Heterozygous Mutation of Vegfr3 Reduces Renal Lymphatics Without Renal Dysfunction

2021 ◽  
pp. ASN.2021010061
Author(s):  
Hao Liu ◽  
Chitkale Hiremath ◽  
Quinten Patterson ◽  
Saumya Vora ◽  
Zhiguo Shang ◽  
...  
Keyword(s):  
Renal Function ◽  
Kidney Disease ◽  
Lymphatic Vessels ◽  
Light Sheet ◽  
Heterozygous Mutation ◽  
Blood Capillaries ◽  
Developmental Abnormalities ◽  
Cortical Volume ◽  
Light Sheet Microscopy ◽  
Lymphatic Density

Background: Lymphatic abnormalities are observed in several types of kidney disease, but the relationship between the renal lymphatic system and renal function is unclear. The discovery of lymphatic-specific proteins, advances in microscopy, and available genetic mouse models provide the tools to help elucidate the role of renal lymphatics in physiology and disease. Methods: We utilized a mouse model containing a missense mutation in Vegfr3 (dubbed Chy) that abrogates its kinase ability. Vegfr3Chy/+ mice were examined for developmental abnormalities and kidney specific outcomes. Control and Vegfr3Chy/+ mice were subjected to cisplatin-mediated injury. We characterized renal lymphatics using tissue clearing, light-sheet microscopy, and computational analyses. Results: In the kidney, VEGFR3 is expressed not only in lymphatic vessels, but also in various blood capillaries. Vegfr3Chy/+ mice had severely reduced renal lymphatics with 100% penetrance, but we found no abnormalities in blood pressure, serum creatinine, BUN, albuminuria, and histology. There was no difference in the degree of renal injury after low dose cisplatin (5 mg/kg), although Vegfr3Chy/+ mice developed perivascular inflammation. Cisplatin-treated controls had no difference in total cortical lymphatic volume and length, but showed increased lymphatic density due to decreased cortical volume. Conclusions: We demonstrate that VEGFR3 is required for development of renal lymphatics. Our studies reveal that reduced lymphatic density does not impair renal function at baseline and induces only modest histological changes after mild injury. We introduce a novel quantification method to evaluate renal lymphatics in 3D and demonstrate that accurate measurement of lymphatic density in chronic kidney disease requires assessment of changes to cortical volume.

scholarly journals Heterozygous mutation of Vegfr3 decreases renal lymphatics but is dispensable for renal function

2021 ◽  
Author(s):  
Hao Liu ◽  
Chitkale Hiremath ◽  
Quinten Patterson ◽  
Saumya Vora ◽  
Zhiguo Shang ◽  
...  
Keyword(s):  
Renal Function ◽  
Kidney Disease ◽  
Lymphatic Vessels ◽  
Light Sheet ◽  
Structure And Function ◽  
Heterozygous Mutation ◽  
Light Sheet Microscopy ◽  
Perivascular Inflammation ◽  
Lymphatic Density ◽  
And Function

ABSTRACTBackgroundLymphatic abnormalities are observed in several types of kidney disease, but the relationship between the renal lymphatic system and renal function is unclear. The discovery of lymphatic-specific proteins, advances in microscopy, and available genetic mouse models provide the tools to help elucidate the role of renal lymphatics in physiology and disease.MethodsWe utilized a mouse model containing a missense mutation in Vegfr3 (dubbed Chy) that abrogates its kinase ability. Vegfr3Chy/+ mice were examined for developmental abnormalities and kidney-specific outcomes. Control and Vegfr3Chy/+ mice were subjected to cisplatin-mediated injury. We characterized renal lymphatics using a combination of tissue clearing, light-sheet microscopy and computational analyses.ResultsIn the kidney, we found Vegfr3 is expressed not only in lymphatic vessels, but also various blood vessels. Vegfr3Chy/+ mice had severely reduced renal lymphatics with 100% penetrance, but we found no abnormalities in blood pressure, renal function and histology. Similarly, there was no difference in the degree of renal injury after cisplatin, although Vegfr3Chy/+ mice developed more perivascular inflammation by histology. Control mice treated with cisplatin had a measurable increase in cortical lymphatic density despite no change in cortical lymphatic volume and length.ConclusionsWe demonstrate that Vegfr3 is required for development of renal lymphatics, but a reduction in lymphatic density does not alter renal function and induces only modest histological changes after injury. Our data suggests that an increase in lymphatic density after cisplatin injury may reflect the loss of cortical volume associated with chronic kidney disease rather than growth of lymphatic vessels.SIGNIFICANCE STATEMENTDefects in renal lymphatics occur in various kidney diseases, but their role in maintaining kidney structure and function is unknown. We combine tissue clearing, light-sheet microscopy and computational analysis to characterize lymphatics and find that mice with a heterozygous mutation in Vegfr3 (Vegfr3Chy/+) have severely reduced renal lymphatics. Strikingly, these mice have indistinguishable renal function and histology compared with controls. Even after cisplatin injury, there are no differences in renal function, although Vegfr3Chy/+ mice developed more perivascular inflammation. Our data present a novel method of lymphatic quantification and suggest that a normal complement of renal lymphatics is dispensable for renal structure and function.

scholarly journals Light sheet microscopy-based 3-dimensional histopathology of the lymphatic vasculature in Emberger syndrome

Phlebologie ◽  
2020 ◽  
Vol 49 (04) ◽  
pp. 242-248
Author(s):  
René Hägerling
Keyword(s):  
Lower Limb ◽  
Lymphatic Vessels ◽  
Light Sheet ◽  
Lower Limbs ◽  
Vascular Pathology ◽  
Histopathological Analysis ◽  
Upper Limbs ◽  
3 Dimensional ◽  
Light Sheet Microscopy ◽  
Lymphatic Vasculature

Abstract Introduction Lymphovascular diseases represent a heterogenous group of inherited and sporadic disorders and refer to a range of possible underlying pathologies and pathogenesis.Emberger Syndrome, an inherited form of lymphedema, is characterized by bilateral lower limb lymphedema, however, upper limbs do not show any signs of swelling.To identify disease-associated histopathological alterations in patients with Emberger Syndrome and to elucidate potential histological differences between the lymphatic vasculature of upper and lower limbs, a detailed knowledge on the 3-dimensional tissue and vessel architecture is essential. However, the current gold standard in 2-dimensional histology provides only very limited spatial information. Material and methods To elucidate the underlying vascular pathology in Emberger Syndrome on the cellular level, we applied the 3-dimensional visualization and analysis approach VIPAR (volume information-based histopathological analysis by 3D reconstruction and data extraction) to entire wholemount immunofluorescence-stained human tissue samples. VIPAR is a light sheet microscopy-based imaging technique, which allows 3-dimensional reconstruction of entire tissue biopsies followed by automated and semi-automated analysis of vascular parameters in 3-dimensional space. Results Using VIPAR we could show that in Emberger Syndrome the dermal lymphatic vasculature is intact and non-disrupted.However, lower limbs showed an hypoplastic lymphatic vasculature with absence of lymphatic valves in pre-collecting and collecting vessels. In contrast to the lower limbs, the lymphatic vasculature of the upper limbs showed no morphological alterations of lymphatic vessels and lymphatic valves compared to healthy controls. Discussion Based on the 3-dimensional histopathological analysis we were able to perform a detailed phenotyping of lymphatic vessels in the upper and lower limb in Emberger Syndrome and to identify the underlying vascular pathology. In addition, we could show vascular alteration between the upper and lower limbs indicating a vascular heterogeneity of dermal lymph vessels causing the lower limb lymphedema.

EFFECTIVENESS OF ANTIAGGREGANT THERAPY ON KIDNEY ACTIVITY IN THE PREDIALYSIS STAGE OF CHRONIC KIDNEY DISEASE

2020 ◽  
Vol 6 (1) ◽  
pp. 55-60
Author(s):  
Khabib Barnoev ◽  
◽  
Sherali Toshpulatov ◽  
Nozima Babajanova ◽  
Keyword(s):  
Chronic Kidney Disease ◽  
Renal Function ◽  
Kidney Disease ◽  
Comparative Study ◽  
Functional Status ◽  
Stage Ii ◽  
Term Administration ◽  
Antiaggregant Therapy

The article presents the results of a study to evaluate the effectiveness of antiaggregant therapy on the functional status of the kidneys in 115 patients with stage II and III chronic kidney disease on the basis of a comparative study of dipyridamole and allthrombosepin. Studies have shown that long-term administration of allthrombosepin to patients has led to improved renal function.

scholarly journals Renal Function as a Predictor of Reamputation After Initial Transmetatarsal Amputation in the Perioperative Period

2018 ◽  
Vol 3 (3) ◽  
pp. 2473011418S0001
Author(s):  
Junho Ahn ◽  
Katherine Raspovic ◽  
Dane Wukich ◽  
George Liu
Keyword(s):  
Chronic Kidney Disease ◽  
Renal Failure ◽  
Renal Function ◽  
Kidney Disease ◽  
Lower Extremity ◽  
Perioperative Period ◽  
Improvement Program ◽  
Acs Nsqip ◽  
Cell Counts ◽  
Insulin Dependent

Category: Midfoot/Forefoot Introduction/Purpose: With increasing rates of patients being newly diagnosed with diabetes mellitus, foot complications are becoming more common, which often lead to amputation. Compared to major lower extremity amputations, transmetatarsal amputations (TMA) are associated with lower cost, better function, and more aesthetically satisfactory results for patients. Renal failure has been shown to be a significant predictor of morbidity and mortality in lower extremity amputations at various levels. However, previous reports examining the effect of renal function on reamputation rates after TMA have been mixed. As a result, the purpose of this study was to evaluate renal dysfunction as a risk factor for reamputation after initial TMA during the 30-day perioperative period in a large population database. Methods: Patients under 90 years of age who underwent a TMA between 2012 and 2015 were retrospectively identified in the prospectively collected American College of Surgeons-National Surgical Quality Improvement Program® (ACS-NSQIP®) database using the Current Procedure Terminology (CPT) code 28805. Failure of the initial TMA was defined as reamputation in the 30-day perioperative period through corresponding CPT codes. From these criteria, a total of 1,775 patients were identified. More than 150 unique patient factors were included in the study, but glycated hemoglobin (HbA1C) was not reported by the ACS-NSQIP® database. Diabetes status was categorized into four groups: “Insulin” dependent, “Non-Insulin” dependent, or “None.” Filtration rate was estimated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, and patients were categorized into stages of chronic kidney disease (CKD). Results: Over the 30-day perioperative period, the rate of reamputation after TMA was 6.5%. No statistical differences in age, gender, race, body-mass index, or level of pre-operative functional status were found between groups. Reamputation rates after TMA was significantly correlated with higher white blood cell counts (p<.00001), greater serum creatinine (p=.021), higher blood urea nitrogen (p=.021), type of glycemic control (p=.002), stage of CKD (p=.003), dialysis (p=.001), and pre-operative blood transfusion (p=.042). Stage IV-V CKD was associated with 75% increased odds of reamputation (OR=1.75, 95% CI=1.12-2.73), and higher stage of CKD was associated with greater reamputation rates (p=.003) where stage II CKD had the lowest reamputation rate (3.6%) and stage V with the highest reamputation rate (10.9%). A similar trend was seen with 30-day mortality (p<.00001). Conclusion: In the current study, CKD was significantly correlated with reamputation rates after TMA as well as 30-day mortality. In contrast to a previous report, dialysis was also associated with TMA failure and need for reamputation. Our findings corroborate previous findings correlating dialysis-dependent renal failure and mortality. Whether patients in certain stages of CKD would achieve better outcomes with higher-level amputation rather than a TMA should be investigated in future studies.

scholarly journals Sex modulates the association of radial artery augmentation index with renal function decline in individuals without chronic kidney disease

2021 ◽  
Author(s):  
Qiao Qin ◽  
Fangfang Fan ◽  
Jia Jia ◽  
Yan Zhang ◽  
Bo Zheng
Keyword(s):  
Chronic Kidney Disease ◽  
Renal Function ◽  
Kidney Disease ◽  
Arterial Stiffness ◽  
Confidence Interval ◽  
Odds Ratio ◽  
Adjusted Odds Ratio ◽  
Augmentation Index ◽  
Renal Function Decline

Abstract Purpose An increase in arterial stiffness is associated with rapid renal function decline (RFD) in patients with chronic kidney disease (CKD). The aim of this study was to investigate whether the radial augmentation index (rAI), a surrogate marker of arterial stiffness, affects RFD in individuals without CKD. Methods A total of 3165 Chinese participants from an atherosclerosis cohort with estimated glomerular filtration rates (eGFR) of ≥ 60 mL/min/1.73 m2 were included in this study. The baseline rAI normalized to a heart rate of 75 beats/min (rAIp75) was obtained using an arterial applanation tonometry probe. The eGFRs at both baseline and follow-up were calculated using the equation derived from the Chronic Kidney Disease Epidemiology Collaboration. The association of the rAIp75 with RFD (defined as a drop in the eGFR category accompanied by a ≥ 25% drop in eGFR from baseline or a sustained decline in eGFR of > 5 mL/min/1.73 m2/year) was evaluated using the multivariate regression model. Results During the 2.35-year follow-up, the incidence of RFD was 7.30%. The rAIp75 had no statistically independent association with RFD after adjustment for possible confounders (adjusted odds ratio = 1.12, 95% confidence interval: 0.99–1.27, p = 0.074). When stratified according to sex, the rAIp75 was significantly associated with RFD in women, but not in men (adjusted odds ratio and 95% confidence interval: 1.23[1.06–1.43], p = 0.007 for women, 0.94[0.76–1.16], p = 0.542 for men; p for interaction = 0.038). Conclusion The rAI might help screen for those at high risk of early rapid RFD in women without CKD.

scholarly journals Efficacy and safety of gout flare prophylaxis and therapy use in people with chronic kidney disease: a Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN)-initiated literature review

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Huai Leng Pisaniello ◽  
Mark C. Fisher ◽  
Hamish Farquhar ◽  
Ana Beatriz Vargas-Santos ◽  
Catherine L. Hill ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Renal Function ◽  
Kidney Disease ◽  
Literature Review ◽  
Interleukin 1 ◽  
Treatment Options ◽  
Cochrane Library ◽  
Efficacy And Safety ◽  
Clinical Trial Results ◽  
Gout Flare

AbstractGout flare prophylaxis and therapy use in people with underlying chronic kidney disease (CKD) is challenging, given limited treatment options and risk of worsening renal function with inappropriate treatment dosing. This literature review aimed to describe the current literature on the efficacy and safety of gout flare prophylaxis and therapy use in people with CKD stages 3–5. A literature search via PubMed, the Cochrane Library, and EMBASE was performed from 1 January 1959 to 31 January 2018. Inclusion criteria were studies with people with gout and renal impairment (i.e. estimated glomerular filtration rate (eGFR) or creatinine clearance (CrCl) < 60 ml/min/1.73 m2), and with exposure to colchicine, interleukin-1 inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), and glucocorticoids. All study designs were included. A total of 33 studies with efficacy and/or safety analysis stratified by renal function were reviewed—colchicine (n = 20), anakinra (n = 7), canakinumab (n = 1), NSAIDs (n = 3), and glucocorticoids (n = 2). A total of 58 studies reported these primary outcomes without renal function stratification—colchicine (n = 29), anakinra (n = 10), canakinumab (n = 6), rilonacept (n = 2), NSAIDs (n = 1), and glucocorticoids (n = 10). Most clinical trials excluded study participants with severe CKD (i.e. eGFR or CrCl of < 30 mL/min/1.73 m2). Information on the efficacy and safety outcomes of gout flare prophylaxis and therapy use stratified by renal function is lacking. Clinical trial results cannot be extrapolated for those with advanced CKD. Where possible, current and future gout flare studies should include patients with CKD and with study outcomes reported based on renal function and using standardised gout flare definition.

scholarly journals Achromatic terahertz Airy beam generation with dielectric metasurfaces

Nanophotonics ◽  
2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Qingqing Cheng ◽  
Juncheng Wang ◽  
Ling Ma ◽  
Zhixiong Shen ◽  
Jing Zhang ◽  
...  
Keyword(s):  
Biomedical Imaging ◽  
Frequency Dispersion ◽  
Light Sheet ◽  
Photonic Devices ◽  
Self Healing ◽  
Beam Focusing ◽  
Light Sheet Microscopy ◽  
Airy Beam ◽  
Potential Applications ◽  
Airy Beams

AbstractAiry beams exhibit intriguing properties such as nonspreading, self-bending, and self-healing and have attracted considerable recent interest because of their many potential applications in photonics, such as to beam focusing, light-sheet microscopy, and biomedical imaging. However, previous approaches to generate Airy beams using photonic structures have suffered from severe chromatic problems arising from strong frequency dispersion of the scatterers. Here, we design and fabricate a metasurface composed of silicon posts for the frequency range 0.4–0.8 THz in transmission mode, and we experimentally demonstrate achromatic Airy beams exhibiting autofocusing properties. We further show numerically that a generated achromatic Airy-beam-based metalens exhibits self-healing properties that are immune to scattering by particles and that it also possesses a larger depth of focus than a traditional metalens. Our results pave the way to the realization of flat photonic devices for applications to noninvasive biomedical imaging and light-sheet microscopy, and we provide a numerical demonstration of a device protocol.

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