TY - JOUR
T1 - Enhanced MCP-1 Release in Early Autosomal Dominant Polycystic Kidney Disease
AU - Janssens, Peter
AU - Decuypere, Jean Paul
AU - De Rechter, Stéphanie
AU - Breysem, Luc
AU - Van Giel, Dorien
AU - Billen, Jaak
AU - Hindryckx, An
AU - De Catte, Luc
AU - Baldewijns, Marcella
AU - Claes, Kathleen B.M.
AU - Wissing, Karl M.
AU - Devriendt, Koen
AU - Bammens, Bert
AU - Meyts, Isabelle
AU - Torres, Vicente E.
AU - Vennekens, Rudi
AU - Mekahli, Djalila
N1 - Funding Information:
The authors thank Elke Behaeghel, Sandra Van Aerschot, Katrien Luyten, and Sofie Jannes for help with cell culture, quantitative polymerase chain reaction, and immunohistochemistry experiments. Steffen Fieuws is thanked for help with statistical analysis. Yiqiang Cai and Ke Dong (Yale University, New Haven, CT) are thanked for providing the IMCD3 cell lines. BRAHMS GmbH, Themoscientific Germany is acknowledged for providing the reagent for copeptin measurements. Otsuka Pharmaceutical Development and Commercialization , Inc. is aknowledged for providing support for sample analyses. This work was supported by the Research Foundation Flanders ( G0C8920N ) and UZ Leuven . PJ received a clinical doctoral grant of the Research Foundation Flanders (grant number 1702419N ). Above all, the authors wish to thank the participating children and their parents, as well as the nurses involved in the care of the patients.
Publisher Copyright:
© 2021 International Society of Nephrology
PY - 2021/6
Y1 - 2021/6
N2 - Introduction: Autosomal dominant polycystic kidney disease (ADPKD) causes kidney failure typically in adulthood, but the disease starts in utero. Copeptin, epidermal growth factor (EGF), and monocyte chemoattractant protein-1 (MCP-1) are associated with severity and hold prognostic value in adults but remain unstudied in the early disease stage. Kidneys from adults with ADPKD exhibit macrophage infiltration, and a prominent role of MCP-1 secretion by tubular epithelial cells is suggested from rodent models. Methods: In a cross-sectional study, plasma copeptin, urinary EGF, and urinary MCP-1 were evaluated in a pediatric ADPKD cohort and compared with age-, sex-, and body mass index (BMI)-matched healthy controls. MCP-1 was studied in mouse collecting duct cells, human proximal tubular cells, and fetal kidney tissue. Results: Fifty-three genotyped ADPKD patients and 53 controls were included. The mean (SD) age was 10.4 (5.9) versus 10.5 (6.1) years (P = 0.543), and the estimated glomerular filtration rate (eGFR) was 122.7 (39.8) versus 114.5 (23.1) ml/min per 1.73 m2 (P = 0.177) in patients versus controls, respectively. Plasma copeptin and EGF secretion were comparable between groups. The median (interquartile range) urinary MCP-1 (pg/mg creatinine) was significantly higher in ADPKD patients (185.4 [213.8]) compared with controls (154.7 [98.0], P = 0.010). Human proximal tubular cells with a heterozygous PKD1 mutation and mouse collecting duct cells with a PKD1 knockout exhibited increased MCP-1 secretion. Human fetal ADPKD kidneys displayed prominent MCP-1 immunoreactivity and M2 macrophage infiltration. Conclusion: An increase in tubular MCP-1 secretion is an early event in ADPKD. MCP-1 is an early disease severity marker and a potential treatment target.
AB - Introduction: Autosomal dominant polycystic kidney disease (ADPKD) causes kidney failure typically in adulthood, but the disease starts in utero. Copeptin, epidermal growth factor (EGF), and monocyte chemoattractant protein-1 (MCP-1) are associated with severity and hold prognostic value in adults but remain unstudied in the early disease stage. Kidneys from adults with ADPKD exhibit macrophage infiltration, and a prominent role of MCP-1 secretion by tubular epithelial cells is suggested from rodent models. Methods: In a cross-sectional study, plasma copeptin, urinary EGF, and urinary MCP-1 were evaluated in a pediatric ADPKD cohort and compared with age-, sex-, and body mass index (BMI)-matched healthy controls. MCP-1 was studied in mouse collecting duct cells, human proximal tubular cells, and fetal kidney tissue. Results: Fifty-three genotyped ADPKD patients and 53 controls were included. The mean (SD) age was 10.4 (5.9) versus 10.5 (6.1) years (P = 0.543), and the estimated glomerular filtration rate (eGFR) was 122.7 (39.8) versus 114.5 (23.1) ml/min per 1.73 m2 (P = 0.177) in patients versus controls, respectively. Plasma copeptin and EGF secretion were comparable between groups. The median (interquartile range) urinary MCP-1 (pg/mg creatinine) was significantly higher in ADPKD patients (185.4 [213.8]) compared with controls (154.7 [98.0], P = 0.010). Human proximal tubular cells with a heterozygous PKD1 mutation and mouse collecting duct cells with a PKD1 knockout exhibited increased MCP-1 secretion. Human fetal ADPKD kidneys displayed prominent MCP-1 immunoreactivity and M2 macrophage infiltration. Conclusion: An increase in tubular MCP-1 secretion is an early event in ADPKD. MCP-1 is an early disease severity marker and a potential treatment target.
KW - ADPKD
KW - chemokine
KW - distal tubule
KW - inflammation
KW - pediatric nephrology
KW - proximal tubule
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U2 - 10.1016/j.ekir.2021.03.893
DO - 10.1016/j.ekir.2021.03.893
M3 - Article
AN - SCOPUS:85105601719
SN - 2468-0249
VL - 6
SP - 1687
EP - 1698
JO - Kidney International Reports
JF - Kidney International Reports
IS - 6
ER -