glomerular capillaries
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Author(s):  
Catherin Ouseph ◽  
Praful Patil

The causative agent of the highly infectious pandemic COVID-19 is SARS-CoV-2. According to WHO, as of August 18th 2020, the number of confirmed cases was and confirmed deaths was 771,635 from 216 countries. The most affected organ system in COVID-19 is the respiratory system. Later studies proved that the virus caused multiorgan infections. Several studies shows that SARS-CoV-2 causes damage to the renal system and; critically ill patients with associated renal damage show a higher mortality rate as compared to those patients with an unaffected renal system .This review article aims at updating the knowledge about associated kidney failure in covid-19 cases and its impact on the morbidity and mortality. The virus damages the renal system through two different mechanisms: Direct and Indirect pathway. The direct pathway explains how the virus damages the renal system by directly acting upon the target cells in the kidney.SARS-CoV-2 gains its entry by binding to the ACE2 receptors on the target cell. The SARS-CoV-2 progresses its journey and extensively spread the infection, damaging the kidneys leading to the failure of the renal system. The indirect pathway of damage speaks about the secondary damage caused to the renal system due to cytokine release syndrome caused by SARS-CoV-2.This pathway also points out the formation of microthrombi in the glomerular capillaries and also kidney hypoperfusion. AKI in covid-19 patients can occur secondary to multiorgan failure. This review aims to build a foundation concerning the direct pathway and indirect pathway by means of which SARS-Cov-2 infects the kidneys by summarizing the numerous researches carried out till date to update the knowledge gained thus far to aid in building better protocols for covid-19 management and decrease morbidity caused due to renal damage.


Author(s):  
Jana Löwen ◽  
Elisabeth Gröne ◽  
Marie-Luise Groß-Weißmann ◽  
Felix Bestvater ◽  
Hermann-Josef Gröne ◽  
...  

Abstract Following our reports on mesangial sclerosis and vascular proliferation in diabetic nephropathy (DN)(25,34) we now describe the advanced stages of DN terminating in glomerular obsolescence and tubulo-interstitial fibrosis based on a total of 918 biopsies. The structural aberrations emerge from two defects: First, an increased synthesis of glomerular basement membrane (GBM) components by podocytes and endothelial cells leading to an accumulation of GBM material in the mesangium. Second, a defect of glomerular vessels consisting of an increased leakiness and an increased propensity to proliferate. Both defects may lead to glomerular degeneration. The progressing compaction of the accumulated worn-out GBM-material together with the retraction of podocytes out of the tuft and the collapse and hyalinosis of capillaries results in a shrunken tuft that fuses with Bowman's capsule to glomerular sclerosis. The most frequent pathway to glomerular decay starts with local tuft expansions that result in contacts of structurally healthy podocytes to the parietal epithelium initiating the formation of tuft adhesions, which include the penetration of glomerular capillaries into BC. Exudation of plasma from such capillaries into the space between the parietal epithelium and its basement membrane causes the formation of insudative fluid accumulations within BC spreading around the glomerular circumference and, via the glomerulo-tubular junction, onto the tubule. Degeneration of the corresponding tubule develops secondarily to the glomerular damage, either due to cessation of filtration in cases of global sclerosis or due to encroachment of the insudative spaces. The degenerating tubules induce the proliferation of myo-fibroblasts resulting in interstitial fibrosis.


Haematologica ◽  
2021 ◽  
Author(s):  
Karina Althaus ◽  
Peter Möller ◽  
Günalp Uzun ◽  
Anurag Singh ◽  
Annika Beck ◽  
...  

The COVID-19 pandemic has resulted in significant morbidity and mortality worldwide. To prevent severe infection, mass COVID-19 vaccination campaigns with several vaccine types are currently underway. We report pathological and immunological findings in 8 patients who developed vaccine-induced immune thrombotic thrombocytopenia (VITT) after administration of SARS-CoV-2 vaccine ChAdOx1 nCoV-19. We analyzed patient material using enzyme immune assays, flow cytometry and heparin-induced platelet aggregation assay and performed autopsies on two fatal cases. Eight patients (5 female, 3 male) with a median age of 41.5 years (range, 24 to 53) were referred to us with suspected thrombotic complications 6 to 20 days after ChAdOx1 nCoV-19 vaccination. All patients had thrombocytopenia at admission. Patients had a median platelet count of 46.5 x109/L (range, 8 to 92). Three had a fatal outcome and 5 were successfully treated. Autopsies showed arterial and venous thromboses in various organs and the occlusion of glomerular capillaries by hyaline thrombi. Sera from VITT patients contain high titer antibodies against platelet factor 4 (PF4) (OD 2.59±0.64). PF4 antibodies in VITT patients induced significant increase in procoagulant markers (P-selectin and phosphatidylserine externalization) compared to healthy volunteers and healthy vaccinated volunteers. The generation of procoagulant platelets was PF4 and heparin dependent. We demonstrate the contribution of antibody-mediated platelet activation in the pathogenesis of VITT.


2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Hermann Gröne ◽  
Wilhelm Kriz ◽  
Jana Loewen ◽  
Elisabeth Groene

Abstract Background and Aims Diabetic nephropathy (DN) is the leading cause of end-stage-renal disease in western countries. Despite of innumerable studies undertaken to elucidate the pathogenesis of DN the underlying morphologic alterations have been insufficiently analyzed. Method Re-evaluation of more than 800 biopsies was done showing several unknown features. Results: 1. Matrix accumulation in the mesangium: Thickening of the glomerular basement membrane (GBM) and expansion of the mesangial matrix are hallmarks of DN, generally considered to emerge from different sites of overproduction: GBM components from podocytes and mesangial matrix from mesangial cells. We show, that the accumulation of matrix in the mesangium emerges from an overproduction of GBM material by podocytes and endothelial cells and an impaired degradation by mesangial cells. The progressing deposition of worn-out GBM material into the mesangium accounts for the advancement from diffuse mesangial sclerosis (DMS) to nodular sclerosis (NS) and to the herniation of the tuft through the glomerular vascular pole to the outside; the latter is associated with the outgrowth of glomerular capillaries into the peri-glomerular space leading to the destruction of the juxtaglomerular apparatus. 2.The role of podocytes Podocytes have frequently been accused to play a central role in DN. This is correct, but in another way than generally assumed. Damage to podocytes cannot be seen in DMS. The albuminuria regularly seen during this stage derives, as previously suggested by others, from an increased leakiness of the glomerular capillary endothelium based on a deranged glycocalyx. Podocyte detachments start at the transition from DMS to NS, based on the loss of cross talk signals with the capillary endothelium: the increasing deposition of matrix leads to the collapse of many capillaries. These podocytes contribute little to the further progression of the damage: they are lost into primary urine or they undergo cell lysis.In addition to their role in increased matrix production, podocytes take an active role in the formation of tuft adhesions to Bowman’s capsule (BC), starting the progression to NS. Expansion of the matrix within the mesangium has led to expansion of the tuft (frequently associated with nodules) towards Bowman’s capsule (BC) or towards the urinary orifice. Podocytes on the surface of these expansions are in their majority structurally intact, exhibiting an intact pattern of foot processes. These podocytes come into contact with parietal epithelial cells and initiate DN-specific tuft adhesions to BC allowing the proliferation of glomerular capillaries into BC. There they deliver an exudate into BC that spreads around the entire circumference of the glomerulus presenting as giant insudative spaces. Moreover, this process encroaches via the glomerulo-tubular junction onto the tubule constituting the major pathway of glomerular damage extending to the tubulointerstitium. 3. Tubulointerstitial fibrosisIt is current opinion that the tubulointerstitial fibrosis may start from tubular damage resulting in an own, glomerular-independent pathway to nephron loss. However, there is scant evidence for such a mechanism. Studying 162 glomerulo-tubular transitions, we did not see a tubular epithelial or interstitial damage in those biopsies without any evidence of a glomerulo-tubular damage transfer. The only exception consists of the well-known prominent thickening of the tubular basement membrane, which may result in functional loss but does not lead to structural epithelial damage. Conclusion We consistently found that tubulo-interstitial damage develops after encroachment of the glomerular damage onto the tubule, leading first to a gradual degeneration of tubules which subsequently initiate the process of interstitial fibrosis.


Author(s):  
Zhenan Liu ◽  
Joonho Yoon ◽  
Chonlarat Wichaidit ◽  
Ankita B. Jaykumar ◽  
Hashem A. Dbouk ◽  
...  

Cytoskeletal structure and its regulation are essential for maintenance of the differentiated state of specific types of cells and their adaptation to physiologic and pathophysiologic conditions. Renal glomerular capillaries, composed of podocytes, endothelial cells, and the glomerular basement membrane, have distinct structural and biophysical properties and are the site of injury in many glomerular diseases. Calcineurin inhibitors, immunosuppressant drugs used for organ transplantation and auto-immune diseases, can protect podocytes and glomerular capillaries from injury by preserving podocyte cytoskeletal structure. These drugs cause complications including hypertension and hyperkalemia which are mediated by WNK (With No Lysine) kinases as well as vasculopathy with glomerulopathy. WNK kinases and their target kinases oxidative stress-responsive kinase 1 (OSR1) and SPS1-related proline/alanine-rich kinase (SPAK) have fundamental roles in angiogenesis and are activated by calcineurin inhibitors, but the actions of these agents on kidney vasculature, and glomerular capillaries are not fully understood. We investigated WNK1 expression in cultured podocytes and isolated mouse glomerular capillaries to determine if WNK1 contributes to calcineurin inhibitor-induced preservation of podocyte and glomerular structure. WNK1 and OSR1/SPAK are expressed in podocytes, and in a pattern similar to podocyte synaptopodin in glomerular capillaries. Calcineurin inhibitors increased active OSR1/SPAK in glomerular capillaries, the Young’s modulus (E) of glomeruli, and the F/G actin ratio, effects all blocked by WNK inhibition. In glomeruli, WNK inhibition caused reduced and irregular synaptopodin-staining, abnormal capillary and foot process structures, and increased deformability. In cultured podocytes, FK506 activated OSR1/SPAK, increased lamellipodia, accelerated cell migration, and promoted traction force. These actions of FK506 were reduced by depletion of WNK1. Collectively, these results demonstrate the importance of WNK1 in regulation of the podocyte actin cytoskeleton, biophysical properties of glomerular capillaries, and slit diaphragm structure, all of which are essential to normal kidney function.


Nutrients ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 241
Author(s):  
Ran Nakamichi ◽  
Kaori Hayashi ◽  
Hiroshi Itoh

Glomerular podocytes are highly differentiated cells that cover glomerular capillaries from the outside and have a characteristic morphology with numerous foot processes. The formation of slit membranes between the foot processes serves as a final filtration barrier for urine filtration from the blood. Podocyte damage causes disruption of the slit membrane, subsequent proteinuria and finally glomerulosclerosis, which is a common pathway in various types of chronic kidney disease (CKD). In recent years, there has been an increase in diabetes, due to rapid lifestyle changes, which is the main cause of CKD. Therefore, understanding the effect of diabetic status on podocytes is of great importance to establish a strategy for preventing CKD progression. In this review, we summarize altered glucose and lipid metabolism in diabetic podocytes and also discuss the reversibility of the changes in podocyte phenotype.


Author(s):  
Seetu Palo ◽  
Debadutta Mishra

Coronavirus Disease 2019 (COVID‑19) is caused by novel Severe Acute Respiratory Syndrome Coronavirus‑2 (SARS‑CoV‑2). The disease was first reported from Wuhan, China, in December 2019 and since then it continues to spread worldwide. Although, there are rapidly increasing number of studies on epidemiologic characteristics and clinical aspects of COVID‑19, its pathology still remains a largely unexplored territory, mainly due to limited autopsy studies. Autopsy studies are essential to demonstrate the spectrum of COVID‑19‑associated organ changes. This article reviews and highlights the important histopathological findings observed in different organ systems as evident from various published and anecdotal reports from across the world. Major histopathological findings in the lungs include different stages of Diffuse Alveolar Damage (DAD) and microthrombi along with variable degree of inflammation. Microscopic analysis of renal parenchyma may show acute tubular injury and fibrin thrombi in the glomerular capillaries. Heart, liver and brain show no significant inflammatory changes.


F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 1372
Author(s):  
Friederike Kessel ◽  
Hannah Kröger ◽  
Michael Gerlach ◽  
Jan Sradnick ◽  
Florian Gembardt ◽  
...  

Background: Intravital microscopy is an emerging technique in life science with applications in kidney research. Longitudinal observation of (patho-)physiological processes in living mice is possible in the smallest functional unit of the kidney, a single nephron (sn). In particular, effects on glomerular filtration rate (GFR) - a key parameter of renal function - can be assessed. Methods: After intravenous injection of C57BL/6 mice with a freely filtered, non-resorbable, fluorescent dye a time series was captured by multiphoton microsopy. Filtration was observed from the glomerular capillaries to the proximal tubule (PT) and the tubular signal intensity shift was analyzed to calculate the snGFR. Results: Previous methods for this analysis relied on two manually defined measurement points in the PT and the tubular volume was merely estimated in 2D images. We extended the workflow in FIJI by adding continuous measurement of intensity along the PT in every frame of the time series. Automatic modelling of actual PT volume in a 3D dataset replaced 2D volume estimation. Subsequent data analysis in R, with a calculation of intensity shifts in every frame and normalization against tubular volume, allowed exact assessment of snGFR by linear regression. Repeated analysis of image data obtained in healthy mice showed a striking increase of reproducibility by reduction of user interaction. Conclusions: These improvements maximize the reliability of a sophisticated intravital microscopy technique for the precise assessment of snGFR, a highly relevant predictor of kidney function.


Nephron ◽  
2020 ◽  
pp. 1-5
Author(s):  
Kenichiro Miura ◽  
Yoko Shirai ◽  
Naoto Kaneko ◽  
Tomoo Yabuuchi ◽  
Kiyonobu Ishizuka ◽  
...  

Glomerular IgG deposition is rarely observed in antibody-mediated rejection. Here, we report chronic active antibody-mediated rejection with linear IgG deposition on glomerular capillary walls in a pediatric kidney transplant recipient. A 6-year-old boy with bilateral renal hypoplasia underwent preemptive deceased-donor kidney transplantation. Five years after the transplantation, an allograft biopsy revealed chronic active antibody-mediated rejection with diffuse linear IgG deposition on glomerular capillaries. Anti-glomerular basement membrane antibody, donor-specific anti-human leukocyte antigen (HLA) antibodies, and anti-angiotensin II type 1 receptor antibody were negative. A multiplex antibody assay identified anti-major histocompatibility complex class I chain-related molecule A antibody. Additionally, a single-antigen bead assay identified autoantibodies to 12 non-HLA antigens, including vimentin and glutathione S-transferase theta-1. To investigate whether IgG autoantibodies in the patient’s serum bind to antigens on glomerular capillaries, we incubated the patient’s serum with 0-h biopsy specimens of tissue donated to the patient and a control subject, both obtained immediately after nephrectomy from respective donors. IgG signals were observed in neither patient nor control samples. Nevertheless, linear IgG deposition may be explained by the binding of autoantibodies to non-HLA antigens that are usually hidden and only exposed via severe endothelial cell injury. Further studies are needed to confirm the significance of non-HLA antibodies in glomerular IgG deposition.


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