Reduced renal elimination of larger molecules is a strong predictor for mortality

Erik Herou, Anders Grubb, Alain Dardashti, Shahab Nozohoor, Igor Zindovic, Per Ederoth, Henrik Bjursten, Erik Herou, Anders Grubb, Alain Dardashti, Shahab Nozohoor, Igor Zindovic, Per Ederoth, Henrik Bjursten

Abstract

Renal dysfunction is a major risk factor for premature death and has been studied extensively. A new renal syndrome, shrunken pore syndrome (SPS), confers higher mortality in all studied populations. SPS is a condition in which cystatin C-based estimation of glomerular filtration rate (eGFRcystatin C) is ≥ 60% than creatinine-based estimation of glomerular filtration rate (eGFRcreatinine). We aimed to study the impact of SPS on mortality in a cohort of patients with follow up of up to 10 years. This was a retrospective single centre cohort study. We enrolled 3993 consecutive patients undergoing elective cardiac surgery. Outcome was evaluated using Kaplan Meier analysis and multivariable Cox regression. 1-, 5- and 10-year survival for patients with SPS was 90%, 59% and 45%, and without SPS 98%, 88% and 80% (p < 0.001). SPS was found to be an independent predictor for mortality with an HR of 1.96 (95% CI 1.63-2.36). SPS negatively affected survival regardless of pre-operative renal function. SPS is an independent predictor for mortality after elective cardiac surgery, equal to or greater than risk factors such as diabetes, impaired left ventricular function or renal dysfunction. SPS affected mortality even in patients with normal eGFR.Clinical registration number: ClinicalTrials.gov, ID NCT04141072.

Conflict of interest statement

The authors declare no competing interests.

© 2022. The Author(s).

Figures

Figure 1
Figure 1
Flow diagram of the study population. CABG coronary artery bypass graft, sAVR surgical aortic valve replacement.
Figure 2
Figure 2
The study population in different mean eGFR strata, all in ml/min/1.73 m2, number of patients on the y-axis to the left. The dotted line depicts the distribution of patients with SPS in the different mean eGFR strata in percent on the y-axis to the right. eGFR estimated glomerular filtration rate, SPS shrunken pore syndrome.
Figure 3
Figure 3
Survival after elective cardiac surgery for all patients, irrespective of eGFR, with Shrunken Pore Syndrome (red solid line) or without SPS (blue solid line) are seen in top left. Patients with eGFR 2 are seen in top right while patients with eGFR 30–60 ml/min/1.73 m2 and > 60 ml/min/1.73 m2 are seen in bottom left and bottom right, respectively. Faded area represents 95% CI.
Figure 4
Figure 4
Survival for patients with and without diabetes but without Shrunken Pore Syndrome after elective cardiac surgery are seen in top graph and with Shrunken Pore syndrome are seen in lower graph, diabetic; red solid line, non-diabetic; blue solid line. Faded area represents 95% CI.

References

    1. Thompson S, James M, Wiebe N, Hemmelgarn B, Manns B, Klarenbach S, et al. Cause of death in patients with reduced kidney function. J. Am. Soc. Nephrol. 2015;26(10):2504–2511. doi: 10.1681/ASN.2014070714.
    1. Webster AC, Nagler EV, Morton RL, Masson P. Chronic kidney disease. Lancet. 2017;389(10075):1238–1252. doi: 10.1016/S0140-6736(16)32064-5.
    1. Tonelli M, Wiebe N, Culleton B, House A, Rabbat C, Fok M, et al. Chronic kidney disease and mortality risk: A systematic review. J. Am. Soc. Nephrol. 2006;17(7):2034–2047. doi: 10.1681/ASN.2005101085.
    1. Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N. Engl. J. Med. 2012;367(1):20–29. doi: 10.1056/NEJMoa1114248.
    1. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation: Modification of diet in renal disease study group. Ann. Intern. Med. 1999;130(6):461–470. doi: 10.7326/0003-4819-130-6-199903160-00002.
    1. Rehberg PB. Studies on kidney function: The rate of filtration and reabsorption in the human kidney. Biochem. J. 1926;20(3):447–460. doi: 10.1042/bj0200447.
    1. Peralta CA, Shlipak MG, Judd S, Cushman M, McClellan W, Zakai NA, et al. Detection of chronic kidney disease with creatinine, cystatin C, and urine albumin-to-creatinine ratio and association with progression to end-stage renal disease and mortality. JAMA. 2011;305(15):1545–1552. doi: 10.1001/jama.2011.468.
    1. Shlipak MG, Matsushita K, Arnlov J, Inker LA, Katz R, Polkinghorne KR, et al. Cystatin C versus creatinine in determining risk based on kidney function. N. Engl. J. Med. 2013;369(10):932–943. doi: 10.1056/NEJMoa1214234.
    1. Shlipak MG, Sarnak MJ, Katz R, Fried LF, Seliger SL, Newman AB, et al. Cystatin C and the risk of death and cardiovascular events among elderly persons. N. Engl. J. Med. 2005;352(20):2049–2060. doi: 10.1056/NEJMoa043161.
    1. Kyhse-Andersen J, Schmidt C, Nordin G, Andersson B, Nilsson-Ehle P, Lindstrom V, et al. Serum cystatin C, determined by a rapid, automated particle-enhanced turbidimetric method, is a better marker than serum creatinine for glomerular filtration rate. Clin. Chem. 1994;40(10):1921–1926. doi: 10.1093/clinchem/40.10.1921.
    1. Grubb A, Simonsen O, Sturfelt G, Truedsson L, Thysell H. Serum concentration of cystatin C, factor D and beta 2-microglobulin as a measure of glomerular filtration rate. Acta Med. Scand. 1985;218(5):499–503. doi: 10.1111/j.0954-6820.1985.tb08880.x.
    1. Dardashti A, Nozohoor S, Grubb A, Bjursten H. Shrunken pore syndrome is associated with a sharp rise in mortality in patients undergoing elective coronary artery bypass grafting. Scand. J. Clin. Lab. Invest. 2016;76(1):74–81. doi: 10.3109/00365513.2015.1099724.
    1. Herou E, Dardashti A, Nozohoor S, Zindovic I, Ederoth P, Grubb A, et al. The mortality increase in cardiac surgery patients associated with shrunken pore syndrome correlates with the eGFRcystatin C/eGFRcreatinine-ratio. Scand. J. Clin. Lab. Invest. 2019;79(3):167–173. doi: 10.1080/00365513.2019.1576101.
    1. Purde MT, Nock S, Risch L, Medina Escobar P, Grebhardt C, Nydegger UE, et al. Ratio of cystatin C and creatinine-based estimates of the glomerular filtration rate predicts mortality in healthy seniors independent of kidney function. Scand. J. Clin. Lab. Invest. 2016;76(4):341–343. doi: 10.3109/00365513.2016.1149882.
    1. Christensson A, Grubb A, Molvin J, Holm H, Gransbo K, Tasevska-Dinevska G, et al. The shrunken pore syndrome is associated with declined right ventricular systolic function in a heart failure population: The HARVEST study. Scand. J. Clin. Lab. Invest. 2016;76(7):568–574. doi: 10.1080/00365513.2016.1223338.
    1. Almen MS, Bjork J, Nyman U, Lindstrom V, Jonsson M, Abrahamson M, et al. Shrunken pore syndrome is associated with increased levels of atherosclerosis-promoting proteins. Kidney Int. Rep. 2019;4(1):67–79. doi: 10.1016/j.ekir.2018.09.002.
    1. Akesson A, Lindstrom V, Nyman U, Jonsson M, Abrahamson M, Christensson A, et al. Shrunken pore syndrome and mortality: A cohort study of patients with measured GFR and known comorbidities. Scand. J. Clin. Lab. Invest. 2020;80(5):412–422. doi: 10.1080/00365513.2020.1759139.
    1. Öberg CM, Lindström M, Grubb A, Christensson A. Potential relationship between eGFRcystatin C/eGFRcreatinine-ratio and glomerular basement membrane thickness in diabetic kidney disease. Scand. J. Clin. Lab. Invest. 2020;76:74.
    1. Grubb A, Lindstrom V, Jonsson M, Back SE, Ahlund T, Rippe B, et al. Reduction in glomerular pore size is not restricted to pregnant women: Evidence for a new syndrome: 'Shrunken pore syndrome'. Scand. J. Clin. Lab. Invest. 2015;75(4):333–340. doi: 10.3109/00365513.2015.1025427.
    1. Grubb A. Shrunken pore syndrome: A common kidney disorder with high mortality: Diagnosis, prevalence, pathophysiology and treatment options. Clin. Biochem. 2020;83:12–20. doi: 10.1016/j.clinbiochem.2020.06.002.
    1. Grubb A. Glomerular filtration and shrunken pore syndrome in children and adults. Acta Paediatr. 2021;110(9):2503–2508. doi: 10.1111/apa.15846.
    1. von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP, et al. The strengthening the reporting of observational studies in epidemiology (STROBE) statement: Guidelines for reporting observational studies. Lancet. 2007;370(9596):1453–1457. doi: 10.1016/S0140-6736(07)61602-X.
    1. .
    1. Grubb A, Horio M, Hansson LO, Bjork J, Nyman U, Flodin M, et al. Generation of a new cystatin C-based estimating equation for glomerular filtration rate by use of 7 assays standardized to the international calibrator. Clin. Chem. 2014;60(7):974–986. doi: 10.1373/clinchem.2013.220707.
    1. Nyman U, Grubb A, Larsson A, Hansson LO, Flodin M, Nordin G, et al. The revised Lund-Malmo GFR estimating equation outperforms MDRD and CKD-EPI across GFR, age and BMI intervals in a large Swedish population. Clin. Chem. Lab. Med. 2014;52(6):815–824. doi: 10.1515/cclm-2013-0741.
    1. O'Brien SM, Feng L, He X, Xian Y, Jacobs JP, Badhwar V, et al. The society of thoracic surgeons 2018 adult cardiac surgery risk models: Part 2-statistical methods and results. Ann. Thorac. Surg. 2018;105(5):1419–1428.
    1. Shahian DM, Jacobs JP, Badhwar V, Kurlansky PA, Furnary AP, Cleveland JC, Jr, et al. The society of thoracic surgeons 2018 adult cardiac surgery risk models: Part 1-background, design considerations, and model development. Ann. Thorac. Surg. 2018;105(5):1411–1418. doi: 10.1016/j.athoracsur.2018.03.002.
    1. Nashef SA, Roques F, Michel P, Gauducheau E, Lemeshow S, Salamon R. European system for cardiac operative risk evaluation (EuroSCORE) Eur. J. Cardiothorac. Surg. 1999;16(1):9–13. doi: 10.1016/S1010-7940(99)00134-7.
    1. Nashef SA, Roques F, Sharples LD, Nilsson J, Smith C, Goldstone AR, et al. EuroSCORE II. Eur. J. Cardiothorac. Surg. 2012;41(4):734–744. doi: 10.1093/ejcts/ezs043.
    1. Ljungberg J, Johansson B, Bergdahl IA, Holmgren A, Naslund U, Hultdin J, et al. Mild impairment of renal function (shrunken pore syndrome) is associated with increased risk for future surgery for aortic stenosis. Scand. J. Clin. Lab. Invest. 2019;79(7):524–530. doi: 10.1080/00365513.2019.1664761.
    1. den Bakker E, Gemke RJ, van Wijk JA, Hubeek I, Stoffel-Wagner B, Bokenkamp A. Evidence for shrunken pore syndrome in children. Scand. J. Clin. Lab. Invest. 2020;80(1):32–38. doi: 10.1080/00365513.2019.1692231.
    1. Xhakollari L, Jujic A, Molvin J, Nilsson P, Holm H, Bachus E, et al. Proteins linked to atherosclerosis and cell proliferation are associated with the shrunken pore syndrome in heart failure patients: Shrunken pore syndrome and proteomic associations. Proteomics Clin. Appl. 2021;15:e2000089. doi: 10.1002/prca.202000089.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit