Kidney Dysfunction in the Recipients of LiverTransplants

Alan Wilkinson and Phuong-Thu Pham

Key Points1. Pretransplant kidney function is an important predic-tor of posttransplant kidney function.2. Chronic kidney disease is present in 20% of liver trans-plant recipients by 5 years.3. Kidney function is impacted by pretransplant manage-ment of the consequences of the hepatorenal syndrome.4. The use of calcineurin inhibitor (CNI)–based immu-nosuppression is an important factor in the developmentof chronic kidney disease, and the use of mycophenolicacid– or sirolimus-based immunosuppression withreduced-dose CNI may be of benefit. (Liver Transpl2005;11:S47-S51.)

Factors Affecting Posttransplant RenalFunction

Postoperative acute renal failure occurs in 17% to 95% ofpatients undergoing orthotopic liver transplantation (OLT).The difference in the incidence reported may be due in part tothe wide disparity in the criteria used to define “acute renalfailure.” Nonetheless the commonly suggested etiologies ofpostoperative acute renal failure include acute tubular necro-sis secondary to ischemic or toxic insult to the kidneys, pre-existing hepatorenal syndrome (HRS), and drug-inducedinterstitial nephritis.1-3 The former may include prolongedhypotension, sepsis or septic shock, sustained prerenal renalfailure, and use of nephrotoxic drugs. Acute renal failure ordeclining renal function associated with the use of cyclospor-ine or tacrolimus in the posttransplantation period has beenwell described and is discussed in more detail below. Preop-erative renal dysfunction, delayed liver graft function or pri-mary graft nonfunction, and higher serum bilirubin level havealso been variably shown to predispose OLT recipients topostoperative acute renal failure.3-5

Chronic renal insufficiency, or chronic kidney disease, hasbeen reported to occur in 4% to more than 80% of OLTrecipients.1,6-8 The wide range in the incidence reported maybe partly due to the difference in the criteria used to definechronic renal failure as well as the difference in the duration offollow-up. The commonly suggested causes or risk factors forthe development of progressive chronic kidney disease or end-stage renal disease (ESRD) in long-term survivors of OLTinclude calcineurin inhibitor nephrotoxicity, pre-OLT HRS,preexisting renal insufficiency, and diabetes mellitus.3,5,7,8

Postoperative acute renal failure, dialysis requirement in thepretransplantation and/or posttransplantation period, hepati-tis C infection, and age have also been variably shown to beassociated with an increased risk for the development ofchronic kidney disease.8-11

In a study conducted by Fisher et al., severe chronic renal

failure developed in 4% of patients surviving 1 year or more.Progression to ESRD occurred in nearly half of these patients. Inalmost all patients who underwent a renal biopsy, the histologicfindings were suggestive of cyclosporine toxicity. Specific patho-logic changes included vascular obliteration, tubular atrophy,interstitial scarring, and glomerular sclerosis.6

In a retrospective study consisting of 834 recipients of liveralone transplantation performed between June 1985 throughthe end of 1999, chronic severe renal dysfunction during thestudy period occurred in 10.3% of the patients, more than50% of whom had ESRD (severe renal dysfunction wasdefined as serum creatinine �2.5 mg/dL or ESRD requiringdialysis or transplantation). At 10-year follow-up, the totalincidence of severe renal dysfunction rose to 14.4%, withmore than 50% of these patients having ESRD (7.9%). Thepresumptive renal diagnoses of those who developed ESRDwere calcineurin inhibitor toxicity (73.3%), nonrecoveredhepatorenal syndrome (6.66%), focal segmental glomerulo-sclerosis (6.66%), progression of underlying renal disease(11.1%), and acute tubular necrosis/amphotericin toxicity(2.22%). For those who survived 13 years beyond the OLT,severe renal dysfunction developed in 18.1%.9 It is likely thatthe incidence of ESRD of both native kidneys (in OLT recip-ients) and of renal allografts (in cadaveric kidney liver trans-plants [CKLT] recipients) increases with time after transplan-tation.

Cyclosporine and Tacrolimus Nephrotoxicity

Although biochemically distinct, cyclosporine and tacrolimusare 2 potent immunosuppressive agents with similar mecha-nism of action as well as clinical and pathologic patterns ofnephrotoxicity. The various clinical and histologic manifesta-tion of cyclosporine and tacrolimus toxicity may include the

Abbreviations: CNI, calcineurin inhibitor; OLT, orthotopicliver transplant; HRS, hepatorenal syndrome; ESRD, end-stage renaldisease; CKLT, cadaveric kidney liver transplant; MMF, mycophe-nolate mofetil; ARF, acute renal failure; RRT, renal replacementtherapy.

From the Department of Medicine, Kidney and Pancreas TransplantProgram, David Geffen School of Medicine at UCLA, Los Angeles, CA.

Address reprint requests to Alan Wilkinson, MD, Department ofMedicine, Kidney and Pancreas Transplant Program, David GeffenSchool of Medicine at UCLA, 200 UCLA Medical Plaza, Suite 365, LosAngeles, CA 90095-1693. Telephone: 310-794-1781; FAX: 310-794-9718; E-mail: awilkinson@mednet.ucla.edu

Copyright © 2005 by the American Association for the Study ofLiver Diseases

Published online in Wiley InterScience (www.interscience.wiley.com).DOI 10.1002/lt.20618

S47Liver Transplantation, Vol 11, No 11, Suppl 1 (November), 2005: pp S47-S51

frequently occurring functional decrease in renal blood flowand GFR and the infrequently occurring thromboticmicroangiopathy.12 Cyclosporine and, to a lesser extent,tacrolimus have been shown to cause an acute, dose-relatedreversible afferent arteriolar vasoconstriction and “preglo-merular-type” renal dysfunction. In liver transplant recipi-ents, the fall in GFR occurs immediately after the introduc-tion of cyclosporine, and this effect is exaggerated when theCNI is administered intravenously. Cyclosporine toxicityusually resolves within 24 to 48 hours of a dose reduction,whereas tacrolimus toxicity may take longer to resolve. Neph-rotoxicity may also develop at apparently low levels of bothdrugs, and some degree of toxicity may be intrinsic to theiruse.12 In contrast to the acute dose-related reversible decreasein glomerular filtration rate, prolonged use of CNIs can causechronic interstitial fibrosis and irreversible chronic kidneydisease. It has been suggested that CNI-induced interstitialfibrosis involves angiotensin-dependent upregulation of pro-fibrotic molecules such as transforming growth factor beta,endothelin-1, and osteopontin, whereas matrix degradation isinhibited, the latter through inhibition of matrix metallopro-teinase activity.13,14 Intense and prolonged vasoconstrictionof the renal microcirculation has also been suggested to be acontributing factor.13

Clinical studies comparing the chronic nephrotoxic effectsof cyclosporine vs. tacrolimus in organ transplant recipientshave yielded variable and conflicting results. Early reports byFisher et al. revealed a similar incidence of severe CRF in OLTpatients receiving tacrolimus or cyclosporine during the samestudy period. Creatinine levels at 4 years were comparable inboth groups.6 In agreement with Fisher et al., Platz et al.found a similar incidence of late renal insufficiency for cyclo-sporine- and tacrolimus-treated patients.7 In contrast to thefindings reported by Fisher et al. and Platz et al., a number ofstudies suggest that renal function is better preserved withtacrolimus compared to cyclosporine. In a retrospective studyconducted to determine long-term renal function in OLTrecipients receiving either cyclosporine or tacrolimus-basedimmunosuppression at discharge, Pham et al.15 have shownthat at 5-year follow-up, nondiabetic OLT recipients treatedwith tacrolimus had better kidney function than those oncyclosporine for the period reviewed (P � 0.01). Similaranalysis for diabetics revealed a comparable trend, but statis-tical significance was not achieved (data obtained from theUnited Network for Organ Sharing database between April 1,1994, and December 31, 1997). In a recent large, population-based cohort study involving more than 32,000 recipients ofOLT reported to the Scientific Registry of Transplant Recip-ients, the risk of chronic renal failure (defined as GFR �29cc/min, or the development of ESRD) associated with the useof calcineurin inhibitor was also found to be higher amongpatients treated with cyclosporine than among those whowere treated with tacrolimus (relative risk, 1.25; P � 0.001).Interestingly, this difference was not seen among patientswith other types of solid organ transplants.10 Recently, somebut not all studies suggest that in long-term OLT recipients

Neoral cyclosporine monitoring using the 2-hour postdose(C2) preserves renal function without increasing the risk ofrejection.16-18 Whether short-term or sustained long-termimprovement in renal function can be achieved in OLT recip-ients receiving Neoral using C2 for dosing determinationremains to be determined.

Modification of nephrotoxic immunosuppressive regi-mens to avoid postoperative acute renal failure and/or chronicrenal failure has met with variable results. Although there is nowell-defined protocol to prevent or minimize cyclosporine ortacrolimus nephrotoxicity, a number of centers advocate theuse of a calcineurin-sparing protocol adjusted for the degree ofrenal dysfunction. Gonwa et al. had previously suggestedwithholding cyclosporine for recipients with HRS or for thosewith moderate to severe renal dysfunction (GFR �30 cc/min)and in its place using azathioprine along with steroids. Induc-tion therapy with an antilymphocyte preparation was usedonly in cases of prolonged renal dysfunction.19 With theadvent of the monoclonal antibodies anti-interleukin 2 recep-tor antibodies (basiliximab and daclizumab), mycophenolatemofetil (MMF), and sirolimus, independent investigatorshave developed various immunosuppressive protocols thatavoid the nephrotoxic side effects associated with CNI ther-apy while providing adequate immunosuppression. In a smallseries consisting of 11 adult transplant recipients (7 heart, 2liver, 2 heart-renal transplants) with established acute renaldysfunction (defined as an increase in serum creatinine to�25% from baseline), withholding cyclosporine in conjunc-tion with the use of basiliximab or daclizumab resulted in animprovement in renal function without an increased risk ofacute rejection.20

In another small series consisting of 19 adults, long-term(�1 year) OLT recipients with renal dysfunction (defined asa decreased creatinine clearance �25% compared with thefirst month posttransplant), Cantarovich et al. have shownthat the introduction of MMF followed by tapering of cyclo-sporine A to a very low dose (25 mg twice a day) resulted in asignificant improvement in renal function. At 1-year follow-up, serum creatinine decreased from 141 � 24 to 105 � 22mmol/L, P � 0.002, and glomerular filtration rate increasedfrom 40 � 13 to 64 � 18 mL/min, P � 0.002. However,acute rejection occurred in 29% of the subjects studied, sug-gesting that this strategy may be associated with a risk of acuterejection.21 In contrast to the results reported by Cantarovichet al. and Neau-Cransac et al. failed to demonstrate any sig-nificant improvement in renal function in OLT recipientswith biopsy-proven chronic CNI nephrotoxicity despitecyclosporine or tacrolimus withdrawal and institution ofeither MMF or azathioprine. On the other hand, there was noincrease in the incidence of graft rejection.22

Sirolimus is a new and potent immunosuppressant with amechanism of action and a side effect profile distinct fromthat of calcineurin inhibitors. When used as base-therapywithout a calcineurin inhibitor, sirolimus has been shown tobe devoid of nephrotoxicity. In a retrospective study consist-ing of 16 long-term (�3 years) OLT recipients with different

S48 Wilkinson and Pham

degrees of renal insufficiency ranging from mild (CCr �70mL/min) to severe (CCr 20-40 mL/min), conversion fromcyclosporine or tacrolimus to sirolimus-based immunosup-pression resulted in variable improvement in renal functionand no rejections at 6-month follow-up.23

Due to the lack of large prospective controlled trials andmixed results obtained from small series of patients, manipu-lation of immunosuppressive therapy to avoid nephrotoxicityshould be best tailored to each patient. In patients with HRS,MMF in conjunction with low-dose tacrolimus and standardsteroid therapy appears to be safe and effective (unpublishedobservation). Although the use of interleukin 2 receptorblocker induction therapy in a calcineurin-sparing protocolhas been reported to result in improvement in renal functionwithout an increased risk of rejection, anecdotal reports havesuggested that interleukin 2 receptor blockers in combinationwith MMF or rapamycin increases the risk of viral reactiva-tion and/or the development of more severe hepatitis C recur-rence after liver transplantation.24,25 Interestingly, anincreased incidence of hepatitis C viral reactivation associatedwith interleukin 2 receptor blockers has also been observed atour center, reemphasizing that modification of immunosup-pressive therapy should be individualized. Although earlystudies suggest that MMF may have ribavirin-like antiviraleffect and may provide synergism when use with interferon-alfa, its use in the posttransplant period has not been consis-tently shown to be beneficial or deleterious. Studies on theassociation between an increased incidence and/or severity ofhepatitis C virus recurrence and the use of polyclonal antilym-phocyte preparations and/or anti-OKT3 monoclonal anti-body have also resulted in contradictory results. In theauthors’ opinion, these agents should be reserved for patientswith delayed graft function and for the treatment of acuterejection. Their routine use in a CNI-sparing protocol asprophylactic therapy is not recommended. In patients withchronic renal insufficiency who have unrelenting renal failuredespite drastic CNI dose reduction or withdrawal, the optionsavailable to prevent further decline in renal function remaincontentious. Although angiotensin-converting enzyme inhib-itors and/or angiotensin receptor blockers have been sug-gested to retard the progression of interstitial fibrosis, the roleof these agents in halting or alleviating the progression ofchronic CNI nephrotoxicity remains to be determined.13

Drug Interactions

Well-substantiated potentiation of renal impairment has beendescribed when amphotericin, aminoglycosides, nonsteroidalanti-inflammatory drugs, angiotensin-converting enzyme inhib-itors, and/or angiotensin receptor antagonists are used in patientsreceiving calcineurin inhibitor therapy. More recently, exacerba-tion of nephrotoxicity has been observed in renal transplantrecipients receiving sirolimus and cyclosporine combinationtherapy. Two phase III clinical trials (The Global and U.S.Rapamune Study Group) have shown that concomitant admin-istration of cyclosporine and sirolimus potentiate cyclosporine-

induced nephrotoxicity.26,27 There has been substantial evidencesuggesting that cyclosporine exposure is increased by a pharma-cokinetic interaction with sirolimus. In rat animal models, siroli-mus has also been shown to increase partitioning into renal tissueto a greater extent than it increases whole blood concentrations.28

When combination therapy is used, a reduction in therapeuticcyclosporine level is desirable, particularly when there is an unex-plained rise in SCr level. The pharmacologic interaction betweensirolimus and tacrolimus has been less rigorously studied. Coad-ministration of tacrolimus and sirolimus has been shown to resultin reduced exposure to tacrolimus at sirolimus doses of � 2mg/day.29 However, in recipients of renal transplant, cases ofacute renal allograft failure following sirolimus-tacrolimus ther-apy have been reported.30 Caution should be exercised whencombination immunosuppressive agents are used.

The Impact of Acute Renal Failure or RenalInsufficiency on Patient and AllograftOutcome Following Orthotopic LiverTransplantation

Studies on the impact of acute renal failure (ARF) or renalinsufficiency on patient and allograft outcomes have yieldedvariable and conflicting results. This section provides an over-view of the literature on the clinical implications of ARF/renalinsufficiency on patient and allograft survival in OLT. Basedon the literature, the authors’ view of the possible impact ofrenal insufficiency on survival in patients undergoing OLT isdiscussed.

Early studies by Cuerva-Mons et al. showed that a preop-erative serum creatinine level of either less than or greater than1.72 mg/dL accurately predicted survival or death in 79% ofcases.31 Similarly, a strong correlation between preoperativerenal dysfunction and postoperative patient survival was laterdemonstrated by Rimola et al.32 In their series of 102 patientsstudied, 26 (25%) had renal impairment at the time of OLT.The causes of renal failure were HRS in 21 patients, acutetubular necrosis in 3 patients, and unclassified in 2 patients.Following OLT, 68 patients (67%) experienced renal dys-function. Twenty-five patients died during the observationperiod (range, 4-167 days). Renal failure was a major contrib-utory cause of death in 13 (52%). Multivariate risk factoranalysis identified serious postoperative infection, graft fail-ure, and preoperative renal function to be independent pre-dictors of mortality.

In contrast to the results reported by Cuerva-Mons et al.and Rimola et al., Gonwa et al. found no difference in graftand patient survival at up to 5 years in non-HRS OLT recip-ients with different levels of pretransplant renal dysfunc-tion.19 In a large retrospective study, the same group of inves-tigators demonstrated that patients who developed ARFrequiring renal replacement therapy (RRT) postoperatively,regardless of the treatment modality, had a significantly lower1-year survival rate compared with those who were started onRRT preoperatively (41% vs. 73.6%, respectively, P �0.03).33 Further analysis revealed that mortality was highest

S49Kidney Function After Liver Transplantation

among patients who developed acute renal failure requiringpostoperative continuous venovenous hemodialysis. The90-day mortality for those who required hemodialysis bothpre- and post-OLT vs. those who required continuous veno-venous hemodialysis both pre- and post- vs. those whorequired only continuous venovenous hemodialysis postoper-atively were 25% vs. 27.7% vs. 50%, respectively (P � notsignificant between groups). Sepsis, primary graft nonfunc-tion, and hepatic artery thrombosis were commonly observedin patients who developed postoperative ARF requiring RRT.

Fraley et al. have previously shown that both pre- andpost-OLT ARF were associated with an increased mortality.When ARF was stratified by pre- vs. post-OLT and by sub-groups who required hemodialysis vs. CRRT vs. no dialysis,highest mortality rates were seen among patients with post-operative ARF requiring CRRT (primarily in the form ofcontinuous venovenous hemodialysis), a finding similar tothat of Gonwa et al. (mortality in ARF pre-OLT: no dialysisvs. HD vs. CRRT: 0% vs. 10% vs. 44%, respectively, com-pared with ARF post-OLT: 15% vs. 22% vs. 67%, respec-tively). The authors further demonstrated that the number ofcomorbid conditions, most notably sepsis, encephalopathy,respiratory failure, and disseminated intravascular coagula-tion correlated best with a worse outcome.34

An association between postoperative acute renal failurerequiring RRT and increased morbidity and mortality wasalso demonstrated by Gainza et al.35 In their series consistingof 259 consecutive liver transplantation performed in 251patients, 4 of whom underwent combined liver-kidney trans-plantation, the mortality rate of patients requiring RRT was52.1%, compared with 6.77% of that of the total populationstudied (P � 0.00001). A higher Child-Turcotte-Pugh scoreand previous renal insufficiency were identified as strong riskfactors for the development of postoperative acute renal fail-ure. Other risk factors included the use of calcineurin inhib-itors, sepsis, liver dysfunction, and nephrotoxic antimicrobi-als, among others.

In conclusion, although the literature on the impact ofrenal insufficiency and patient and allograft survival areinconsistent, the commonly identified factors predicting aworse outcome appear to be renal failure associated with sepsisand/or renal failure requiring RRT particularly among thosewho required CRRT(commonly performed because of hemo-dynamic instability associated with sepsis as a major comorbidcondition) in the postoperative period.

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