Context: Soluble urokinase-type plasminogen activator -(suPAR) is an inflammatory signal with pleiotropic biological effects depending on context and post-translational modifications. Recently, [Hayek, et al: Nat Med 2017; 23: 945–953] it has been found that there is a link between suPAR and renal disease in several guises, and a key question is whether it is a driver or a marker of renal disease, and if so of which types of kidney damage. Subject of Review: Circulating suPAR has been postulated to cause acute proteinuric kidney disease, specifically focal segmental glomerulosclerosis (FSGS), though both the animal models and clinical data in the original reports have been challenged. More recently, suPAR levels are linked to the risk of progression of chronic kidney disease (CKD) by directly activating signaling pathways in the podocyte or as a sensitive early biomarker. Second Opinion: The evidence for suPAR as a driver of FSGS proteinuria is not yet established, and more needs to be done, particularly by measuring different circulating suPAR fragments and identifying “second hits,” to clarify if any role exists. The evidence for suPAR as a sensitive biomarker for CKD progression is currently stronger, and needs further independent validation as well as prospective serial suPAR measurements in CKD cohorts. Whether it is a surrogate marker for ongoing inflammatory drivers of kidney disease, or has direct mechanistic effects in podocytes will depend on further studies, as well as trials of suPAR removal or direct blockade of downstream pathways.

Keywords:
Focal segmental glomerular sclerosis, Renal disease, Soluble urokinase-type plasminogen activator
1.
Sappino AP, et al: Sites of synthesis of urokinase and tissue-type plasminogen activators in the murine kidney. J Clin Invest 1991; 87: 962–970.
2.
Thuno M, Macho B, Eugen-Olsen J: suPAR: the molecular crystal ball. Dis Markers 2009; 27: 157–172.
3.
Behrendt N, et al: The ligand-binding domain of the cell surface receptor for urokinase-type plasminogen activator. J Biol Chem 1991; 266: 7842–7847.
4.
Sidenius N, et al: Shedding and cleavage of the urokinase receptor (uPAR): identification and characterisation of uPAR fragments in vitro and in vivo. FEBS Lett 2000; 475: 52–56.
5.
Wei Y, et al: Identification of the urokinase receptor as an adhesion receptor for vitronectin. J Biol Chem 1994; 269: 32380–32388.
6.
Ploug M, et al: Photoaffinity labeling of the human receptor for urokinase-type plasminogen activator using a decapeptide antagonist. Evidence for a composite ligand-binding site and a short interdomain separation. Biochemistry 1998; 37: 3612–3622.
7.
Hillig T et al: A composite role of vitronectin and urokinase in the modulation of cell morphology upon expression of the urokinase receptor. J Biol Chem 2008; 283: 15217–15223.
8.
van Veen M, et al: Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cells. Elife 2017; 6:e23649.
9.
Mustjoki S, et al: Soluble urokinase receptor levels correlate with number of circulating tumor cells in acute myeloid leukemia and decrease rapidly during chemotherapy. Cancer Res 2000; 60: 7126–7132.
10.
Pliyev BK: Activated human neutrophils rapidly release the chemotactically active D2D3 form of the urokinase-type plasminogen activator receptor (uPAR/CD87). Mol Cell Biochem 2009; 321: 111–122.
11.
Alfano M, et al: Urokinase-urokinase receptor interaction mediates an inhibitory signal for HIV-1 replication. Proc Natl Acad Sci U S A 2002; 99: 8862–8867.
12.
Fazioli F, et al: A urokinase-sensitive region of the human urokinase receptor is responsible for its chemotactic activity. EMBO J 1997; 16: 7279–7286.
13.
Gozdzik W, et al: Unchanged plasma levels of the soluble urokinase plasminogen activator receptor in elective coronary artery bypass graft surgery patients and cardiopulmonary bypass use. PLoS One 2014; 9:e98923.
14.
Myohanen HT, et al: Distribution and lateral mobility of the urokinase-receptor complex at the cell surface. J Histochem Cytochem 1993; 41: 1291–1301.
15.
Estreicher A, et al: The receptor for urokinase type plasminogen activator polarizes expression of the protease to the leading edge of migrating monocytes and promotes degradation of enzyme inhibitor complexes. J Cell Biol 1990; 111: 783–792.
16.
Duriseti S, et al: Antagonistic anti-urokinase plasminogen activator receptor (uPAR) antibodies significantly inhibit uPAR-mediated cellular signaling and migration. J Biol Chem 2010; 285: 26878–26888.
17.
Kugler MC, Wei Y, Chapman HA: Urokinase receptor and integrin interactions. Curr Pharm Des 2003; 9: 1565–1574.
18.
Furlan F, et al: The soluble D2D3(88–274) fragment of the urokinase receptor inhibits monocyte chemotaxis and integrin-dependent cell adhesion. J Cell Sci 2004; 117: 2909–2916.
19.
Jo M, et al: Soluble urokinase-type plasminogen activator receptor inhibits cancer cell growth and invasion by direct urokinase-independent effects on cell signaling. J Biol Chem 2003; 278: 46692–46698.
20.
Wei C, et al: Modification of kidney barrier function by the urokinase receptor. Nat Med 2008; 14: 55–63.
21.
Wei C, et al: Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat Med 2011; 17: 952–960.
22.
Maas RJ, Deegens JK, Wetzels JF: Serum suPAR in patients with FSGS: trash or treasure? Pediatr Nephrol 2013; 28: 1041–1048.
23.
Wada T, Nangaku M: A circulating permeability factor in focal segmental glomerulosclerosis: the hunt continues. Clin Kidney J 2015; 8: 708–715.
24.
Cathelin D, et al: Administration of recombinant soluble urokinase receptor per se is not sufficient to induce podocyte alterations and proteinuria in mice. J Am Soc Nephrol 2014; 25: 1662–1668.
25.
Spinale JM, et al: A reassessment of soluble urokinase-type plasminogen activator receptor in glomerular disease. Kidney Int 2015; 87: 564–574.
26.
Wu CZ, et al: Urokinase plasminogen activator receptor and its soluble form in common biopsy-proven kidney diseases and in staging of diabetic nephropathy. Clin Biochem 2015; 48: 1324–1329.
27.
Hahm E, et al: Bone marrow-derived immature myeloid cells are a main source of circulating suPAR contributing to proteinuric kidney disease. Nat Med 2017; 23: 100–106.
28.
Delville M, et al: A circulating antibody panel for pretransplant prediction of FSGS recurrence after kidney transplantation. Sci Transl Med 2014; 6: 256ra136.
29.
Ploug M, et al: A soluble form of the glycolipid-anchored receptor for urokinase-type plasminogen activator is secreted from peripheral blood leukocytes from patients with paroxysmal nocturnal hemoglobinuria. Eur J Biochem 1992; 208: 397–404.
30.
Clark DA, et al: The kidneys in paroxysmal nocturnal hemoglobinuria. Blood 1981; 57: 83–89.
31.
Meijers B, et al: Soluble urokinase receptor is a biomarker of cardiovascular disease in chronic kidney disease. Kidney Int 2015; 87: 210–216.
32.
Bertozzi P, et al: Depressed bronchoalveolar urokinase activity in patients with adult respiratory distress syndrome. N Engl J Med 1990; 322: 890–897.
33.
Idell S et al: Local abnormalities in coagulation and fibrinolytic pathways predispose to alveolar fibrin deposition in the adult respiratory distress syndrome. J Clin Invest 1989; 84: 695–705.
34.
Masucci MT, Pedersen N, Blasi F: A soluble, ligand binding mutant of the human urokinase plasminogen activator receptor. J Biol Chem 1991; 266: 8655–8658.
35.
Sisson TH, et al: Inducible lung-specific urokinase expression reduces fibrosis and mortality after lung injury in mice. Am J Physiol Lung Cell Mol Physiol 2002; 283:L1023–L1032.
36.
Emrah A, et al: Increased circulating soluble urokinase-type plasminogen activator receptor (suPAR) levels in patients with slow coronary flow. Arch Med Sci Atheroscler Dis 2016; 1:e53–e59.
37.
Hayek SS, et al: Soluble urokinase receptor and chronic kidney disease. N Engl J Med 2015; 373: 1916–1925.
38.
Hayek SS, et al: Cardiovascular disease biomarkers and suPAR in predicting decline in renal function: a prospective cohort study. Kidney Int Rep 2017; 2: 425–432.
39.
Schaefer F, et al: Association of serum soluble urokinase receptor levels with progression of kidney disease in children. JAMA Pediatr 2017; 171:e172914.
40.
Schulz CA, et al; Soluble irokinase-type plasminogen activator receptor (suPAR) and impaired kidney function in the population-based Malmo Diet and Cancer Study. Kidney Int Rep 2017; 2: 239–247.
41.
Mossanen JC, et al: Elevated soluble urokinase plasminogen activator receptor and proenkephalin serum levels predict the development of acute kidney injury after cardiac surgery. Int J Mol Sci 2017; 18:pii:E1662 .
42.
Parsa A, et al: APOL1 risk variants, race, and progression of chronic kidney disease. N Engl J Med 2013; 369: 2183–2196.
43.
Hayek SS, et al: A tripartite complex of suPAR, APOL1 risk variants and alphavbeta3 integrin on podocytes mediates chronic kidney disease. Nat Med 2017; 23: 945–953.
44.
Ding WY, et al: Initial steroid sensitivity in children with steroid-resistant nephrotic syndrome predicts post-transplant recurrence. J Am Soc Nephrol 2014; 25: 1342–1348.
45.
Bierzynska A et al: Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management. Kidney Int 2017; 91: 937–947.
46.
Wei C et al: Circulating suPAR in two cohorts of primary FSGS. J Am Soc Nephrol 2012; 23: 2051–2059.
47.
Quaglia M, Musetti C, Cantaluppi V: Soluble urokinase receptor and chronic kidney disease. N Engl J Med 2016; 374: 890.
48.
Bowe B, et al: Association between monocyte count and risk of incident CKD and progression to ESRD. Clin J Am Soc Nephrol 2017; 12: 603–613.
49.
Heine GH, et al: Monocyte subpopulations and cardiovascular risk in chronic kidney disease. Nat Rev Nephrol 2012; 8: 362–369.
50.
Kim EY, Roshanravan H, Dryer SE: Changes in podocyte TRPC channels evoked by plasma and sera from patients with recurrent FSGS and by putative glomerular permeability factors. Biochim Biophys Acta 2017; 1863: 2342–2354.
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2018
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