Abstract
Over the past few decades, there has been increasing recognition of kidney disease in children with non-kidney solid organ transplantation. The risk of kidney disease in children undergoing heart or liver transplantation is higher than the general population as the underlying disease and its associated management may directly impair kidney function. Both heart and liver failures contribute to hypoperfusion and kidney ischemia before patients reach the point of transplant. The transplant surgery itself can often be complicated by acute kidney injury (AKI), which may be further exacerbated by a complicated postoperative course. In the short- and long-term post-transplant period, these children are at risk of acute illness, exposed to nephrotoxic medications, and susceptible to rare but severe infections and immunologic insults that may contribute to AKI and chronic kidney disease (CKD). In some, CKD can progress to kidney failure with replacement therapy (KFRT). CKD and KFRT are associated with increased morbidity and mortality in this patient population. Therefore, it is critical to monitor for and recognize the risk factors for kidney injury in this population and mitigate these risks. In this paper, the authors provide an overview of kidney disease pertaining to heart and liver transplantation in children with guidance on monitoring, diagnosis, prevention, and management.
This is a preview of subscription content, access via your institution.

References
- 1.
Ruebner RL, Reese PP, Denburg MR, Abt PL, Furth SL (2013) End-stage kidney disease after pediatric nonrenal solid organ transplantation. Pediatrics 132:e1319–e1326
- 2.
Hingorani S (2008) Chronic kidney disease after liver, cardiac, lung, heart–lung, and hematopoietic stem cell transplant. Pediatr Nephrol 23:879–888
- 3.
Kamath BM, Spinner NB, Rosenblum ND (2013) Renal involvement and the role of Notch signalling in Alagille syndrome. Nat Rev Nephrol 9:409–418
- 4.
Shneider BL, Magid MS (2005) Liver disease in autosomal recessive polycystic kidney disease. Pediatr Transplant 9:634–639
- 5.
Spada M, Riva S, Maggiore G, Cintorino D, Gridelli B (2009) Pediatric liver transplantation. World J Gastroenterol 15:648–674
- 6.
Zappitelli M, Parikh CR, Kaufman JS, Go AS, Kimmel PL, Hsu CY, Coca SG, Chinchilli VM, Greenberg JH, Moxey-Mims MM, Ikizler TA, Cockovski V, Dyer AM, Devarajan P, ASsessment, Serial Evaluation, and Subsequent Sequelae in Acute Kidney Injury (ASSESS-AKI) Investigators (2020) Acute kidney injury and risk of CKD and hypertension after pediatric cardiac surgery. Clin J Am Soc Nephrol 15:1403–1412. https://doi.org/10.2215/CJN.00150120
- 7.
Downes KJ, Cowden C, Laskin BL, Huang YS, Gong W, Bryan M, Fisher BT, Goldstein SL, Zaoutis TE (2017) Association of acute kidney injury with concomitant vancomycin and piperacillin/tazobactam treatment among hospitalized children. JAMA Pediatr 171:e173219–e173219
- 8.
Kramer H, Trampisch H, Rammos S, Giese A (1990) Birth weight of children with congenital heart disease. Eur J Pediatr 149:752–757
- 9.
Luyckx VA, Brenner BM (2005) Low birth weight, nephron number, and kidney disease. Kidney Int 68:S68–S77
- 10.
Kamath BM, Schwarz KB, Hadžić N (2010) Alagille syndrome and liver transplantation. J Pediatr Gastroenterol Nutr 50:11–15
- 11.
Bloom RD, Reese PP (2007) Chronic kidney disease after nonrenal solid-organ transplantation. J Am Soc Nephrol 18:3031–3041
- 12.
Cochat P, Hulton SA, Acquaviva C, Danpure CJ, Daudon M, De Marchi M, Fargue S, Groothoff J, Harambat J, Hoppe B, Jamieson NV, Kemper MJ, Mandrile G, Marangella M, Picca S, Rumsby G, Salido E, Straub M, van Woerden CS, OxalEurope (2012) Primary hyperoxaluria type 1: indications for screening and guidance for diagnosis and treatment. Nephrol Dial Transplant 27:1729–1736
- 13.
KDIGO (2012) Kidney disease: improving global outcomes (KDIGO) acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl 2:1–138
- 14.
Dipchand AI, Edwards LB, Kucheryavaya AY, Benden C, Dobbels F, Levvey BJ, Lund LH, Meiser B, Yusen RD, Stehlik J, International Society of Heart and Lung Transplantation (2014) The Registry of the International Society for Heart and Lung Transplantation: Seventeenth Official Pediatric Heart Transplantation Report—2014; Focus Theme: Retransplantation. J Heart Lung Transplant 33:985–995
- 15.
Norozi K, Oechslin E (2016) Renal dysfunction in adults with congenital heart defects. Prog Pediatr Cardiol 41:51–57
- 16.
Martinelli J, Habes D, Majed L, Guettier C, Gonzalès E, Linglart A, Larue C, Furlan V, Pariente D, Baujard C, Branchereau S, Gauthier F, Jacquemin E, Bernard O (2018) Long-term outcome of liver transplantation in childhood: a study of 20-year survivors. Am J Transplant 18:1680–1689
- 17.
Ginès P, Solà E, Angeli P, Wong F, Nadim MK, Kamath PS (2018) Hepatorenal syndrome. Nat Rev Dis Primer 4:23
- 18.
Moffett BS, Goldstein SL (2011) Acute kidney injury and increasing nephrotoxic-medication exposure in noncritically-ill children. Clin J Am Soc Nephrol 6:856–863
- 19.
Zappitelli M, Moffett BS, Hyder A, Goldstein SL (2011) Acute kidney injury in non-critically ill children treated with aminoglycoside antibiotics in a tertiary healthcare centre: a retrospective cohort study. Nephrol Dial Transplant 26:144–150
- 20.
Downes KJ, Hayes M, Fitzgerald JC, Pais GM, Liu J, Zane NR, Goldstein SL, Scheetz MH, Zuppa AF (2020) Mechanisms of antimicrobial-induced nephrotoxicity in children. J Antimicrob Chemother 75:1–13
- 21.
Tjon J, Teoh CW (2020) Medication-induced nephrotoxicity in children. Curr Pediatr Rep 8:122–133
- 22.
KDIGO (2013) KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 3:5–14
- 23.
Williams C, Borges K, Banh T, Vasilevska-Ristovska J, Chanchlani R, Ng VL, Dipchand AI, Solomon M, Hebert D, Kim SJ, Astor BC, Parekh RS (2018) Patterns of kidney injury in pediatric nonkidney solid organ transplant recipients. Am J Transplant 18:1481–1488
- 24.
MacDonald C, Norris C, Alton GY, Urschel S, Joffe AR, Morgan CJ, Western Canadian Complex Pediatric Therapies Follow-Up Group (2016) Acute kidney injury after heart transplant in young children: risk factors and outcomes. Pediatr Nephrol 31:671–678
- 25.
Hamada M, Matsukawa S, Shimizu S, Kai S, Mizota T (2017) Acute kidney injury after pediatric liver transplantation: incidence, risk factors, and association with outcome. J Anesth 31:758–763
- 26.
Zhang Y, Xiang B, Wu Y, Xie X, Wang J, Jin S (2019) Risk factors and associated outcomes of early acute kidney injury in pediatric liver transplant recipients: a retrospective study. J Pediatr Surg 55:446–450. https://doi.org/10.1016/j.jpedsurg.2019.07.019
- 27.
Fine RN (2005) Renal function following liver transplantation in children. Pediatr Transplant 9:680–684
- 28.
Saner FH, Cicinnati VR, Sotiropoulos G, Beckebaum S (2012) Strategies to prevent or reduce acute and chronic kidney injury in liver transplantation. Liver Int 32:179–188
- 29.
Menon S, Pollack AH, Sullivan E, Murphy T, Smith J (2020) Acute kidney injury and chronic kidney disease after non-kidney solid organ transplantation. Pediatr Transplant 24:e13753. https://doi.org/10.1111/petr.13753
- 30.
Leung KCW, Tonelli M, James MT (2013) Chronic kidney disease following acute kidney injury—risk and outcomes. Nat Rev Nephrol 9:77–85
- 31.
Gude E, Andreassen AK, Arora S, Gullestad L, Grov I, Hartmann A, Leivestad T, Fiane AE, Geiran OR, Vardal M, Simonsen S (2010) Acute renal failure early after heart transplantation: risk factors and clinical consequences. Clin Transpl 24:E207–E213
- 32.
Türker M, Zeyneloglu P, Sezgin A, Pirat A, Arslan G (2013) RIFLE criteria for acute kidney dysfunction following heart transplantation: incidence and risk factors. Transplant Proc 45:3534–3537
- 33.
Nolin TD, Himmelfarb J (2010) Mechanisms of drug-induced nephrotoxicity. In: Uetrecht J (ed) Adverse drug reactions. Handbook of experimental pharmacology, vol 196. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-00663-0_5
- 34.
Mouzaki M, Yap J, Avinashi V, Babu A, Fu A, Deangelis M, Van Roestel K, Ghanekar A, Kamath B, Avitzur Y, Fecteau A, Jones N, Ling S, Grant D, Ng V (2013) Basiliximab with delayed introduction of calcineurin inhibitors as a renal-sparing protocol following liver transplantation in children with renal impairment. Pediatr Transplant 17:751–756
- 35.
Rossano JW, Cherikh WS, Chambers DC, Goldfarb S, Hayes D Jr, Khush KK, Kucheryavaya AY, Toll AE, Levvey BJ, Meiser B, Stehlik J (2018) The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Twenty-first pediatric heart transplantation report—2018; Focus theme: Multiorgan Transplantation. J Heart Lung Transplant 37:1184–1195
- 36.
Campbell K, Ng V, Martin S, Magee J, Goebel J, Anand R, Martz K, Bucuvalas J, SPLIT Renal Function Working Group (2010) Glomerular filtration rate following pediatric liver transplantation-the SPLIT experience. Am J Transplant 10:2673–2682
- 37.
Schmitz V, Laudi S, Moeckel F, Puhl G, Stockmann M, Tran ZV, Kahl A, Neumann U, Neuhaus P (2008) Chronic renal dysfunction following liver transplantation. Clin Transpl 22:333–340
- 38.
Naesens M, Kuypers DRJ, Sarwal M (2009) Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 4:481–508
- 39.
Bloom RD, Doyle AM (2006) Kidney disease after heart and lung transplantation. Am J Transplant 6:671–679
- 40.
English RF, Pophal SA, Bacanu SA, Fricker J, Boyle GJ, Ellis D, Harker K, Sutton R, Miller SA, Law YM, Pigula FA, Webber SA (2002) Long-term comparison of tacrolimus- and cyclosporine-induced nephrotoxicity in pediatric heart-transplant recipients. Am J Transplant 2:769–773
- 41.
Reich DJ, Clavien PA, Hodge EE (2005) Mycophenolate mofetil for renal dysfunction in liver transplant recipients on cyclosporine or tacrolimus: randomized, prospective, multicenter pilot study results. Transplantation 80:18–25
- 42.
Pageaux GP, Rostaing L, Calmus Y, Duvoux C, Vanlemmens C, Hardgwissen J, Bernard PH, Barbotte E, Vercambre L, Bismuth M, Puche P, Navarro F, Larrey D (2006) Mycophenolate mofetil in combination with reduction of calcineurin inhibitors for chronic renal dysfunction after liver transplantation. Liver Transpl 12:1755–1760
- 43.
Cantarovich M, Tzimas GN, Barkun J, Deschênes M, Alpert E, Tchervenkov J (2003) Efficacy of mycophenolate mofetil combined with very low-dose cyclosporine microemulsion in long-term liver-transplant patients with renal dysfunction. Transplantation 76:98–102
- 44.
Castroagudín JF, Molina E, Romero R, Otero E, Tomé S, Varo E (2009) Improvement of renal function after the switch from a calcineurin inhibitor to everolimus in liver transplant recipients with chronic renal dysfunction. Liver Transpl 15:1792–1797
- 45.
Masetti M, Montalti R, Rompianesi G, Codeluppi M, Gerring R, Romano A, Begliomini B, Di Benedetto F, Gerunda GE (2010) Early withdrawal of calcineurin inhibitors and everolimus monotherapy in de novo liver transplant recipients preserves renal function. Am J Transplant 10:2252–2262
- 46.
DuBay D, Smith RJ, Qiu KG, Levy GA, Lilly L, Therapondos G (2008) Sirolimus in liver transplant recipients with renal dysfunction offers no advantage over low-dose calcineurin inhibitor regimens. Liver Transpl 14:651–659
- 47.
Fairbanks KD, Eustace JA, Fine D, Thuluvath PJ (2003) Renal function improves in liver transplant recipients when switched from a calcineurin inhibitor to sirolimus. Liver Transpl 9:1079–1085
- 48.
Falger JC, Mueller T, Arbeiter K, Boehm M, Regele H, Balzar E, Aufricht C (2006) Conversion from calcineurin inhibitor to sirolimus in pediatric chronic allograft nephropathy. Pediatr Transplant 10:565–569
- 49.
Letavernier E, Pe’raldi M-N, Pariente A, Morelon E, Legendre C (2005) Proteinuria following a switch from calcineurin inhibitors to sirolimus. Transplantation 80:1198–1203
- 50.
Letavernier E, Legendre C (2008) mToR inhibitors-induced proteinuria: mechanisms, significance, and management. Transplant Rev 22:125–130
- 51.
Roche SL, Kaufmann J, Dipchand AI, Kantor PF (2008) Hypertension after pediatric heart transplantation is primarily associated with immunosuppressive regimen. J Heart Lung Transplant 27:501–507
- 52.
Rothbaum Perito E, Lau A, Rhee S, Roberts JP, Rosenthal P (2012) Posttransplant metabolic syndrome in children and adolescents after liver transplantation: a systematic review. Liver Transpl 18:1009–1028
- 53.
Roche SL, O’Sullivan JJ, Kantor PF (2010) Hypertension after pediatric cardiac transplantation: detection, etiology, implications and management. Pediatr Transplant 14:159–168
- 54.
Scherrer U, Vissing SF, Morgan BJ, Rollins JA, Tindall RS, Ring S, Hanson P, Mohanty PK, Victor RG (1990) Cyclosporine-induced sympathetic activation and hypertension after heart transplantation. N Engl J Med 323:693–699
- 55.
Hoorn EJ, Walsh SB, McCormick JA, Zietse R, Unwin RJ, Ellison DH (2012) Pathogenesis of calcineurin inhibitor–induced hypertension. J Nephrol 25:269–275
- 56.
Penninga L, Møller CH, Gustafsson F, Steinbrüchel DA, Gluud C (2010) Tacrolimus versus cyclosporine as primary immunosuppression after heart transplantation: systematic review with meta-analyses and trial sequential analyses of randomised trials. Eur J Clin Pharmacol 66:1177–1187
- 57.
Rabkin JM, Corless CL, Rosen HR, Olyaei AJ (2002) Immunosuppression impact on long-term cardiovascular complications after liver transplantation. Am J Surg 183:595–599
- 58.
Aurora P, Edwards LB, Christie J, Dobbels F, Kirk R, Kucheryavaya AY, Rahmel AO, Taylor DO, Hertz MI (2008) Registry of the International Society for Heart and Lung Transplantation: Eleventh Official Pediatric Lung and Heart/Lung Transplantation Report—2008. J Heart Lung Transplant 27:978–983
- 59.
Cuenca AG, Kim HB, Vakili K (2017) Pediatric liver transplantation. Semin Pediatr Surg 26:217–223
- 60.
Verbiest A, Pirenne J, Dierickx D (2014) De novo thrombotic microangiopathy after non-renal solid organ transplantation. Blood Rev 28:269–279
- 61.
Renner B, Klawitter J, Goldberg R, McCullough JW, Ferreira VP, Cooper JE, Christians U, Thurman JM (2013) Cyclosporine induces endothelial cell release of complement-activating microparticles. J Am Soc Nephrol 24:1849–1862
- 62.
Puliyanda DP, Amet N, Dhawan A, Hilo L, Radha RK, Bunnapradist S, Czer L, Martin P, Jordan S, Toyoda M (2006) Isolated heart and liver transplant recipients are at low risk for polyomavirus BKV nephropathy. Clin Transpl 20:289–294
- 63.
Ali FN, Meehan SM, Pahl E, Cohn RA (2010) Native BK viral nephropathy in a pediatric heart transplant recipient. Pediatr Transplant 14:E38–E41
- 64.
Butts RJ, Uber WE, Savage AJ (2012) Treatment of BK viremia in a pediatric heart transplant recipient. J Heart Lung Transplant 31:552–553
- 65.
Lorica C, Bueno TG, Garcia-Buitrago MT, Rusconi P, Gonzalez IA (2013) BK virus nephropathy in a pediatric heart transplant recipient with post-transplant lymphoproliferative disorder: a case report and review of literature. Pediatr Transplant 17:E55–E61
- 66.
Sahney S, Yorgin P, Zuppan C, Cutler D, Kambham N, Chinnock R (2010) BK virus nephropathy in the native kidneys of a pediatric heart transplant recipient. Pediatr Transplant 14:E11–E15
- 67.
Lee Y, Yae-Jean K, Cho H (2019) BK virus nephropathy and multiorgan involvement in a child with heart transplantation. Clin Nephrol 91:107
- 68.
Zeng Y, Magil A, Hussaini T, Yeung CK, Erb SR, Marquez-Alazagara V, Yoshida EM (2015) First confirmed case of native Polyomavirus BK nephropathy in a liver transplant recipient seven years post-transplant. Ann Hepatol 14:137–140
- 69.
Brinkert F, Briem-Richter A, Ilchmann C, Kemper MJ, Ganschow R (2010) Prevalence of polyomavirus viruria (JC virus/BK virus) in children following liver transplantation. Pediatr Transplant 14:105–108
- 70.
Greenberg JH, Coca S, Parikh CR (2014) Long-term risk of chronic kidney disease and mortality in children after acute kidney injury: a systematic review. BMC Nephrol 15:184
- 71.
Filler G, Melk A, Marks SD (2016) Practice recommendations for the monitoring of renal function in pediatric non-renal organ transplant recipients. Pediatr Transplant 20:352–363
- 72.
Ruebner RL, Reese PP, Denburg MR, Rand EB, Abt PL, Furth SL (2012) Risk factors for end-stage kidney disease after pediatric liver transplantation. Am J Transplant 12:3398–3405
- 73.
Gupta J, Amaral S, Mahle WT (2008) Renal transplantation after previous pediatric heart transplantation. J Heart Lung Transplant 27:217–221
- 74.
Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–637
- 75.
Mammen C, Al Abbas A, Skippen P, Nadel H, Levine D, Collet JP, Matsell DG (2012) Long-term risk of CKD in children surviving episodes of acute kidney injury in the intensive care unit: a prospective cohort study. Am J Kidney Dis 59:523–530
- 76.
Lebel A, Teoh CW, Zappitelli M (2020) Long-term complications of acute kidney injury in children. Curr Opin Pediatr 32:367–375
- 77.
Hilk K, Zerofsky M, Rhee S, Rosenthal P, Perito ER (2019) Center variation in screening for and management of metabolic syndrome in pediatric liver transplant recipients: a survey of SPLIT centers. Pediatr Transplant 23:e13347
- 78.
Flynn JT, Kaelber DC, Baker-Smith CM, Blowey D, Carroll AE, Daniels SR, de Ferranti SD, Dionne JM, Falkner B, Flinn SK, Gidding SS, Goodwin C, Leu MG, Powers ME, Rea C, Samuels J, Simasek M, Thaker VV, Urbina EM, Subcommittee on Screening and Management of High Blood Pressure in Children (2017) Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics 140:e20171904
- 79.
Goldstein SL (2012) Acute kidney injury in children and its potential consequences in adulthood. Blood Purif 33:131–137
Author information
Affiliations
Corresponding author
Additional information
Answers
1. b; 2. a; 3. c; 4. d; 5. d
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Kirpalani, A., Teoh, C.W., Ng, V.L. et al. Kidney disease in children with heart or liver transplant. Pediatr Nephrol (2021). https://doi.org/10.1007/s00467-021-04949-5
Received:
Revised:
Accepted:
Published:
Keywords
- Children
- Heart transplantation
- Liver transplantation
- Acute kidney injury
- Chronic kidney disease
- Kidney failure with replacement therapy
- Risk factors