Liver and spleen volume and stiffness in patients post-Fontan procedure and patients with ARPKD compared to normal controls.

2022

147-154

07/2022

1873-4499

PURPOSE: Both congestive (patients post-Fontan hepatopathy) and congenital (patients with ARPKD) disease can lead to hepatic fibrosis and portal hypertension with eventual development of splenomegaly. We investigated liver and spleen stiffness as measured by MRE between post-Fontan, ARPKD patients and controls independent of organ volume.

METHODS: Our study included 122 subjects (70 Fontan patients, 14 ARPKD patients, and 38 controls). The mean MRE liver and spleen stiffness values of Fontan patients and patients with ARPKD were compared to controls. Similarly, the liver and spleen volumes of the Fontan patients and patients with ARPKD were then compared to the volumes of controls.

RESULTS: Post-Fontan and ARPKD patients, mean liver stiffness, mean liver volume as well as mean spleen stiffness and mean spleen volume were higher than mean liver stiffness, mean liver volume, mean spleen stiffness, and mean spleen volume of controls. While liver stiffness correlated to liver volume in controls, we found no correlation between stiffness and volume in either Fontan or ARPKD patients, which indicates MRE's ability to act as an independent biomarker. However, these findings are not true in the spleen, where there is significant association between volume and stiffness in patients with ARPKD, but not in Fontan patients or controls.

CONCLUSION: Liver and spleen stiffness and volumes are significantly different among Fontan patients, ARPKD patients, and controls. Our findings suggest that beyond diagnosing fibrosis, MRE cut-off values could be disease-specific since not only the severity but the underlying pathology causing organ congestion or fibrosis influences MRE results.

10.1016/j.clinimag.2022.06.022

Clin Imaging

35835018

Decreased Neural Connectivity in the Default Mode Network Among Youth and Young Adults With Chronic Kidney Disease.

2021

455-461

2021 Sep

1558-4488

<p>An increasing amount of literature has indicated that chronic kidney disease (CKD) is associated with cognitive deficits that increase with worsening disease severity. Although abnormalities in brain structure have been widely documented, few studies to date have examined the functioning of brain areas associated with the specific cognitive domains affected by CKD (namely, attention and executive functions). Furthermore, few studies have examined functional connectivity among CKD youth who are relatively early in the course of the disease. The present study used functional magnetic resonance imaging to examine the resting state connectivity in 67 youth with CKD (mean age, 17 y) and 58 age-matched healthy controls. Using seed-based multiple regression, decreased connectivity was observed within the anterior cingulate portion of the default mode network. In addition, decreased connectivity within the dorsolateral prefrontal cortex, paracingulate gyrus, and frontal pole were correlated significantly with disease severity. These data indicate that connectivity deficits in circuits implementing attentional processes may represent an early marker for cognitive decline in CKD.</p>

10.1016/j.semnephrol.2021.09.008

Semin Nephrol

34916007

Multi-parametric MRI of kidney disease progression for autosomal recessive polycystic kidney disease: mouse model and initial patient results.

2021

157-162

2021 01

1530-0447

<p><strong>BACKGROUND: </strong>Autosomal recessive polycystic kidney disease (ARPKD) is a rare but potentially lethal genetic disorder typically characterized by diffuse renal microcysts. Clinical trials for patients with ARPKD are not currently possible due to the absence of sensitive measures of ARPKD kidney disease progression and/or therapeutic efficacy.</p>

<p><strong>METHODS: </strong>In this study, animal and human magnetic resonance imaging (MRI) scanners were used to obtain quantitative kidney T1 and T2 relaxation time maps for both excised kidneys from bpk and wild-type (WT) mice as well as for a pediatric patient with ARPKD and a healthy adult volunteer.</p>

<p><strong>RESULTS: </strong>Mean kidney T1 and T2 relaxation times showed significant increases with age (p &lt; 0.05) as well as significant increases in comparison to WT mice (p &lt; 2 × 10). Significant or nearly significant linear correlations were observed for mean kidney T1 (p = 0.030) and T2 (p = 0.054) as a function of total kidney volume, respectively. Initial magnetic resonance fingerprinting assessments in a patient with ARPKD showed visible increases in both kidney T1 and T2 in comparison to the healthy volunteer.</p>

<p><strong>CONCLUSIONS: </strong>These preclinical and initial clinical MRI studies suggest that renal T1 and T2 relaxometry may provide an additional outcome measure to assess cystic kidney disease progression in patients with ARPKD.</p>

<p><strong>IMPACT: </strong>A major roadblock for implementing clinical trials in patients with ARPKD is the absence of sensitive measures of ARPKD kidney disease progression and/or therapeutic efficacy. A clinical need exists to develop a safe and sensitive measure for kidney disease progression, and eventually therapeutic efficacy, for patients with ARPKD. Mean kidney T1 and T2 MRI relaxation times showed significant increases with age (p &lt; 0.05) as well as significant increases in comparison to WT mice (p &lt; 2 ×10), indicating that T1 and T2 may provide sensitive assessments of cystic changes associated with progressive ARPKD kidney disease. This preclinical and initial clinical study suggests that MRI-based kidney T1 and T2 mapping could be used as a non-invasive assessment of ARPKD kidney disease progression. These non-invasive, quantitative MRI techniques could eventually be used as an outcome measure for clinical trials evaluating novel therapeutics aimed at limiting or preventing ARPKD kidney disease progression.</p>

10.1038/s41390-020-0883-9

Pediatr Res

32283547

Two-dimensional (2D) morphologic measurements can quantify the severity of liver disease in children with autosomal recessive polycystic kidney disease (ARPKD).

2021

2021 Jun 26

2366-0058

<p><strong>PURPOSE: </strong>To evaluate the correlation of 2D shape-based features with magnetic resonance elastography (MRE)-derived liver stiffness and portal hypertension (pHTN) in children with ARPKD-associated congenital hepatic fibrosis.</p>

<p><strong>METHODS: </strong>In a prospective IRB-approved study, 14 children with ARPKD (mean age ± SD = 13.8 ± 5.8&nbsp;years) and 14 healthy controls (mean age ± SD = 13.7 ± 3.9&nbsp;years) underwent liver MRE. A 2D region of interest (ROI) outlining the left liver lobe at the level of the abdominal aorta was drawn on sagittal T2-weighted images. Eight shape features (perimeter, major axis length, maximum diameter, perimeter to surface ratio (PSR), elongation, sphericity, minor axis length, and mesh surface) describing the 2D-ROI were calculated. Spearman's correlation was calculated between shape features and MRE-derived liver stiffness (kPa) (n = 28). Shape features were compared between participants with ARPKD with pHTN (splenomegaly and thrombocytopenia), (n = 4) and without pHTN (n = 8) using the Mann Whitney U test. Receiver operating characteristic (ROC) curves were generated to examine the diagnostic accuracy of shape features in identifying cases with liver stiffness &gt; 2.9&nbsp;kPa.</p>

<p><strong>RESULTS: </strong>In ARPKD participants and healthy controls, all eight shape features, except elongation, showed moderate to strong correlation with liver stiffness (kPa); the perimeter surface ratio had the strongest correlation (rho = - 0.75, p &lt; 0.001). In ROC analysis, a cut-off of PSR ≤ 0.057&nbsp;mm gave 100% (95% CI: 59.0-100.0) sensitivity and 100% (95% CI: 83.9-100.0) specificity in identifying ARPKD participants with liver stiffness &gt; 2.9&nbsp;kPa, with an area under the ROC curve (AUC) of 1.0 (95% CI: 0.88-1.00). Individuals with pHTN had a lower median PSR (mean ± SD = 0.05 ± 0.01) than those without (0.07 ± 0.01; p = 0.027) with an AUC of 0.91 (95% CI: 0.60-0.99) in differentiating the participants with and without pHTN.</p>

<p><strong>CONCLUSION: </strong>Shape-based features of the left liver lobe show potential as non-invasive biomarkers of liver fibrosis and portal hypertension in children with ARPKD.</p>

10.1007/s00261-021-03189-3

Abdom Radiol (NY)

34173844

Predictors of progression in autosomal dominant and autosomal recessive polycystic kidney disease.

2021

2021 Jan 21

1432-198X

<p>Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are characterized by bilateral cystic kidney disease leading to progressive kidney function decline. These diseases also have distinct liver manifestations. The range of clinical presentation and severity of both ADPKD and ARPKD is much wider than was once recognized. Pediatric and adult nephrologists are likely to care for individuals with both diseases in their lifetimes. This article will review genetic, clinical, and imaging predictors of kidney and liver disease progression in ADPKD and ARPKD and will briefly summarize pharmacologic therapies to prevent progression.</p>

10.1007/s00467-020-04869-w

Pediatr Nephrol

33474686

Ciliopathies: Coloring outside of the lines.

2020

2020 Dec 25

1552-4833

<p>Ciliopathy syndromes are a diverse spectrum of disease characterized by a combination of cystic kidney disease, hepatobiliary disease, retinopathy, skeletal dysplasia, developmental delay, and brain malformations. Though generally divided into distinct disease categories based on the pattern of system involvement, ciliopathy syndromes are known to display certain phenotypic overlap. We performed next-generation sequencing panel testing, clinical exome sequencing, and research-based exome sequencing reanalysis on patients with suspected ciliopathy syndromes with additional features. We identified biallelic pathogenic variants in BBS1 in a child with features of cranioectodermal dysplasia, and biallelic variants in BBS12 in a child with the clinical stigmata of Bardet-Biedl syndrome, but also with anal atresia. We additionally identified biallelic pathogenic variants in WDR35 and DYNC2H1 in children with predominant liver disease and ductal plate malformation without skeletal dysplasia. Our study highlights the phenotypic and genetic diversity of ciliopathy syndromes, the importance of considering ciliopathy syndromes as a disease-spectrum and screening for all associated complications in all patients, and describes exclusive extra-skeletal manifestations in two classical skeletal dysplasia syndromes.</p>

10.1002/ajmg.a.62013

Am J Med Genet A

33369054

Magnetic resonance elastography to quantify liver disease severity in autosomal recessive polycystic kidney disease.

2020

2020 Aug 05

2366-0058

<p><strong>OBJECTIVES: </strong>To evaluate whether liver and spleen magnetic resonance elastography (MRE) can measure the severity of congenital hepatic fibrosis (CHF) and portal hypertension (pHTN) in individuals with autosomal recessive polycystic kidney disease (ARPKD), and to examine correlations between liver MRE and ultrasound (US) elastography.</p>

<p><strong>METHODS: </strong>Cross-sectional study of nine individuals with ARPKD and 14 healthy controls. MRE was performed to measure mean liver and spleen stiffness (kPa); US elastography was performed to measure point shear wave speed (SWS) in both liver lobes. We compared: (1) MRE liver and spleen stiffness between controls vs. ARPKD; and (2) MRE liver stiffness between participants with ARPKD without vs. with pHTN, and examined correlations between MRE liver stiffness, spleen length, platelet counts, and US elastography SWS. Receiver operating characteristic (ROC) analysis was performed to examine diagnostic accuracy of liver MRE.</p>

<p><strong>RESULTS: </strong>Participants with ARPKD (median age 16.8 [IQR 13.3, 18.9] years) had higher median MRE liver stiffness than controls (median age 14.7 [IQR 9.7, 16.7&nbsp;years) (2.55 vs. 1.92&nbsp;kPa, p = 0.008), but MRE spleen stiffness did not differ. ARPKD participants with pHTN had higher median MRE liver stiffness than those without (3.60&nbsp;kPa vs 2.49&nbsp;kPa, p = 0.05). Liver MRE and US elastography measurements were strongly correlated. To distinguish ARPKD vs. control groups, liver MRE had 78% sensitivity and 93% specificity at a proposed cut-off of 2.48&nbsp;kPa [ROC area 0.83 (95% CI 0.63-1.00)].</p>

<p><strong>CONCLUSION: </strong>Liver MRE may be a useful quantitative method to measure the severity of CHF and pHTN in individuals with ARPKD.</p>

10.1007/s00261-020-02694-1

Abdom Radiol (NY)

32757071

Depression and neurocognitive dysfunction in pediatric and young adult chronic kidney disease.

2019

1575-1582

2019 09

1432-198X

<p><strong>BACKGROUND: </strong>Depression affects 7-35% of children with chronic kidney disease (CKD), and in adults with CKD, the presence of depression links to poorer medical outcomes, social functioning difficulties, and neurocognitive impairments. The relationship between depression and neurocognitive function in youth with CKD is unclear. We sought to identify factors associated with depression in youth with CKD and to determine whether depression affects neurocognitive performance.</p>

<p><strong>METHODS: </strong>We conducted cross-sectional analyses in 71 CKD and 64 control participants aged 8 to 25&nbsp;years who completed depression inventories and neurocognitive assessments as part of the Neurocognitive Assessment and Magnetic Resonance Imaging Analysis of Children and Young Adults with CKD Study. In the CKD group, multivariable logistic regression analysis determined associations between clinical and demographic factors and depression. In the full study cohort, multivariable linear regression analyses, including an interaction term between CKD status and depression evaluated the effect of depression on 11 neurocognitive outcome domains.</p>

<p><strong>RESULTS: </strong>Obesity significantly associated with depression in the CKD group (OR 10.25, P = 0.01). In adjusted analyses, depressed youth with CKD scored worse than non-depressed CKD participants by 0.6-1.0 standard deviations in 5 neurocognitive domains: attention, visual memory, visual-spatial, visual working memory, and problem solving.</p>

<p><strong>CONCLUSIONS: </strong>CKD youth with obesity are more likely to be depressed, and those who are depressed exhibit worse neurocognitive performance. Depression may represent a therapeutic target to improve neurocognitive performance in youth with CKD.</p>

10.1007/s00467-019-04265-z

Pediatr. Nephrol.

31049719

Magnetic resonance elastography SE-EPI vs GRE sequences at 3T in a pediatric population with liver disease.

2019

894-902

2019 03

2366-0058

<p><strong>PURPOSE: </strong>The goal of our study is to compare hepatic stiffness measures using gradient-recalled echo (GRE) versus spin-echo echo planar imaging (SE-EPI)-based MR Elastography (MRE) at 3T used to measure hepatic stiffness in a patients with suspected liver diseases.</p>

<p><strong>MATERIALS AND METHODS: </strong>This retrospective study included 52 patients with liver disease who underwent a 3T MRE exam including both an investigational SE-EPI-based technique and a product GRE-based technique. Regions of interest (ROI) were placed on the elastograms to measure elastography-derived liver stiffness as well as the area included within the ROIs. The mean liver stiffness values and area of ROIs were compared.</p>

<p><strong>RESULTS: </strong>The mean liver stiffness was 3.72 kilopascal (kPa) ± 1.29 using GRE MRE and 3.78&nbsp;kPa ± 1.13 using SE-EPI MRE. Measurement of liver stiffness showed excellent agreement between the two pulse sequences with a mean bias of - 0.1&nbsp;kPa (range - 1.8 to 1.7&nbsp;kPa) between sequences. The mean measurable ROI area was higher with SE-EPI (313.8&nbsp;cm ± 213.8) than with the GRE technique (208.6&nbsp;cm ± 114.8), and the difference was statistically significant (P &lt; 0.05).</p>

<p><strong>CONCLUSIONS: </strong>Our data shows excellent agreement of measured liver stiffness between GRE and SE-EPI-based sequences at 3T. Our results show the advantage of a SE-EPI MRE sequence in terms of image quality, ROI size and acquisition time with equivalent liver stiffness measurements as compared to GRE-MRE sequence.</p>

10.1007/s00261-018-1884-6

Abdom Radiol (NY)

30600386

Tissue metabolic profiling shows that saccharopine accumulates during renal ischemic-reperfusion injury, while kynurenine and itaconate accumulate in renal allograft rejection.

2020

65

2020 May 04

1573-3890

<p>To examine metabolic differences between renal allograft acute cellular rejection (ACR) and ischemic-reperfusion injury (IRI), we transplanted MHC-mismatched kidneys and induced 28&nbsp;min warm-IRI, and collected the ACR and IRI kidneys as well as their respective native and collateral control kidneys. We extracted metabolites from the kidney tissues and found the lysine catabolite saccharopine 12.5-fold enriched in IRI kidneys, as well as the immunometabolites itaconate and kynurenine in ACR kidneys. Saccharopine accumulation is known to be toxic to mitochondria and may contribute to IRI pathophysiology, while itaconate and kynurenine may be reflective of counterregulatory responses to immune activation in ACR.</p>

10.1007/s11306-020-01682-2

Metabolomics

32367163