobes of the left and right lungs for each subject. RESULTS: In comparison to healthy controls, CF subjects showed a significant decrease in nT1 values in the upper lobe of the left lung as well as in the upper and anterior lobes of the right lung (p<0.001). Similar nT1 differences were observed with in the CF cohort in comparison to their respective posterior lobes (p<0.001). Pulmonary perfusion for the CF subjects was also significantly reduced in the upper lobe of the right lung (p<0.05). Significant correlations with spirometry were also observed for both nT1 (left upper lobe: p<0.01) and perfusion (left and right upper lobes (p≤0.05)). Additionally, significant correlations were observed between nT1 and perfusion in the upper lobes of the left (p=0.05) and right lungs (p=0.005). CONCLUSIONS: This pilot study confirms that both the nT1 and non-contrast perfusion MRI techniques can sensitively detect regional lung changes in patients with CF. While both imaging methods were able to detect regional lung disease, the additional nT1 reductions in the CF patients suggests that nT1 may be more sensitive to regional CF lung disease.

Lipid elimination with an echo-shifting N/2-ghost acquisition (LEENA) MRI.

PURPOSE: The Dixon techniques provide uniform water-fat separation but require multiple image sets, which extend the overall acquisition time. Here, an alternative rapid single acquisition method, lipid elimination with an echo-shifting N/2-ghost acquisition (LEENA), was introduced. METHODS: The LEENA method utilized a fast imaging with steady-state free precession sequence to obtain a single k-space dataset in which successive k-space lines are acquired to allow the fat magnetization to precess 180°. The LEENA data were then unghosted using either image-domain (LEENA-S) or k-space domain (LEENA-G) parallel imaging techniques to reconstruct water-only and fat-only images. An off-resonance correction technique was incorporated to improve the uniformity of the water-fat separation. RESULTS: Uniform water-fat separation was achieved for both the LEENA-S and LEENA-G methods for phantom and human body and leg imaging applications at 1.5T and 3T. The resultant water and fat images were qualitatively similar to conventional 2-point Dixon and fat-suppressed images. CONCLUSION: The LEENA-S and LEENA-G methods provide uniform water and fat images from a single MRI acquisition. These straightforward methods can be adapted to 1.5T and 3T clinical MRI scanners and provide comparable fat/water separation with conventional 2-point Dixon and fat-suppression techniques.