Skip to main content

Advertisement

SpringerLink
Log in

Long-Term Renal Involvement in Association with Fontan Circulation

  • Research
  • Published:
Pediatric Cardiology Aims and scope Submit manuscript

Abstract

Multiorgan dysfunction is a concern of Fontan patients. To clarify the pathophysiology of Fontan nephropathy, we characterize renal disease in the long-term observational study. Medical records of 128 consecutive Fontan patients [median age: 22 (range 15–37) years old] treated between 2009 and 2018 were reviewed to investigate the incidence of nephropathy and its association with other clinical variables. Thirty-seven patients (29%) showed proteinuria (n = 34) or < 90 mL/min/1.73 m2 of estimated glomerular filtration rate (eGFR) (n = 7), including 4 overlapping cases. Ninety-six patients (75%) had liver dysfunction (Forns index > 4.21). Patients with proteinuria received the Fontan procedure at an older age [78 (26–194) vs. 56 (8–292) months old, p = 0.02] and had a higher cardiac index [3.11 (1.49–6.35) vs. 2.71 (1.40–4.95) L/min/m2, p = 0.02], central venous pressure [12 (7–19) vs. 9 (5–19) mmHg, p < 0.001], and proportion with > 4.21 of Forns index (88% vs. 70%, p = 0.04) than those without proteinuria. The mean renal perfusion pressure was lower in patients with a reduced eGFR than those without it [55 (44–65) vs. 65 (45–102) mmHg, p = 0.03], but no other variables differed significantly. A multivariable analysis revealed that proteinuria was associated with an increased cardiac index (unit odds ratio 2.02, 95% confidence interval 1.12–3.65, p = 0.02). Seven patients with severe proteinuria had a lower oxygen saturation than those with no or mild proteinuria (p = 0.01, 0.03). Proteinuria or a decreased eGFR differentially occurred in approximately 30% of Fontan patients. Suboptimal Fontan circulation may contribute to the development of proteinuria and reduced eGFR.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. d’Udekem Y, Iyengar AJ, Galati JC, Forsdick V, Weintraub RG, Wheaton GR, Bullock A, Justo RN, Grigg LE, Sholler GF, Hope S, Radford DJ, Gentles TL, Celermajer DS, Winlaw DS (2014) Redefining expectations of long-term survival after the Fontan procedure: twenty-five years of follow-up from the entire population of Australia and New Zealand. Circulation 130:S32-38. https://doi.org/10.1161/CIRCULATIONAHA.113.007764

    Article  PubMed  Google Scholar 

  2. Dimopoulos K, Diller GP, Koltsida E, Pijuan-Domenech A, Papadopoulou SA, Babu-Narayan SV, Salukhe TV, Piepoli MF, Poole-Wilson PA, Best N, Francis DP, Gatzoulis MA (2008) Prevalence, predictors, and prognostic value of renal dysfunction in adults with congenital heart disease. Circulation 117:2320–2328. https://doi.org/10.1161/CIRCULATIONAHA.107.734921

    Article  PubMed  Google Scholar 

  3. Morgan C, Al-Aklabi M, Garcia Guerra G (2015) Chronic kidney disease in congenital heart disease patients: a narrative review of evidence. Can J Kidney Health Dis 2:27. https://doi.org/10.1186/s40697-015-0063-8

    Article  PubMed  PubMed Central  Google Scholar 

  4. Pujol C, Schiele S, Maurer SJ, Hock J, Fritz C, Hager A, Ewert P, Tutarel O (2020) Patients with single-ventricle physiology over the age of 40 years. J Clin Med. https://doi.org/10.3390/jcm9124085

    Article  PubMed  PubMed Central  Google Scholar 

  5. Anne P, Du W, Mattoo TK, Zilberman MV (2009) Nephropathy in patients after Fontan palliation. Int J Cardiol 132:244–247. https://doi.org/10.1016/j.ijcard.2007.11.079

    Article  PubMed  Google Scholar 

  6. Sharma S, Ruebner RL, Furth SL, Dodds KM, Rychik J, Goldberg DJ (2016) Assessment of kidney function in survivors following Fontan palliation. Congenit Heart Dis 11:630–636. https://doi.org/10.1111/chd.12358

    Article  PubMed  Google Scholar 

  7. Opotowsky AR, Baraona FR, Mc Causland FR, Loukas B, Landzberg E, Landzberg MJ, Sabbisetti V, Waikar SS (2017) Estimated glomerular filtration rate and urine biomarkers in patients with single-ventricle Fontan circulation. Heart 103:434–442. https://doi.org/10.1136/heartjnl-2016-309729

    Article  CAS  PubMed  Google Scholar 

  8. Broda CR, Sriraman H, Wadhwa D, Wang Y, Tunuguntla H, Akcan-Arikan A, Ermis PR, Price JF (2018) Renal dysfunction is associated with higher central venous pressures in patients with Fontan circulation. Congenit Heart Dis 13:602–607. https://doi.org/10.1111/chd.12617

    Article  PubMed  Google Scholar 

  9. Khuong JN, Wilson TG, Grigg LE, Bullock A, Celermajer D, Disney P, Wijesekera VA, Hornung T, Zannino D, Iyengar AJ, d’Udekem Y (2020) Fontan-associated nephropathy: predictors and outcomes. Int J Cardiol 306:73–77. https://doi.org/10.1016/j.ijcard.2020.01.014

    Article  PubMed  Google Scholar 

  10. Horio M, Imai E, Yasuda Y, Watanabe T, Matsuo S, Developing C, the Japanese Equation for Estimated GFR, (2013) GFR estimation using standardized serum cystatin C in Japan. Am J Kidney Dis 61:197–203. https://doi.org/10.1053/j.ajkd.2012.07.007

    Article  CAS  PubMed  Google Scholar 

  11. Levin A, Stevens PE, Bilous RW, Coresh J, De Francisco ALM, De Jong PE, Griffith KE, Hemmelgarn BR, Iseki K, Lamb EJ, Levey AS, Riella MC, Shlipak MG, Wang H, White CT, Winearls CG (2013) Kidney disease: improving global outcomes (KDIGO) CKD work group. KDIGO. https://doi.org/10.1038/kisup.2012.73

    Article  Google Scholar 

  12. Forns X, Ampurdanes S, Llovet JM, Aponte J, Quinto L, Martinez-Bauer E, Bruguera M, Sanchez-Tapias JM, Rodes J (2002) Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model. Hepatology 36:986–992. https://doi.org/10.1053/jhep.2002.36128

    Article  PubMed  Google Scholar 

  13. Baek JS, Bae EJ, Ko JS, Kim GB, Kwon BS, Lee SY, Noh CI, Park EA, Lee W (2010) Late hepatic complications after Fontan operation; non-invasive markers of hepatic fibrosis and risk factors. Heart 96:1750–1755. https://doi.org/10.1136/hrt.2010.201772

    Article  CAS  PubMed  Google Scholar 

  14. Ackerman T, Geerts A, Van Vlierberghe H, De Backer J, Francois K (2018) Hepatic changes in the Fontan circulation: identification of liver dysfunction and an attempt to streamline follow-up screening. Pediatr Cardiol 39:1604–1613. https://doi.org/10.1007/s00246-018-1937-1

    Article  CAS  PubMed  Google Scholar 

  15. Rajpal S, Alshawabkeh L, Almaddah N, Joyce CM, Shafer K, Gurvitz M, Waikar SS, Mc Causland FR, Landzberg MJ, Opotowsky AR (2018) Association of albuminuria with major adverse outcomes in adults with congenital heart disease: results from the Boston adult congenital heart biobank. JAMA Cardiol 3:308–316. https://doi.org/10.1001/jamacardio.2018.0125

    Article  PubMed  PubMed Central  Google Scholar 

  16. Aimo A, Fabiani I, Vergaro G, Arzilli C, Chubuchny V, Pasanisi EM, Petersen C, Poggianti E, Taddei C, Pugliese NR, Bayes-Genis A, Lupon J, Giannoni A, Ripoli A, Georgiopoulos G, Passino C, Emdin M (2021) Prognostic value of reverse remodelling criteria in heart failure with reduced or mid-range ejection fraction. ESC Heart Fail 8:3014–3025. https://doi.org/10.1002/ehf2.13396

    Article  PubMed  PubMed Central  Google Scholar 

  17. Rathgeber SL, Lam C, Harris KC, Grewal J (2022) Hepatic and renal consequences of single-ventricle physiology palliated with the Fontan operation. Can J Cardiol 38:1002–1011. https://doi.org/10.1016/j.cjca.2022.04.022

    Article  PubMed  Google Scholar 

  18. Baek JS, Park CS, Choi ES, Yun TJ, Kwon BS, Yu JJ, Kim YH (2021) The impact of additional antegrade pulmonary blood flow at bidirectional Glenn shunt on long-term outcomes. J Thorac Cardiovasc Surg 162(1346–1355):e1344. https://doi.org/10.1016/j.jtcvs.2021.01.022

    Article  Google Scholar 

  19. Kartik SV, Sasidharan B, Gopalakrishnan A, Kurup HKN, Krishnamoorthy KM, Sasikumar D, Thulaseedharan JV, Valaparambil A, Tharakan J, Sivasubramonian S (2021) A comparative study of invasive modalities for evaluation of pulmonary arteriovenous fistula after bidirectional Glenn shunt. Pediatr Cardiol 42:1818–1825. https://doi.org/10.1007/s00246-021-02670-6

    Article  PubMed  Google Scholar 

  20. Inatomi J, Matsuoka K, Fujimaru R, Nakagawa A, Iijima K (2006) Mechanisms of development and progression of cyanotic nephropathy. Pediatr Nephrol 21:1440–1445. https://doi.org/10.1007/s00467-006-0220-5

    Article  PubMed  Google Scholar 

  21. Martinez-Quintana E, Rodriguez-Gonzalez F, Fabregas-Brouard M, Nieto-Lago V (2009) Serum and 24-hour urine analysis in adult cyanotic and noncyanotic congenital heart disease patients. Congenit Heart Dis 4:147–152. https://doi.org/10.1111/j.1747-0803.2009.00273.x

    Article  PubMed  Google Scholar 

  22. Hongsawong N, Khamdee P, Silvilairat S, Chartapisak W (2018) Prevalence and associated factors of renal dysfunction and proteinuria in cyanotic congenital heart disease. Pediatr Nephrol 33:493–501. https://doi.org/10.1007/s00467-017-3804-3

    Article  PubMed  Google Scholar 

  23. Luciano RL, Moeckel GW (2019) Update on the native kidney biopsy: core curriculum 2019. Am J Kidney Dis 73:404–415. https://doi.org/10.1053/j.ajkd.2018.10.011

    Article  PubMed  Google Scholar 

  24. Krishnan S, Suarez-Martinez AD, Bagher P, Gonzalez A, Liu R, Murfee WL, Mohandas R (2021) Microvascular dysfunction and kidney disease: challenges and opportunities? Microcirculation 28:e12661. https://doi.org/10.1111/micc.12661

    Article  PubMed  Google Scholar 

  25. Mullens W, Abrahams Z, Francis GS, Sokos G, Taylor DO, Starling RC, Young JB, Tang WHW (2009) Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol 53:589–596. https://doi.org/10.1016/j.jacc.2008.05.068

    Article  PubMed  PubMed Central  Google Scholar 

  26. Zafar F, Lubert AM, Katz DA, Hill GD, Opotowsky AR, Alten JA, Goldstein SL, Alsaied T (2020) Long-term kidney function after the Fontan operation: JACC review topic of the week. J Am Coll Cardiol 76:334–341. https://doi.org/10.1016/j.jacc.2020.05.042

    Article  PubMed  Google Scholar 

  27. Ohuchi H, Miyazaki A, Negishi J, Hayama Y, Nakai M, Nishimura K, Ichikawa H, Shiraishi I, Yamada O (2017) Hemodynamic determinants of mortality after Fontan operation. Am Heart J 189:9–18. https://doi.org/10.1016/j.ahj.2017.03.020

    Article  PubMed  Google Scholar 

  28. An HS, Choi YH, Song MK, Lee SY, Kim GB, Bae EJ (2020) Early development of hepatic fibrosis after Fontan procedure: a non-invasive study of a subclinical liver disease. Int J Cardiol 320:64–69. https://doi.org/10.1016/j.ijcard.2020.08.009

    Article  PubMed  Google Scholar 

  29. Agnoletti G, Ferraro G, Bordese R, Marini D, Gala S, Bergamasco L, Ferroni F, Calvo PL, Barletti C, Cisaro F, Longo F, Pace Napoleone C (2016) Fontan circulation causes early, severe liver damage. Should we offer patients a tailored strategy? Int J Cardiol 209:60–65. https://doi.org/10.1016/j.ijcard.2016.02.041

    Article  PubMed  Google Scholar 

  30. Hebson CL, McCabe NM, Elder RW, Mahle WT, McConnell M, Kogon BE, Veledar E, Jokhadar M, Vincent RN, Sahu A, Book WM (2013) Hemodynamic phenotype of the failing Fontan in an adult population. Am J Cardiol 112:1943–1947. https://doi.org/10.1016/j.amjcard.2013.08.023

    Article  PubMed  PubMed Central  Google Scholar 

  31. Miranda WR, Borlaug BA, Hagler DJ, Connolly HM, Egbe AC (2019) Haemodynamic profiles in adult Fontan patients: associated haemodynamics and prognosis. Eur J Heart Fail 21:803–809. https://doi.org/10.1002/ejhf.1365

    Article  PubMed  Google Scholar 

  32. Targher G, Chonchol MB, Byrne CD (2014) CKD and nonalcoholic fatty liver disease. Am J Kidney Dis 64:638–652. https://doi.org/10.1053/j.ajkd.2014.05.019

    Article  PubMed  Google Scholar 

  33. Clark AL, Kalra PR, Petrie MC, Mark PB, Tomlinson LA, Tomson CR (2019) Change in renal function associated with drug treatment in heart failure: national guidance. Heart 105:904–910. https://doi.org/10.1136/heartjnl-2018-314158

    Article  CAS  Google Scholar 

  34. Marup FH, Peters CD, Christensen JH, Birn H (2022) Can patiromer allow for intensified renin-angiotensin-aldosterone system blockade with losartan and spironolactone leading to decreased albuminuria in patients with chronic kidney disease, albuminuria and hyperkalaemia? An open-label randomised controlled trial: MorphCKD. BMJ Open 12:e057503. https://doi.org/10.1136/bmjopen-2021-057503

    Article  PubMed  PubMed Central  Google Scholar 

  35. Wheeler DS, Giugliano RP, Rangaswami J (2016) Anticoagulation-related nephropathy. J Thromb Haemost 14:461–467. https://doi.org/10.1111/jth.13229

    Article  CAS  PubMed  Google Scholar 

  36. Brodsky SV, Satoskar A, Hemminger J, Rovin B, Hebert L, Ryan MS, Nadasdy T (2019) Anticoagulant-related nephropathy in kidney biopsy: a single-center report of 41 cases. Kidney Med 1:51–56. https://doi.org/10.1016/j.xkme.2019.03.002

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank Dr. Brian Quinn (Japan Medical Communication, Fukuoka, Japan) for editing the manuscript.

Funding

This research was supported by JSPS KAKENHI Grant Numbers JP20K08449 [K.Y.], JP21K08031 [H.N.], AMED (JP19ek0109260h0003 [S.O.]), and AMED (JP20ek0109481h0001 [S.O.]).

Author information

Authors and Affiliations

  1. Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan

    Mamoru Muraoka, Hazumu Nagata, Kenichiro Yamamura, Yoshimi Eguchi, Shoji Fukuoka, Kiyoshi Uike, Yusaku Nagatomo, Yuichiro Hirata, Kei Nishiyama & Shouichi Ohga

  2. Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Ichiro Sakamoto, Ayako Ishikita, Akiko Nishizaki & Hiroyuki Tsutsui

Authors
  1. Mamoru Muraoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hazumu Nagata
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kenichiro Yamamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ichiro Sakamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ayako Ishikita
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Akiko Nishizaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoshimi Eguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shoji Fukuoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kiyoshi Uike
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yusaku Nagatomo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yuichiro Hirata
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kei Nishiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hiroyuki Tsutsui
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Shouichi Ohga
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MM carried out the primary analyses, drafted the initial manuscript, and critically reviewed and revised the manuscript. HN and KY conceptualized and designed the study, drafted the manuscript, and critically reviewed and revised the manuscript. IS, AI, AN, and HT managed the patients and critically reviewed and revised the manuscript. YE, SF, KU, YN, YH, and KN assisted in implementing the examinations and interventions and critically reviewed and revised the manuscript. SO helped complete the project and critically reviewed and revised the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work.

Corresponding author

Correspondence to Hazumu Nagata.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest in association with the present study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Muraoka, M., Nagata, H., Yamamura, K. et al. Long-Term Renal Involvement in Association with Fontan Circulation. Pediatr Cardiol 45, 340–350 (2024). https://doi.org/10.1007/s00246-023-03334-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00246-023-03334-3

Keywords

Search

Navigation