Cholemic nephropathy causes acute kidney injury and is accompanied by loss of aquaporin 2 in collecting ducts

Impairment of renal function often occurs in patients with liver disease. Hepatorenal syndrome is a significant cause of acute kidney injury (AKI) in cirrhotic patients (HRS-AKI, type 1). Causes of non-HRS AKI include cholemic nephropathy (CN), a disease that is characterized by intratubular bile casts and tubular injury. As data on patients with CN is mostly obtained from case reports or autopsy studies, we aimed to investigate the frequency and clinical course of CN. We identified 149 patients who underwent kidney biopsy between 2000 to 2016 at the Department of Gastroenterology, Hepatology and Endocrinology. Of these, 79 had a history of liver disease and deterioration of renal function. When applying recent EASL criteria 45 of the 79 patients (57%) presented with AKI, whereas 34 patients (43%) had chronic kidney disease (CKD) (43%). Renal biopsy revealed the diagnosis of CN in 8 of the 45 patients with AKI (17.8%), whereas none of the patients with CKD was diagnosed with CN. Univariate analysis identified serum bilirubin, alkaline phosphatase and urinary bilirubin and urobilinogen as predictive factors for the diagnosis of CN. Histological analysis of AKI patients with normal bilirubin, elevated bilirubin and the diagnosis of CN revealed loss aquaporin 2 (AQP2) expression in collecting ducts in patients with elevated bilirubin and CN. Biopsy related complications requiring medical intervention occurred in four of 79 patients (5.1%). In conclusion, CN is a common finding in patients with liver disease, AKI and highly elevated bilirubin. Loss of AQP2 in AKI patients with elevated bilirubin and CN might be the result of toxic effects of cholestasis and be in part responsible for the impairment of renal function

Cholemic Nephropathy Causes Acute Kidney Injury and Is Accompanied by Loss of Aquaporin 2 in Collecting Ducts

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Cholemic Nephropathy Causes Acute Kidney Injury and Is Accompanied by Loss of Aquaporin 2 in Collecting Ducts

Impairment of renal function often occurs in patients with liver disease. Hepatorenal syndrome is a significant cause of acute kidney injury (AKI) in cirrhotic patients (HRS-AKI, type 1). Causes of non-HRS AKI include cholemic nephropathy (CN), a disease that is characterized by intratubular bile casts and tubular injury. As data on patients with CN is mostly obtained from case reports or autopsy studies, we aimed to investigate the frequency and clinical course of CN. We identified 149 patients who underwent kidney biopsy between 2000 to 2016 at the Department of Gastroenterology, Hepatology and Endocrinology. Of these, 79 had a history of liver disease and deterioration of renal function. When applying recent EASL criteria 45 of the 79 patients (57%) presented with AKI, whereas 34 patients (43%) had chronic kidney disease (CKD) (43%). Renal biopsy revealed the diagnosis of CN in 8 of the 45 patients with AKI (17.8%), whereas none of the patients with CKD was diagnosed with CN. Univariate analysis identified serum bilirubin, alkaline phosphatase and urinary bilirubin and urobilinogen as predictive factors for the diagnosis of CN. Histological analysis of AKI patients with normal bilirubin, elevated bilirubin and the diagnosis of CN revealed loss aquaporin 2 (AQP2) expression in collecting ducts in patients with elevated bilirubin and CN. Biopsy related complications requiring medical intervention occurred in four of 79 patients (5.1%). In conclusion, CN is a common finding in patients with liver disease, AKI and highly elevated bilirubin. Loss of AQP2 in AKI patients with elevated bilirubin and CN might be the result of toxic effects of cholestasis and be in part responsible for the impairment of renal function

Multiparametric Functional MRI: Non-Invasive Imaging of Inflammation and Edema Formation after Kidney Transplantation in Mice

<div><p>Background</p><p>Kidney transplantation (ktx) in mice is used to learn about rejection and to develop new treatment strategies. Past studies have mainly been based on histological or molecular biological methods. Imaging techniques to monitor allograft pathology have rarely been used.</p><p>Methods</p><p>Here we investigated mice after isogenic and allogenic ktx over time with functional MRI with diffusion-weighted imaging (DWI) and mapping of T2-relaxation time (T2-mapping) to assess graft inflammation and edema formation. To characterize graft pathology, we used PAS-staining, counted CD3-positive T-lymphocytes, analyzed leukocytes by means flow cytometry.</p><p>Results</p><p>DWI revealed progressive restriction of diffusion of water molecules in allogenic kidney grafts. This was paralleled by enhanced infiltration of the kidney by inflammatory cells. Changes in tissue diffusion were not seen following isogenic ktx. T2-times in renal cortex were increased after both isogenic and allogenic transplantation, consistent with tissue edema due to ischemic injury following prolonged cold ischemia time of 60 minutes. Lack of T2 increase in the inner stripe of the inner medulla in allogenic kidney grafts matched loss of tubular autofluorescence and may result from rejection-driven reductions in tubular water content due to tubular dysfunction and renal functional impairment.</p><p>Conclusions</p><p>Functional MRI is a valuable non-invasive technique for monitoring inflammation, tissue edema and tubular function. It permits on to differentiate between acute rejection and ischemic renal injury in a mouse model of ktx.</p></div

Functional MRI parameters after isogenic and allogenic ktx and in control animals.

<p>Functional MRI parameters after isogenic and allogenic ktx and in control animals.</p

Inflammation and tissue edema in isogenic and allogenic kidney grafts measured by T2-mapping and histology.

<p>T2 maps of a control kidney (A, first column) and isogenic (second column) and allogenic kidney grafts (third column) at day 1 (B) and day 6 (C) are shown. Differentiation of renal compartments such as cortex (C), outer (OSOM) and inner stripe of the outer medulla (ISOM) is visualized in panel A. Note the loss of T2-difference between cortex and ISOM in allogenic grafts at d6 after ktx. This corresponds with the loss of tubular autofluorescence (green), which was associated with rejection and loss of tubular function in allogenic ktx (D). PAS stain shows severe endothelialitis and concomitant surrounding edema in allogenic graft (D). Bar represents 50 μm. *p<0.05, **p<0.01, ***p<0.001, ### p<0.001 compared to allogenic kidney grafts.</p

Diagnostic accuracy of functional MRI parameters to discriminate allografts with acute rejection from isografts without rejection.

<p>ROC curve analysis shows diagnostic accuracies of ADC values (A) and T2 relaxation times (B) to discriminate allografts with acute rejection from isografts without rejection. Area under the curve, Youden selected thresholds as well as sensitivities and specificities are given in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0162705#pone.0162705.t002" target="_blank">Table 2</a>.</p

Inflammation and cell infiltration in isogenic and allogenic kidney grafts measured by DWI and histology.

<p>Representative ADC maps of a control kidney (A, first column) and isogenic (second column) and allogenic kidney grafts (third column) at day 1 (B) and day 6 (C) are shown after adjustment for multiple comparisons. Mean ADC values in cortex and outer medulla as well as significant group differences are indicated. Corresponding to ADC reduction in allogenic kidney grafts histology revealed elevated tubulo-interstitial inflammation. This correlated with enhanced DAPI positive nuclei visualized in blue (D). Representative DAPI stains, overlaid with tubular autofluorescence for anatomical orientation, of an isograft (second column) and an allograft (third column) are shown. Inflammation was scored semi-quantitatively in PAS stained sections (magnificatin 200 fold). *p<0.05, **p<0.01, ## p<0.01 and ### p<0.001 compared to allogenic kidney grafts.</p

Characterization of infiltrating leukocyte subtypes.

<p>Immunohistochemistry with staining for CD3-positive cells showed mild baseline CD3-positive T-lymphocyte expression isogenic kidney grafts. Allogenic kidney grafts had dense infiltrates of CD3-positive lymphocytes (red) at day 7 after transplantation (magnificatin 200-fold). The tubular autofluorescence is overlaid in green for anatomical orientation. Flow cytometric analysis confirmed that in allogenic ktx βTCR-positive (TCR+) cells were the most abundant leukocyte subset, while in isogenic ktx slightly enhanced TCR+ cell infiltration was present (gating examples among live, CD11b+ cells). More details on the cell sorting process are provided in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0162705#pone.0162705.s001" target="_blank">S1 Fig</a>. *p<0.05, ## p<0.01 and ### p<0.001 in comparison to allogenic group.</p

Histopathology in isogenic and allogenic kidney grafts.

<p>PAS stainings illustrating histopathology of mouse isografts (A, B) and allografts (C-F). Isografts showed almost normal renal morphology with some focal interstitial inflammatory infiltrates (A and B). Mouse allografts revealed severe rejection (C and D). In addition, allografts with arterial endothelialitis (Banff IIA, E) and transmural arteriitis (Banff III, F) are shown. Bars represent 20 μm in A and B, 50 μm in B and D and 100 μm in E and F.</p