optical-clearing-and-imaging-of-immunolabeled-kidney-tissue

Optical Clearing and Imaging of Immunolabeled Kidney Tissue

Optical clearing techniques render tissue transparent by equilibrating the refractive index throughout a sample for subsequent three-dimensional (3-D) ...

University Hospital RWTH Aachen

A 64-year-old woman with end-stage renal disease and retinopathy secondary to type 2 diabetes mellitus presented with recurrent episodes of left ocular pain and acute loss of visual acuity during hemodialysis. During these episodes, markedly elevated intraocular pressures were measured. Several local and systemic antiglaucoma drugs were administered without improvement of intraocular pressure, resulting in the necessity of a glaucoma drainage device (Ahmed valve). Due to a local infection, it had to be removed, after which intraocular pressure elevations recurred during hemodialysis. Assuming that intraocular changes in osmolality during hemodialysis caused the intraocular pressure increases, intradialytic administration of a 20% glucose solution (100mL/h) was initiated. This completely abrogated the development of both intraocular pain and increases in intraocular pressure. 

Management of intraocular hypertension during hemodialysis by intravenous glucose administration.

Glomerulonephritis triggered by a chronically infected left ventricular assist device.

In patients with chronic kidney disease, data on blood pressure (BP) pattern and its association with target organ damage, which indicates elevated cardiovascular risk, are sparse. In 305 treated hypertensive chronic kidney disease patients, we assessed BP pattern, left ventricular mass (magnetic resonance imaging), intima-media thickness (ultrasound), 24-hour-pulse wave velocity and 24-hour-central augmentation index (Mobil-O-Graph). Controlled hypertension (normal office and ambulatory BP) was found in 41% and sustained uncontrolled hypertension (elevated office and ambulatory BP) in 30% of patients. Misclassification of BP status occurred in 29%: white coat uncontrolled hypertension (elevated office but normal ambulatory BP) was detected in 11% and masked uncontrolled hypertension (normal office but elevated ambulatory BP) in 18% of patients. Left ventricular mass was increased in white coat uncontrolled hypertension (+11.2 g), masked uncontrolled hypertension (+9.4 g), and sustained uncontrolled hypertension (+16.6 g) compared with controlled hypertension. Intima-media thickness was similar across all 4 BP groups. Twenty-four hour-pulse wave velocity and 24-hour-central augmentation index were increased in masked uncontrolled hypertension (+0.5 m/sec and +2.5%) and sustained uncontrolled hypertension (+0.5 m/sec and +2.9%) compared with controlled hypertension. In conclusion, based on office BP measurements, misclassification of true BP status occurred in almost one-third of chronic kidney disease patients. Both types of misclassification (white coat uncontrolled hypertension and masked uncontrolled hypertension) were associated with parameters of target organ damage. Ambulatory BP monitoring should be used routinely to identify chronic kidney disease patients at high cardiovascular risk.

Blood Pressure Pattern and Target Organ Damage in Patients With Chronic Kidney Disease.

Distal nephron remodeling contributes to the pathophysiology of many clinically relevant scenarios, including diuretic resistance and certain Mendelian disorders of blood pressure. However, constitutive genetic disruptions are likely to have substantial developmental effects in this segment, and whether tubule remodeling upon physiological stimuli is a normal homeostatic mechanism is not known. Since the distal nephron acts as a potassium sensor, we assessed proliferation and tubule length in three dimensions upon dietary or inducible genetic manipulation by using optical clearing of adult mouse kidneys, whole-mount immunolabeling, and advanced light microscopy. We show that dietary potassium restriction leads promptly to proliferation of various nephron segments, including the distal convoluted tubule, whereas disruption of the potassium sensor Kir4.1 causes atrophy, despite ambient hypokalemia. These results provide proof that kidney tubules adapt rapidly to diet and indicate the power of clearing approaches to assess cell number and tubule length in healthy and diseased kidney.

Optical Clearing in the Kidney Reveals Potassium-Mediated Tubule Remodeling.

The high burden of left ventricular (LV) abnormalities in patients with advanced chronic kidney disease (CKD) is well established. However, less is known about the prevalence, patterns, and determinants of LV abnormalities in patients with early CKD.

Left Ventricular Structure in Patients With Mild-to-Moderate CKD-a Magnetic Resonance Imaging Study.

Cullin 3 (CUL3) is part of the ubiquitin proteasomal system and controls several cellular processes critical for normal organ function including the cell cycle, and Keap1/Nrf2 signaling. Kidney tubule-specific Cul3 disruption causes tubulointerstitial fibrosis, but little is known about the mechanisms. Therefore, we tested the hypothesis that dysregulation of the cell cycle and Keap1/Nrf2 pathway play a role in initiating the kidney injury upon Cul3 disruption. Cul3 deletion increased expression of cyclin E and p21, associated with uncontrolled proliferation, DNA damage, and apoptosis, all of which preceded proximal tubule injury. The cdk2-cyclin E inhibitor roscovitine did not prevent the effects of Cul3 deletion, but instead exacerbated the kidney injury. Injury occurred despite accumulation and activation of CUL3 substrate Keap1/Nrf2, proposed to be protective in kidney injury. Cul3 disruption led to progressive interstitial inflammation, functionally relevant renal fibrosis and death. Finally, we observed reduced CUL3 expression in several AKI and CKD mouse models and in fibrotic human kidney tissue. These data establish CUL3 knockout mice as a novel genetic CKD model in which dysregulation of the cell cycle may play a primary role in initiating tubule injury, and that CUL3 dysregulation could contribute to acute and fibrotic kidney disease.

Article	Year
Management of intraocular hypertension during hemodialysis by intravenous glucose administration. American journal of kidney diseases : the official journal of the National Kidney Foundation\| PubMed ID: 24189474	2014
Glomerulonephritis triggered by a chronically infected left ventricular assist device. Lancet (London, England)\| PubMed ID: 26681291	2015
Blood Pressure Pattern and Target Organ Damage in Patients With Chronic Kidney Disease. Hypertension (Dallas, Tex. : 1979)\| PubMed ID: 30354716	2018
Optical Clearing in the Kidney Reveals Potassium-Mediated Tubule Remodeling. Cell reports\| PubMed ID: 30517856	2018
Left Ventricular Structure in Patients With Mild-to-Moderate CKD-a Magnetic Resonance Imaging Study. Kidney international reports\| PubMed ID: 30775623	2019
Disruption of CUL3-mediated ubiquitination causes proximal tubule injury and kidney fibrosis. Scientific reports\| PubMed ID: 30872636	2019

Turgay Saritas

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