19 research outputs found
SuPAR, an emerging biomarker in kidney and inflammatory diseases
No full textSoluble urokinase plasminogen activator receptor (suPAR) is a circulating form of a physiological and pathophysiological important cell surface receptor, implicated in inflammation. Recent studies showed that suPAR is a promising biomarker, useful for diagnosis, assessment and prognosis of several diseases. This review summarises the majority of preliminary studies and analyses the significance and the clinical application of suPAR in various clinical conditions. SuPAR seems to have a significant value in the diagnosis as well as prognosis of many diseases; nonetheless, it merits large-scale studies to set cut-off values that help physicians in following up their patients and accordingly tailor their treatment plans. © Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ
Soluble urokinase receptor (suPAR) predicts microalbuminuria in patients at risk for type 2 diabetes mellitus
No full textEarly identification of patients at risk of developing diabetic nephropathy is essential. Elevated serum concentrations of soluble urokinase receptor (suPAR) associate with diabetes mellitus and predict onset and loss of renal function in chronic kidney disease. We hypothesize, that suPAR may be an early risk indicator for diabetic nephropathy, preceding microalbuminuria. The relationship of baseline suPAR and incident microalbuminuria was assessed in a prospective long-term cohort of subjects at increased risk for type 2 diabetes (TULIP, n = 258). Association with albuminuria at later stages of disease was studied in a cross-sectional cohort with manifest type 2 diabetes (ICEPHA, n = 266). A higher baseline suPAR was associated with an increased risk of new-onset microalbuminuria in subjects at risk for type 2 diabetes (hazard ratio 5.3 (95% CI 1.1-25.2, p = 0.03) for the highest vs. lowest suPAR quartile). The proportion of subjects with prediabetes at the end of observation was higher in subjects with new-onset microalbuminuria. suPAR consistently correlated with albuminuria in a separate cohort with manifest type 2 diabetes. Elevated baseline suPAR concentrations independently associate with new-onset microalbuminuria in subjects at increased risk of developing type 2 diabetes. suPAR may hence allow for earlier risk stratification than microalbuminuria. © The Author(s) 2017
Utilization of Prognostic Biomarker Soluble Urokinase Plasminogen Activator Receptor in the Emergency Department : A Tool for Safe and More Efficient Decision-making
No full textINTRODUCTION: Risk stratification in the emergency departments (EDs) is in critical need for new applications due to ED overcrowding and hospitalization of older people. We aimed to evaluate the expediency, efficiency and safety of a prognostic biomarker. soluble urokinase plasminogen activator receptor (suPAR), as a tool for the risk assessment of patients arriving at the ED. METHODS: We performed a comparative cross-sectional study in 2 emergency departments (EDs), suPAR measurements being incorporated into routine blood sampling in the intervention ED. The primary outcome was the number of discharges from the ED. The importance of the outcomes was examined by appropriate multi- or bivariate analysis. RESULTS: The absolute and relative number of discharges were similar between the intervention and control groups [121 (55.3%) vs 62 (55.9%)]. No significant differences between the groups were seen in the length of stays in the ED. Patients with low suPAR values were more likely discharged and patients with high suPAR values more likely admitted to hospital. Two admitted patients with low suPAR values could have been discharged safely. CONCLUSION: The utilization of suPAR did not increase the risk for neither positive nor negative outcomes. Low suPAR values could be potential in discharging more patients safely. Instead of unselected patient populations. the benefits of suPAR measurements in the ED could emerge in the assessment of a more precisely determined and selected group of patients.Peer reviewe
Soluble Urokinase-Type Plasminogen Activator Receptor and Arterial Stiffness in Patients with COPD
No full textIntroduction: Soluble urokinase-type plasminogen activator receptor (suPAR) is upregulated by inflammation and plays a role in the pathogenesis of atherosclerosis. Chronic obstructive pulmonary disease (COPD) is associated with enhanced systemic inflammation and increased risk for atherosclerosis, however, studies analysing the circulating suPAR levels in COPD are contradictory. The aim of the study was to investigate plasma suPAR concentrations together with markers of arterial stiffness in COPD. Materials and Methods: Twenty-four patients with COPD and 18 non-COPD, control subjects participated in the study. Plasma suPAR was measured, together with lung volumes, symptom burden, exacerbation history, markers of arterial stiffness and soluble inflammatory biomarkers, such as endothelin-1, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6). Results: Plasma suPAR levels were higher in COPD (2.84 ± 0.67 ng/ml vs. 2.41 ± 0.57 ng/ml, p = 0.03) and were related to lung function measured with FEV 1 (r = − 0.65, p < 0.01) and symptom burden determined with the modified Medical Research Council questionnaire (r = 0.55, p < 0.05). Plasma suPAR concentrations correlated with various measures of arterial stiffness in all subjects, but only with ejection duration in COPD (r = − 0.44, p = 0.03). Conclusions: Plasma suPAR levels are elevated in COPD and relate to arterial stiffness. Our results suggest that suPAR may be a potential link between COPD and atherosclerosis. © 2019, The Author(s)
Prognostic Role of Soluble Urokinase Plasminogen Activator Receptor at the Emergency Department: A Position Paper by the Hellenic Sepsis Study Group
No full textIn light of the accumulating evidence on the negative predictive value of soluble urokinase plasminogen activator receptor (suPAR), a group of experts from the fields of intensive care medicine, emergency medicine, internal medicine and infectious diseases frame a position statement on the role of suPAR in the screening of patients admitted to the emergency department. The statement is framed taking into consideration existing publications and our own research experience. The main content of this statement is that sUPAR is a non-specific marker associated with a high negative predictive value for unfavourable outcomes; levels < 4 ng/ml indicate that it is safe to discharge the patient, whereas levels > 6 ng/ml are an alarming sign of risk for unfavourable outcomes. However, the suPAR levels should always be interpreted in light of the patient's history. © 2020, The Author(s)
Soluble urokinase-type plasminogen activator receptor improves early risk stratification in cardiogenic shock
No full textAims Soluble urokinase–type plasminogen activator receptor (suPAR) is a biomarker reflecting the level of immune activation. It has been shown to have prognostic value in acute coronary syndrome and heart failure as well as in critical illness. Considering the complex pathophysiology of cardiogenic shock (CS), we hypothesized suPAR might have prognostic properties in CS as well. The aim of this study was to assess the kinetics and prognostic utility of suPAR in CS. Methods and results SuPAR levels were determined in serial plasma samples (0–96 h) from 161 CS patients in the prospective, observational, multicentre CardShock study. Kinetics of suPAR, its association with 90-day mortality, and additional value in risk-stratification were investigated. The median suPAR-level at baseline was 4.4 [interquartile range (IQR) 3.2–6.6)] ng/mL. SuPAR levels above median were associated with underlying comorbidities, biomarkers reflecting renal and cardiac dysfunction, and higher 90-day mortality (49% vs. 31%; P = 0.02). Serial measurements showed that survivors had significantly lower suPAR levels at all time points compared with nonsurvivors. For risk stratification, suPAR at 12 h (suPAR12h) with a cutoff of 4.4 ng/mL was strongly associated with mortality independently of established risk factors in CS: OR 5.6 (95% CI 2.0–15.5); P = 0.001) for death by 90 days. Adding suPAR12h > 4.4 ng/mL to the CardShock risk score improved discrimination identifying high-risk patients originally categorized in the intermediate-risk category. Conclusion SuPAR associates with mortality and improves risk stratification independently of other previously known risk factors in CS patients. © The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology
Plasma Soluble Urokinase Receptor Level Is Correlated with Podocytes Damage in Patients with IgA Nephropathy.
No full textFocal segmental glomerulosclerosis (FSGS) lesions are similar in characteristics to S lesions of the Oxford classification of IgA nephropathy (IgAN) and may predict poor prognosis. In the present study, we aimed to explore the association between plasma soluble urokinase receptor (suPAR) levels and S lesions and podocytes damage in IgAN patients.We enrolled 569 IgAN patients with follow-up data and detected plasma suPAR levels at renal biopsy by enzyme-linked immunosorbent assay.Plasma suPAR levels in IgAN patients with or without S lesions did not differ significantly (P = 0.411). However, suPAR levels were positively correlated with proteinuria (r = 0.202, P < 0.001), and negatively correlated with estimated glomerular filtration rate (eGFR, r = -0.236, P < 0.001). In the partial correlation to adjust for eGFR, plasma suPAR levels remained positively correlated with proteinuria (r = 0.112, P = 0.023). In a Cox proportional hazards model, higher levels of plasma suPAR were not associated with poor renal outcome. Plasma suPAR levels of IgAN and primary FSGS patients with nephrotic syndrome were not significantly different (P = 0.306). Plasma suPAR levels in patients with extensive effacement of the epithelial cell foot processes of glomerular podocytes were significantly higher than those with segmental effacement on the basis of comparable eGFR (P = 0.036).In IgAN patients, plasma suPAR levels were not associated with S lesions. However, they were positively associated with proteinuria and negatively associated with eGFR. In addition, plasma suPAR levels were positively associated with the effacement degree of the foot processes, which might partially contribute to the development of proteinuria in patients with IgAN
Urinary soluble urokinase receptor levels are elevated and pathogenic in patients with primary focal segmental glomerulosclerosis
No full textBackground: Focal segmental glomerulosclerosis (FSGS) is a major cause of end-stage renal disease. Recent studies have proposed that plasma soluble urokinase receptor (suPAR) might be a causative circulating factor but this proposal has caused controversy. This study aimed to measure urinary suPAR levels in patients with primary FSGS and its significance in the pathogenesis of FSGS. Methods: Sixty-two patients with primary FSGS, diagnosed between January 2006 and January 2012, with complete clinical and pathologic data were enrolled, together with disease and normal controls. Urinary suPAR levels were measured using commercial ELISA kits and were corrected by urinary creatinine (Cr). The associations between urinary suPAR levels and clinical data at presentation and during follow up were analyzed. Conditionally immortalized human podocytes were used to study the effect of urinary suPAR on activating beta 3 integrin detected by AP5 staining. Results: The urinary suPAR level of patients with primary FSGS (500.56, IQR 262.78 to 1,059.44 pg/mu mol Cr) was significantly higher than that of patients with minimal change disease (307.86, IQR 216.54 to 480.18 pg/mu mol Cr, P = 0.033), membranous nephropathy (250.23, IQR 170.37 to 357.59 pg/mu mol Cr, P < 0.001), secondary FSGS (220.45, IQR 149.38 to 335.54 pg/mu mol Cr, P < 0.001) and normal subjects (183.59, IQR 103.92 to 228.78 pg/mu mol Cr, P < 0.001). The urinary suPAR level of patients with cellular variant was significantly higher than that of patients with tip variant. The urinary suPAR level in the patients with primary FSGS was positively correlated with 24-hour urine protein (r = 0.287, P = 0.024). During follow up, the urinary suPAR level of patients with complete remission decreased significantly (661.19, IQR 224.32 to 1,115.29 pg/mu mol Cr versus 217.68, IQR 121.77 to 415.55 pg/mu mol Cr, P = 0.017). The AP5 signal was strongly induced along the cell membrane when human differentiated podocytes were incubated with the urine of patients with FSGS at presentation, and the signal could be reduced by a blocking antibody specific to uPAR. Conclusions: Urinary suPAR was specifically elevated in patients with primary FSGS and was associated with disease severity. The elevated urinary suPAR could activate beta 3 integrin on human podocytes.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000338244600001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701Medicine, General & InternalSCI(E)[email protected]
Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis,”NatureMedicine,
No full textFocal segmental glomerulosclerosis (FSGS) is a cause of proteinuric kidney disease, compromising both native and transplanted kidneys. Treatment is limited because of a complex pathogenesis, including unknown serum factors. Here we report that serum soluble urokinase receptor (suPAR) is elevated in two-thirds of subjects with primary FSGS, but not in people with other glomerular diseases. We further find that a higher concentration of suPAR before transplantation underlies an increased risk for recurrence of FSGS after transplantation. Using three mouse models, we explore the effects of suPAR on kidney function and morphology. We show that circulating suPAR activates podocyte b 3 integrin in both native and grafted kidneys, causing foot process effacement, proteinuria and FSGS-like glomerulopathy. Our findings suggest that the renal disease only develops when suPAR sufficiently activates podocyte b 3 integrin. Thus, the disease can be abrogated by lowering serum suPAR concentrations through plasmapheresis, or by interfering with the suPAR-b 3 integrin interaction through antibodies and small molecules targeting either uPAR or b 3 integrin. Our study identifies serum suPAR as a circulating factor that may cause FSGS. A R T I C L E S NATURE MEDICINE VOLUME 17 | NUMBER 8 | AUGUST 2011 953 It can be elevated in some malignant neoplasms (for example, ovarian cancer 21 ) as well as in HIV infection In conclusion, our study suggests circulating suPAR as a previously undescribed cause for both primary and recurrent FSGS. RESULTS suPAR is increased in serum of subjects with FSGS We found that suPAR serum concentrations are significantly elevated in people with FSGS when compared to healthy subjects We then stratified the FSGS cases into three different subpopulations: primary FSGS, recurrent FSGS in the allograft and FSGS without recurrence after transplantation. We found the highest suPAR concentrations in pretransplantation blood from subjects with FSGS who later developed recurrent FSGS after transplantation We also compared suPAR serum concentrations in transplanted FSGS patients 1 year after transplantation and found significantly higher suPAR serum concentrations in patients that developed recurrent FSGS than in FSGS patients who received kidney transplants and then had normal renal function A R T I C L E S 954 VOLUME 17 | NUMBER 8 | AUGUST 2011 NATURE MEDICINE As multiple forms of suPAR have been attributed to domain cleavage or alternative splicing Concentrations of the ligand of uPAR, urokinase (uPA), are often elevated in certain types of cancers that also present with elevated suPAR concentrations in various body fluids 27 . Thus, we measured serum uPA concentrations in the groups within our glomerular disease cohort. Notably, and unlike suPAR, we found no difference in the serum uPA concentrations among the groups ( We hypothesized that suPAR could activate 3 integrin in a similar manner to membrane-bound uPAR in podocytes 18 . The activity of 3 integrin is typically measured using the activation epitope-recognizing antibodies such as the 3 integrin-specific antibody AP5 (refs. 29,30). We used human differentiated podocytes 31 and incubated them either with FSGS serum that contains high concentrations of suPAR or with recombinant suPAR, in the absence or presence of a blocking antibody to uPAR or with the 3 integrin small molecule-inhibitor cycloRGDfV A R T I C L E S NATURE MEDICINE VOLUME 17 | NUMBER 8 | AUGUST 2011 955 adhesions are known to be the location of 3 integrin 32 . We also found that this effect could be blocked by a blocking antibody specific to uPAR or by cycloRGDfV To show that circulating suPAR affects the transplanted kidney by activating podocyte 3 integrin, we used double immunofluorescent staining with synaptopodin, a podocyte marker 33 , to analyze aftertransplantation graft biopsies for the presence of AP5 signal in podocytes. We found that 3 integrin activity is low in graft podocytes before reperfusion, whereas it is markedly increased 2 h after reperfusion in recurrent FSGS, but not in nonrecurrent FSGS suPAR and b 3 integrin activity during plasmapheresis To further define the relationship between suPAR and podocyte 3 integrin activity, we did fluorescence-activated cell sorting (FACS) analysis for 3 integrin activity in cultured human podocytes g h e f Figure 3 suPAR serum concentrations and podocyte 3 integrin activity determine treatment response to plasmapheresis in recurrent FSGS. (a) Human podocytes incubated with different pooled serum samples and assayed for 3 integrin activity. MFI, mean fluorescence intensity. *P < 0.05 for nonrecurrent FSGS versus normal subjects, ***P < 0.001 for recurrent versus nonrecurrent FSGS or versus healthy subjects. The respective suPAR concentration of the pooled sera is marked in red. NS, normal (healthy) subject; NR, nonrecurrent FSGS; REC, recurrent FSGS (representative of three experiments). (b) Pharmacological modulation of 3 integrin activity in podocytes. **P < 0.01 for cylcoRGDfv co-treated cells versus recurrent FSGS serum alone; ***P < 0.001 for uPAR-specific mAb co-treated cells versus recurrent FSGS serum alone. (c) suPAR in serum from subjects with recurrent FSGS (n = 4) before and after a course of plasmapheresis. **P < 0.01. (d) Effect of plasmapheresis on 3 integrin activity in podocytes incubated with recurrent FSGS serum (n = 6), collected before and after serial treatment with plasmapheresis. ***P < 0.001. (e-h) Clinical cases of recurrent FSGS. Top graphs show serum suPAR, urine protein/creatinine ratio (g/g) and individual plasmapheresis treatment as indicated by arrows and plotted over time (d) from before (−1) to after transplantation. Bottom graphs and images show podocyte 3 integrin activity measured by FACS (left) and immunofluorescence (right) as a result of incubation with pretransplantation serum, or with the after-transplantation serum collected after repetitive plasmapheresis treatments. As a reference, the mean concentration of AP5 from a is marked as a dashed line. (e,f) Patients who obtained full remission after pheresis. (g,h) Patients who did not achieve remission after pheresis. Scale bars, 30 m. Whiskers in plots of AP5 activity and serum suPAR show minimum to maximum. A R T I C L E S 956 VOLUME 17 | NUMBER 8 | AUGUST 2011 NATURE MEDICINE incubated with serum from healthy subjects (n = 5) or with pretransplantation serum from subjects with nonrecurrent (n = 10) and recurrent FSGS (n = 15). We found that incubation with recurrent FSGS pretransplantation serum significantly elevated 3 integrin activity compared to serum from subjects with nonrecurrent FSGS or from healthy subjects Mouse models showing that suPAR causes proteinuria and FSGS To determine whether suPAR is a cause or a consequence of FSGS, we established three different mouse models: (i) uPAR-knockout (Plaur −/− ) mice injected with recombinant suPAR, (ii) hybrid-transplant mice modeling endogenous suPAR release and (iii) genetically engineered wild-type mice that drive expression of a suPAR plasmid in the skin, leading to increased serum suPAR concentrations. First, we examined whether exogenous circulating suPAR could deposit into kidneys and cause albuminuria. We used Plaur −/− mice and injected escalating doses of recombinant mouse suPAR protein intravenously into Plaur −/− mice. We found that low-dose injection at 2 and 10 g did not cause albuminuria, which is consistent with the physiological low concentrations of suPAR we observed in the blood of healthy subjects A R T I C L E S NATURE MEDICINE VOLUME 17 | NUMBER 8 | AUGUST 2011 957 that this deposition was associated with an increase in 3 integrin activity in podocytes, as shown by increased AP5 labeling that, again, is suPAR dose dependent Third, to explore whether prolonged elevation of suPAR in the serum of mice causes a progressive glomerulopathy, we engineered wild-type mice that drive expression of suPAR in the skin. We generated a mouse plasmid (sPlaur WT ) based on a known coding sequence for secreted suPAR 26 that contains the D I and D II domains. We delivered this plasmid into mice by in vivo electroporation into the skin. As a control, we generated a 3 integrin binding-deficient suPAR mutant, sPlaur E134A . This mutant has a point mutation (E134A) in the D II domain We next studied the ultrastructure of podocytes after 4 weeks and noted prominent foot process effacement consistent with glomerular disease; however, we only observed this in mice that expressed suPAR capable of binding 3 integrin A R T I C L E S 958 VOLUME 17 | NUMBER 8 | AUGUST 2011 NATURE MEDICINE To further study the disease-causing effects of suPAR, we also carried out experiments that blocked suPAR action. We administered an uPAR-specific monoclonal antibody to mice expressing sPlaur WT and found protection of proteinuria whereas proteinuria was high when using an IgG isotype control DISCUSSION The present study identifies suPAR as a circulating, causative FSGS factor that is elevated in the serum of approximately two-thirds of primary FSGS patients. suPAR-mediated activation of 3 integrin on podocyte foot processes is the mechanism of injury caused by high suPAR blood concentrations. Since the first clinical description of nephrotic syndrome recurrence after kidney transplantation The amount of podocyte 3 integrin activity that is driven by circulating systemic suPAR depends on the amount of individual serum suPAR and, possibly, also on suPAR post-translational modifications (such as glycosylation status). In addition, podocyte 3 integrin activity can also be driven by augmented podocyte uPAR expression, which is sufficient to initiate podocyte foot process effacement and proteinuria 18 . Podocyte 3 integrin activity seems to be independent of total serum uPA concentrations; this is in contrast to the suPARuPA associations in some forms of cancer Several modes of interference can protect from suPAR-mediated podocyte injury: (i) blockade of suPAR using a blocking antibody specific to suPAR; (ii) protecting 3 integrin from increased activation by cycloRGDfV or 3 integrin-specific antibody 18 ; (iii) blocking suPAR-3 integrin interaction by modulating the suPAR-3 integrin binding site (E134A) and (iv) removing suPAR by plasmapheresis to levels that decrease podocyte 3 integrin activity. Using assays that measure all suPAR forms, we noted that ~70% of subjects with primary FSGS presented with significantly elevated concentrations of serum suPAR before transplantation when compared to other primary glomerulopathies. In addition, we found that total suPAR concentrations remained significantly elevated after kidney transplantation in people who have developed recurrent FSGS compared to those with proper renal function. On the basis of these clinical observations, we created mouse models that could explore the cause or effect nature of suPAR and demonstrate the kidney pathogenicity of elevated systemic suPAR. Notably, we found different forms of suPAR that correspond to different domain fragments in the serum of subjects with FSGS, with molecular weights ranging from 22 to 45 kDa. This is close to the molecular range (30 to 50 kDa) of the factor predicted by others Our study provides the rationale for a more measurable prediction of FSGS risk in subjects with FSGS before and after transplantation. Approximately 70% of subjects with FSGS have elevated concentrations of suPAR compared to other glomerular diseases such as membranous nephropathy, MCD or preeclampsia. This further separates FSGS from other glomerulopathies involving phospholipase A2 receptorspecific antibodies in membranous nephropathy 39 and factors such as angiopoietin-like 40 or c-mip in MCD 41 . Because suPAR is detectable both in healthy human subjects and normal mice, physiological suPAR concentrations or physiological suPAR domain combinations do not seem to be harmful. It is also important to note that there might be species differences with respect to the pathogenic strength of various suPAR domain combinations. Future studies with new and more A R T I C L E S NATURE MEDICINE VOLUME 17 | NUMBER 8 | AUGUST 2011 959 specific suPAR domain-specific antibodies should clarify this question and focus more on the role of suPAR glycosylation in FSGS. Another interesting question is why a few FSGS patients without elevated suPAR still develop FSGS as well as recurrent FSGS. An obvious answer would be that suPAR can act in concert with podocyte uPAR 18 and this might drive FSGS even in the absence of high suPAR concentrations. Another reason might be that native FSGS is caused by a mutation in a podocyte gene 6 . Also, the current ELISA assay for serum suPAR is likely to measure all suPAR domains, and thus it might be possible that FSGS subjects with low total suPAR do have a higher portion of pathological suPAR fragments that current tests cannot readily detect. Once new reagents are developed, even more subjects with FSGS might test positive for pathological suPAR, thereby further increasing the clinical prediction of the test. Alternatively, there is the possibility of the presence of yet-to-be-identified additional permeability factor candidates 17 or the absence of protective podocyte factors Podocyte 3 integrin expression and activation responses must also be evaluated further. Future studies will have to focus more on the expression of the 3 integrin-encoding gene (ITGB3) in the graft In conclusion, we show that suPAR is a circulating factor that can cause FSGS before and after transplantation. Our studies will allow better risk stratification of patients with FSGS by measuring serum and urine concentrations of suPAR, and they will provide the conceptual framework for refined treatment options that remove or neutralize suPAR to a level insufficient to activate podocyte 3 integrin. Regardless of the source of the stimulant (podocyte or systemic), a pathological activation of podocyte 3 integrin is emerging as a key event for the initiation of proteinuric glomerular disease; it is likely to be important in some forms of secondary FSGS, such as diabetic nephropathy 18 , as well. Accordingly, pharmacological modulation of excessive podocyte 3 integrin activation is a promising target for achieving protection from renal disease. METHODS Methods and any associated references are available in the online version of the paper at http://www.nature.com/naturemedicine/. Note: Supplementary information is available on the Nature Medicine website. ACKNOWLEDGMENTS We thank N. Sidenius (Foundation FIRC Institute of Molecular Oncology, Italy) for help with the suPAR assay in mouse samples. We are grateful to L.H. Beck, Jr. and D. Salant (Boston University Medical Center) for providing the membranous nephropathy patient cohort. We thank S. Hsiesh for help with sample collection. We thank G. Høyer-Hansen (the Finsen Laboratory, Denmark) for additional suPAR assays and discussions. The authors are grateful to P.J. Goldschmidt for helpful scientific discussions regarding the manuscript and to M.J. Tracy for critical reading of the manuscript. This work was supported in part by the US National Institutes of Health (grants DK073495 and DK089394 to J.R., DK-82636 to A.F., DK070011 to G.B.), the Halpin Foundation-American Society of Nephrology Research Grant (to C.W.), a grant from the American Diabetes Association (7-09-JF-23 to A.F.), and a grant from the Diabetes Research Institute Foundation (to A.F.). The authors also wish to acknowledge the generous support of the Katz Family Fund. AUTHOR CONTRIBUTIONS J.R. conceived the study. J.R. and C.W. designed the experiments, coordinated the study, analyzed the data and wrote the manuscript. C.W., S.E.H., J.L., D.M., Q.Z., B.N., P.D., V.G. performed the experiments. A.F., N.G., G.B., J.S., S.A.K., H.-K.Y., M.Saleem, A.C., E.S., A.T., M.Salifu, M.M.S., F.S., C.M., V.S., M.Z., D.R., M.P.R., P.R., J.R. contributed to clinical samples and clinical information. M.P.R. and P.R. provided pathology service. COMPETING FINANCIAL INTERESTS The authors declare competing financial interests: details accompany the full-text HTML version of the paper at http://www.nature.com/naturemedicine/. Published online at http://www.nature.com/naturemedicine/. Reprints and permissions information is available online at http://www.nature.com/ reprints/index.html. A R T I C L E S NATURE MEDICIN
