|Year : 2016 | Volume
| Issue : 1 | Page : 1-8
|Effect of pediatric liver transplantation on renal function
Hasan M.A. Isa1, Afaf M Mohamed2, Amer E Alderazi3
1 Pediatric Department, Salmaniya Medical Complex, Manama, Kingdom of Bahrain
2 NBB Dair Health Center, Manama, Kingdom of Bahrain
3 General Surgery Department, Salmaniya Medical Complex, Manama, Kingdom of Bahrain
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|Date of Web Publication||15-Jan-2016|
| Abstract|| |
The aim of this review is to define the incidence of renal dysfunction among pediatric liver transplant (LT) survivors, to identify the associated risk factors and to outline the therapeutic options. Renal dysfunction is a common problem after pediatric LT. The measured glomerular filtration rate is considered the "gold-standard" for assessment of renal function. Renal dysfunction in pediatric LT recipients is multifactorial. Renal-sparing immunosuppressive strategies are essential to reverse renal dysfunction and to prevent end-stage renal disease.
|How to cite this article:|
Isa HM, Mohamed AM, Alderazi AE. Effect of pediatric liver transplantation on renal function. Saudi J Kidney Dis Transpl 2016;27:1-8
|How to cite this URL:|
Isa HM, Mohamed AM, Alderazi AE. Effect of pediatric liver transplantation on renal function. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2020 Jun 2];27:1-8. Available from: http://www.sjkdt.org/text.asp?2016/27/1/1/174041
| Introduction|| |
Solid-organ transplantation is an established therapy for children with end-stage heart, lung, liver and kidney diseases. ,, The majority of pediatric transplant recipients survive into adulthood. , Pediatric liver transplant (LT) has significantly advanced over the past decade. ,,, LT is currently considered the preferred treatment option for a wide range of previously fatal liver diseases. , If children pass the first year after LT, they will very likely survive up to 10 years.  As the survival rate has improved, health care providers have started to focus on the impact of LT on long-term outcome. ,, Maintaining allograft function and minimizing complications related to immunosuppressive therapy are evolving challenges. , Post-LT renal dysfunction may negatively impact patients' survival. ,,
The use of calcineurin inhibitors (CNIs) such as tacrolimus (TAC) and cyclosporine A (CsA) result in a dramatic increase of patient and graft survival. ,, However, this was associated with nephrotoxicity. ,,,,,,,, Because children have a greater cumulative exposure to CNIs, they are potentially at greater risk of severe renal dysfunction and end-stage renal disease (ESRD). ,,, Data on the incidence and risk factors of renal dysfunction among pediatric LT recipients are scanty and controversial. ,
The aim of this review is to define the incidence of renal dysfunction among pediatric LT survivors, to identify the associated risk factors and to outline the available therapeutic options. We used the PubMed, Ovid, Medline and Google search engines to retrieve full papers reported on the diagnosis, incidence, risk factors and management of acute and chronic kidney diseases (CKDs) pre-and post-LT.
| Renal Function Assessment|| |
The assessment of renal function pre- and post-LT can be achieved by several methods. Creatinine clearance (C CR ), inulin clearance (C IN ) or clearance of radiolabeled material [chromium EDTA CR 51 or sodium diethylene triamine pentaacetic acid indium 111 (DTPA IN 111)] had been used to determine the "true glomerular filtration rate (GFR)."  Most of the studies used serum creatinine level, C CR  and the Schwartz formula to calculate GFR (cGFR). ,, Although creatinine-based equations provide a cost-effective, rapid and non-invasive method of GFR estimation, their precision is limited , and may be factitious.  Serum creatinine can be affected by gender, nutrition, fluid balance and muscle mass. ,,,, These factors make these formulae inaccurate, particularly in patients with end-stage liver disease. ,, Serum creatinine levels and the Schwartz formula overestimate the true GFR and, subsequently, underestimate the frequency of CKD. ,,, The plasma clearance of an injected isotope is considered the most accurate measurement of true GFR in pediatric LT recipients. ,, It is considered the "gold standard" and many centers perform measured GFR (mGFR) routinely as a screening test. ,,,,, Unfortunately, these tests are expensive and time consuming and require specialized training and are not usually available for smaller children. ,,,, Based on the mGFR, the National Kidney Foundation criteria are usually used to classify renal dysfunction.  Cystatin C is a widely expressed protein and its serum levels are not affected by height, gender or body composition.  Its based equation is also used for the assessment of renal function in the long term after pediatric LT,  and it is more reliable with less-invasive estimations that may represent a good tool to the bedside clinician. ,, Beta trace protein can also be used as an alternative diagnostic mean to detect the post-LT reduction of GFR.  A wide selection of cytokines and chemokines have been used as biomarkers for acute kidney injury (AKI), such as urinary interleukins (IL) and neutrophil gelatinase-associated lipocalin (NGAL). 
| Renal Function Before Liver Transplantation|| |
Pre-operative renal function has long been identified as an important factor in determining survival post-LT.  An elevated pre-LT GFR above the normal range can be explained by glomerular hyperfiltration (GHF).  Wiesmayr et al  proposed that the post-LT fall in GFR is not a true fall but a normalization into normal range of GFR. Patients with end-stage liver disease often experience a hepato-renal syndrome before LT, which is reversible once there is a functioning liver. ,,
| Short- and Long-Term Incidences of Post-LT Renal Dysfunction|| |
The short-term incidence of renal dysfunction in pediatric LT recipients has been variable, with the majority of studies indicating a modest reduction in GFR.  Stelle et al  showed a significant decline in C CR during the early post-operative phase. The maximum decrease in GFR occurs in the first few months post-LT; ,, this is followed by a gradual improvement and long-term stabilization.  In a multicenter, cross-sectional pediatric study, 17.6% had a mGFR <90 mL/min/1.73 m 2 ≥1 year post-LT.  In the McCulloch et al  study of 79 pediatric LT recipients with a mean follow-up of two years, 30% of the patients had GFR <75 mL/min/1.73 m 2 . Similarly, Stelle et al,  in their study, found GFR levels between 60 and 90 mL/min/1.73 m 2 in 20% of their patients three years post-LT. The long-term incidence of significantly reduced GFR in adult allograft recipients has been approximately 10%.  In an adult study of 221 patients, post-LT chronic renal failure (CRF) was common, with a five-year cumulative incidence of 22%.  CKD and kidney failure necessitating renal replacement therapy (RRT) are significant post-LT complications in adults, with 12% having CKD Stages 4-5 at five years and 29% after 10 years.  In pediatric recipients, the long-term incidence of a reduced post-LT GFR has also been variable.  Campbell et al  found that almost one-third of pediatric LT patients had a mGFR <70 mL/min/1.73 m 2 at long-term follow-up. In a 20-year national cohort of pediatric LT recipients, Ruebner et al  studied a total of 8976 recipients and found that 167 (2%) developed ESRD with a mean follow-up of eight years. Another large study with a long-term follow-up showed a prevalence of post-pediatric LT CRF of ~30% in the first five years and CKD in 7.6% after five to 10 years.  In the Calvo-Garcia et al  study, of 235 long-term LT survivors, 39% had stage 2 CKD and 17% had stage 3 CKD.
| Risk Factors of Renal Dysfunction|| |
Renal dysfunction of the pediatric LT population is multifactorial.  While the logistic regression model in the Brinkert et al  study could not find any significant predictor, Campbell et al  found a number of common risk factors such as immunosuppression, age at LT, cGFR at LT and growth failure. Similarly, in a total of 8976 pediatric LT recipients, older age (>15 years), hepatitis, liver re-transplant, black race and male sex were the risk factors for ESRD.  The etiology of renal dysfunction following pediatric LT can be divided into three main categories: (1) pre-existing renal disease, (2) peri-operative factors and (3) post-operative factors. 
Pre-existing renal disease
Most children with chronic liver disease have marginal renal functions.  However, there is a high-risk group of diseases for primary kidney dysfunction, such as Alagille syndrome, alpha1-antitrypsin deficiency, Wilson's disease, glycogen storage disease, tyrosinemia and congenital hepatic fibrosis. , These diseases might result in deterioration of renal function post-LT. , Pre-LT hepatorenal syndrome is also an important risk factor for AKI  and acute cystic kidney disease (ACKD)  after LT. Even a mild decrease in pre-LT cGFR is associated with an increased odds of post-LT renal dysfunction.  In patients with a known risk for renal dysfunction, it will be difficult to reduce the risk of ESRD subsequently.  However, in patients with moderate renal dysfunction, LT is still feasible with favorable outcomes.  LT for Wilson disease is not only a lifesaving procedure but also cures renal defects. 
The risk of renal dysfunction is directly associated with older age at LT.  In adults, decreased pre-LT cGFR may result in further renal impairment, while in children pre-LT GHF normalizes and may lead to stability even in long-term follow-up.  Data interpretation of patients transplanted within the first year of life should be assessed carefully as normal values in this age are rapidly increasing. , Younger age may have a protective effect , due to increased renal plasticity and/or regenerative potential.  Children with end-stage liver disease are invariably malnourished.  Children weighing <10 kg are considered a high-risk group for LT.  Low height Z-score may be a surrogate marker for a specific type of cholestatic diseases associated with an increased risk of post-LT kidney dysfunction. 
Renal ischemia and dysfunction can develop because of the surgical procedure itself as it may accompany hemodynamic instability, sepsis and introduction of nephrotoxic drugs. , Extended caval vein cross-clamping time, perioperative hypotension and large volume transfusion along with pre-operative hepatorenal syndrome are the main perioperative risk factors.  Diuretic-induced volume contraction probably exacerbates the renal insult. 
Early post-LT renal dysfunction is a significantly independent risk factor for the development of CKD long after LT. , After the first year, patients with a progressive decline in mGFR show long-term renal dysfunction, while patients with a stable or improving mGFR show normal long-term renal function. ,,,
There is a growing concern regarding the development of CKD in up to 80% of LT patients due to the long-term CNI therapy. , CNIs not only play a noticeable role on primary post-LT renal dysfunction but possibly act as a secondary insult in patients with preexisting renal disease and/or a genetic predisposition for renal dysfunction. , Longterm exposure to CNIs may result in renal damage, both in children and in adults.  Yet, the contribution of CNI nephrotoxicity to post-LT renal dysfunction in children may be greater as they have a longer life expectancy  and usually lack many of the coexisting risk factors common in adults, such as coronary artery disease, hepatitis C, hypertension and diabetes.  Most of the data describing renal dysfunction were patients treated with CsA. ,, The toxic effect of CsA on the kidney has both an acute and a chronic element. , Pediatric LT survivors on CsA are at most risk for ACKD and renal dysfunction on long-term follow-up.  In adults, TAC is associated with better renal functions compared with CsA. , Detailed longitudinal studies in pediatric recipients on TAC are rare.  However, TAC use in pediatric LT recipients is effective and revealed a favorable safety profile. , Many studies compared both CsA and TAC with regard to renal side effects.  There are scarce data to indicate a difference between the two CNIs in nephrotoxicity. , In the study by Campbell et al,  CsA immunosuppression was the strongest predictor of a long-term renal dysfunction when compared with TAC. This was supported by other studies, , where the CsA-treated patients had a significantly lower GFR compared with TAC-treated patients. Loo et al  showed no difference between CsA and TAC on renal function. CNIs may also cause a chronic tubulopathy.  The effect of CNIs on tubular function has been less examined.  Renal histologic studies show tubular injury when CsA is given to transplant recipients with no underlying renal disease.  However, the response of the kidneys to LT in terms of tubulopathy was excellent.  CNI levels seem to play an important role in the post-LT decline of renal function.  At one year post-LT, CsA >150 ng/mL or TAC >10 ng/mL was considered a significant predictor of kidney failure requiring RRT.  Although CNI has been involved in the genesis of the tubular defects, it has not been possible to attribute the exact CNI dosage or level to the clinical manifestations. 
Hypertension at one year post-LT was inversely related to renal dysfunction. ,,, The incidence of hypertension in pediatric LT is not known.  The incidence has varied in previous reports without uniform linkage to GFR fluctuation or CNI dosage and levels.  McLin et al  showed that hypertension existed in as many as 27.5% of pediatric LT patients aged ≥5 years post-LT. Children who were transplanted before the age of one year were spared the risk of long-term hypertension.  Hypertension is a common side-effect of steroids and CNI use. , TAC is less likely to cause hypertension than CsA.  The use of antihypertensive drugs served as a surrogate marker to estimate the frequency of hypertension. 
| Management of Post-LT Renal Dysfunction|| |
Efforts should be made in several directions to prevent the LT patients from proceeding to ESRD and the prospect of renal transplantation, especially in the pediatric age group. , This can be achieved via tight blood pressure control, immunosuppression tapering and the use of renal-sparing immunosuppressive agents such as sirolimus (SRL) and mycophenolate mofetil (MMF).  Careful blood pressure monitoring and early treatment of hypertension in pediatric LT is necessary to avoid long-term renal dysfunction. , Angiotensin-converting enzyme inhibitors may be useful due to the good control of hypertension and the nephroprotective effect.  Steroid-free protocols are also important for patients with post-LT complications.  Renal-sparing immunosuppressive regimens are implemented due to increased concerns of renal dysfunction associated with long-term CNI therapy.  A meta-analysis of 32 controlled studies and a total of 1383 patients revealed a significant renal function improvement in the CNI minimization group.  CNI reduction, CNI withdrawal and complete avoidance of CNIs are the three main CNI-sparing strategies to preserve renal function. ,,
Minimization of CNI use and/or dosage reduction has been effective in improving GFR; ,, however, the development of clinical rejection may limit such approaches. , There are encouraging reports about the shortterm safety and efficacy of CNI minimization in adults , and children, but long-term data are required. , Although CNIs still represent the backbone of most maintenance immunosuppressive regimens,  current regimens have limited reliance on CNIs as the primary longterm immunosuppressive agents. 
Several drugs with different mechanisms of action are used in order to reduce CNIs' renal side-effects, including lymphocyte antibodies, antimetabolites and inhibitors of the mammalian target of rapamycin (mTOR).  Induction immunosuppression with an IL-2 receptor blocker and steroid followed by delayed start of CNIs on Days 3-5 post-LT was the first approach used.  Currently, pediatric LT immunosuppression generally includes induction with IL-2 antibodies, low-dose TAC and MMF. ,, Monoclonal antibodies, e.g. basiliximab, were shown to be effective at induction, while by no means generally accepted, allowing a significant reduction in CNI levels in the critical first few weeks without an increase in acute rejection episodes. 
MMF, an immunosuppressive drug, through suppression of proliferation of T and B lymphocytes, almost lacks drug-related nephrotoxicity. , Currently, MMF is the best proven drug used to minimize the CNI nephrotoxicity and is an essential part of renalsparing immunosuppression protocols in many pediatric LT units. ,,, An MMF-based regimen presents a clear protection benefit on renal function when compared with SRLbased and everolimus (ERL)-based regimens.  MMF should be started as early as renal function deteriorates. , In 92% of children with renal dysfunction post-LT, MMF provided a safe and effective option and allowed CNIs to be reduced or discontinued. ,, In adults, leukopenia and diarrhea were more common in patients receiving MMF.  Steroids are introduced temporarily when changing from CNIs to MMF to minimize the risk of rejection.  Concerns still exist about whether CNI reduction with the addition of MMF yields sufficient immunosuppression in the long term. 
Another approach to preserve renal function is to replace CNIs by mTOR inhibitors such as SRL or ERL.  SRL, a lipophilic macrolide, is a renal-sparing immunosuppressive agent that has a long half-life of 62 h,  and it is a potent inhibitor of T and B cell antigen-induced proliferation and antibody production.  Unfortunately, the experience with SRL in pediatric LT is still limited.  Early conversion to SRL might ameliorate chronic nephrotoxicity before development of severe renal impairment. , Increased incidence of wound infection, hepatic artery thrombosis, hyperlipidemia  and myelosuppression are the major side-effects of mTOR inhibitors. ,, ERL was found to facilitate early TAC minimization with similar efficacy and superior renal function compared with a standard TAC-based regimen. ,
Many European transplant programs accepted early withdrawal or weaning practice of CNIs to avoid chronic renal toxicity.  Replacement CNIs with MMF or SRL may have the potential to improve renal function. ,, However, extreme caution is required when adding any drug that interacts with immune suppression, lowers or raises serum levels or causes renal damage.  In practice, McLin et al  continue to taper CsA as early and as much as possible.
Development of true tolerance would lead to complete avoidance of the CNIs and their long-term effects.  Once tolerance occurs, the graft antigens should sustain T-cell-mediated regulation preventing graft rejection without the use of CNIs.  Although there is some experience with the CNI-free induction regimens in pediatric renal and cardiac transplant patients, there are no such studies in pediatric LT to date. 
| Conclusion|| |
Renal dysfunction is a common problem after pediatric LT. Renal dysfunction in pediatric LT recipients is evidently multifactorial. A multicenter prospective study is required to investigate the possible risk factors of renal dysfunction in LT patients. Clear concepts on how to modify the immunosuppression protocols to be less nephrotoxic can reverse renal dysfunction and prevent development of ESRD.
| Disclosure|| |
The authors do not have not any affiliation or financial involvement with organizations or entities with a direct interest in the subject matter or materials discussed in the manuscript. No funding was received for this work from any organization.
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Hasan M.A. Isa
Pediatric Department, Salmaniya Medical Complex, P.O. Box 12, Manama
Kingdom of Bahrain
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