P0513NECROINFLAMMATION VERSUS CRYSTAL CLOTS AS THERAPEUTIC TARGET IN CHOLESTEROL CRYSTAL EMBOLISM-RELATED KIDNEY INFARCT

Abstract Background and Aims Cholesterol crystal embolism (CCE) is usually a consequence of the rupture of atheromatous plaques in patients with advanced atherosclerosis. We hypothesized that necroinflammation contributes to CCE-related kidney injury/disease (AKI/AKD). Method Injection of cholesterol crystal (CC) into C56BL/6 WT mice kidney via the left kidney artery induced vascular obstruction, kidney infarction, and GFR loss (measured by transcutaneous monitoring of sinistrin clearance in awake and unrestricted mice). GFR recovered to baseline at 2 weeks despite persistent kidney injury and scarring, probably because the non-injected right kidney developed compensatory hypertrophy. To study the role of necroinflammation in this process, we injected CC to either Mlkl-/- mice or WT mice pre-treated with PBS, the necroptosis inhibitor Nec-1s or the NLRP3 inhibitor MCC950 30 min before CC injection. Results At 24h, Nec-1s, MCC950 treatment had significantly reduced infarct size, kidney injury, neutrophil infiltration, and vascular injury compared to PBS control group. Reduced infarct size, e.g. with Nec-1s persistented until day 14. CC injection into Mlkl-/- mice gave the same results. However, none of these interventions had an effect on GFR loss, i.e. AKI because they did not affect crystal clot formation in the arteria afferent to glomerular perfusion. In contrast, anticoagulant treatment prevented infarcts and GFR loss. Conclusion In this new model of unilateral CCE-induced AKI/AKD global kidney function recovers within 14 d, presumably due to adaptive responses in the contralateral kidney as the post-infarct tissue injury persists and leads to kidney atrophy. As both the NLRP3 inflammasome as well as necroptosis are involved in kidney infarct formation, we conclude on necroinflammation as the central mechanism of CCE-induced AKI/AKD. However, what defines AKI is renal function. We found that crystal clot formation is upstream of kidney infarction but independent of necroinflammation. We conclude, despite necroinflammation is central in kidney infarct formation, crystal clots are the better therapeutic target to prevent CCE-related AKI.

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Crystal Clots as Therapeutic Target in Cholesterol Crystal Embolism

Circulation Research ◽

10.1161/circresaha.119.315625 ◽

2020 ◽

Vol 126 (8) ◽

Cited By ~ 2

Author(s):

Chongxu Shi ◽

Tehyung Kim ◽

Stefanie Steiger ◽

Shrikant R. Mulay ◽

Barbara M. Klinkhammer ◽

...

Keyword(s):

Organ Failure ◽

Molecular Mechanisms ◽

Left Kidney ◽

Arterial Occlusion ◽

Dnase I ◽

Extracellular Dna ◽

Dependent Manner ◽

Cholesterol Crystal ◽

Cholesterol Crystal Embolism ◽

Acute Kidney Disease

Rationale: Cholesterol crystal embolism can be a life-threatening complication of advanced atherosclerosis. Pathophysiology and molecular targets for treatment are largely unknown. Objective: We aimed to develop a new animal model of cholesterol crystal embolism to dissect the molecular mechanisms of cholesterol crystal (CC)–driven arterial occlusion, tissue infarction, and organ failure. Methods and Results: C57BL/6J mice were injected with CC into the left kidney artery. Primary end point was glomerular filtration rate (GFR). CC caused crystal clots occluding intrarenal arteries and a dose-dependent drop in GFR, followed by GFR recovery within 4 weeks, that is, acute kidney disease. In contrast, the extent of kidney infarction was more variable. Blocking necroptosis using mixed lineage kinase domain–like deficient mice or necrostatin-1s treatment protected from kidney infarction but not from GFR loss because arterial obstructions persisted, identifying crystal clots as a primary target to prevent organ failure. CC involved platelets, neutrophils, fibrin, and extracellular DNA. Neutrophil depletion or inhibition of the release of neutrophil extracellular traps had little effects, but platelet P2Y12 receptor antagonism with clopidogrel, fibrinolysis with urokinase, or DNA digestion with recombinant DNase I all prevented arterial occlusions, GFR loss, and kidney infarction. The window-of-opportunity was <3 hours after CC injection. However, combining Nec-1s (necrostatin-1s) prophylaxis given 1 hour before and DNase I 3 hours after CC injection completely prevented kidney failure and infarcts. In vitro, CC did not directly induce plasmatic coagulation but induced neutrophil extracellular trap formation and DNA release mainly from kidney endothelial cells, neutrophils, and few from platelets. CC induced ATP release from aggregating platelets, which increased fibrin formation in a DNase-dependent manner. Conclusions: CC embolism causes arterial obstructions and organ failure via the formation of crystal clots with fibrin, platelets, and extracellular DNA as critical components. Therefore, our model enables to unravel the pathogenesis of the CC embolism syndrome as a basis for both prophylaxis and targeted therapy.

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Galectin-3 in septic acute kidney injury: a translational study

Critical Care ◽

10.1186/s13054-021-03538-0 ◽

2021 ◽

Vol 25 (1) ◽

Author(s):

Haibing Sun ◽

Huiping Jiang ◽

Amity Eliaz ◽

John A. Kellum ◽

Zhiyong Peng ◽

...

Keyword(s):

Acute Kidney Injury ◽

Therapeutic Target ◽

Cecal Ligation ◽

Kidney Injury ◽

Apache Ii Score ◽

Control Group ◽

Potential Utility ◽

Icu Mortality ◽

Translational Study ◽

Galectin 3

Abstract Background Galectin-3 (Gal-3) is a pleiotropic glycan-binding protein shown to be involved in sepsis and acute kidney injury (AKI). However, its role has never been elucidated in sepsis-associated AKI (S-AKI). We aimed to explore Gal-3’s role and its potential utility as a therapeutic target in S-AKI. Methods In 57 patients admitted to the intensive care unit (ICU) with sepsis, serum Gal-3 was examined as a predictor of ICU mortality and development of AKI. In a rat model of S-AKI induced by cecal ligation and puncture (CLP), 7-day mortality and serum Gal-3, Interleukin-6 (IL-6), and creatinine were examined at 2, 8, and 24 hours (h) post-CLP. Two experimental groups received the Gal-3 inhibitor modified citrus pectin (P-MCP) at 400 mg/kg/day and 1200 mg/kg/day, while the control group received water only (n = 18 in each group). Results Among 57 patients, 27 developed AKI and 8 died in the ICU. Serum Gal-3 was an independent predictor of AKI (OR = 1.2 [95% CI 1.1–1.4], p = 0.01) and ICU mortality (OR = 1.4 [95% CI 1.1–2.2], p = 0.04) before and after controlling for age, AKI, and acute physiology and chronic health evaluation (APACHE II) score. In the CLP rat experiment, serum Gal-3 peaked earlier than IL-6. Serum Gal-3 was significantly lower in both P-MCP groups compared to control at 2 h post-CLP (400 mg: p = 0.003; 1200 mg: p = 0.002), and IL-6 was significantly lower in both P-MCP groups at all time points with a maximum difference at 24 h post-CLP (400 mg: p = 0.015; 1200 mg: p = 0.02). In the Gal-3 inhibitor groups, 7-day mortality was significantly reduced from 61% in the control group to 28% (400 mg P-MCP: p = 0.03) and 22% (1200 mg P-MCP: p = 0.001). Rates of AKI per RIFLE criteria were significantly reduced from 89% in the control group to 44% in both P-MCP groups (400 mg: p = 0.007; 1200 mg: p = 0.007). Conclusions This translational study demonstrates the importance of Gal-3 in the pathogenesis of S-AKI, and its potential utility as a therapeutic target. Graphic abstract

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Galectin-3 In Septic Acute Kidney Injury: A Translational Study

10.21203/rs.3.rs-138545/v1 ◽

2021 ◽

Author(s):

Haibing Sun ◽

Huiping Jiang ◽

Amity Eliaz ◽

John A. Kellum ◽

Zhiyong Peng ◽

...

Keyword(s):

Acute Kidney Injury ◽

Therapeutic Target ◽

Cecal Ligation ◽

Kidney Injury ◽

Apache Ii Score ◽

Control Group ◽

Potential Utility ◽

Icu Mortality ◽

Translational Study ◽

Galectin 3

Abstract Background Galectin-3 (Gal-3) is a pleiotropic glycan-binding protein shown to be involved in sepsis and acute kidney injury (AKI). However, its role has never been elucidated in sepsis-associated AKI (S-AKI). We aimed to explore Gal-3’s role and its potential utility as a therapeutic target in S-AKI. MethodsIn 57 patients admitted to the intensive care unit (ICU) with sepsis, serum Gal-3 was examined as a predictor of ICU mortality and AKI. In a rat model of S-AKI induced by cecal ligation and puncture (CLP), 7-day mortality and serum Gal-3, IL-6, and creatinine were examined at baseline, 2, 8, and 24 hours (h) post-CLP. Two experimental groups received the Gal-3 inhibitor modified citrus pectin (P-MCP) at 400 mg/kg/day and 1200 mg/kg/day, while the control group received water only (n = 18 in each group). ResultsAmong 57 patients, 27 developed AKI and 8 died in the ICU. Serum Gal-3 was an independent predictor of AKI (OR = 1.2 [95% CI 1.1-1.4], p = 0.01) and ICU mortality (OR = 1.4 [95% CI 1.1-2.2], p = 0.04) before and after controlling for age, AKI, and acute physiology and chronic health evaluation (APACHE II) score. In the CLP rat experiment, serum Gal-3 peaked earlier than Interleukin-6 (IL-6). Serum Gal-3 was significantly lower in both P-MCP-treated groups compared to control at 2 h post-CLP (400 mg: p = 0.003; 1200 mg: p = 0.002), and IL-6 was significantly lower in both P-MCP-treated groups at all time points with a maximum difference at 24 h post-CLP (400 mg: p = 0.015; 1200 mg: p = 0.02). In the Gal-3 inhibitor groups, 7-day mortality was significantly reduced from 61% in the control group to 28% (400 mg P-MCP: p = 0.03) and 22% (1200 mg P-MCP: p = 0.001). Rates of AKI per RIFLE criteria were significantly reduced from 89% in the control group to 44% in both P-MCP-treated groups (400mg: p = 0.007; 1200mg: p = 0.007). ConclusionsThis translational study demonstrates the importance of Gal-3 in the pathogenesis of S-AKI, and its potential utility as a therapeutic target.

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Renoprotective Effects of Artesunate against Renal Ischemia-Reperfusion Injury in Rat Model

International Journal of Research in Pharmaceutical Sciences ◽

10.26452/ijrps.v9ispl1.1405 ◽

2018 ◽

Vol 9 (SPL1) ◽

Author(s):

Bassim I Mohammed ◽

Najah R Hadi ◽

Jabber Huda ◽

Galal Elkilany ◽

RB Singh

Keyword(s):

Acute Kidney Injury ◽

Renal Function ◽

Tissue Injury ◽

Ischemia Reperfusion ◽

Plasma Concentrations ◽

Kidney Tissue ◽

Kidney Injury ◽

Renal Ischemia ◽

Control Group ◽

Tissue Concentrations

Renal ischemia-reperfusion (Renal I/R) leads to acute kidney injury (AKI),a major kidney disease associated with an increasing prevalence and high mortality rates. A variety of experimental models,both in vitro and in vivo,have been used to study the pathogenic mechanisms of ischemic AKI and to test reno-protective strategies. Aim: To study potential protective effects of artesunate on renal I/R injury. Renal I/R injury was unilaterally induced in adult (3 to 5 months) male Sprague-Dawely rats,whose weights ranged from 180 to 390 g. Thereafter,the animals were pre-treated with artesunate intra-peritoneally,and at the end of reperfusion sacrificed humanely. Plasma,serum and tissue samples were obtained for analysis. Plasma concentrations of NGAL (neutrophil gelatinase associated lipocalin),an iron-trafficking protein involved in multiple processes such as apoptosis,innate immunity and renal development,and tissue concentrations of IL-18 (Interleukin-18) were measured via ELISA analysis. Serum urea and creatinine were also measured in the samples. Artesunate improved renal ischemia reperfusion,including renal function and brought about reductions in inflammatory mediators and kidney tissue injury. Plasma concentrations of NGAL and tissue concentrations of IL-18 were significantly (p < 0.05) lower in the artesunatepretreated group than in the vehicle and control groups. Furthermore,serum concentrations of urea and creatinine were significantly (p < 0.05) decreased in the pretreated group as compared to the control group. Artesunate can significantly improve renal function following I/R through down-regulation of inflammatory parameters and NGAL expression. Furthermore,it could serve as a potential therapy in ischemia reperfusion-induced acute kidney injury.

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MO468NEW URINARY BIOMARKERS DETECT SUBCLINICAL RENAL DAMAGE AFTER SEVERAL ACUTE KIDNEY INJURY EPISODES

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab090.0030 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Giampiero A Massaro ◽

Joana Mercado-Hernandez ◽

Ana Carbajo-Uña ◽

Isabel Fuentes-Calvo ◽

Sandra M Sancho Martinez ◽

...

Keyword(s):

Acute Kidney Injury ◽

Renal Function ◽

Ischemia Reperfusion ◽

Left Kidney ◽

Kidney Injury ◽

Renal Ischemia ◽

Urinary Biomarkers ◽

Control Group ◽

Clinical Parameters ◽

Group 5

Abstract Background and Aims Acute kidney injury (AKI) represents a clinical problem due to its increasing prevalence and association with further morbidities. Observational studies have shown that AKI increases the risk of a new AKI episode, chronic kidney disease (CKD), CKD progression, end-stage renal disease (ESRD), and mortality. Serum creatinine (sCr) is the parameter most used by clinicians for determining AKI and the subsequent recovery, however its use presents several limitations. sCr lacks sensitivity for AKI and provides minimal insight into the renal structure. Indeed, increases in sCr are observed only when glomerular filtration rate decreases more than 50%. Therefore, new markers need to be identified to predict recovery after AKI and to detect residual structural alterations that can cause progression to CKD. We hypothesised that after AKI, there are renal structural abnormalities that cannot be detected by common clinical parameters but may be detected by urinary biomarkers. Method We used 4 weeks old male Wistar rats. Animals were divided into 5 experimental groups: Control group: SHAM operated rats, saline solution i.p.; “CDDP5-SHAM” group: 5 mg/kg cisplatin i.p.; “Ctrl-I/R60” group: 60-minute renal ischemia reperfusion in the left kidney; “CDDP5-I/R60” group: 5 mg/kg cisplatin i.p. and after renal function normalization, 60-minute ischemia-reperfusion (I/R60); “5/6 NEF” group: 5/6 nephrectomy. Blood and urine were collected at: day 0 (basal); day 4 (AKI development); day 8 (normalized renal function after AKI and induction of renal ischemia); day 9 (1 day after ischemia); day 13, day 20 and every week thereafter. Renal function was analyzed by sCr, creatinine clearance, blood urea nitrogen and proteinuria determination using colorimetric methods. Urinary biomarkers were analyzed at day 20 (12 days after the second damage and 20 after the first one) by western blot and ELISA. Animals were sacrificed at the same time point in which urinary biomarkers were determined, and renal tissue samples were stained with Masson´s trichrome, Sirius Red and Periodic Acid-Schiff for histological analysis. Results Frequency of AKI episodes is related to the amount and degree of subclinical alterations detected in the kidneys, even though renal filtration is apparently normal. We characterized a novel panel of urinary biomarkers (bk1-bk4) several days after the last insult (day 20) when renal function appeared normal; these biomarkers were present in highest concentrations in the CDDP5-I/R60 experimental group. Conclusion These results demonstrate the importance of the clinical implementation of biomarkers as useful tools for medical support and underline the limitations of the clinical parameters (e.g. sCr, estimated GFR) currently used for renal function assessment. The frequency of AKI episodes is related to a poor prognosis, so a follow up is necessary after AKI episodes in order to prevent mortality and progression of the disease.

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Cholesterol Crystal Embolism

Kidney Protection ◽

10.1093/med/9780190611620.003.0044 ◽

2019 ◽

pp. 439-446

Author(s):

Alain Meyrier

Keyword(s):

Renal Function ◽

Renal Insufficiency ◽

Lower Limb ◽

Kidney Injury ◽

Cholesterol Crystal ◽

Muscle Involvement ◽

Small Arteries ◽

Blood Eosinophilia ◽

Common Features ◽

Cholesterol Crystal Embolism

Cholesterol crystal embolism (CCE) is a frequent complication of aortic atherosclerotic plaques triggered by vascular radiology, vascular surgery, and/or anticoagulation. Crystals lodge in small arteries and induce early thrombosis followed by delayed, definitive obstruction by endarteritis. Lower limb cutaneous involvement with livedo reticularis and blue/purple toes along with blood eosinophilia are common features of diagnostic interest. Massive CCE leads to early oligoanuria and often death from multivisceral compromise. In subacute forms, clinical manifestation of kidney injury may be delayed by several weeks following the triggering event. The chronic subset can be easily mistaken for nephrosclerosis. Cutaneous, retinal, and muscle involvement allow diagnosis without resort to kidney biopsy in about 80% of cases. Treatment of acute/subacute forms of renal insufficiency consists of stopping anticoagulation and forbidding any new triggering procedure along with supportive measures including dialysis, parenteral nutrition, corticosteroids, and statins. About 40% of survivors do not recover renal function and remain on dialysis.

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FC 003HYPERURICEMIA HAS VASOACTIVE EFFECTS IN CHOLESTEROL CRYSTAL-INDUCED ACUTE KIDNEY INJURY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab142.003 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Luying Yang ◽

Elmina Mammadova-Bach ◽

Attila Braun ◽

Thomas Gudermann ◽

Hans-Joachim Anders ◽

...

Keyword(s):

Acute Kidney Injury ◽

Platelet Aggregation ◽

Infarct Size ◽

Kidney Injury ◽

Chow Diet ◽

Cholesterol Crystal ◽

Contralateral Kidney ◽

Arterial Blood

Abstract Background and Aims Numerous observational studies have reported an association between hyperuricemia (HU) and cardiovascular disease where atherosclerosis is a leading cause. In advanced atherosclerosis, cholesterol crystal (CC) embolism is a life-threatening complication with an average mortality of 62.8%. Clinical manifestations include skin necrosis, intestinal injury and acute kidney injury (AKI). Autopsies and tissue biopsies reveal CC inside the arterial lumen. In a new model of CC-induced AKI, we recently found that fibrin clots formed around CC obstruct peripheral arteries and cause tissue infarction and organ failure. However, the role of asymptomatic HU in CC-induced AKI is currently unknown. Thus, we hypothesized that asymptomatic HU improves the outcomes after CC-induced AKI. Method In vivo, 6 weeks old Alb-creERT2;Glut9lox/lox and Glut9lox/lox control mice were intraperitoneally injected with tamoxifen to deplete hepatic Glut9 expression. Both groups of mice were placed on a standard chow diet enriched with inosine for two weeks. Afterward, a solution of CCs was injected into the left kidney arteries of mice to induce AKI. Serum and kidneys were collected 24 hours later, and kidney function, infarct size and kidney injury evaluated using GFR measurement, colorimetric assays, ELISA and immunohistochemistry of kidney sections. For in vitro studies, we isolated platelets from healthy mice and cultured them in the presence or absence of soluble uric acid (sUA) prior to CC activation. After stimulation, platelet aggregation assays and flow cytometry were performed. Results Our in vivo data showed that Alb-creERT2;Glut9lox/lox mice developed asymptomatic HU without kidney impairment (serum UA levels 9-15 mg/dL), while Glut9lox/lox control mice remained healthy. HU mice displayed a rapid decline in GFR of approx. 80% as compared to only 30% in healthy mice after CC-induced AKI, which was in line with increased serum BUN and IL-6 levels. The rapid GFR decline was due to vasoconstriction in arteries of the contralateral kidney as determined by αSMA/fibrin staining and a reduced ratio of lumen versus artery area in mice with HU after AKI. HU mice also had significantly less kidney infarct size as well as reduced kidney injury (necrosis and edema) and arterial occlusion. The in vitro data showed that sUA had no impact on platelet aggregation, activation and degranulation as compared to medium control in response to CCs. Conclusion We now show that HU has vasoconstrictive effects in the contralateral kidney by reducing GFR, while at the same time protects mice from CC-induced AKI suggesting a compensatory physiological mechanism of autoregulation to protect nephrons. On the other hand, in patients with chronic kidney disease, HU-related vasoconstriction might lead to increased arterial blood pressure; thus, increasing the risk for cardiovascular complications due to platelet activation and aggregation.

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Apigenin alleviates methotrexate-induced liver and kidney injury in mice

Human & Experimental Toxicology ◽

10.1177/09603271211009964 ◽

2021 ◽

pp. 096032712110099

Author(s):

F Sahindokuyucu-Kocasari ◽

Y Akyol ◽

O Ozmen ◽

SB Erdemli-Kose ◽

S Garli

Keyword(s):

Oxidative Stress ◽

Protective Effect ◽

Tissue Injury ◽

Inflammatory Diseases ◽

Kidney Injury ◽

Treated Group ◽

Control Group ◽

Oxidative Stress Biomarkers ◽

Kidney Toxicity ◽

Liver And Kidney

Methotrexate (MTX) is a drug used in the treatment of various types of cancer and inflammatory diseases, but its clinical use has been restricted due to its toxicity. Apigenin (API) is an effective flavonoid with antioxidant and anti-inflammatory properties. The aim of this study was to determine the protective effect of API against MTX-induced liver and kidney toxicity. Four groups with 12 male mice each were used. The control and API groups were received 0.9% saline (ip) and API (3 mg/kg ip) for 4 days, respectively. The MTX group were given a single dose of MTX (20 mg/kg ip) on the fourth day. The MTX + API group were administered API for 7 days and then MTX on fourth day. Blood, liver and kidney were collected to evaluate tissue injury markers, oxidative stress biomarkers, and histopathological and immunohistochemical assessments. In MTX-treated group, significant increases in aminotransferases activities, creatinine and malondialdehyde (MDA) levels and significant decreases in catalase (CAT), glutathione peroxidase (GSH-Px) and superoxide dismutase1 (SOD1) activities and glutathione (GSH) levels were determined compared to the control group. Furthermore, histopathological changes and significant increases in caspase-3, C-reactive protein (CRP), granulocyte colony-stimulating factor (G-CSF), and inducible nitric oxide synthase (iNOS) expressions were detected in both liver and kidney tissues of MTX-treated mice. Pretreatment with API alleviates liver and kidney toxicity by attenuating oxidative stress and tissue injury markers, histopathological alterations, and apoptosis and inflammation. These results suggest that API has a protective effect against oxidative stress and liver-kidney toxicity induced by MTX.

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Assessment of Subclinical Renal Glomerular and Tubular Dysfunction in Children with Beta Thalassemia Major

Children ◽

10.3390/children8020100 ◽

2021 ◽

Vol 8 (2) ◽

pp. 100

Author(s):

Asmaa A. Mahmoud ◽

Doaa M. Elian ◽

Nahla MS. Abd El Hady ◽

Heba M. Abdallah ◽

Shimaa Abdelsattar ◽

...

Keyword(s):

Cystatin C ◽

Kidney Injury ◽

Thalassemia Major ◽

Beta Thalassemia ◽

Good Survival ◽

Control Group ◽

Healthy Children ◽

Serum Cystatin C ◽

Serum Cystatin ◽

Beta Thalassemia Major

Background: A good survival rate among patients with beta thalassemia major (beta-TM) has led to the appearance of an unrecognized renal disease. Therefore, we aimed to assess the role of serum cystatin-C as a promising marker for the detection of renal glomerular dysfunction and N-acetyl beta-D-glucosaminidase (NAG) and kidney injury molecule 1 (KIM-1) as potential markers for the detection of renal tubular injury in beta-TM children. Methods: This case-control study was implemented on 100 beta-TM children receiving regular blood transfusions and undergoing iron chelation therapy and 100 healthy children as a control group. Detailed histories of complete physical and clinical examinations were recorded. All subjected children underwent blood and urinary investigations. Results: There was a significant increase in serum cystatin-C (p < 0.001) and a significant decrease in eGFR in patients with beta-TM compared with controls (p = 0.01). There was a significant increase in urinary NAG, KIM-1, UNAG/Cr, and UKIM-1/Cr (p < 0.001) among thalassemic children, with a significant positive correlation between serum cystatin-C, NAG and KIM-1 as regards serum ferritin, creatinine, and urea among thalassemic patients. A negative correlation between serum cystatin-C and urinary markers with eGFR was noted. Conclusion: Serum cystatin-C is a good marker for detection of glomerular dysfunction. NAG and KIM-1 may have a predictive role in the detection of kidney injury in beta-TM children.

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CD73 Overexpression in Podocytes: A Novel Marker of Podocyte Injury in Human Kidney Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22147642 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7642

Author(s):

Zoran V. Popovic ◽

Felix Bestvater ◽

Damir Krunic ◽

Bernhard K. Krämer ◽

Raoul Bergner ◽

...

Keyword(s):

Kidney Disease ◽

Kidney Diseases ◽

Kidney Injury ◽

Membranous Glomerulonephritis ◽

Human Kidney ◽

Protective Role ◽

Control Group ◽

Podocyte Injury ◽

Ccr2 Expression ◽

Cd73 Expression

The CD73 pathway is an important anti-inflammatory mechanism in various disease settings. Observations in mouse models suggested that CD73 might have a protective role in kidney damage; however, no direct evidence of its role in human kidney disease has been described to date. Here, we hypothesized that podocyte injury in human kidney diseases alters CD73 expression that may facilitate the diagnosis of podocytopathies. We assessed the expression of CD73 and one of its functionally important targets, the C-C chemokine receptor type 2 (CCR2), in podocytes from kidney biopsies of 39 patients with podocytopathy (including focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranous glomerulonephritis (MGN) and amyloidosis) and a control group. Podocyte CD73 expression in each of the disease groups was significantly increased in comparison to controls (p < 0.001–p < 0.0001). Moreover, there was a marked negative correlation between CD73 and CCR2 expression, as confirmed by immunohistochemistry and immunofluorescence (Pearson r = −0.5068, p = 0.0031; Pearson r = −0.4705, p = 0.0313, respectively), thus suggesting a protective role of CD73 in kidney injury. Finally, we identify CD73 as a novel potential diagnostic marker of human podocytopathies, particularly of MCD that has been notorious for the lack of pathological features recognizable by light microscopy and immunohistochemistry.

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