Trachtman BMC Medicine 2014, 12:82http://www.biomedcentral.com/1741-7015/12/82

COMMENTARY Open Access

suPAR and Team NephrologyHoward Trachtman

Abstract

Primary focal segmental glomerulosclerosis (FSGS) accounts for nearly 10 % of patients who require renalreplacement therapy. Elevated circulating levels of soluble urokinase receptor (suPAR) have been identified as abiomarker to discriminate primary FSGS from other glomerulopathies. Subsequent reports have questioned thediagnostic utility of this test. In a study in BMC Medicine, Huang et al. demonstrate that urinary soluble urokinasereceptor (suPAR) excretion assists in distinguishing primary FSGS from other glomerular diseases, and that highplasma suPAR concentrations are not directly linked to a decline in glomerular filtration rate (GFR). This observationsuggests that further investigation of suPAR is warranted in patients with FSGS. It should be interpreted in light of arecent report that B7-1 is expressed in the podocytes of a subset of patients with FSGS, and that blocking thismolecule may represent the first successful targeted intervention for this disease. These advances highlight therapid pace of scientific progress in the field of nephrology. Nephrologists should work together, share resources,and expedite the design of protocols to evaluate these novel biomarkers in a comprehensive and scientifically validmanner.

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Keywords: Focal segmental glomerulosclerosis (FSGS), Soluble urokinase receptor (suPAR), Podocyte, B7.1

IntroductionThere appears to be a basic drive in human beings to try tobecome members of teams. It is part of our nature as socialanimals to define ourselves based on our self-perception ofwho we are and how we differ from those outside ourgroup [1]. Doctors do not change their stripes just becausetwo letters are added to their name after 4 years of medicaltraining, and they are hard-wired, like all people, to joingroups. There are large teams such as surgeons, internists,and psychiatrists, and smaller teams such as nephrologists.Within nephrology, there are other sub-identities fromwhich people can choose, such as transplant nephrologist,hypertension specialist, or geriatric nephrologist.In the past, members of the glomerular team constituted

a small cohesive group of specialists who labored hardin the care of patients with glomerular disease. Theywere fairly unified because there was not too much tosplinter the group. The pathophysiology of glomerulardisease remained a black box, and therapeutic optionswere limited. Perceived differences were not sufficientto start a new team.

Correspondence: howard.trachtman@nyumc.orgNYU Langone Medical Center, Department of Pediatrics, Division ofNephrology, CTSI, 227 E 30th Street, Room #110, New York, NY, USA

© Trachtman; licensee BioMed Central LCommons Attribution License (http://creativecreproduction in any medium, provided the or

2014

However, if you have an interest in glomerular disease,then these are very exciting times. Whole exome sequen-cing, enhanced interaction with other disciplines, improve-ments in experimental techniques, expanded bioinformaticscapacity, and development of systems biology approacheshave resulted in dramatic advances in our understanding ofhow the glomerulus functions in health and disease [2]. Apredictable consequence of these striking discoveries is theemergence of teams of devotees who promote the import-ance of particular mediators of disease or potential thera-peutic interventions, to the exclusion of other approaches.That is what being a member of the team means.The story of the association between elevated circulating

levels of soluble urokinase receptor (suPAR) as a potentialmarker of primary focal segmental glomerulosclerosis(FSGS) is a vivid illustration of this social phenomenon.FSGS is an important cause of glomerular disease inchildren and adults, and accounts for nearly 10% of patientswho develop end stage kidney disease. Moreover, thedisease can recur in nearly 25% of patients who undergokidney transplantation [3]. These clinical features emphasizethe compelling need to distinguish FSGS from otherforms of glomerular disease. Although suPAR has beenrecognized for many years as a marker of inflammation

td. This is an Open Access article distributed under the terms of the Creativeommons.org/licenses/by/4.0), which permits unrestricted use, distribution, andiginal work is properly cited.

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and specific infections [4-7], it burst onto the nephrologyscene in 2011, when Jochen Reiser’s group reported thata high plasma concentration of this biomarker indicatedthe presence of primary FSGS versus other forms ofprimary glomerular disease [8]. suPAR was associatedwith recurrent glomerular disease after kidney transplant-ation. Moreover, the molecule appeared to be more thansimply an epiphenomenon in FSGS, because in vitro studiesindicated that suPAR binds to β3 integrin in the podocytemembrane, activates intracellular signaling, promotesfoot process effacement, and disrupts glomerular bar-rier function, leading to proteinuria [7]. This excitingobservation was followed by several supportive reports[9-11]. However, over the past year there have been sixreports from various cohorts of patients with FSGS andother glomerular diseases indicating that plasma suPARconcentration does not discriminate FSGS from otherglomerular diseases, and that the primary determinantof the suPAR level may be the glomerular filtration rate(GFR) [12-17].

Can suPAR distinguish FSGS from other glomerular diseases?It is in this context that the report of Huang et al. [18]in BMC Medicine should be read. In their series of pa-tients with primary glomerular disease, urinary suPARexcretion was significantly higher in patients with primaryFSGS (n = 62) compared with all other varieties of glom-erular disorders. The cellular variant of FSGS was asso-ciated with higher urinary levels than other subtypes,and the excretion correlated with proteinuria in all forms.Urinary suPAR excretion fell in response to effective ther-apy. The urinary suPAR excretion was biologically activebecause it induced AP5 expression in cultured humanpodocytes. The robust findings in this article support therelevance of suPAR as a contributing factor in the patho-genesis of primary FSGS in patients with a preserved GFR.It is consistent with a report that higher urinary suPARexcretion may identify patients with recurrent FSGS intheir transplanted kidney [19]. The strengths of this studyare the large patient sample, a meaningful approach todistinguishing primary from secondary FSGS based onthe extent of epithelial cell foot process effacement,and the incorporation of studies to demonstrate thein vitro activity of urinary suPAR. The limitations shouldbe acknowledged, and include a lack of studies to assessstability of suPAR in the urine, an inability to distinguishbetween various subtypes of suPAR based on processingof the molecule, and lack of long-term follow-up [20].Nonetheless, the study allows assessment of suPAR to beperformed routinely in a readily accessible body fluid thatmay reflect intra-renal effects more closely than changesin the plasma concentration. It is likely that the membersof the suPAR team will be heartened by this report, whilethe skeptics will express concern about the adequacy of

methods used to measure suPAR in the urine and thecriteria that were applied to categorize the patients.

Are other factors causal in FSGS?There is another exciting recent discovery that is alsodriving those in the nephrology field to join competingteams. It represents the identification of another factorthat might be causal in FSGS, and which could be usedboth for diagnosis and targets for therapy. Yu et al.[21] recently described five patients (four with recur-rent FSGS after kidney transplantation and one withFSGS in native kidneys) who were treated with abatacept(cytotoxic T-lymphocyte–associated antigen 4–immuno-globulin fusion protein [CTLA-4–Ig]) based on positivestaining for B7-1 in glomerular podocytes. All five pa-tients experienced a clinically significant reduction inproteinuria. This has prompted a surge in the abataceptclub membership. However, within 4 months, two briefreports have appeared questioning the validity of thesefindings, and suggesting that the B7-1 pathway is not ac-tive in glomerular disease and is not a therapeutic target[22,23]. The community is splitting up into teams: thosewho consider suPAR, B7-1, or other favorite candidates tobe the main causal factor for FSGS.

ConclusionsThe current position of suPAR in the setting of glomeru-lar disease has been succinctly summarized in a recent,balanced editorial commentary [24]. Editorials on B7-1will follow in short order. Rather than simply rehearsearguments that have already been made in the literature,I will address the following open question: will the pres-sure to join nephrology teams interfere with a rationaland comprehensive evaluation of these new pathways inthe pathogenesis of FSGS and other glomerular diseases?What is the thoughtful nephrologist to do in this chal-lenging era of enormous growth in the knowledge basefor glomerular disease? I suggest we should applaudthe innovative efforts of clinical scientists such as JochenReiser and Peter Mundel, who are uncovering novelpathways in the development of kidney disease. It wouldseem prudent to maintain the glomerular disease teamas a large inclusive club that welcomes all comers.Membership should be defined by a commitment torigorously study newly identified biomarkers and valid-ate disease targets in well-designed clinical trials. Theefforts of investigators such as Huang should be ana-lyzed carefully by Team Nephrology, and added to themix as the community works to clarify the value andutility of new discoveries like suPAR and B7-1. Fortunately,the scientific advances are being reinforced by the creationof a stable infrastructure to promote ongoing evaluationof new biomarkers and novel therapies for glomerulardisease. The National Institute of Diabetes and Digestive

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and Kidney Diseases (NIH-NIDDK) has demonstrated itsstrong commitment to improving the outcomes for patientswith primary glomerular disease by investing vital resourcesin establishing the Nephrotic Syndrome Study Network(NEPTUNE) and Cure Glomerulonephropathy (CureGN)prospective cohort studies [25]. Research in glomerular dis-ease is moving forward on all fronts. For nephrologists,Charles Dickens had it wrong. It is the best of times, it isan age of wisdom, it is a season of light, it is a spring ofhope, and we have everything before us.

Competing interestsNo competing interests to report.

Authors’ informationHT author is a participant in the NEPTUNE and CureGN observational cohortstudies, and has been the principal investigator for clinical trials in FSGS.

Received: 8 April 2014 Accepted: 10 April 2014Published:

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Cite this article as: Trachtman: suPAR and Team Nephrology. BMCMedicine

10.1186/1741-7015-12-82

2014, 12:82

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