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World Journal of Transplantation World J Transplant 2020 June 29; 10(6): 147-182 ISSN 2220-3230 (online) Published by Baishideng Publishing Group Inc
World Journal ofTransplantation
World J Transplant 2020 June 29; 10(6): 147-182
ISSN 2220-3230 (online)
Published by Baishideng Publishing Group Inc
W J T World Journal ofTransplantation
Contents Irregular Volume 10 Number 6 June 29, 2020
REVIEW147 Treatment options for localised renal cell carcinoma of the transplanted kidney
Motta G, Ferraresso M, Lamperti L, Di Paolo D, Raison N, Perego M, Favi E
162 Interrelationship between Toll-like receptors and infection after orthotopic liver transplantationEl-Bendary M, Naemattalah M, Yassen A, Mousa N, Elhammady D, Sultan AM, Abdel-Wahab M
ORIGINAL ARTICLE
Prospective Study
173 Living kidney donor assessment: Kidney length vs differential functionAkoh JA, Schumacher KJ
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ContentsWorld Journal of Transplantation
Volume 10 Number 6 June 29, 2020
ABOUT COVER Editorial Board Member of World Journal of Transplantation, Luca Toti, MD,PhD, Assistant Professor, Lecturer, Transplant Unit, Policlinico Tor Vergata,Rome 00133, Italy
AIMS AND SCOPE The primary aim of World Journal of Transplantation (WJT, World J Transplant)is to provide scholars and readers from various fields of transplantationwith a platform to publish high-quality basic and clinical research articlesand communicate their research findings online. WJT mainly publishes articles reporting research results obtained in thefield of transplantation and covering a wide range of topics including bonemarrow transplantation, bone transplantation, bone-patellar tendon-bonegrafting, brain tissue transplantation, corneal transplantation, descemetstripping endothelial keratoplasty, fetal tissue transplantation, hearttransplantation, kidney transplantation, liver transplantation, lungtransplantation, pancreas transplantation, skin transplantation,transplantation immunology, and vascularized compositeallotransplantation.
INDEXING/ABSTRACTING The WJT is now abstracted and indexed in PubMed, PubMed Central, China National
Knowledge Infrastructure (CNKI), and Superstar Journals Database.
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NAME OF JOURNALWorld Journal of Transplantation
ISSNISSN 2220-3230 (online)
LAUNCH DATEDecember 24, 2011
FREQUENCYIrregular
EDITORS-IN-CHIEFSami Akbulut, Vassilios Papalois, Maurizio Salvadori
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PUBLICATION DATEJune 29, 2020
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W J T World Journal ofTransplantation
Submit a Manuscript: https://www.f6publishing.com World J Transplant 2020 June 29; 10(6): 147-161
DOI: 10.5500/wjt.v10.i6.147 ISSN 2220-3230 (online)
REVIEW
Treatment options for localised renal cell carcinoma of thetransplanted kidney
Gloria Motta, Mariano Ferraresso, Luca Lamperti, Dhanai Di Paolo, Nicholas Raison, Marta Perego,Evaldo Favi
ORCID number: Gloria Motta(0000-0002-6945-6853); MarianoFerraresso (0000-0003-3410-9090);Luca Lamperti(0000-0002-6903-532X); Dhanai DiPaolo (0000-0002-2706-4173);Nicholas Raison(0000-0003-0496-4985); Marta Perego(0000-0002-1981-4122); Evaldo Favi(0000-0001-6465-428X).
Author contributions: Motta Gcontributed to literature review,data collection, data analysis, datainterpretation, drafting the article,final approval; Ferraresso M,literature review, critical revision,and final approval; Lamperti L andDi Paolo D contributed to literaturereview, data collection, and finalapproval; Raison N contributed todrafting the article, languagerevision, and final approval;Perego M contributed to datacollection, data analysis, editingthe article, and final approval; FaviE contributed to literature review,data interpretation, drafting thearticle, critical revision, and finalapproval.
Conflict-of-interest statement: Theauthors do not have any conflictinginterests.
Open-Access: This article is anopen-access article that wasselected by an in-house editor andfully peer-reviewed by externalreviewers. It is distributed inaccordance with the CreativeCommons AttributionNonCommercial (CC BY-NC 4.0)license, which permits others todistribute, remix, adapt, buildupon this work non-commercially,
Gloria Motta, Urology, IRCCS Policlinico San Donato, San Donato Milanese 27288, Italy
Mariano Ferraresso, Luca Lamperti, Dhanai Di Paolo, Marta Perego, Evaldo Favi, RenalTransplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan 20122,Italy
Mariano Ferraresso, Evaldo Favi, Department of Clinical Sciences and Community Health,University of Milan, Milan 20122, Italy
Nicholas Raison, MRC Centre for Transplantation, King’s College London, London WC2R2LS, United Kingdom
Corresponding author: Evaldo Favi, MD, PhD, Senior Lecturer, Surgeon, Consultant inTransplant and Vascular Access Surgery, Renal Transplantation, Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico, Via Francesco Sforza n. 28, Milan 20122, Italy. [email protected]
AbstractCurrently, there is no consensus among the transplant community about thetreatment of renal cell carcinoma (RCC) of the transplanted kidney. Untilrecently, graftectomy was universally considered the golden standard, regardlessof the characteristics of the neoplasm. Due to the encouraging results observed innative kidneys, conservative options such as nephron-sparing surgery (NSS)(enucleation and partial nephrectomy) and ablative therapy (radiofrequencyablation, cryoablation, microwave ablation, high-intensity focused ultrasound,and irreversible electroporation) have been progressively used in carefullyselected recipients with early-stage allograft RCC. Available reports showexcellent patient survival, optimal oncological outcome, and preserved renalfunction with acceptable complication rates. Nevertheless, the rarity and theheterogeneity of the disease, the number of options available, and the lack oflong-term follow-up data do not allow to adequately define treatment-specificadvantages and limitations. The role of active surveillance andimmunosuppression management remain also debated. In order to offer a betterinsight into this difficult topic and to help clinicians choose the best therapy fortheir patients, we performed and extensive review of the literature. We focusedon epidemiology, clinical presentation, diagnostic work up, staging strategies,tumour characteristics, treatment modalities, and follow-up protocols. Ourresearch confirms that both NSS and focal ablation represent a valuablealternative to graftectomy for kidney transplant recipients with American Joint
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and license their derivative workson different terms, provided theoriginal work is properly cited andthe use is non-commercial. See:http://creativecommons.org/licenses/by-nc/4.0/
Manuscript source: Invitedmanuscript
Received: February 1, 2020Peer-review started: February 1,2020First decision: March 15, 2020Revised: April 7, 2020Accepted: May 26, 2020Article in press: May 26, 2020Published online: June 29, 2020
P-Reviewer: Budai B, Wang GYS-Editor: Ma YJL-Editor: AE-Editor: Wu YXJ
Committee on Cancer stage T1aN0M0 RCC. Data on T1bN0M0 lesions are scarcebut suggest extra caution. Properly designed multi-centre prospective clinicaltrials are warranted.
Key words: Renal cell carcinoma; Kidney transplant; Graftectomy; Nephron-sparingsurgery; Focal ablation; Review
©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
Core tip: Nephron-sparing surgery and ablative therapy have been increasinglyrecognised as a valuable alternative to transplantectomy in carefully selected kidneyrecipients with allograft renal cell carcinoma (RCC). The complexity of the disease, thenumerosity of the treatments available, the lack of long-term follow-up data, and therelatively poor quality of the studies addressing this topic do not allow to properly definespecific advantages and limitations of these conservative strategies. We performed anextensive review of the literature focusing on epidemiology, clinical presentation,diagnostic work up, staging strategies, tumour characteristics, treatment modalities, andfollow-up protocols of localised RCC of the transplanted kidney.
Citation: Motta G, Ferraresso M, Lamperti L, Di Paolo D, Raison N, Perego M, Favi E.Treatment options for localised renal cell carcinoma of the transplanted kidney. World JTransplant 2020; 10(6): 147-161URL: https://www.wjgnet.com/2220-3230/full/v10/i6/147.htmDOI: https://dx.doi.org/10.5500/wjt.v10.i6.147
INTRODUCTIONKidney transplant (KTx) recipients have a survival advantage compared to patientson chronic dialysis or remaining on the transplant waiting list (TWL)[1,2]. Nevertheless,due to the synergistic effect of end-stage renal disease (ESRD) and prolongedexposure to powerful immunosuppressive agents, higher incidences of malignanciesand inferior cancer-specific survivals than the general population have beenreported[3-6]. Among neoplastic complications, renal cell carcinoma (RCC) of thetransplanted kidney has been increasingly recognised as an important cause ofmorbidity and premature allograft loss[7-9]. Management can be exceptionallychallenging because in this complex subset of patients the theoretical benefit ofoptimal oncological control must be carefully weighed against the substantial risk ofdeath arising from technically demanding surgical procedures, peri-operativecomplications, and return to dialysis[8,10].
For many years, transplantectomy has been universally considered the goldenstandard, regardless of the characteristics of the lesion[11]. More recently, widespreadand successful application of nephron-sparing surgery (NSS) and ablative therapy(AT) for the treatment of solid neoplasms in native kidneys[12] has favoured the use ofconservative approaches in renal allografts[13]. Enucleation, partial nephrectomy (PN),radiofrequency ablation (RFA), cryoablation, microwave ablation (MWA), high-intensity focused ultrasound (HIFU), and irreversible electroporation (IRE) have beenproposed as valuable alternatives to graftectomy in carefully selected recipients withlocalised RCC but evidence remain weak[13,14]. The rarity of the disease, the numerosityof the techniques, and the quality of the studies (mostly case reports or smallretrospective case series) do not allow to adequately assess treatment-specificoutcomes and to clearly define indications and limitations[13,14]. In particular, noclinical guidelines or comprehensive meta-analyses have been published and there isstill concern in the transplant community regarding long-term efficacy and safety. Inorder to offer a better insight into this difficult topic and to help clinicians choose thebest therapy for their patients, we performed and extensive review of the literaturefocusing on conservative treatments of localised RCC.
LITERATURE RESEARCHPubMed was searched for manuscripts reporting on RCC of the transplanted kidney.
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No time limits were applied. The following key words combinations were used:“kidney transplant neoplasm”, “kidney transplant tumour”, “kidney transplantmass“, “kidney transplant cancer”, “kidney transplant renal cell carcinoma”, “renaltransplant neoplasm”, “renal transplant tumour”, “renal transplant mass“, “renaltransplant cancer”, “renal transplant renal cell carcinoma”, “kidney allograftneoplasm”, “kidney allograft tumour”, “kidney allograft mass“, “kidney allograftcancer”, “kidney allograft renal cell carcinoma”, “renal allograft neoplasm”, “renalallograft tumour”, “renal allograft mass“, “renal allograft cancer”, “renal allograftrenal cell carcinoma”, “nephrectomy”, “transplantectomy”, “graftectomy”, “nephron-sparing surgery”, “ablation”, “radiofrequency ablation”, “cryoablation”, “microwaveablation”, “high-intensity focused ultrasound”, “irreversible electroporation”,“surveillance”, and “watchful waiting”. Preliminary screening was performed byMotta G, Ferraresso M, Lamperti L, Di Paolo D, and Favi E. Manuscripts reporting onlocalised kidney allograft RCC were further evaluated by Motta G and Favi E as apotential source of information for the review. Considered sub-topics were:Epidemiology, clinical presentation, diagnosis, staging, neoplasms’ characteristics,treatment options, and follow-up strategies.
EPIDEMIOLOGYReported incidence of primary RCC in kidney allografts varies between 0.2% and0.5%, depending on the series[7,15-18]. However, taking into account the progressiveaging of the patients on the TWL[19], the increased utilization of expanded-criteriadonors[20], and the significant amelioration of long-term recipient survival[2], it isreasonable to expect that the cumulative incidence of the disease will riseconsiderably in the next few years. KTx patients are approximately at 2-fold increasedrisk of developing malignancies than healthy controls[21]. Compared to the generalpopulation, the risk of developing RCC is 10-fold higher[22]. Even though, severalstudies have demonstrated an association between specific primary renal diseases,ESRD, long-term dialysis, immunosuppressive therapy and post-transplant RCC, thereason behind this increased susceptibility remains unknown[13,17,18,23,24].
Higher incidences of allograft RCC have been shown among patients receiving akidney from a deceased donor compared to living donor recipients[7,13,14]. As pointedout by Griffith et al[7], this trend probably mirrors the disparity between the number ofdeceased and living donor transplants performed in most countries. Age differencesand disparities in cancer screening protocols between donor types may also play arole[14,25]. Other possible variables such as deceased donor category, ethnicity, genderor age have not been extensively investigated. Regarding recipient’s characteristics, adisproportion of male patients with RCC of the transplanted kidney was observed byTillou et al[13].
Allograft RCC are predominantly of donor origin[25]. However, lesions arising fromrecipient-derived cells have been reported[26]. Albeit generally neglected by currentdiagnostic and staging protocols, discriminating between transmitted and acquiredallograft neoplasms might have relevant therapeutic and prognostic consequencesthat should encourage further investigation.
CLINICAL PRESENTATIONOverall, no more than 20% of the patients exhibit clinical manifestations of thedisease[7]. The vast majority of lesions are asymptomatic and incidentally discoveredduring imaging studies performed as a part of the routine post-transplant follow-upor to rule out other conditions [7 ,13 ,14 ,18 ,27 ]. According to the largest studiesavailable[7,13,14,18], most frequently reported symptoms eventually leading to thediagnosis of allograft RCC are haematuria, abdominal pain, asthenia, weight loss,fever, flu-like syndrome, hypertension, recurrent urinary tract infections, and allograftdysfunction.
DIAGNOSISLocalised allograft RCC often represents an incidental finding[27]. Reported timeintervals between transplantation and diagnosis are extremely variable[9,14,15,28]. Colour-Doppler ultrasound (US) is widely considered the first line modality for theevaluation of solid masses of the transplant[16,27,29]. In case of indeterminate lesions,contrast-enhanced computed tomography (CT) scan and magnetic resonance imaging
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(MRI) with or without contrast dye are the preferred options[14,18]. More recently,excellent results have been demonstrated using contrast-enhanced US (CEUS)[30]. Mainadvantages of CEUS over contrast-enhanced CT scan and MRI are lack of radiationexposure, avoidance of contrast-induced nephropathy (CIN) or nephrogenic systemicsclerosis, and cost savings[31]. In order to avoid diagnostic delays that maycompromise the chance of conservative treatment or unnecessary interventions thatmay irreversibly damage the transplanted kidney, an allograft biopsy should beobtained whenever possible[7,14,18]. Histology not only allows to assess type, grading,and origin of the neoplasm but also provides fundamental information forepidemiological and clinical purposes.
STAGINGSince accepted indication for conservative treatment of allograft RCC is restricted tolocalised neoplasms, careful staging is mandatory. The staging system proposed bythe American Joint Committee on Cancer (AJCC) for RCC in native kidneys iscurrently the most used tool in combination with the Fuhrman grading score[32,33].However, the transplanted kidney has peculiar anatomical characteristics that maylimit the use of standard staging tools. In this regard, the modified version of theAJCC staging system proposed by the Comité de Transplantation de l’AssociationFrançaise d’Urologie seems a better option[18]. According to Tillou et al[18], T3 tumoursextend into major veins or invade renal sinus fat or peritoneum whereas T4 lesionsinvade perinephric organs such as psoas muscle, iliac vessels wall, bladder, smallintestine or colon. There is no consensus among the transplant community on theoptimal staging work up. Contrast-enhanced abdomen CT scan and MRI with orwithout contrast material are the preferred imaging techniques in most centres[7,14,18,34].Albeit recommended by the American Urology Association (AUA) guidelines[32] andthe European Association of Urology (EAU) guidelines[33], contrast-enhanced chest CTscan is seldom included in KTx RCC staging protocols.
CANCER CHARACTERISTICSSimilarly to native kidneys, three main variants of RCC have been identified in renalallografts: Clear cell, papillary, and chromophobe[7,14,18]. Compared to the generalpopulation, a significantly higher prevalence of papillary type over clear cell type hasbeen observed among KTx patients[7,14,18]. The reason behind this difference is obscure.Even though, papillary RCC is generally less aggressive than clear cell RCC, its multi-focality has been often considered a relative contraindication to conservativetreatments[18,35-37]. More recently, results achieved with AT[14] have demonstrated thatpatients with papillary type RCC can be excellent candidate for allograft preservationstrategies. Another interesting data is the high proportion of endophytic lesionssuccessfully treated with AT[14]. Endophytic masses have been generally consideredless suitable for AT than exophytic ones. The outcomes reported in renal allograftsseem to contradict this opinion and suggest that tumour growth pattern may not be arelevant prognostic factor of primary treatment failure. According to the literature,the vast majority of localised allograft RCC successfully treated with NNS or AT isless than 4 cm in maximal diameter, Fuhrman grade 1-2, and staged T1aN0M0[14,18,34].Conservative management of T1bN0M0 RCC remains anecdotal and seems to offermixed outcomes[14,38-41].
TREATMENT OPTIONS AND TREATMENT-SPECIFICOUTCOMES
GraftectomyFor many years, graftectomy has represented the only acceptable option for RCC ofthe transplanted kidney[14,42]. However, death rates as high as 3% with up to 50% of thepatients experiencing severe post-operative complications have been reportedfollowing this aggressive surgical procedure[43]. Studies comparing NNS and AT tograftectomy, especially in recipients with T1aN0M0 lesions, have shown comparableoncological outcomes with fewer complications [ 7 , 1 4 , 4 2 ] . For these reasons,transplantectomy should be currently restricted to patients with irreversible allograftdysfunction, sarcomatoid type RCC, multi-focal papillary type RCC, RCC greater than7 cm in maximal diameter (AJCC stage II), locally-invasive or metastatic RCC (AJCC
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stage III or IV), and RCC infiltrating critical structures. Recent data support thisposition and demonstrate that for T1aN0M0 RCC a 5-year survival rate of 95% can beexpected[9,44] whereas 5-year survival rate after allograft removal and return to dialysisis only 34%[8]. Analyses of non-cancer specific mortality after KTx failure also confirmthe long-term survival benefit of maintained renal function[45,46].
NSSNSS techniques such as enucleation, wedge resection, and PN are now considered thetreatment of choice for patients with T1aN0M0 RCC in native kidneys[32,33]. Albeitencouraging, experience in recipients with allograft RCC is limited[7,9,11,39,42,47]. Availablestudies demonstrate that with NSS excellent oncological outcomes can be obtained inpatients with T1aN0M0 lesions. Local recurrence rates of less than 5%, lower post-operative complication rates (between 15% and 21%, depending on the series),marginal impact on allograft function, and the possibility to treat residual or relapsingneoplasms with further conservative strategies support NSS over transplantectomy.Successful resection of localised RCC greater than 4 cm in maximal diameter remainsanecdotal and therefore should not favour the use of NSS over graftectomy[39,41]. Mainlimitations of NSS compared to AT are invasiveness, higher technical difficulty, andincreased risk of peri-operative complications[7,14,18]. Most cases of NSS in transplantsetting have been performed using an open technique but minimally invasiveapproaches have been also described[39,41]. The tumour can be resected getting access tothe allograft via a retro- or an intra-peritoneal route depending on the location of themass[39]. In case of lesions very close to the vessels, renal pedicle control is advised[39].
RFARFA is the preferred AT for KTx neoplasms (approximately, 80% of all the proceduresreported in the literature)[14,48]. Excellent oncological and functional outcomes in thetreatment of solid masses in native kidneys have undoubtedly favoured itsapplication in the transplant setting[49-52]. RFA uses high-frequency alternatingelectrical current to force extra- and intra-cellular ions to follow the same route as thecurrent thus generating agitation, frictional heat, and coagulative necrosis[53].Relatively wide thermal dispersion and subsequent risk of thermal damage to criticalperi-lesional structures represent the main limitations of the technique[53]. RFA hasbeen mostly utilized to treat small exophytic lesions distant from the renal hilum[49,53].However, experience in allograft RCC demonstrates that it can be effectively used forboth exophytic and endophytic masses[14]. According to a recent systematic review[14],among 78 T1aN0M0 RCC treated with percutaneous US- or CT-guided RFA, only twoepisodes of primary treatment failure and one episode of local recurrence could beidentified. Moreover, persistent and relapsing tumours were successfully managed byrepeated ablation. Safety profile was also encouraging as no peri-operative deathswere recorded and complication rates did not exceed 15%. The most relevant adverseevents were transient lower limb pain due to thermal injury to nerves or muscles andurinary leakage secondary to thermal damage to the renal pelvis. Renal functionpreservation was obtained in the vast majority of patients included in the analysis.
CryoablationCryoablation uses a cryogenic freezing unit connected with special hollow needles todeliver a cooled fluid into the target-tissue and to simultaneously remove heat from it.At a cellular level, such a technique promotes ice crystal formation, irreversiblemembrane damage, cell lysis, and apoptosis whereas at a supra-cellular level, itcauses ischemic necrosis secondary to intra-vascular coagulation[53]. Compared to RFAand MWA, cryoablation entails a lower risk of thermal damage to surroundingstructures. For this reason, it is widely considered the most selective AT and it isparticularly indicated for centrally located lesions[53]. Minimal impact on renalfunction represents another important feature[54]. Possible limitations, at least asshown in native kidneys, are higher risk of intra-operative bleeding[55], higher rate ofprimary treatment failure in case of neoplasms greater than 3 cm in maximaldiameter[56-58], and higher recurrence rate for tumours with an endophytic growthpattern[59]. To date, only 10 cases of biopsy-proven T1aN0M0 and 1 case of biopsy-proven T1bN0M0 RCC of the transplanted kidney treated by cryoablation have beendocumented[34,60-63]. The procedures were mostly performed percutaneously under US-or CT-guidance with no persisting disease, no local relapse (post-ablation follow-upranging from 1 to 59 mo), and excellent allograft function. Overall, there were 2episodes of peri-operative bleeding[14].
MWAMWA is a thermal ablation modality that uses microwaves to cause oscillation ofpolar molecules into the target-lesion thus generating frictional heat and coagulative
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necrosis[53]. Major advantages compared to other AT are the ability to deliver higherintra-lesion temperatures, a marginal dependency on tissue-specific electricalconductivity, simultaneous treatment of multiple neoplasms, and the possibility toablate the puncture tract[53,64-66]. There are several studies supporting the application ofMWA for malignant tumours in native kidneys[67,68] but experience in renal allograftsis limited to a couple of small case series. Successful ablation of one Fuhrman grade 1-2, T1aN0M0 clear cell RCC and two Fuhrman grade 1-2, T1aN0M0 papillary RCC wasfirst reported by Gul et al[63]. The procedures were performed under CT-guidance via apercutaneous or a trans-osseous approach with no serious complications, no allograftdysfunction, and no recurrence after a follow-up ranging from 8 to 61 mo. Other twocases of MWA of RCC of the transplanted kidney were more recently described byour group[69]. More in details, we treated one Fuhrman grade 2, T1aN0M0 papillaryRCC and one Fuhrman grade 1, T1aN0M0 clear cell RCC. Ablations were carried outunder US-guidance using an open retro-peritoneal route for the first patient and apercutaneous approach for the other one. Complete tumour destruction was achievedin both the operations without complications, loss of allograft function or recurrenceafter 3 and 5 years of follow-up, respectively.
HIFUHIFU incorporates multiple US beams directed into a three-dimensional focal point toproduce tissue destruction by combined effects of thermal and mechanical energies(more precisely, cavitation, micro-streaming, and radiation forces)[70]. Potentialbenefits of HIFU are fast action, minimal thermal dispersion, and reducedinvasiveness as it does not require direct contact with the target-lesion[71,72]. On thecontrary, recognised limitations of the technique are the need for an optimal acousticwindow, the inability to reach deep organs or tissues due to US penetrance, andcomplex pre-operative planning[71,72]. Excellent results have been reported in nativekidneys[73-75] but in KTx setting data are scarce. Searching the literature, we could findonly three cases of allograft RCC treated by HIFU. US-guided percutaneous ablationof two T1aN0M0 papillary RCC was described by Di Candio et al[76] with excellentshort-term oncological outcomes (6-mo follow-up) and no peri-operative adverseevents whereas multiple unsuccessful attempts in a patient with a 55 mm T1bN0M0clear cell RCC were reported by Chakera et al[77].
IREIRE is a non-thermal AT with extraordinary connective tissue-sparing properties thathas been successfully used to treat renal[78] and extra-renal neoplasms[79]. This noveltreatment modality utilizes an electrical field to generate nanopores into target-cellsand induce permanent membrane permeability, disruption of homeostasis, andapoptosis[80,81]. It is particularly indicated in case of neoplastic lesions close toimportant vessels or structures. There is only one study describing the use of IRE inKTx tumours[63]. The procedure was performed percutaneously under CT-guidance toablate a Fuhrman grade 3, T1aN0M0 clear cell RCC. The post-operative course wasuneventful with preserved allograft function and no recurrence after 3 years offollow-up.
Active surveillanceThere are no reports describing active surveillance (AS) in KTx recipients with RCC ofthe allograft. A major concern is that chronic immunosuppression may increase therisk of cancer spreading compared to the general population. Actually, such anassumption has never been confirmed. Recent studies have shown that growth rateand metastatic potential of transplant neoplasms are overall similar to those observedin native kidneys and in healthy controls[7,9,13,14,18,34]. As such, no hard recommendationscan be made against the use of AS in the transplant setting. A reasonable approachwould be to follow the principles stated by the AUA guidelines[32] and to considerboth patient-related and tumour-related characteristics. As pointed out by Griffith etal[7], given the higher incidence of papillary RCC observed in recipients with allograftneoplasms[14,18,82], a lower threshold for renal mass biopsy is advised.
Immunosuppression modificationImmunosuppression is a well-recognised risk factor for the development ofmalignancies, particularly infectious-related ones and non-melanoma skin cancers(NMSC)[83]. Increased susceptibility to long-lasting viral infections with oncogenicpotential and partial loss of immune-surveillance processes are considered the mainreasons behind this phenomenon [ 2 1 , 8 4 , 8 5 ] . Associations between specificimmunosuppressive drugs and risk of cancer after solid organ transplantation havebeen extensively investigated. Considering the role of NK[86], CD4+, and CD8+ Tcells[87] in virus-specific immunity and in eliminating neoplastic cells, lymphocyte-
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depleting agents such as anti-thymocyte polyclonal antibodies[88] or anti-CD52monoclonal antibody alemtuzumab[83,89] and calcineurin inhibitors (CNI) cyclosporineand tacrolimus[90] seem to play a major role. In particular, CNI have been shown toexert their action through indirect inhibition of T cells activation/proliferation (viadecreased IL-2 production) and direct up-regulation of VEGF and TGF-b1[91,92]. Asignificant link between chronic azathioprine exposure and squamous cell carcinomaof the skin has been also demonstrated [93]. An accepted explanation is thatazathioprine inhibits T cells proliferation and alters DNA repair mechanisms thusleading to impaired immune-surveillance and cell transformation. Data on cancer-related side effects of mycophenolic acid (MPA)[83,94,95] and results of the studiesaddressing the role of steroids in cancer development[83,87] remain unclear. There ismounting evidence that proliferation signal inhibitors (PSI)/mammalian target ofrapamycin inhibitors (mTOR-I) sirolimus and everolimus may have important anti-neoplastic properties[83]. Main immunosuppressive action of mTOR-I is inhibition of Tcells activation/proliferation through down-regulation of IL-2 and cell-cycle block.Nevertheless, the mTOR pathway regulates amino acid biosynthesis, glucosehomeostasis, adipogenesis, actin cytoskeleton polarization, nutrient-responsetranscription programs, ribosome biosynthesis, size, growth, proliferation, aging,survival, and life-span of every human cell[96,97]. As such, mTOR signalling is alsoprimarily involved in cancer growth, angiogenesis, and metastasis formation[96].Outside the transplant setting, PSI have been successfully used for the treatment ofneuro-endocrine tumours[98] and advanced RCC[99]. Encouraging results have been alsoobtained in KTx recipients with NMSC[100] and Kaposi’s sarcoma[101]. Currently, thereare no formal recommendations on how to manage immunosuppression in patientswith post-transplant malignancies but common trend is to reduce CNI and switchfrom MPA to mTOR-I whenever possible[83]. Recent reports suggest that using mTOR-I may be a valid option also in recipients with localised allograft RCC but largerpopulations and long-term outcomes are needed to confirm this hypothesis[7,9,13,18].Increased risk of rejection[102] and severe drug-related side effects[103] are the maindrawbacks of the strategy and therefore a tailored approach based on specificpatient’s and cancer’s characteristics should be preferred.
FOLLOW-UP STRATEGIESIn our review, we found minimal information regarding follow-up protocols.Proposed strategies were also quite heterogeneous in terms of timing andtechniques[7,14,18]. Overall, the risk of local recurrence and metastatic disease aftersuccessful treatment of T1aN0M0 and T1bN0M0 RCC in native kidneys is extremelylow[32]. Albeit limited, experience in KTx suggests that cancer-specific outcomes arenot significantly different[7,14,18,34]. As such, it seems reasonably safe to adopt whatrecommended by current AUA[32] or EAU guidelines[104]. Considering the risk and theburden of CIN in KTx recipients, colour-Doppler US, CEUS or MRI should bepreferred over CT scan with contrast media[105]. After AT, discriminating betweennecrosis, inflammation, neoplastic tissue and normal parenchyma can bechallenging[14]. In this context, protocol ablation-site biopsy may help promptly detectpersistent or recurrent neoplasms[106].
CONCLUSIONKidney allograft RCC represents a difficult challenge for the transplant community.Maximal renal function preservation is paramount to achieve the best outcome. In thisregards, post-transplant routine follow-up colour-Doppler US may help detect lesionsamenable of conservative treatment. Renal mass biopsy is advised for diagnosticpurpose and proper treatment planning. Ideally, RCC should be assessed using theFuhrman grading score and the modified AJCC staging system. Compared to thegeneral population, higher incidences of papillary type RCC have been demonstratedamong recipients with allograft neoplasms. Over years, improved surgical techniquesand technological advances have favoured the use of NSS and AT over graftectomy.Available data on T1aN0M0 RCC are reassuring as they show excellent cancer-relatedoutcomes, acceptable complication rates, and optimal allograft function whereasexperience with T1bN0M0 remains mostly anecdotal (Table 1). RCC type and growthpatter do not seem to affect primary treatment efficacy and relapse rates. Due to therarity of the disease and the lack of properly designed studies, no hardrecommendation can be made (Table 2). A reasonable approach would be to choose atailored strategy considering both patient’s and tumour’s characteristics. Individual
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surgical risk and local expertise are also important. Multi-centre prospectivecomparative trials are warranted.
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Table 1 Summary of conservative treatments of localised allograft renal cell carcinoma1
RFA CA MWA HIFU IRE NSS
Ref. Charboneau et al[107] Shingleton et al[60] Gul et al[63] Chakera et al[77] Gul[63] Chambade et al[11]
Baughman et al[108] Cornelis et al[61] Favi et al[69] Di Candio et al[76] Varotti et al[39]
Roy et al[35] Ploussard et al[62] Tillou et al[42]
Goeman et al[109] Guleryuz et al[34] Barama et al[47]
Aron et al[106] Gul et al[63] Kaouk et al[41]
Matevossian et al[110] Mundel et al[122]
Veltri et al[111] Ribal et al[123]
Sanchez et al[112] Lamb et al[124]
Elkentaoui et al[113]
Olivani et al[114]
Cornelis et al[61]
Leveridge et al[115]
Tillou et al[18]
Swords et al[116]
Végső et al[117]
Su et al[118]
Christensen et al[119]
Hernández-Socorro et al[120]
Guleryuz et al[34]
Cool et al[121]
Iezzi et al[48]
Di Candio et al[76]
Patients (n) 70 11 5 3 1 61
Lesions (n) 78 11 5 3 1 63
FU (range) 3-71 mo 1-59 mo 8-61 mo 73-81 mo 34 mo 5-109 mo
RCC type
CC (n) 10 7 2 1 1 24
PA (n) 41 3 3 2 0 33
Other (n) 5 1 0 0 0 2
NA (n) 22 0 0 0 0 4
Size (range) 0.5-4.0 cm 1-4.1 cm 2.2-3.1 cm 0.8-5.5 cm 1.6 cm 0.9-7.0 cm
TNM2
T1aN0M0 (n) 78 10 5 2 1 60
T1bN0M0 (n) 0 1 0 1 0 3
PTF (n) 2 0 0 1 0 0
Relapse (n) 1 0 0 0 0 0
DSM (n) 0 0 0 0 0 0
1Summaries based on individual cases should not considered as an estimate of the “real world”.2American Joint Committee on Cancer Tumour Node Metastasis Staging System. RFA: Radiofrequency ablation; CA: Cryoablation; MWA: Microwaveablation; HIFU: High-intensity focused ultrasound; IRE: Irreversible electroporation; NSS: Nephron-sparing surgery; FU: Follow-up; RCC: Renal cellcarcinoma; CC: Clear cell; PA: Papillary; NA: Not available; TNM: Tumour node metastasis; PTF: Primary treatment failure; DSM: Disease-specificmortality.
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Table 2 Advantages and limitations of conservative treatments of localised allograft renal cell carcinoma
Advantages Limitations
Nephron-sparing surgery Complete tumour removal Technically demanding
Definitive histology Invasive
Easy imaging-based follow-up Higher peri-operative complication rate
Good preliminary results with T1bN0M0 Higher risk of allograft dysfunction
Focal ablation Minimally invasive Higher risk of primary treatment failure
Highly selective Lack of definitive histology
Can treat centrally located lesions Difficult imaging-based follow-up
Lower peri-operative complication rate Dubious results with T1bN0M0
Better allograft function preservation
ACKNOWLEDGEMENTSWe thank Paolo San for logistic support.
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85 Campistol JM, Cuervas-Mons V, Manito N, Almenar L, Arias M, Casafont F, Del Castillo D, Crespo-Leiro MG, Delgado JF, Herrero JI, Jara P, Morales JM, Navarro M, Oppenheimer F, Prieto M, Pulpón LA,Rimola A, Román A, Serón D, Ussetti P; ATOS Working Group. New concepts and best practices formanagement of pre- and post-transplantation cancer. Transplant Rev (Orlando) 2012; 26: 261-279 [PMID:22902168 DOI: 10.1016/j.trre.2012.07.001]
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88 Wang K, Xu X, Fan M. Induction therapy of basiliximab versus antithymocyte globulin in renal allograft:a systematic review and meta-analysis. Clin Exp Nephrol 2018; 22: 684-693 [PMID: 28986715 DOI:10.1007/s10157-017-1480-z]
89 Hall EC, Engels EA, Pfeiffer RM, Segev DL. Association of antibody induction immunosuppression withcancer after kidney transplantation. Transplantation 2015; 99: 1051-1057 [PMID: 25340595 DOI:10.1097/TP.0000000000000449]
90 Crespo E, Fernandez L, Lúcia M, Melilli E, Lauzurica R, Penin RM, Quer A, Luque S, Quero M,Manonelles A, Torras J, Cruzado JM, Cañas L, Grinyó JM, Bestard O. Effector Antitumor and RegulatoryT Cell Responses Influence the Development of Nonmelanoma Skin Cancer in Kidney Transplant Patients.Transplantation 2017; 101: 2102-2110 [PMID: 28403126 DOI: 10.1097/TP.0000000000001759]
91 Maluccio M, Sharma V, Lagman M, Vyas S, Yang H, Li B, Suthanthiran M. Tacrolimus enhancestransforming growth factor-beta1 expression and promotes tumor progression. Transplantation 2003; 76:597-602 [PMID: 12923450 DOI: 10.1097/01.TP.0000081399.75231.3B]
92 Engels EA, Jennings L, Kemp TJ, Chaturvedi AK, Pinto LA, Pfeiffer RM, Trotter JF, Acker M, Onaca N,Klintmalm GB. Circulating TGF-β1 and VEGF and risk of cancer among liver transplant recipients.Cancer Med 2015; 4: 1252-1257 [PMID: 25919050 DOI: 10.1002/cam4.455]
93 Jiyad Z, Olsen CM, Burke MT, Isbel NM, Green AC. Azathioprine and Risk of Skin Cancer in OrganTransplant Recipients: Systematic Review and Meta-Analysis. Am J Transplant 2016; 16: 3490-3503[PMID: 27163483 DOI: 10.1111/ajt.13863]
94 Robson R, Cecka JM, Opelz G, Budde M, Sacks S. Prospective registry-based observational cohort studyof the long-term risk of malignancies in renal transplant patients treated with mycophenolate mofetil. Am JTransplant 2005; 5: 2954-2960 [PMID: 16303010 DOI: 10.1111/j.1600-6143.2005.01125.x]
95 Geissler EK. Post-transplantation malignancies: here today, gone tomorrow? Nat Rev Clin Oncol 2015;12: 705-717 [PMID: 26483298 DOI: 10.1038/nrclinonc.2015.186]
96 Pópulo H, Lopes JM, Soares P. The mTOR signalling pathway in human cancer. Int J Mol Sci 2012; 13:1886-1918 [PMID: 22408430 DOI: 10.3390/ijms13021886]
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98 Lamberti G, Brighi N, Maggio I, Manuzzi L, Peterle C, Ambrosini V, Ricci C, Casadei R, Campana D.The Role of mTOR in Neuroendocrine Tumors: Future Cornerstone of a Winning Strategy? Int J Mol Sci
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100 Stucker F, Marti HP, Hunger RE. Immunosuppressive drugs in organ transplant recipients--rationale forcritical selection. Curr Probl Dermatol 2012; 43: 36-48 [PMID: 22377918 DOI: 10.1159/000335148]
101 Stallone G, Schena A, Infante B, Di Paolo S, Loverre A, Maggio G, Ranieri E, Gesualdo L, Schena FP,Grandaliano G. Sirolimus for Kaposi's sarcoma in renal-transplant recipients. N Engl J Med 2005; 352:1317-1323 [PMID: 15800227 DOI: 10.1056/NEJMoa042831]
102 Lim WH, Eris J, Kanellis J, Pussell B, Wiid Z, Witcombe D, Russ GR. A systematic review of conversionfrom calcineurin inhibitor to mammalian target of rapamycin inhibitors for maintenanceimmunosuppression in kidney transplant recipients. Am J Transplant 2014; 14: 2106-2119 [PMID:25088685 DOI: 10.1111/ajt.12795]
103 Nguyen LS, Vautier M, Allenbach Y, Zahr N, Benveniste O, Funck-Brentano C, Salem JE. Sirolimus andmTOR Inhibitors: A Review of Side Effects and Specific Management in Solid Organ Transplantation.Drug Saf 2019; 42: 813-825 [PMID: 30868436 DOI: 10.1007/s40264-019-00810-9]
104 Donat SM, Diaz M, Bishoff JT, Coleman JA, Dahm P, Derweesh IH, Herrell SD, Hilton S, Jonasch E, LinDW, Reuter VE, Chang SS. Follow-up for Clinically Localized Renal Neoplasms: AUA Guideline. J Urol2013; 190: 407-416 [PMID: 23665399 DOI: 10.1016/j.juro.2013.04.121]
105 Cheungpasitporn W, Thongprayoon C, Mao MA, Mao SA, D'Costa MR, Kittanamongkolchai W,Kashani KB. Contrast-induced acute kidney injury in kidney transplant recipients: A systematic reviewand meta-analysis. World J Transplant 2017; 7: 81-87 [PMID: 28280699 DOI: 10.5500/wjt.v7.i1.81]
106 Aron M, Hegarty NJ, Remer E, O'Malley C, Goldfarb D, Kaouk JH. Percutaneous radiofrequency ablationof tumor in transplanted kidney. Urology 2007; 69: 778.e5-778.e7 [PMID: 17445675 DOI: 10.1016/j.uro-logy.2007.01.090]
107 Charboneau JW, O'Loughlin MT, Milliner DS, Engen DE. Sonographically guided percutaneous radiofrequency ablation of a renal cell carcinoma in a transplanted kidney. J Ultrasound Med 2002; 21: 1299-1302 [PMID: 12418770 DOI: 10.7863/jum.2002.21.11.1299]
108 Baughman SM, Sexton WJ, Glanton CW, Dalrymple NC, Bishoff JT. Computerized tomography guidedradio frequency ablation of a renal cell carcinoma within a renal allograft. J Urol 2004; 172: 1262-1263[PMID: 15371819 DOI: 10.1097/01.ju.0000140138.97968.ca]
109 Goeman L, Joniau S, Oyen R, Van Poppel H. Percutaneous ultrasound-guided radiofrequency ablation ofrecurrent renal cell carcinoma in renal allograft after partial nephrectomy. Urology 2006; 67: 199 [PMID:16413367 DOI: 10.1016/j.urology.2005.07.039]
110 Matevossian E, Novotny A, Vogelsang B, Mehler J, Stangl M, Thorban S, Dobritz M. Noninvasivetherapy of incidental de novo renal cell carcinoma in a kidney allograft 12 years after transplantation:report of a case and review of literature. Transplant Proc 2008; 40: 915-917 [PMID: 18555077 DOI:10.1016/j.transproceed.2008.03.042]
111 Veltri A, Grosso M, Castagneri F, Garetto I, Sacchetto P, Tosetti I, Stratta P, Terrone C, Fava C.Radiofrequency thermal ablation of small tumors in transplanted kidneys: an evolving nephron-sparingoption. J Vasc Interv Radiol 2009; 20: 674-679 [PMID: 19299170 DOI: 10.1016/j.jvir.2009.01.018]
112 Sanchez K, Barr RG. Contrast-enhanced ultrasound detection and treatment guidance in a renal transplantpatient with renal cell carcinoma. Ultrasound Q 2009; 25: 171-173 [PMID: 19956049 DOI:10.1097/RUQ.0b013e3181b4f9cf]
113 Elkentaoui H, Robert G, Pasticier G, Bernhard JC, Couzi L, Merville P, Ravaud A, Ballanger P, FerrièreJM, Wallerand H. Therapeutic management of de novo urological malignancy in renal transplantrecipients: the experience of the French Department of Urology and Kidney Transplantation fromBordeaux. Urology 2010; 75: 126-132 [PMID: 19864001 DOI: 10.1016/j.urology.2009.06.106]
114 Olivani A, Iaria M, Missale G, Capocasale E, Biasini E, Mazzoni MP, Lombardelli L, Luzi E, Frattini A,Pelosi G. Percutaneous ultrasound-guided radiofrequency ablation of an allograft renal cell carcinoma: acase report. Transplant Proc 2011; 43: 3997-3999 [PMID: 22172886 DOI:10.1016/j.transproceed.2011.08.089]
115 Leveridge M, Musquera M, Evans A, Cardella C, Pei Y, Jewett M, Robinette M, Finelli A. Renal cellcarcinoma in the native and allograft kidneys of renal transplant recipients. J Urol 2011; 186: 219-223[PMID: 21575970 DOI: 10.1016/j.juro.2011.03.032]
116 Swords DC, Al-Geizawi SM, Farney AC, Rogers J, Burkart JM, Assimos DG, Stratta RJ. Treatmentoptions for renal cell carcinoma in renal allografts: a case series from a single institution. Clin Transplant2013; 27: E199-E205 [PMID: 23419131 DOI: 10.1111/ctr.12088]
117 Végső G, Toronyi É, Deák PÁ, Doros A, Langer RM. Detection and management of renal cell carcinomain the renal allograft. Int Urol Nephrol 2013; 45: 93-98 [PMID: 22941752 DOI:10.1007/s11255-012-0274-1]
118 Su MZ, Campbell NA, Lau HM. Management of renal masses in transplant allografts at an Australiankidney-pancreas transplant unit. Transplantation 2014; 97: 654-659 [PMID: 24212503 DOI:10.1097/01.TP.0000437333.38786.fd]
119 Christensen SF, Hansen JM. Donor Kidney With Renal Cell Carcinoma Successfully Treated WithRadiofrequency Ablation: A Case Report. Transplant Proc 2015; 47: 3031-3033 [PMID: 26707334 DOI:10.1016/j.transproceed.2015.10.039]
120 Hernández-Socorro CR, Henríquez-Palop F, Santana-Toledo L, Gallego-Samper R, Rodríguez-Pérez JC.Radiofrequency ablation as an alternative therapy for renal neoplasms in graft recipients. A preliminarystudy. Nefrologia 2015; 35: 514-516 [PMID: 26306951 DOI: 10.1016/j.nefro.2015.03.005]
121 Cool DW, Kachura JR. Radiofrequency Ablation of T1a Renal Cell Carcinomas within Renal TransplantAllografts: Oncologic Outcomes and Graft Viability. J Vasc Interv Radiol 2017; 28: 1658-1663 [PMID:28916346 DOI: 10.1016/j.jvir.2017.07.023]
122 Mundel TM, Schaefer KL, Colombo-Benkmann M, Dietl KH, Diallo-Danebrock R, Senninger N.Nephron-sparing surgery of a low grade renal cell carcinoma in a renal allograft 12 years aftertransplantation. Cancer Biol Ther 2007; 6: 1700-1703 [PMID: 17986871 DOI: 10.4161/cbt.6.11.5165]
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W J T World Journal ofTransplantation
Submit a Manuscript: https://www.f6publishing.com World J Transplant 2020 June 29; 10(6): 162-172
DOI: 10.5500/wjt.v10.i6.162 ISSN 2220-3230 (online)
REVIEW
Interrelationship between Toll-like receptors and infection afterorthotopic liver transplantation
Mahmoud El-Bendary, Mustafa Naemattalah, Ahmed Yassen, Naser Mousa, Dina Elhammady,Ahmed M Sultan, Mohamed Abdel-Wahab
ORCID number: Mahmoud El-Bendary (0000-0002-3751-5927);Mustafa Naemattalah(0000-0003-2793-7357); AhmedYassen (0000-0002-7164-8045);Nasser Mousa(0000-0000-8329-2587); DinaElhammady (0000-0002-7444-2798);Ahmad M Sultan(0000-0001-5776-1837); MohamedAbdel-Wahab(0000-0003-0004-6036).
Author contributions: El-BendaryM and Naemattalah M wereinvolved in study conception anddesign; Yassen A, Sultanand MA,and Abdel-Wahab M acquired thedata; El-Bendary M and Mousa Nwrote the review; Elhammady Dedit the review; all authors wereinvolved in the drafting and criticalrevision of the manuscript; allauthors approved the final versionof the manuscript.
Conflict-of-interest statement:Authors declare no conflict ofinterests for this article.
Open-Access: This article is anopen-access article that wasselected by an in-house editor andfully peer-reviewed by externalreviewers. It is distributed inaccordance with the CreativeCommons AttributionNonCommercial (CC BY-NC 4.0)license, which permits others todistribute, remix, adapt, buildupon this work non-commercially,and license their derivative workson different terms, provided theoriginal work is properly cited andthe use is non-commercial. See:http://creativecommons.org/licen
Mahmoud El-Bendary, Ahmed Yassen, Naser Mousa, Dina Elhammady, Department of TropicalMedicine and Hepatology, Faculty of Medicine, Mansoura University, Mansoura 35111, Egypt
Mustafa Naemattalah, Department of Medical Biochemistry, Faculty of Medicine, MansouraUniversity, Mansoura 35111, Egypt
Ahmed M Sultan, Mohamed Abdel-Wahab, Gastroenterology Surgical Centre, Faculty ofMedicine, Mansoura University, Mansoura 35111, Egypt
Corresponding author: Mahmoud El-Bendary, MD, Professor, Department of TropicalMedicine and Hepatology, Faculty of Medicine, Mansoura University, Elgomhoria Street,Mansoura 35111, Egypt. [email protected]
AbstractEarly microbial recognition by the innate immune system is accomplished byToll-like receptors (TLRs), with resultant initiation of a pro-inflammatoryresponse against infecting organisms. In spite of presence of an abundance ofToll-like receptors on the surface of the liver, gut bacteria does not elicit aninflammatory reaction in healthy individuals due to tolerance to these TLRs,suggesting that the inflammatory responses seen in the liver are the result ofbreakdown of this tolerance. While orthotopic liver transplantation is often lifesaving in many instances, death following this procedure is most commonly dueto infection that occurs in up to 80% of transplant recipients, most commonly dueto microbial causes in up to 70% of cases and viral infections in 20%, while fungalinfections affect only 8% of cases. The probability of acquiring infection followinghepatic transplantation is heightened due to affection of the innate immunedefense mechanisms of the host following this procedure. Single nucleotidepolymorphisms of TLRs have been associated with increased likelihood of eitherdevelopment of post-transplant infection or eradication of infecting organism.However, conflicting reports from other studies reveal that prevalence of thissingle nucleotide polymorphism is not increased in infected patients.
Key words: Toll like receptors; Infection; Liver transplantation; Cirrhosis; Immunity;Orthotopic
©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
Core tip: Microbial recognition by the innate immunity is accomplished by Toll-like
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ses/by-nc/4.0/
Manuscript source: Invitedmanuscript
Received: February 24, 2020Peer-review started: February 24,2020First decision: April 22, 2020Revised: May 9, 2020Accepted: May 21, 2020Article in press: May 21, 2020Published online: June 29, 2020
P-Reviewer: Boteon YL, Rubbini MS-Editor: Gong ZML-Editor: AE-Editor: Wu YXJ
receptors (TLRs). In spite of presence of an abundance of TLRs on the surface of theliver, gut bacteria does not elicit an inflammatory reaction in healthy individuals due totolerance to these TLRs suggesting that the inflammatory responses seen in the liver arethe result of breakdown of this tolerance. The probability of acquiring infectionfollowing hepatic transplantation is heightened due to affection of the innate immunity ofthe host. There is controversy about the association between genetic polymorphism ofTLRs with the development of post-transplant infection.
Citation: El-Bendary M, Naemattalah M, Yassen A, Mousa N, Elhammady D, Sultan AM,Abdel-Wahab M. Interrelationship between Toll-like receptors and infection after orthotopicliver transplantation. World J Transplant 2020; 10(6): 162-172URL: https://www.wjgnet.com/2220-3230/full/v10/i6/162.htmDOI: https://dx.doi.org/10.5500/wjt.v10.i6.162
INTRODUCTIONHost protection against invading pathogens is dependent on the coordinatedreactions of both innate and adaptive immune systems beginning with the earlydetection and subsequent initiation of a pro-inflammatory response against infectingorganisms[1], while the adaptive immune system is responsible for pathogen removalin the later stages of infection and creation of immunological memory[2]. Earlymicrobial recognition by the innate immune system is done by use of germ-lineencoded pattern recognition receptors (PRRs) capable of identifying moleculararrangements particular to the invading microbe known as pathogen-associatedmolecular patterns (PAMPs) as well as those arising from direct injury to host cellstermed damage-associated molecule patterns (DAMPs)[3,4].
Recognition of PAMPs and DAMPs is carried out by a subgroup of PRRs calledToll-like receptors (TLRs) of which there are ten identified human types. Thesereceptors consist of a membrane-spanning glycoprotein and a 200 amino acid regionin their highly conserved C-terminal known as the Toll/IL-1R (TIR) domain[4]. WhileTLR4 was the first TLR to be identified mainly for its recognition of lipopoly-saccharide (LPS) such as that present in the outer membranes of Gram-negativebacteria, every TLR subsequently identified has the ability to recognize specificsequences of PAMPs. Furthermore, on the basis of subcellular localization, TLRs canbe classified into two main groups. TLRs 1, 2, 4, 5, and 6 are receptors situated on thecell surface and are primarily responsible for recognition of bacterial PAMPs, whileTLRs 3, 7, 8, 8, and 11 are intracellular receptors for detection of viral PAMPs andDNA. TLR 11 also has the added ability to recognize uropathogenic bacteria[5].
Joining of the Toll-receptor with its respective ligand, by way of its leucine-richrepeat (LRR) domain, initiates a downstream cascade resulting in upregulation of pro-inflammatory cytokines and chemokines and signaling of interferon secretion. WhileTLRs are primarily a part of host innate immunity, they connect the innate with theadaptive immune systems by playing a role in dendritic cell maturation, antigenpresentation, and T and B-cell recruitment and activation[6], immune reactions that areimportant in host infection with viral agents, including hepatitis C virus (HCV)infection. Initiation of the afore mentioned signaling cascade occurs by joining of theTIR domain to any of four primary adaptor molecules, namely myeloid differentiationfactor 88 (MyD88), TIR-domain containing adaptor-inducing interferon-beta (TRIF),TIR-associated protein (TIRAP), and TRIF-related adaptor molecule (TRAM)[7].
All TLRs utilize MyD88 except TLR3 that employs TRIF. TLRs 2 and 4 signalingrequires TIRAP in conjunction with MyD88, while induction of antiviral interferonresponse and stimulation of nuclear factor kappa B (NFκB) by TLR 3 and 4 isdependent on TRIF, the TLR4-TRIF signaling pathway further utilizing TRAM[6]. BothMyD88-dependent and -independent pathways are vital signal transductionpathways that enable host TLRs to initiate immune reactions in response torecognition of pathogenic microorganisms including hepatitis viruses B and C[8,9].
TLRS AND LIVERThe liver is the first defensive structure against bacteria and their derivativespersistently received from the gut by way of the portal circulation[10]. In spite of
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presence of an abundance of TLRs on the surface of parenchymal, as well as non-parenchymal, hepatic cells[8], the continuous exposure of hepatic cells to gut bacteriadoes not elicit a inflammatory reaction in healthy individuals, demonstrating thedevelopment of a type of tolerance to TLR ligands and giving rise to the suggestionthat the inflammatory responses seen in the liver are the result of breakdown of thistolerance[11].
Kupffer cellsStimulation of TLRs 2, 3, 4, and 9 expressed on hepatic Kupffer cells faced with gutpathogen associated molecular patterns (PAMPs) leads to generation of a number ofcytokines including tumour necrosis factor α (TNF-α), interleukin (IL)-1b, IL-6, IL-12and IL-10[12]. In addition, these cells partake in the fibrogenetic process by inducingthe secretion of transforming growth factor-β (TGF-β), platelet-derived growth factor(PDGF), matrix metalloproteinases, and reactive oxygen species (ROS)[8].
HepatocytesTLRs 2, 3, 4, and 5 are expressed in low amounts, in contrast to Kupffer cells, onhepatocytes where they function to capture and remove endotoxins introduced intothe liver from portal, as well as hepatic, circulation. In addition, stimulation of TLRsby their ligands results in induction of a pro-inflammatory cytokine response, albeitmuch less defined than that observed with Kupffer cells[12].
Hepatic stellate cellsTLRs 4 and 9 are expressed on hepatic stellate cells where they cause chemokine andadhesion molecule upregulation. In addition, stimulation of TLR4 also promotessignaling of transforming growth factor-β (TGF-β) and induction of fibrogenesis whileparticipating in cell defense through the TLR4-MyD88-mediated inflammatoryresponse upon exposure to LPS[6,9,12,13]. As a result, single nucleotide polymorphisms(SNPs) of TLR4 are associated with enhanced risk of fibrosis progression in patientswith chronic HCV infection[13], and offer an approach to recognize fibrosis riskgenes[14-16].
Biliary epithelial cellsThese cells express TLRs 2, 3, 4, and 5, of which TLR 2 and 4 stimulation leads toupregulation of interleukin-1 receptor-associated kinase (IRAK) with resultanttolerance to LPS, a particularly important host protection mechanism againstuncontrolled TLR signaling brought about by the activation of biliary epithelial cellsspecific pathogen-related molecular arrangement located in the intestinal lumen[17].
Other hepatic cellsStimulation of TLR4 expressed on liver sinusoidal endothelial cells activates a nuclearfactor kappa β (NFκB) dependent pathway resulting in secretion of TNF-α andreactive oxygen species[18], while hepatic dendritic cells (DCs), the primary antigenpresenting cells (APCs) of the liver, primary sources of interferon α (IFN-α) releasedin response to ligand-induced stimulation of TLRs 4, 7, and 9[19].
POST ORTHOTOPIC LIVER TRANSPLANTATIONINFECTIONSWhile orthotopic liver transplantation is often lifesaving in many instances, deathfollowing this procedure is most commonly due to infection that occurs in up to 80%of transplant recipients, most commonly due to microbial causes in up to 70% of caseswith viral infections coming second at 20% and fungal infections affecting only aminority of cases at 8% (Table 1) [20]. Risk of infection to recipients of livertransplantation is reliant on strength of the infectious agent in conjunction with hostimmune state[21], as evidenced by the increased likelihood of patients with patientswith end-stage liver disease (ESLD) acquiring infections due to associated conditionsof defective immunity, including neutropenia, weakness of the mucocutaneous wall,occurrence of necrotic tissue, ischemia, and diabetes mellitus[22].
Post-transplant infection occurs from a number of different sources including denovo infection or recurrence of infection in the recipient patient, transplantation ofinfected graft, and nosocomial infection during hospital stay. Cause of the infectionmay be ascertained from the period directly following the transplant. Theimmunosuppressive state of these patients is dependent on the amount, type, andduration of the immunosuppressive agent used[21].
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Table 1 Types of infections after orthotopic liver transplantation
First month post transplant 1-6 mo post transplant > 6 mo post transplant
Bacterial infections Staph aurus, Strptoccoi enterococci,Salmonella pseudomonas, MRSA, VRE,Anerobes, Clostridium difficile
Multidrug resistant bacteria, Listeriaspp
Multidrug resistant bacteria
Viral Human herpes virus 6 CMV, HCV, EBV, VZV HHV8, HEV, EBV, Parvovirus B19
Fungal Candida, Asprgillus Mucormucosis, Pneumocystitisjerovicii (PJP)
Nocardia, Rhodococcus, Legionella,Cryptococcus, Blastomycosis,histoplasmosis
Mycobacterial TB TB, Non tuberculous Mycobacteria(Mycobacterial avium complex,Myco. triplex)
Protozoal Strongyloiodosis, toxoplasmosis;Echinococcosis, Chagas disease
Types of infections Wound infections, Abdominalinfections, catheter related infections,pneumonia, UTI, abscess, cholangitis,peritonitis
Community acquired infections,Invasive fungal infection
Community acquired pathogens,Opportunistic infections
CMV: Cytomegalovirus; EBV: Epstein–Barr virus; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HEV: Hepatitis E virus; HHV: Human herpes virus;HIV: Human immune deficiency virus; HSV: Herpes simplex virus; MRSA: Methicillin-resistant Staphylococcus aureus; VRE: Vancomycin-resistantEnterococcus; VZV: Varicella zoster virus.
RISK FACTORS FOR INFECTION FOLLOWING LIVERTRANSPLANTATIONRecipients of orthotopic liver transplantation become more susceptible to infectiveagents in situations of present underlying causative, immunosuppressive state of therecipient with regards to type of immunosuppressive drug administered and theextent of the disease, technical complications during the transplant procedure, andexposure to pathogens within the hospital and public environment[23].
TLRS AND INFECTION AFTER LIVER TRANSPLANTATION
TLRs and infectious liver diseasesPathophysiology of a number of infectious diseases, including Listeria, Salmonella, andthe Plasmodium species, is affected by TLRs. Following the invasion of hepatic tissue,Listeria monocytogenes replicates in hepatocytes and Kupffer cells, prompting theinfected Kupffer cells to subsequently initiate a counterattack through aTLR2/MyD88-dependent pathway to secrete of the pro-inflammatory cytokinestumour necrosis factor-α (TNF-α) and interleukin-12. While this extensive pro-inflammatory release of cytokines in response to L. monocytogenes infection is defectivein MyD88-deficient rats, giving rise to a higher rate of mortality[12], TLR2-deficientmice show normal clearance of the infection in spite of a diminished cytokineresponse. This suggests that although TLR2 does participate in the cytokine cascade,clearance of L. monocytogenes is dependent on a number of collaborating TLRs[24].
Infection with Salmonella typhimurium is typically cleared by Kupffer cells in theliver through an antimicrobial response involving TLR4 and nitric oxide,consequently leading to granuloma formation[25], while infection with Salmonellacholeraesuis results in liver injury by induction of TLR2-mediated upregulation of Fas-ligand on natural killer cells[26]. In spite of these TLRs playing a major role in thepathogenesis of Salmonella, elimination of S. choleraesuis does not depend on theactions of TLR2 and TLR4, as intracellular growth of this pathogen had diminished onactivation of TLR9, suggesting that eradication of Salmonella is also dependent onseveral TLRs[27].
Malaria causes liver injury in humans by infection with Plasmodium falciparum andin mice by Plasmodium berghei through a TLR/MyDD88-mediated pathway leading tolymphocytic infiltration and subsequent death of hepatocytes[28]. Variants of TLRs 1and 6 were found to be associated with milder forms of malaria, while TLR9 (1486C/T) variant was more likely related to higher levels of malarial parasitemia[29].
Other SNPs of TLRs have also been associated with increased likelihood ofinfection. SNP of TLR2 (R753Q), resulting in impaired TLR2 signaling, has beenassociated with increased susceptibility to tuberculosis infection in a Turkish study[30],
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while a Tunisian study reported that tuberculosis patients demonstrated higherfrequency of TLR2 (Arg677Trp) polymorphism than healthy control subjects,suggesting that presence of this polymorphism was a risk factor for pulmonarytuberculosis[31]. This finding was contradicted, however, in another study showingthat TLR2 (Arg677Trp) polymorphism did not convey risk to tuberculosis in apopulation of Iranian and Indian subjects[32].
TLR signaling and HCV recurrence following liver transplantationThe probability of acquiring infection following hepatic transplantation is heighteneddue to affection of the innate immune defense mechanisms of the host following thisprocedure. That said, recurrence of HCV infection after liver transplantation (LT) is auniversal occurrence, with the course of infection being greatly accelerated whencompared to infection outside of the transplant setting[33].
TLR2 signaling pathway plays a major role in recurrence of HCV following livertransplantation. Homozygosity of TLR2 (Arg753Gln) polymorphism has beenassociated with higher mean fibrosis levels as well as higher graft cirrhosis and loss,leading to higher mortality of HCV cases post-transplantation. On the other hand,SNPs of TLR4 (Asp299Gly) and (Thr399Ile) showed no association with any seriouscomplications following liver transplantation[34]. However, TLR2 (R753Q) SNP hasbeen reported to hinder immune recognition of HCV core and NS3 proteins that isreliant on TLR2, possibly explaining why allograft failure develops in patients withchronic hepatitis C who undergo liver transplantation[35].
Abnormal blood mononuclear cell secretion of interferon-α and NK CD56dim cellsecretion of interferon-γ due to impaired TLR7/8-mediated pathway are associatedwith more aggressive post-transplantation recurrence of HCV infection in comparisonto slower course HCV infections following liver transplantation[36]. Furthermore,patients demonstrating rapid progression of fibrosis show impaired bloodmononuclear cell secretion of tumour necrosis factor-α (TNF-α) and interleukin-6 bothat baseline and with TLR3 receptor stimulation. TLR3 receptors are functionalreceptors expressed on monocytes where they are dominant initiators of host antiviralresponses[37-39]. Therefore, it is reasonable to assume that hindered secretion of TLR3-mediated monocyte-derived TNF-α and interleukin-6 results in impaired NK anddendritic cell stimulation leading to increased fibrosis[36].
Natural killer CD56 dim cells secrete IFN-γ that stimulates dendritic cells and Tcells, thereby aiding Th1 anti-viral cytokine responses. Impairment of this secretoryrelease promotes Th2 rather than Th1 cytokine response[40,41], leading to impairedHCV-directed T cell response, particularly with regards to CD4+T cell protectionagainst progression of liver disease[42]. Rapid progression of fibrosis in HCV patients isattributed to inadequate viral control by the immune system[43,44], leading toheightened production of pro-inflammatory cytokines with increased stimulation ofpro-fibrogenic pathways[15,45,46].
Secretion of interferon-α and interferon-γ has been shown to be extremelyimportant in host viral defense mechanisms, with emphasis on the fundamental roleof TLR7/8 signaling pathways in recurrence of HCV infection post-LT. Thisconsideration becomes even more eminent when coupled with data demonstratingthe negative effect of calcineurin inhibitors on TLR7/8-mediated human NKCD56dim cell secretion of interferon-γ in patients having undergone livertransplantation[36,47].
Polymorphism of TLR2 and infections with Gram-positive bacteria after livertransplantationIt is generally accepted that cell wall components of Gram-positive bacteria,particularly peptidoglycan and lipoteichoic acid, are recognized by TLR2[48]. SNPs incertain TLR genes have been reported to negatively impact responses of thesereceptors to their corresponding ligands[35]. TLR2 (R753Q) SNP, caused by substitutionof arginine for glutamine at position 753, was shown to result in defective intracellularsignaling resulting in modification of cytokine secretion in response to stimulation bypeptidoglycan, lipopeptides, and other bacterial components leading to increasedsusceptibility to bacterial infections[35]. In addition, this SNP showed high associationwith Gram-positive septic shock infections and staphylococcal infections[49].
Similarly, cell membrane constituents of S. aureus did not elicit TNF-α responsefrom TLR2-deficient macrophages[50]. Compared with wild-type rats, those with TLR2-deficiency showed increased susceptibility to infection with S. aureus. These TLR2-deficient rats demonstrated increased mortality rates of 80% on day 8 and 90% on day14 after being subjected to experimentally high infectious doses S. aureus, compared torates of 0% and 40%, respectively, in wild-type rats. Moreover, cirrhotic patients havebeen shown to demonstrate increased susceptibility to spontaneous bacterialperitonitis with presence of the variant SNP TLR2 (R753Q)[50,51].
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Nevertheless, post-transplantation susceptibility to infection in patients with TLR2(Arg753Gln) polymorphism remains inconclusive, with one study showing noassociation of this SNP with infections of viral or fungal nature followingtransplantation of allogeneic stem cells, although there has been an associationbetween TLR2 (Arg753Gln) SNP and CMV infection and replication post-LT[52].However, other reports provide conflicting results, revealing that prevalence of thisSNP was not increased in patients with Gram-positive bacteremia[53], a difference thatmay be attributed to the variation in patient sample as this study included cases ofHIV infection, Gram-positive bacterial infections, and septic shock[53,54]. Another studyevaluating S. aureus infection of prosthetic joints demonstrated that frequency of TLR2(R753Q) SNP was relatively similar between infected patients and controls, with thelikelihood of developing complications of S. aureus infection was basically similarbetween patients with wild-type TLR2 gene and those with polymorphism[55].Furthermore, no association could be ascertained between aggressive S. aureusinfection and presence of mutant TLR2 (R753Q) SNP[56]. A lack of difference in TLR2(R753Q) SNP between patients with and without Gram-positive infections has alsobeen reported, these infections found in transplant patients with TLR2 (R753Q) SNPin similar frequencies as in those with wild-type gene[57].
While these results appear to propose a lack of significant impact of TLR2 in humaninfection, other data has suggested the contrary. The same study by Lee et al[57] alsoreported that TLR2 (R753Q) SNP showed marked association with increased risk ofseptic shock, in addition to a relatively insignificant tendency towards risk ofrecurring infection. However, no significant relationship could be determinedbetween TLR2 (R753Q) SNP and 90-d all-cause death. This can be partly attributed topresence of other receptors playing a role in pathogen recognition, such asidentification of Gram-positive infections through the nucleotide oligodimerizationdomain[58]. Similarly, infection with S. aureus in an animal model is recognized byseveral types of TLRs, including TLR2[50]. Another explanation for the apparentclinical irrelevance between TLR2 and infection may the dose of infectious pathogen,as TLR2 and survival form S. aureus infection were found to be correlated only incases of infections with large dose of pathogen[50].
Relationship between polymorphism of TLR2 and infection with cytomegalovirusfollowing liver transplantationThe report of TLR2 (R753Q) SNP inhibiting TLR2 signaling on exposure tocytomegalovirus glycoprotein B may provide the basis for association of thispolymorphism with human cytomegalovirus disease[59]. Homozygosity of TLR2(Arg753Gln) SNP has been reported to be associated with high incidence of CMVinfection post-transplantation of liver and the kidney[60,61], in addition to indicatingrisk for CMV infection, especially tissue-invasive type, following liver transplan-tation[62].
TLRs have been reported to take part in the innate defense mechanisms againstinfection with CMV, with CMV-induced activation of TLR2 resulting in production ofcytokines via a nuclear factor kappa B (NFκB)-mediated pathway [ 6 3 ] .TLR2(Arg753Gln) SNP requires presence of only a single functional wild-type allele tocontrol CMV infection, as cells with heterozygosity for this polymorphism functionsimilarly as those with wild-type gene, having the capability to respond on activationwith TLR2 agonist[64]. Conversely, cases with homozygosity for TLR2 (Arg753Gln)SNP show replication of cytomegalovirus and manifest clinical disease. However, itshould be noted that CMV disease is less manifest in cases with heterozygosity forthis SNP, in spite of the fact that viral replication is more pronounced[60].
Effects of Cyclosporine and Tacrolimus on TLR signaling after liver transplantationThe deficient peripheral blood mononuclear cell (PBMC) pro-inflammatory cytokinesecretion observed on stimulation of TLRs 2, 4, and 7/8 on administration oftacrolimus and cyclosporine therapy in patients when compared to healthy controlsubjects suggests a class effect for calcineurin inhibitors on function of these TLRs.However, examination by flowcytometry demonstrated that no specific individualcell subtype could be identified as accountable for the functional modification of thesereceptors, suggesting that the suppressive effect of calcineurin inhibitors on TLRs 2, 4,and 7/8 is apparent in PBMCs but variable in individual cell subtypes[65].
Similarly, calcineurin inhibitors have also been shown to down-regulate TLR4stimulated by lipopolysaccharides, although pre-treatment of cells with tacrolimusresulted in diminished inflammatory response to lipopolysaccharides, suggestinginitiation of lipopolysaccharide intolerance (73). Impaired secretion of tumor necrosisfactor-α (TNF-α) and interleukin-6 mediated through TLRs 2, 4, and 7/8 pathwayshas been demonstrated from PBMCs cultured with both TLR agonist and calcineurininhibitors when compared with controls[65].
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CONCLUSIONThe liver is the first host defensive structure against the bacteria and bacterialproducts that are persistently received from the gut by way of the portal circulation.However, this massive influx of gut bacteria does not elicit an inflammatory reactionin healthy individuals due to tolerance of the abundantly present TLRs on the surfaceof hepatic cells. While orthotopic liver transplantation is often lifesaving in manyinstances, death following this procedure is most commonly due to infection thatoccurs in up to 80% of transplant recipients. SNPs in certain TLR genes have beenassociated with increased susceptibility to infections (Table 2). SNPs of TLR2 havebeen associated with both Gram-positive and Gram-negative bacteria (e.g., Listeria,Salmonella), mycobacteria tuberculosis and the Plasmodium species, in addition to CMVinfection and the universal recurrence of HCV following liver transplantation.Similarly, impaired TLR7/8-mediated pathway has been associated with moreaggressive post-transplantation recurrence of HCV infection, while reports on TLR3polymorphism have demonstrated comparable results.
Our hypothesis is that TLR genes and their proteins have influence in the outcomeof post liver transplantation infection. This risk factor are responsible for mortalityrate of liver transplant. Understanding the genetic variation of TLR gene in livertransplant may clarify the underling mechanisms behind the post-transplant infection.It may also enables the development of early diagnostic tests for predication of eitherthe persistence or clearance of infection. Genetic study may be also open somewindows for new treatments, or interventions to prevent disease onset or minimizedisease severity.
Association between TLRs genotypes and post transplant infection havetraditionally been studied by determining the genotype of known markers. However.these associations studies of single gene typically explain less than 25% of theheritable risk estimated for each of those diseases. Furthermore, the heterogeneity,ethnic variation and complex relationship between genotype and phenotype may alsodifficult, to predict which genes are most likely to be implicated as a candidate genefor a particular outcome. We recommended several approaches to investigate theassociation of TLR (1-10) genes with the outcome of post-transplant infection. Theseapproaches include: (1) Genome wide association study (GWAS) using next-generation sequencing techniques (NGS) for the whole genome to identify the entireunderlying genetic variation and its disease relevance. Applying NGS to GWAS willhelp for better identification of candidate genes in a short time, and in an efficientway. (2) Gene expression epigenetic analyses of TLR gene may also provide moreinformation about the underlying mechanism of these factors for the disease outcome.(3) Furthermore, correlation study of different genotype with serum levels of cytokinenet levels are also required. And (4) Multicentric well-designed studies of largesample size are needed to avoid false negative results that may arise from under-evaluation of interactions involving gene-to-gene relations or gene environmentamong different ethnic populations.
Limitations of the studyThe major limitation of this article is the study design, as it is a narrative reviewarticle. It is well known that narrative review articles are more susceptible to selectionbias and this may affect its conclusion. Systematic review articles adhere to strictmethodology, thus are, potentially, more reliable scientifically.
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Table 2 Association of Toll-like receptors alleles with infections post liver transplantation and their clinical significance
Type of Infection Type of organism TLR alleles Clinical significance
Bacterial infections Staph aurus TLR2 (Arg753Gln) Inconclusive association with septicshock
TLR2 (R753Q) May correlated only in cases ofinfections with large dose ofpathogen
Listeria monocytogenes TLR2/MyD88-dependent pathway Participate in cytokine cascade Norole in clearance
Salmonella typhimurium TLR4 Granuloma formation
Salmonella choleraesuis TLR2, TLR4 Have role in pathogenesis; No role inclearance
TLR9 Has role in clearance
Protozoal Plasmodium falciparum TLR1, TLR6 Mild form of malaria
TLR9 (1486 C/T) Severe form of malaria
Mycobacterium Mycobaterial tuberculosis TLR2 (R753Q) Increased susceptibility to T.B inTurkish
TLR2 (Arg677Trp) Increased susceptibility to T.B inTunisian but not to Iranian andIndian populations.
Viral Hepatitis C virus (HCV) TLR2 (Arg753Gln) Recurrence of HCV post transplant(PT) with higher graft cirrhosis andgraft failure
TLR2 (R753Q) Higher rate of graft failure
TLR3 Increased liver fibrosis
TLR4 (Asp299Gly) and (Thr399Ile) No associated PT complications
TLR7/8-mediated pathway Aggressive PT recurrence of HCV
Cytomegalovirus (CMV) TLR2 (R753Q) TLR2 (Arg753Gln) Increased incidence of CMV PT
TLR: Toll-like receptor.
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35 Brown RA, Gralewski JH, Eid AJ, Knoll BM, Finberg RW, Razonable RR. R753Q single-nucleotidepolymorphism impairs toll-like receptor 2 recognition of hepatitis C virus core and nonstructural 3proteins. Transplantation 2010; 89: 811-815 [PMID: 20090572 DOI: 10.1097/TP.0b013e3181cbac18]
36 Howell J, Sawhney R, Skinner N, Gow P, Angus P, Ratnam D, Visvanathan K. Toll-like receptor 3 and7/8 function is impaired in hepatitis C rapid fibrosis progression post-liver transplantation. Am JTransplant 2013; 13: 943-953 [PMID: 23425350 DOI: 10.1111/ajt.12165]
37 Rehermann B. Hepatitis C virus versus innate and adaptive immune responses: a tale of coevolution andcoexistence. J Clin Invest 2009; 119: 1745-1754 [PMID: 19587449 DOI: 10.1172/JCI39133]
38 Hart OM, Athie-Morales V, O'Connor GM, Gardiner CM. TLR7/8-mediated activation of human NKcells results in accessory cell-dependent IFN-gamma production. J Immunol 2005; 175: 1636-1642[PMID: 16034103 DOI: 10.4049/jimmunol.175.3.1636]
39 El-Bendary M, Neamatallah M, Elalfy H, Besheer T, El-Setouhy M, Youssef MM, Zein M, ElhammadyD, Hegazy A, Esmat G. Association of genetic polymorphisms of chemokines and their receptors withclearance or persistence of hepatitis C virus infection. Br J Biomed Sci 2019; 76: 11-16 [PMID: 30175654DOI: 10.1080/09674845.2018.1518299]
40 Guo H, Qiao Z, Zhu L, Wang H, Su L, Lu Y, Cui Y, Jiang B, Zhu Q, Xu L. Th1/Th2 cytokine profiles andtheir relationship to clinical features in patients following nonmyeloablative allogeneic stem cell
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transplantation. Am J Hematol 2004; 75: 78-83 [PMID: 14755372 DOI: 10.1002/ajh.10443]41 El-Bendary M, Neamatallah M, Esmat G, Kamel E, Elalfy H, Besheer T, Eldeib D, Eladl AH, El-Setouhy
M, El-Gilany AH, El-Waseef A. Associations of human leucocyte antigen class II-DQB1 alleles withhepatitis C virus infection in Egyptian population: a multicentre family-based study. J Viral Hepat 2016;23: 961-970 [PMID: 27599887 DOI: 10.1111/jvh.12573]
42 El-Bendary M, Neamatallah M, Elalfy H, Besheer T, Kamel E, Mousa H, Eladl AH, El-Setouhy M, El-Gilany AH, El-Waseef A, Esmat G. HLA Class II-DRB1 Alleles with Hepatitis C Virus InfectionOutcome in Egypt: A Multicentre Family-based Study. Ann Hepatol 2019; 18: 68-77 [PMID: 31113612DOI: 10.5604/01.3001.0012.7864]
43 Papatheodoridis GV, Barton SG, Andrew D, Clewley G, Davies S, Dhillon AP, Dusheiko G, DavidsonB, Rolles K, Burroughs AK. Longitudinal variation in hepatitis C virus (HCV) viraemia and early courseof HCV infection after liver transplantation for HCV cirrhosis: the role of different immunosuppressiveregimens. Gut 1999; 45: 427-434 [PMID: 10446114 DOI: 10.1136/gut.45.3.427]
44 Attallah AM, Omran MM, Farid K, El-Bendary M, Emran TM, Albannan MS, El-Dosoky I. Developmentof a novel score for liver fibrosis staging and comparison with eight simple laboratory scores in largenumbers of HCV-monoinfected patients. Clin Chim Acta 2012; 413: 1725-1730 [PMID: 22759976 DOI:10.1016/j.cca.2012.06.031]
45 Bataller R, Paik YH, Lindquist JN, Lemasters JJ, Brenner DA. Hepatitis C virus core and nonstructuralproteins induce fibrogenic effects in hepatic stellate cells. Gastroenterology 2004; 126: 529-540 [PMID:14762790 DOI: 10.1053/j.gastro.2003.11.018]
46 El-Bendary M, Nour D, Arafa M, Neamatallah M. Methylation of tumour suppressor genes RUNX3,RASSF1A and E-Cadherin in HCV-related liver cirrhosis and hepatocellular carcinoma. Br J Biomed Sci2020; 77: 35-40 [PMID: 31790342 DOI: 10.1080/09674845.2019.1694123]
47 El-Bendary M, Neamatallah M, Elalfy H, Besheer T, El-Setouhy M, Kasim N, Abou El-Khier NT, KamelE, Eladl AH, El-Waseef A, Abdel-Aziz AF, Esmat G. Association of interferon gamma genepolymorphism and susceptibility to hepatitis C virus infection in Egyptian patients: A multicenter, family-based study. JGH Open 2017; 1: 140-147 [PMID: 30483551 DOI: 10.1002/jgh3.12024]
48 Van Amersfoort ES, Van Berkel TJ, Kuiper J. Receptors, mediators, and mechanisms involved inbacterial sepsis and septic shock. Clin Microbiol Rev 2003; 16: 379-414 [PMID: 12857774 DOI:10.1128/cmr.16.3.379-414.2003]
49 Lorenz E, Mira JP, Cornish KL, Arbour NC, Schwartz DA. A novel polymorphism in the toll-likereceptor 2 gene and its potential association with staphylococcal infection. Infect Immun 2000; 68: 6398-6401 [PMID: 11035751 DOI: 10.1128/iai.68.11.6398-6401.2000]
50 Takeuchi O, Hoshino K, Akira S. Cutting edge: TLR2-deficient and MyD88-deficient mice are highlysusceptible to Staphylococcus aureus infection. J Immunol 2000; 165: 5392-5396 [PMID: 11067888 DOI:10.4049/jimmunol.165.10.5392]
51 Nischalke HD, Berger C, Aldenhoff K, Thyssen L, Gentemann M, Grünhage F, Lammert F, Nattermann J,Sauerbruch T, Spengler U, Appenrodt B. Toll-like receptor (TLR) 2 promoter and intron 2 polymorphismsare associated with increased risk for spontaneous bacterial peritonitis in liver cirrhosis. J Hepatol 2011;55: 1010-1016 [PMID: 21356257 DOI: 10.1016/j.jhep.2011.02.022]
52 Carvalho A, Cunha C, Carotti A, Aloisi T, Guarrera O, Di Ianni M, Falzetti F, Bistoni F, Aversa F,Pitzurra L, Rodrigues F, Romani L. Polymorphisms in Toll-like receptor genes and susceptibility toinfections in allogeneic stem cell transplantation. Exp Hematol 2009; 37: 1022-1029 [PMID: 19539691DOI: 10.1016/j.exphem.2009.06.004]
53 Yoon HJ, Choi JY, Kim CO, Park YS, Kim MS, Kim YK, Shin SY, Kim JM, Song YG. Lack of Toll-likereceptor 4 and 2 polymorphisms in Korean patients with bacteremia. J Korean Med Sci 2006; 21: 979-982[PMID: 17179672 DOI: 10.3346/jkms.2006.21.6.979]
54 Horcajada JP, Lozano F, Muñoz A, Suarez B, Fariñas-Alvarez C, Almela M, Smithson A, Martínez E,Mallolas J, Mensa J, Gatell JM. Polymorphic receptors of the innate immune system (MBL/MASP-2 andTLR2/4) and susceptibility to pneumococcal bacteremia in HIV-infected patients: a case-control study.Curr HIV Res 2009; 7: 218-223 [PMID: 19275590 DOI: 10.2174/157016209787581382]
55 El-Helou O, Berbari EF, Brown RA, Gralewski JH, Osmon DR, Razonable RR. Functional assessment ofToll-like receptor 2 and its relevance in patients with Staphylococcus aureus infection of joint prosthesis.Hum Immunol 2011; 72: 47-53 [PMID: 20937339 DOI: 10.1016/j.humimm.2010.10.001]
56 Moore CE, Segal S, Berendt AR, Hill AV, Day NP. Lack of association between Toll-like receptor 2polymorphisms and susceptibility to severe disease caused by Staphylococcus aureus. Clin Diagn LabImmunol 2004; 11: 1194-1197 [PMID: 15539529 DOI: 10.1128/CDLI.11.6.1194-1197.2004]
57 Lee SO, Brown RA, Kang SH, Abdel-Massih RC, Razonable RR. Toll-like receptor 2 polymorphism andGram-positive bacterial infections after liver transplantation. Liver Transpl 2011; 17: 1081-1088 [PMID:21563293 DOI: 10.1002/lt.22327]
58 Kapetanovic R, Nahori MA, Balloy V, Fitting C, Philpott DJ, Cavaillon JM, Adib-Conquy M.Contribution of phagocytosis and intracellular sensing for cytokine production by Staphylococcus aureus-activated macrophages. Infect Immun 2007; 75: 830-837 [PMID: 17118979 DOI: 10.1128/IAI.01199-06]
59 Brown RA, Gralewski JH, Razonable RR. The R753Q polymorphism abrogates toll-like receptor 2signaling in response to human cytomegalovirus. Clin Infect Dis 2009; 49: e96-e99 [PMID: 19814623DOI: 10.1086/644501]
60 Kijpittayarit S, Eid AJ, Brown RA, Paya CV, Razonable RR. Relationship between Toll-like receptor 2polymorphism and cytomegalovirus disease after liver transplantation. Clin Infect Dis 2007; 44: 1315-1320[PMID: 17443468 DOI: 10.1086/514339]
61 Cervera C, Lozano F, Saval N, Gimferrer I, Ibañez A, Suárez B, Linares L, Cofán F, Ricart MJ, EsforzadoN, Marcos MA, Pumarola T, Oppenheimer F, Campistol JM, Moreno A. The influence of innate immunitygene receptors polymorphisms in renal transplant infections. Transplantation 2007; 83: 1493-1500 [PMID:17565323 DOI: 10.1097/01.tp.0000264999.71318.2b]
62 Kang SH, Abdel-Massih RC, Brown RA, Dierkhising RA, Kremers WK, Razonable RR. Homozygosityfor the toll-like receptor 2 R753Q single-nucleotide polymorphism is a risk factor for cytomegalovirusdisease after liver transplantation. J Infect Dis 2012; 205: 639-646 [PMID: 22219347 DOI:10.1093/infdis/jir819]
63 Razonable RR, Rivero A, Brown RA, Hart GD, Espy MJ, van Cruijsen H, Wilson J, Groettum C,Kremers W, Smith TF, Paya CV. Detection of simultaneous beta-herpesvirus infections in clinicalsyndromes due to defined cytomegalovirus infection. Clin Transplant 2003; 17: 114-120 [PMID:12709076 DOI: 10.1034/j.1399-0012.2003.02104]
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64 von Aulock S, Schröder NW, Traub S, Gueinzius K, Lorenz E, Hartung T, Schumann RR, Hermann C.Heterozygous toll-like receptor 2 polymorphism does not affect lipoteichoic acid-induced chemokine andinflammatory responses. Infect Immun 2004; 72: 1828-1831 [PMID: 14977997 DOI:10.1128/iai.72.3.1828-1831.2004]
65 Howell J, Sawhney R, Testro A, Skinner N, Gow P, Angus P, Ratnam D, Visvanathan K. Cyclosporineand tacrolimus have inhibitory effects on toll-like receptor signaling after liver transplantation. LiverTranspl 2013; 19: 1099-1107 [PMID: 23894100 DOI: 10.1002/lt.23712]
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W J T World Journal ofTransplantation
Submit a Manuscript: https://www.f6publishing.com World J Transplant 2020 June 29; 10(6): 173-182
DOI: 10.5500/wjt.v10.i6.173 ISSN 2220-3230 (online)
ORIGINAL ARTICLE
Prospective Study
Living kidney donor assessment: Kidney length vs differentialfunction
Jacob A Akoh, Katharina J Schumacher
ORCID number: Jacob A Akoh(0000-0002-8366-1984); Katharina JSchumacher (0000-0001-5096-3866).
Author contributions: Akoh JA andSchumacher KJ collected data;Akoh JA: designed study, analyseddata, wrote paper, and criticallyappraised manuscript; SchumacherKJ collected data and wrote aspectsof paper; all authors have read andapproved the final manuscript.
Institutional review boardstatement: The study wasreviewed and approved by theUniversity Hospitals PlymouthNHS Trust Institutional ReviewBoard. Ethics approval andindividual informed consent wasnot required.
Clinical trial registration statement:Not Applicable for thisManuscript.
Informed consent statement: NotApplicable for this Manuscript.
Conflict-of-interest statement: Bothauthors have no conflict ofinterests to declare.
Data sharing statement: There is noadditional data available.
CONSORT 2010 statement: Theauthors have read the CONSORT2010 Statement, and themanuscript was prepared andrevised according to theCONSORT 2010 Statement.
Open-Access: This article is anopen-access article that wasselected by an in-house editor andfully peer-reviewed by externalreviewers. It is distributed in
Jacob A Akoh, Katharina J Schumacher, Department of Surgery, Derriford Hospital, UniversityHospitals Plymouth NHS Trust, Plymouth PL6 8DH, Devon, United Kingdom
Jacob A Akoh, South West Transplant Centre, Derriford Hospital, University HospitalsPlymouth NHS Trust, Plymouth PL6 8DH, Devon, United Kingdom
Corresponding author: Jacob A Akoh, FRCS (Ed), FRCS (Gen Surg), MBBS, AssociateProfessor, Consultant General and Transplant Surgeon, Department of Surgery, DerrifordHospital, University Hospitals Plymouth NHS Trust, Derriford Road, Plymouth PL6 8DH,Devon, United Kingdom. [email protected]
AbstractBACKGROUNDThe key question in living kidney donor assessment is how best to determine thecontribution of each kidney to overall renal function and guide selection of whichkidney to donate, ensuring safety of procedure and good outcome for bothrecipient and donor. It is thought that a length difference > 2 cm may indicatesignificant difference in function and therefore need for measurement ofdifferential function.
AIMTo determine the effect of using kidney length to decide which kidney to donatein a retrospective cohort of potential donors.
METHODSAll 333 potential living kidney donors between January 2009 and August 2018who completed assessment were retrospectively evaluated. Donor assessmentwas performed as per United Kingdom guidelines. Data included age, sex,kidney length (cranio-caudal) obtained by computed tomography/ultrasono-graphy,51-chromium ethylenediamine tetraacetatic acid measured glomerularfiltration rate, mercapto acetyl tri glycine split function and vascular anatomy.There were 48 exclusions due to inadequate data or incomplete investigations.Statistical analysis was performed using Excel pivot tables and GraphPad Prism.Correlation between kidney length and differential function was determined withPearson’s correlation coefficient.
RESULTSOf 285 potential donors included in the study, there were 144 males (mean age49.9 ± 14.75) and 141 females (mean age 51.2 ± 11.23). Overall, the Pearson’scorrelation between differences in length and divided function of kidney pairs
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accordance with the CreativeCommons AttributionNonCommercial (CC BY-NC 4.0)license, which permits others todistribute, remix, adapt, buildupon this work non-commercially,and license their derivative workson different terms, provided theoriginal work is properly cited andthe use is non-commercial. See:http://creativecommons.org/licenses/by-nc/4.0/
Manuscript source: Unsolicitedmanuscript
Received: February 24, 2020Peer-review started: February 24,2020First decision: April 18, 2020Revised: May 19, 2020Accepted: May 21, 2020Article in press: May 21, 2020Published online: June 29, 2020
P-Reviewer: Parajuli S,Sureshkumar KS-Editor: Wang JL-Editor: AE-Editor: Wu YXJ
was 0.1630, P = 0.0058. Of 73 with significant difference (> 10%) in dividedfunction, 18 (24.7%) had no difference in kidney length; 54 (74%) had a differenceof < 2 cm and only one of > 2 cm. Using a length difference of > 1 cm would onlypredict significant difference in divided function in 8/34 (23.5%) of cases. Using adifference of > 2 cm as cut off for performing split function would lead to falsereassurance in 72 patients (6 had > 20% difference in divided function whereas 66had 10%-20% difference).
CONCLUSIONLength difference between kidney pairs alone is not sufficient to replacemeasurement of divided function. This issue requires a randomised controlledtrial to resolve it.
Key words: Kidney transplantation; Living kidney donor assessment; Kidney length;Kidney volume; Differential function; Glomerular filtration rate
©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
Core tip: Selection of which kidney to donate is of critical importance in living kidneydonation. The decision-making process based on divided function and vascular anatomywas used to validate a retrospective “what if” analysis of prospectively reported kidneylength measurements in a cohort of 285 potential donors. This study shows a significantrisk for making wrong/harmful decision (removing the significantly better functioningkidney) if kidney length alone is used for decision making -25% if using 2 cm differenceas cut off. Difference in length between kidney pairs alone is not sufficient to replacemeasurement of divided function.
Citation: Akoh JA, Schumacher KJ. Living kidney donor assessment: Kidney length vsdifferential function. World J Transplant 2020; 10(6): 173-182URL: https://www.wjgnet.com/2220-3230/full/v10/i6/173.htmDOI: https://dx.doi.org/10.5500/wjt.v10.i6.173
INTRODUCTIONThe continuing scarcity of deceased organs coupled with the evidently better resultsassociated with living donor transplantation has focused attention on living donorwellbeing and long-term outcome. The risk of developing end-stage renal disease,cardiovascular disease and increased all-cause mortality in donors[1] demands thatevery effort must be made to eliminate risks in living donors. This is in line with thewell-known principle of “primum non nocere” (“first do no harm”). The goals ofassessment of living kidney donors are to ensure the donor is well enough to gothrough the donation process with minimal or no morbidity and avoidance ofmortality; that the recipient achieves an uncomplicated transplant with a beneficiallong-term outcome. Donor welfare and safety is paramount; therefore, potentialcandidates must have sufficient renal function post donation in order to minimizefuture risks when living with a single kidney. The aim is to retrieve the kidney thatwill allow the donor to preserve the better kidney[2]. Sometimes this means that amulti-artery left kidney is preferable to a right kidney[3].
Determining whether both kidneys contribute equally or significantly differently tooverall function is fundamental to the decision as to which kidney to donate. In thecontext of living kidney donation, this involves accurate determination of the donorglomerular filtration rate (GFR) and ensuring that it is within the recommended rangeas advised by the British Transplantation Society/Renal Association (BTS/RA)Guidelines[2]; and evaluation of renal parenchyma, urinary system and vascularanatomy by means of ultrasonography (US), Computed tomography (CT) or magneticresonance angiography; and only removing the kidney with the lower contributionwhen the divided function is significantly different. The key question is how best todetermine the contribution of each kidney to the overall function. Isotope differentialrenal function is not uniformly performed in all transplant centres, with many relyingon kidney size measurements. Such an approach is supported by the BTS/RA LivingDonor Kidney Transplantation Guidelines (2018)[2] which states that differential
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kidney function, determined by 99mTechnitium dimercaptosuccinic acid (99mTcDMSA)is recommended where there is > 10% variation in kidney size or significant renalanatomical abnormality. It further states that, “A difference in size of 2 cm or moreindicates the possibility of a significant difference in GFR between the two kidneys”.Until the recent BTS/RA Guidelines[2], our centre performed mercapto acetyl triglycine (MAG3) split function and CT and/or US imaging for all patients. This studyaimed to determine the effect of using kidney length to decide which kidney to donatein a retrospective cohort of potential donors. It also studied the correlation betweendifferences in kidney length and split renal function; whether a difference in length of> 2 cm is associated with significant differences in divided function; and whether a <1 cm difference is sufficient evidence that the split renal function is not significantlydifferent between both kidneys.
MATERIALS AND METHODSThis retrospective evaluation of prospectively collected data on potential livingkidney donors was approved by the institutional review board and individualinformed consent was waived. During the period between January 2009 and August2018, all potential living kidney donors who completed the assessment process up toCT angiography were studied whether they proceeded to donation or not. Donorassessment was performed as per United Kingdom guidelines.
Kidney lengthPole to pole (cranio-caudal) length as determined by CT and/or ultrasound scan (US)was documented for each kidney in all prospective donors. Where data from bothmodalities of imaging were available, CT length measurement was used preferentiallyover US imaging to assess length of kidney. Length measured on US scan was onlyused where CT was not reported, not completed, or unavailable as completed atdifferent centres, or where CT reports were not specific to true length of kidneys.Other dimensions of the kidney were not reported in this centre.
Determination of GFR and divided functionEach potential donor underwent 51-chromium ethylenediamine tetraacetatic acid(51Cr-EDTA) scans for GFR measurement (Brochner-Mortensen GFR for 1.73 m2 BSA).To determine the split or divided function, a radioisotope renogram with diureticfollowed by an indirect micturating cystourethrogram combined with a MAG3 scanwas performed with the diuretic administered at the same time as theradiopharmaceutical to ensure good diuresis. Divided function was calculated usinggeometric mean data. Uptake of tracer in both kidneys as well as normal drainage andexcretion bilaterally; evidence of obstruction in either kidney; evidence of reflux onthe indirect micturition cystogram component of the study were determined/reported.
Pre-donation assessment culminated in CT imaging in order to assess lengthmeasurement, renal pathology and vascular anatomy. For potential donors withqualifying GFR, the divided function (if ≤ 20%) in conjunction with the vascularanatomy was used to guide suitability decision for donation and appropriate selectionof which kidney to donate. The renal length was not utilised in the decision makingprocess during the study period.
The list of potential donors and their key data was maintained prospectively on anExcel spreadsheet. Further information was retrieved from the renal computer system– VitalData Clinical Information System (Vitalpulse Limited 1997-2019). Imagingresults were obtained from Insignia Medical Systems [Insight PACS (PictureArchiving and Communication Systems)].
Data collected included donor age, sex, GFR, differential function, US kidneylength, CT kidney length and donated GFR. The differences in length and thedifferential function between left and right kidney pairs were categorised as shown inTable 1 for the purpose of analysis. The donated GFR was calculated as a percentageof the total donor GFR according to the split function of the donated or potentiallydonated kidney[4].
ExclusionsForty eight potential donors were excluded from the study: 31 due to inadequatereporting of imaging (no length measurement was available, either from CT or US); 14due to incomplete investigations (late withdrawal from the process, no CT or noMAG3); and three due to inadequate data from an external unit that performed theassessment.
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Table 1 Categorisation according to different parameters
Length difference Difference in divided function Category
> 2 cm > 20% 4
1.01-2.0 cm 10%-20% 3
0.01-1.0 cm < 10% 2
0 0% 1
Statistical analysisDetailed information on the potential donors were entered in to an Excel database andanalysed using Excel pivot tables. Further statistical analysis was conducted usingGraphPad Prism (GraphPad Software, San Diego, CA, United States). The differencebetween means was tested using the unpaired t-test. Correlation between kidneylength and divided function; and difference in length of kidney pairs versusdifferential function were determined using Pearson’s correlation coefficient. A P <0.05 was regarded as statistically significant.
RESULTSOf the 285 included in the study, there were 144 males (mean age 49.9 ± 14.75) and 141females (mean age 51.2 ± 11.23). The difference between the means of 1.3 [95%confidence interval (CI): −1.7615 to 4.3615; t = 0.8358; u = 283] was not statisticallysignificant (P = 0.4040). The average GFR of female potential donors of 86.85 ± 13.51mL/min was comparable to the 89.63 ± 14.66 mL/min for male potential donors. Thedifference between the means of -2.78 (95%CI from -6.0707 to 0.5073; t = 1.6648; u =283; SED = 1.671) was not statistically significant (P = 0.0971).
The length of kidneys was determined by CT scan in 237 (83.2%) potential donorsand by US alone in 48 (16.8%). Correlation between the cranio-caudal length ofkidneys and their contribution to overall function is shown in Figure 1. Whereas therewas no significant association with the left kidneys (Pearson r = −0.0029 (95%CI:−0.1191 to 0.1133); R2 = 8.687e-006; P = 0.9605), there was a statistically significantcorrelation with the right kidneys [Pearson r = 0.1303 (95%CI: 0.01438 to 0.2429); R2 =0.01699; P = 0.0278].
Correlation between difference in length according to imaging modality anddivided function of kidney pairs is shown in Figure 2. Though weak, CT-measuredkidney length provided a stronger correlation with divided function than US-measured length in this series (R2 = 0.0378 vs 0.0019 respectively). Overall, thecorrelation between differences in length and differential function of kidney pairs was0.1630 (Pearson’s) (95%CI from 0.0477 to 0.2740; R2 = 0.0266; P = 0.0058; Figure 3).
The frequency distribution of the differences in length and divided functionbetween 285 kidney pairs is shown in Figure 4. Fifty seven (20%) donors had nodifference in the length of their kidneys compared to 40 who had no difference in thedivided function of their kidney pairs – x2 = 3.5904, P = 0.058. However, when theproportion of donors with a difference in length above 1 cm (34/285) was comparedwith those with a differential function of 10% or higher (73/285), this was found to behighly statistically significant – x2 = 17.5001, P = 0.00003. Of 34 potential donors with adifference in length of at least 1 cm, seven had differential function of 10%-20% withone over 20% (Table 2). Conversely, of seven patients with > 20% difference infunction, only one had > 2 cm difference in length (2.3 cm; Table 3). In the remainingsix the difference in length ranged from −1 to 0.3. Three of these have donated, threewere declined, one donor has moved from the area.
Of 73 with a significant difference in divided function (categories 3 and 4, Table 2),18 (24.7%) had no difference in kidney length; 54 (74%) had a difference of < 2 cm andonly one of > 2 cm. Only these 73 (25.6%) potential donors would present anydilemma regarding which kidney to select for donation, if at all. Of these, usingdifference in length alone would lead to a false reassurance in 65 as the difference inlength would be < 1.0 cm - only eight would raise the need for measurement ofdifferential function. Similarly, using a difference in length of 2 cm as cut off forperforming split function would lead to false reassurance in 72 patients (6 had > 20%difference in divided function whereas 66 had 10%-20% difference).
The data on number of vessels was missing in two patients. Of the remaining 283,there were single vessels in 207 left kidneys and 200 right kidneys; and there were twoor more vessels in 76 left kidneys and 83 right kidneys. The distribution of multiple
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Figure 1
Figure 1 Correlation of kidney length with divided function (differential function x donor glomerular filtration rate) for 285 kidney pairs.
vessels between left and right kidneys was not statistically different x2 = 0.4286; P =0.5126.
DISCUSSIONThe key findings in this study include the following: Equal sex distribution amongpotential donors whose mean ages and GFRs were comparable; weak correlationbetween difference in length and divided function of kidney pairs (CT-measuredkidney length provided a stronger correlation than US-measured length); theproportion of donors with a difference in length above 1 cm (34/285) was statisticallysignificantly different from those with a differential function of 10% or higher(73/285); and of 73 with a split function greater than 10, 18 (24.7%) had no differencein kidney length; 54 (74%) had a difference of < 2 cm and only one of > 2 cm.Furthermore, using a difference in length of 2 cm as cut off for performing splitfunction would lead to false reassurance in 72 patients (25%).
This study is unique in presenting the results of a retrospective “what if” analysisof prospectively reported kidney length measurements that were not used in thedecision-making process as to which organ to donate. The decisions were made on thebasis of divided function and vascular anatomy. Analysis of a large number ofpotential donors this way provides a useful tool in validating the use of kidney sizealone in making decisions about which kidney to donate. Our study measured kidneylength by CT and US in line with many authors. In a study of 100 living kidneydonors, Ninan and co-workers[5] demonstrated that ultrasonographically measuredbipolar kidney length was more accurate than measurements using plain X-ray,intravenous urography, and renal angiogram. However, they also found that UStends to underestimate while radiological methods overestimated the size of thekidney. Widjaja et al[6] showed there was significant correlation between ultrasoundmeasured length and CT volume (r = 0.74, P < 0.01). Our decision to prefer CT-measured kidney length is supported by Kang and co-workers[7] who showed thatabdominal coronal CT section assessed kidney length more accurately than otherradiological methods.
Our study shows low but significant correlation between differences in lengthbetween kidney pairs and divided function (Figure 3). The distribution of thedifferences in length and divided function was not similar (Figure 4). Kidney size canbe estimated by measuring renal length, renal volume, cortical volume, or renalweight. Kidney length provides a good indication of kidney size[8] and closecorrelation with GFR[9,10]. However, Sanusi et al[11] showed a positive correlationbetween US-determined kidney volume and GFR and suggested that kidney volumewas a better indicator of kidney size in health or renal disease. Though the donorkidney size (length, weight or volume) is now largely accepted as a predictive factorfor recipient allograft function[9,10,12] and as an important predictor of long term donorkidney function[13], volumetric measurement of the donor kidneys provide better
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Figure 2
Figure 2 Correlation between difference in length and divided function of kidney pairs according to imaging modality. CT: Computed tomography; US:Ultrasonography.
correlation with donor kidney function and possibly with outcomes[6,9,12,14]. It is notclear why right kidneys had better (significant) correlation between length anddivided function (Figure 1). We speculate that this may have to do with the shapes ofthe kidneys and that such differences would be eliminated on volume-based analysis.
This study highlights the significant potential for making wrong/harmful decision(removing the significantly better functioning kidney) if kidney length alone is usedfor decision making. A wrong decision would be made possible in 65/285 (23%) if thetrigger for measuring split function were a difference in length of 1 cm; and in 72/285(25%) if 2 cm were used in the presence of significantly different divided function. Iflength difference alone was used all could have been allowed to donate except onewith a difference of 2.3 cm and a differential function of 54. A length differencegreater than 1 cm would only predict a significant difference in divided function in8/34 (23.5%) of cases. By measuring the split function, it would be possible toconsider donation even in potential donors with a greater than 20% differentialfunction. As shown in Table 3, if the concept of donated GFR was considered whenusing kidneys with the smaller contribution to overall function in potential donorswith significant difference in divided function, three or possibly four of these donorswould qualify.
Renal volume is thought to be the most precise predictor of kidney size[15,16]. There issufficient evidence for correlation from CT based volume measurements to split renalfunction, that CT volumetric measurement of kidney size could replace the need forsplit function assessment[17,18]. Halleck et al[17] compared CT-measured renal cortexvolume with DTPA-clearance combined with MAG3-scintigraphy in 167 consecutiveliving kidney donors and showed a strong correlation between CT-measured splitcortex volume and MAG3-measured split renal function (r = 0.93; P < 0.001). Gardanand co-workers[19] determined pre-donation kidney volume for 105 donors using threemethods: Total parenchymal three-dimensional renal volume, total parenchymal renalvolume contouring, and renal cortical volume and tested for correlation of eachvolume with measured GFR. They found that for all methods, total kidney volumewas significantly associated with pre-donation GFR (P < 0.001) and concluded thatcortical volumetry was the best volumetric technique to use as a surrogate toscintigraphy for estimating pre-donation split renal function. Other workers showedthat renal volume calculation using the ellipsoid method (length x antero-posteriordiameter x lateral diameter x π/6) compared favourably with volume determined usingvolumetric software[20]. CT volume can replace nuclear renography for evaluation ofrelative function, as volume has been shown as a surrogate marker for nephronmass[12,21-24].
This study has important limitations. The retrospective analytical nature of thisstudy resulted in a large number of exclusions due to insufficient, unavailable or non-specific data; and acceptance of kidney length measurements determined by CT orUS. It is not clear whether the CT length measurements were all performed in thecoronal plane. During the study period, measurement of kidney length was notregarded as a critical component of CT renal angiography and the quality and detailof the reporting varied between radiologists. There is also the possibility of inter-
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Figure 3
Figure 3 Correlation between differences in length and function of 285 potential donors.
observer variability in reporting kidney lengths. Only measurement for kidney lengthwas available at our centre – other dimensions of the kidney were not reported and itwas therefore not possible to calculate kidney volumes using the ellipsoid formula.Furthermore, data on the body habitus of potential donors was scanty and thereforenot included in the analysis. Despite the foregoing, the findings of this study providejustification for avoiding the use of kidney length alone in making decisions aboutwhich kidney to donate or who needs split function.
In conclusion, length difference between kidney pairs alone is not sufficient toreplace measurement of divided function. It may well be that after excluding caseswith anatomical abnormalities, volume differences may restrict but not totallyeliminate isotopic measurement of divided function in prospective donors. This issueis of vital importance and requires a randomised controlled trial to resolve it.
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Table 2 Length difference vs differential function (see Table 1 for definition of categories)
Differential functioncategoryCategory of length difference
Total1 2 3 4
1 8 29 3 40
2 32 117 22 1 172
3 15 44 7 66
4 3 3 1 7
Total 58 193 32 2 285
Table 3 Seven patients with differential function > 20%
Patient 1 2 3 4 5 6 7
Donor GFR 63 69 69 69 87 93 109
Length difference 0.0 0.0 0.0 2.3 0.3 −0.7 −1.0
MAG3 left (%) 35 61 63 77 61 38 64
MAG3 right (%) 65 39 37 23 39 62 36
ND −30 22 26 54 22 −24 28
“Donated” GFR of kidney with less function (mL/min) 22.1 26.9 25.5 15.9 33.9 35.3 39.2
Donated No Yes No No Yes No1 Yes
1Moved out of the area. GFR: Glomerular filtration rate; MAG3: Mercapto acetyl tri glycine; ND: No difference.
Figure 4
Figure 4 The frequency distribution of the differences in length and divided function between 285 kidney pairs.
ARTICLE HIGHLIGHTSResearch backgroundPotential candidates for kidney donation must have sufficient renal function post donation inorder to minimize future risks when living with a single kidney. Currently most transplant unitsuse split function between the kidney pairs in addition to other factors to make a decision onwhich kidney to donate. However, isotope differential renal function is not uniformly performedin all transplant centres, with many relying on kidney size measurements. Such an approach issupported by the BTS/RA Living Donor Kidney Transplantation Guidelines (2018) which statethat differential kidney function, determined by 99mTechnitium dimercaptosuccinic acid(99mTcDMSA) is recommended where there is > 10% variation in kidney size or significant renalanatomical abnormality. It further states that, “A difference in size of 2 cm or more indicates thepossibility of a significant difference in GFR between the two kidneys”. Hence this study.
Research motivation
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The key question in living kidney donor assessment is how best to determine the contribution ofeach kidney to overall renal function and guide selection of which kidney to donate, ensuringsafety of procedure and good outcome for both recipient and donor. With many units,particularly in the United Kingdom adopting the use of kidney length in the decision makingprocess, there is risk of making wrong or harmful decisions with respect to living kidney donorsunless it can be demonstrated that there is strong correlation between kidney length and splitfunction.
Research objectivesThis study aimed to determine the effect of using kidney length to decide which kidney todonate in a retrospective cohort of potential donors. Realisation of this objective would confirmthe new approach as safe and reliable otherwise alternative approaches would need to beadopted such as use of kidney volume measurements and where indicated isotope differentialrenal function.
Research methodsAll potential living kidney donors who completed assessment over a ten years period wereretrospectively evaluated. Donor assessment was performed as per UK guidelines. This study isunique in presenting the results of a retrospective “what if” analysis of prospectively reportedkidney length measurements that were not used in the decision-making process as to whichorgan to donate. During the study period, decisions were made on the basis of divided functionand vascular anatomy. Analysis of a large number of potential donors in this way provides auseful tool in validating the use of kidney size alone in making decisions about which kidney todonate.
Research resultsThe key findings in this study include the following: Equal sex distribution among potentialdonors whose mean ages and GFRs were comparable; weak correlation between difference inlength and divided function of kidney pairs (CT-measured kidney length provided a strongercorrelation than US-measured length); the proportion of donors with a difference in length above1 cm (34/285) was statistically significantly different from those with a differential function of10% or higher (73/285); and of 73 with a split function greater than 10, 18 (24.7%) had nodifference in kidney length; 54 (74%) had a difference of < 2 cm and only one of > 2 cm.Furthermore, using a difference in length of 2 cm as cut off for performing split function wouldlead to false reassurance in 72 patients (25%).
Research conclusionsThis study highlights the significant potential for making wrong/harmful decision (removingthe significantly better functioning kidney) if kidney length alone is used for decision making. Awrong decision would be made possible in 65/285 (23%) if the trigger for measuring splitfunction were a difference in length of 1 cm; and in 72/285 (25%) if 2 cm were used in thepresence of significantly different divided function. Length difference between kidney pairsalone is not sufficient to replace measurement of divided function. The findings of this studyhave important practical implications for clinical practice in avoiding potential harm to livingkidney donors. This issue requires a randomised controlled trial to resolve it.
Research perspectivesThis study has shown unequivocally that kidney length alone is not sufficient to determinewhich kidney to donate. It raises the question about the role of kidney volume measurement.The literature suggests that renal volume is the most precise predictor of kidney size. It has beenshown by other workers that renal volume calculation using the ellipsoid method (length xantero-posterior diameter x lateral diameter x π/6) compares favourably with volume determinedusing volumetric software. CT based volume measurements of kidneys, (particularly corticalvolumetry) correlates well with split renal function, raising the possibility that CT volumetricmeasurement of kidney size could replace the need for split function assessment. This issue is ofvital importance and requires a randomised controlled trial to resolve whether CT-measuredsplit cortex volume, for example is equivalent to MAG3-measured split renal function.
ACKNOWLEDGEMENTSWe acknowledge the meticulous and accurate records of potential donors maintainedby Mrs Sara L Stacey, Living Donor Co-ordinator, South West Transplant Centre. Weare grateful to Leanne Savage for her help in obtaining data particularly for donorsout of our area.
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