Soluble Urokinase Plasminogen Activator Receptor and Decline in Kidney Function in Autosomal Dominant Polycystic Kidney Disease

Salim S Hayek, Douglas P Landsittel, Changli Wei, Martin Zeier, Alan S L Yu, Vicente E Torres, Sharin Roth, Christina S Pao, Jochen Reiser, Salim S Hayek, Douglas P Landsittel, Changli Wei, Martin Zeier, Alan S L Yu, Vicente E Torres, Sharin Roth, Christina S Pao, Jochen Reiser

Abstract

Background: Levels of soluble urokinase plasminogen activator receptor (suPAR), an inflammation marker, are strongly predictive of incident kidney disease. Patients with autosomal dominant polycystic kidney disease (ADPKD) experience progressive decline in renal function, but rates of decline and outcomes vary greatly. Whether suPAR levels are predictive of declining kidney function in patients with ADPKD is unknown.

Methods: We assessed suPAR levels in 649 patients with ADPKD who underwent scheduled follow-up for at least 3 years, with repeated measurements of height-adjusted total kidney volume and creatinine-derived eGFR. We used linear mixed models for repeated measures and Cox proportional hazards to characterize associations between baseline suPAR levels and follow-up eGFR or incident ESRD.

Results: The median suPAR level was 2.47 ng/ml and median height-adjusted total kidney volume was 778, whereas mean eGFR was 84 ml/min per 1.73 m2. suPAR levels were associated with height-adjusted total kidney volume (β=0.02; 95% confidence interval, 0.01 to 0.03), independent of age, sex, race, hypertension, and eGFR. Patients in the lowest suPAR tertile (<2.18 ng/ml) had a 6.8% decline in eGFR at 3 years and 22% developed CKD stage 3, whereas those in the highest tertile (suPAR>2.83 ng/ml) had a 19.4% decline in eGFR at 3 years and 68% developed CKD stage 3. suPAR levels >2.82 ng/ml had a 3.38-fold increase in the risk of incident ESRD.

Conclusions: suPAR levels were associated with progressive decline in renal function and incident ESRD in patients with ADPKD, and may aid early identification of patients at high risk of disease progression.

Keywords: eGFR; end-stage renal disease; polycystic kidney disease; suPAR.

Copyright © 2019 by the American Society of Nephrology.

Figures

Graphical abstract
Graphical abstract
Figure 1.
Figure 1.
SuPAR levels are higher with increasing kidney volumes.
Figure 2.
Figure 2.
Patients with higher suPAR levels had a steeper decline in kidney function.
Figure 3.
Figure 3.
Patients in the highest suPAR tertile were more likely to require dialysis at long-term follow-up.

References

    1. Ong AC, Devuyst O, Knebelmann B, Walz G; ERA-EDTA Working Group for Inherited Kidney Diseases : Autosomal dominant polycystic kidney disease: The changing face of clinical management. Lancet 385: 1993–2002, 2015
    1. Karihaloo A: Role of inflammation in polycystic kidney disease. In: Polycystic Kidney Disease, edited by Li X, Brisbane (AU), 2015
    1. Menon V, Rudym D, Chandra P, Miskulin D, Perrone R, Sarnak M: Inflammation, oxidative stress, and insulin resistance in polycystic kidney disease. Clin J Am Soc Nephrol 6: 7–13, 2011
    1. Thunø M, Macho B, Eugen-Olsen J: suPAR: The molecular crystal ball. Dis Markers 27: 157–172, 2009
    1. Wei C, Möller CC, Altintas MM, Li J, Schwarz K, Zacchigna S, et al. .: Modification of kidney barrier function by the urokinase receptor. Nat Med 14: 55–63, 2008
    1. Huai Q, Mazar AP, Kuo A, Parry GC, Shaw DE, Callahan J, et al. .: Structure of human urokinase plasminogen activator in complex with its receptor. Science 311: 656–659, 2006
    1. Botha S, Fourie CMT, Schutte R, Eugen-Olsen J, Pretorius R, Schutte AE: Soluble urokinase plasminogen activator receptor as a prognostic marker of all-cause and cardiovascular mortality in a black population. Int J Cardiol 184: 631–636, 2015
    1. Eapen DJ, Manocha P, Ghasemzadeh N, Patel RS, Al Kassem H, Hammadah M, et al. .: Soluble urokinase plasminogen activator receptor level is an independent predictor of the presence and severity of coronary artery disease and of future adverse events. J Am Heart Assoc 3: e001118, 2014
    1. Hodges GW, Bang CN, Wachtell K, Eugen-Olsen J, Jeppesen JL: suPAR: A new biomarker for cardiovascular disease? Can J Cardiol 31: 1293–1302, 2015
    1. Lyngbæk S, Marott JL, Sehestedt T, Hansen TW, Olsen MH, Andersen O, et al. .: Cardiovascular risk prediction in the general population with use of suPAR, CRP, and Framingham Risk Score. Int J Cardiol 167: 2904–2911, 2013
    1. Meijers B, Poesen R, Claes K, Dietrich R, Bammens B, Sprangers B, et al. .: Soluble urokinase receptor is a biomarker of cardiovascular disease in chronic kidney disease. Kidney Int 87: 210–216, 2015
    1. Hahm E, Wei C, Fernandez I, Li J, Tardi NJ, Tracy M, et al. .: Bone marrow-derived immature myeloid cells are a main source of circulating suPAR contributing to proteinuric kidney disease. Nat Med 23: 100–106, 2017
    1. Hayek SS, Ko YA, Awad M, Ahmed H, Gray B, Hosny KM, et al. .: Cardiovascular disease biomarkers and suPAR in predicting decline in renal function: A prospective cohort study. Kidney Int Rep 2: 425–432, 2017
    1. Luo S, Coresh J, Tin A, Rebholz CM, Chen TK, Hayek SS, et al. .: Soluble urokinase-type plasminogen activator receptor in black Americans with CKD. Clin J Am Soc Nephrol 13: 1013–1021, 2018
    1. Schaefer F, Trachtman H, Wühl E, Kirchner M, Hayek SS, Anarat A, et al. .: ESCAPE Trial Consortium and the 4C Study Group : Association of serum soluble urokinase receptor levels with progression of kidney disease in children. JAMA Pediatr 171: e172914, 2017
    1. Schulz CA, Persson M, Christensson A, Hindy G, Almgren P, Nilsson PM, et al. .: Soluble urokinase-type plasminogen activator receptor (suPAR) and impaired kidney function in the population-based malmö diet and cancer study. Kidney Int Rep 2: 239–247, 2017
    1. Maile LA, Busby WH, Gollahon KA, Flowers W, Garbacik N, Garbacik S, et al. .: Blocking ligand occupancy of the αVβ3 integrin inhibits the development of nephropathy in diabetic pigs. Endocrinology 155: 4665–4675, 2014
    1. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, et al. .: TEMPO 3:4 Trial Investigators : Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 367: 2407–2418, 2012
    1. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Koch G, et al. .: REPRISE Trial Investigators : Tolvaptan in later-stage autosomal dominant polycystic kidney disease. N Engl J Med 377: 1930–1942, 2017
    1. Cornec-Le Gall E, Audrézet MP, Rousseau A, Hourmant M, Renaudineau E, Charasse C, et al. .: The PROPKD score: A new algorithm to predict renal survival in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 27: 942–951, 2016
    1. Xue C, Zhou C, Mei C: Total kidney volume: The most valuable predictor of autosomal dominant polycystic kidney disease progression. Kidney Int 93: 540–542, 2018
    1. Irazabal MV, Rangel LJ, Bergstralh EJ, Osborn SL, Harmon AJ, Sundsbak JL, et al. .: CRISP Investigators : Imaging classification of autosomal dominant polycystic kidney disease: A simple model for selecting patients for clinical trials. J Am Soc Nephrol 26: 160–172, 2015
    1. Torres VE, Meijer E, Bae KT, Chapman AB, Devuyst O, Gansevoort RT, et al. .: Rationale and design of the TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes) 3-4 study. Am J Kidney Dis 57: 692–699, 2011
    1. Torres VE, Grantham JJ, Chapman AB, Mrug M, Bae KT, King BF Jr., et al. .: Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) : Potentially modifiable factors affecting the progression of autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 6: 640–647, 2011
    1. Hayek SS, Sever S, Ko YA, Trachtman H, Awad M, Wadhwani S, et al. .: Soluble urokinase receptor and chronic kidney disease. New England Journal of Medicine 373: 1916–1925, 2015
    1. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. . CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) : A new equation to estimate glomerular filtration rate. Ann Intern Med 150: 604–612, 2009
    1. Grantham JJ, Torres VE, Chapman AB, Guay-Woodford LM, Bae KT, King BF Jr., et al. .: CRISP Investigators : Volume progression in polycystic kidney disease. N Engl J Med 354: 2122–2130, 2006
    1. Uno H, Cai T, Pencina MJ, D’Agostino RB, Wei LJ: On the C-statistics for evaluating overall adequacy of risk prediction procedures with censored survival data. Stat Med 30: 1105–1117, 2011
    1. Pencina MJ, D’Agostino RB Sr., Steyerberg EW: Extensions of net reclassification improvement calculations to measure usefulness of new biomarkers. Stat Med 30: 11–21, 2011
    1. Uno H, Tian L, Cai T, Kohane IS, Wei LJ: A unified inference procedure for a class of measures to assess improvement in risk prediction systems with survival data. Stat Med 32: 2430–2442, 2013
    1. Pencina MJ, D’Agostino RB Sr., D’Agostino RB Jr., Vasan RS: Evaluating the added predictive ability of a new marker: From area under the ROC curve to reclassification and beyond. Stat Med 27: 157–172, discussion 207–212, 2008
    1. Brosnahan GM: Volume progression in polycystic kidney disease. N Engl J Med 355: 733, author reply 733–734, 2006
    1. Alam A, Dahl NK, Lipschutz JH, Rossetti S, Smith P, Sapir D, et al. .: Total kidney volume in autosomal dominant polycystic kidney disease: A biomarker of disease progression and therapeutic efficacy. Am J Kidney Dis 66: 564–576, 2015
    1. Chapman AB, Bost JE, Torres VE, Guay-Woodford L, Bae KT, Landsittel D, et al. .: Kidney volume and functional outcomes in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 7: 479–486, 2012
    1. Iglesias CG, Torres VE, Offord KP, Holley KE, Beard CM, Kurland LT: Epidemiology of adult polycystic kidney disease, Olmsted County, Minnesota: 1935-1980. Am J Kidney Dis 2: 630–639, 1983
    1. Wilson PD: Polycystic kidney disease. N Engl J Med 350: 151–164, 2004
    1. Schrier RW, Abebe KZ, Perrone RD, Torres VE, Braun WE, Steinman TI, et al. .: HALT-PKD Trial Investigators : Blood pressure in early autosomal dominant polycystic kidney disease. N Engl J Med 371: 2255–2266, 2014
    1. Cadnapaphornchai MA, George DM, McFann K, Wang W, Gitomer B, Strain JD, et al. .: Effect of pravastatin on total kidney volume, left ventricular mass index, and microalbuminuria in pediatric autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 9: 889–896, 2014
    1. Oguro M, Kogure Y, Hoshino J, Ubara Y, Mizuno H, Sekine A, et al. .: Tolvaptan in Japanese patients with later-stage autosomal dominant polycystic kidney disease. J Nephrol 31: 961–966, 2018
    1. Hayek SS, Koh KH, Grams ME, Wei C, Ko YA, Li J, et al. .: A tripartite complex of suPAR, APOL1 risk variants and αvβ3 integrin on podocytes mediates chronic kidney disease. Nat Med 23: 945–953, 2017
    1. Wei C, Trachtman H, Li J, Dong C, Friedman AL, Gassman JJ, et al. .: PodoNet and FSGS CT Study Consortia: Circulating suPAR in two cohorts of primary FSGS. J Am Soc Nephrol 23: 2051–2059, 2012

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe