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Late Onset of Bladder Urothelial Carcinoma After Kidney Transplantationfor End-Stage Aristolochic Acid Nephropathy: A Case Series With

15-Year Follow-upAnne Lemy, MD,1 Karl M. Wissing, MD, PhD,1 Sandrine Rorive, MD,2 Alexandre Zlotta, MD, PhD,3

Thierry Roumeguere, MD,3 Marie-Carmen Muniz Martinez, MD,1 Christine Decaestecker, PhD,2

Isabelle Salmon, MD, PhD,2 Daniel Abramowicz, MD, PhD,1

Jean-Louis Vanherweghem, MD, PhD,1 and Joëlle Nortier, MD, PhD1

Background: Aristolochic acids are nephrotoxins and predispose to upper-tract urothelial carcinoma.The risk of bladder urothelial carcinoma after kidney transplantation and its relationship to upper-tracturothelial carcinoma is not well defined.

Study Design: Case series.Setting & Participants: Single-center cohort of 38 women given kidney transplants for end-stage

aristolochic acid nephropathy.Outcomes & Measurements: The prevalence of upper urinary tract urothelial carcinoma was

determined by collecting pathological results of specimens obtained by means of bilateral ureteronephrec-tomy. We also established the cumulative incidence of bladder urothelial carcinoma in biopsiesperformed during prospective screening cystoscopies during a 15-year follow-up.

Results: Upper-tract urothelial carcinoma was found in 17 patients with aristolochic acid nephropathy(44.7%). During follow-up, bladder urothelial carcinoma was diagnosed in 15 patients 68 to 169 monthsafter cessation of aristolochic acid exposure (39.5%): 8 urothelial carcinoma in situ, 4 noninvasivelow-grade papillary urothelial carcinoma, and 3 infiltrating urothelial carcinoma. 12 of 17 patients (71%)with a history of upper-tract urothelial carcinoma developed bladder urothelial carcinoma duringfollow-up, whereas this occurred in only 3 of 21 patients (14%) without upper-tract urothelial carcinoma(P � 0.01). Despite local and/or systemic chemotherapy, 3 patients died and 2 radical cystectomieswere performed.

Limitations: Small sample size of this case series.Conclusions: Upper-tract and bladder urothelial carcinoma are dramatic complications in kidney

transplant recipients with aristolochic acid nephropathy, confirming the carcinogenic properties ofaristolochic acids. We identified upper-tract urothelial carcinoma as a potent risk factor for thesubsequent development of bladder urothelial carcinoma after kidney transplantation for aristolochicacid nephropathy. Because this complication may occur years after aristolochic acid discontinuation, wesuggest regular cystoscopies in addition to the bilateral ureteronephrectomy in kidney transplantrecipients with aristolochic acid nephropathy.Am J Kidney Dis 51:471-477. © 2008 by the National Kidney Foundation, Inc.

INDEX WORDS: Aristolochic acid; kidney transplantation; urinary tract carcinoma.

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n the early 1990s, we and others describedrapidly progressive kidney failure secondary

o an interstitial renal fibrosis with extensiveubular atrophy that was suspected to be relatedo an intake of the plant extracts from herbalupplements containing aristolochic acid (AA).1-3

he causative role of these compounds present inristolochia species was confirmed by the dem-nstration of specific AA-DNA adducts formedn the patients’ kidney tissue and by the experi-ental reproduction of similar kidney lesions byA administration in rabbits and rats.4-7 Since

he initial report in 1993, other cases were re-orted worldwide from Japan to the United States,ncluding France, Spain, the United Kingdom,

nd Germany.8 It must be taken into account that

merican Journal of Kidney Diseases, Vol 51, No 3 (March), 2008

lants containing AA are still in use in traditionalastern medicine (China, Taiwan, Japan, andndia), and a substantial number of herbal prod-

From the Departments of 1Nephrology, 2Pathology, andUrology, Erasme Hospital, Université Libre de Bruxelles,russels, Belgium.Received July 23, 2007. Accepted in revised form Novem-

er 14, 2007. Originally published online as doi:0.1053/j.ajkd.2007.11.015 on January 31, 2008.

Address correspondence to Joëlle Nortier, MD, PhD,ephrology Department, Erasme Hospital, Université Libree Bruxelles, 808, route de Lennik, B-1070 Brussels, Bel-ium. E-mail: jnortier@ulb.ac.be© 2008 by the National Kidney Foundation, Inc.0272-6386/08/5103-0017$34.00/0

doi:10.1053/j.ajkd.2007.11.015

: pp 471-477 471

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cts containing Aristolochia species are still avail-ble for sale through the Internet despite safetylerts published by the US Food and Drug Admin-stration and other regulatory agencies from west-rn countries.9 However, AA is a potent carcino-en, and herbal remedies containing species ofhe genus Aristolochia were recently classified asarcinogenic to humans by the Internationalgency for Research on Cancer.10 Not surpris-

ngly, the development of a significant propor-ion of upper-tract urothelial carcinoma (UC)as found in patients with end-stage AA-relatedephropathy, sometimes much later after the on-et of the nephropathy.5,11-13

In the Belgian experience, the onset of theisease was because a popular clinic of aes-hetic medicine had prescribed large amountsf herbal medicine containing AA from 1990o 1992 as part of a weight-reducing regimen.1

ecause most patients from this cluster at-ended our nephrology department, we had thepportunity to follow up a cohort of patientsith AA-related nephropathy since 1992. Con-

idering the worldwide character of the so-alled Chinese herb nephropathy, now rede-ned as AA nephropathy (AAN), and the lateevelopment of urinary tract carcinoma, iteems to us of interest to report on our 15-yearxperience by focusing on the development ofC in our transplant recipients with AAN. The

ims of the study are to determine the preva-ence of upper-tract UC at the time of bilateralreteronephrectomy and the cumulative inci-ence of bladder UC in our transplant recipi-nts with AAN and report our clinical experi-nce in this long-term follow-up.

METHODS

etting andParticipants

One hundred twelve patients with AAN (111 women)ere seen by our Nephrology Department (Erasme Hospital,niversité Libre de Bruxelles, Belgium) from 1992 to 2007.rom this cohort, 54 patients reached end-stage renal dis-ase. These patients with end-stage AAN were selected forhe present study on the basis of the following criteriaefined on March 31, 2007: (1) have a functional kidneyransplant; (2) underwent surgical removal of their nativeidneys and ureters as a prophylactic measure to prevent UCccurrence; this was associated with a concomitant biopsyf the bladder; and (3) accepted regular cystoscopies untilhe end of the follow-up period or, for deceased patients, just

efore death. u

Of 54 patients with end-stage renal disease, 46 received aidney transplant. Two patients were readmitted for hemodi-lysis therapy for chronic graft rejection and 6 chose not toave cystoscopic follow-up. The remaining 38 transplantecipients were enrolled in the present study: 5 died (sys-emic spread of UC, 3 patients; hepatocarcinoma, 1 patient;ardiovascular origin, 1 patient) and 33 had a functionalidney graft on March 31, 2007.Thirty-two of 38 patients are those reported in the refer-

nce publication.5 The 7 remaining patients from this publi-ation could not be included in the present study because 2ied before kidney transplantation and 5 chose not to havehe regular bladder follow-up. Six additional patients in-luded in the present study were transplant recipients whonderwent ureterobinephrectomy after the reference publica-ion.5

ristolochia ExposureAssessment

For all these patients, cumulative doses of ingested Aris-olochia were available from medical prescriptions, as previ-usly detailed and reported.5,14

Except for 1 patient, specific AA-DNA adducts wereetected in tissue samples obtained from native kidneys andreters by use of a phosphorus-32 postlabeling analysisescribed elsewhere.4,5,15

ladder Follow-up

Bladder follow-up consisted of a systematic biopsy ofhe trigonal zone, a splashing of the bladder, washings,nd/or brushings of remnant ureteral stumps. Urineamples were fixed in alcoholic carbowax (6% polyethyl-neglycol 1500 [VWR ref-26604296, Leuven, Belgium]iluted in isopropanol 100). Papanicolaou staining waspplied after spreading out the cells in a monolayerThinprep technique). A total of 422 bladder biopsypecimens obtained from 38 patients was reviewed by 2ndependent pathologists (S.R., I.S.), and discordant re-ults (7.1%) were carefully reexamined by both of themimultaneously. Urothelial tumors were graded and stagedccording to the 2004 World Health Organization Classi-cation of Tumours and the 2002 Union of Internationalancer Classification-Tumor Node Metastasis Classifica-

ion, respectively.16,17 Pathological data related to UC ofhe upper tract were previously reviewed and reported.5

tatistical Analysis

The prevalence of upper-tract UC and cumulative inci-ence of bladder UC were assessed by calculating the ratiof the total number of patients who developed upper-tract orladder UC to the total number of kidney transplant recipi-nts with AAN. Hypothesis testing of categorical data wasone by using Fisher exact test, and of continuous data, bysing Student t-test. Considering the carcinogenicity of AAnd the possible onset of UC, we considered the end of AAngestion as the starting point of the interval of ascertain-ent. Survival free of bladder UC was calculated by using

he Kaplan-Meier method, and hypothesis testing of patientsith and without a history of upper-tract UC was done by

sing the Gehan-Wilcoxon test. All statistical analyses were

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Bladder Cancer in Aristolochic Acid Nephropathy 473

erformed using Stata 8.0 for Windows (StataCorp, Collegetation, TX).

RESULTS

atient Characteristics

All our transplant recipients with AAN wereomen (mean age at time of kidney transplan-

ation, 52.1 � 7.3 years). Four received areemptive kidney transplant from a cadavericonor. The remaining 34 patients were onong-term dialysis therapy during a mean timef 606.3 � 477 days. All 34 patients received aidney transplant from a cadaveric donor ex-ept for 2 patients who received a kidneyransplant from a living related donor. Fourere active smokers. Standard induction andaintenance immunosuppressive regimens (as-

ociation of calcineurin inhibitors, azathio-rine, or mycophenolate mofetil, and corti-oids) were used.

pper-Tract andBladder Carcinoma inransplant RecipientsWithAAN

Abnormal histological results from surgicalpecimens of ureterobinephrectomy and bladderiopsy samples were classified according to theighest grade and stage. Of 38 transplant recipi-nts with AAN, 17 cases of upper-tract UC (renalelvis and/or ureters) were found on ureterobi-ephrectomy specimens (prevalence, 44.7%).hree cases of infiltrating multifocal cancer, 13ases of UC in situ (CIS), and 1 case of noninva-ive papillary UC were diagnosed (Table 1).rothelial dysplasia was detected in 19 of the

Table 1. Histological Staging and Outcomes of UrotUreters and Bladder Biopsy Samples From 38 Tra

No. of Patients Pelvis and/or Ureter

1 T3 High1 T2 pTis1 T1 pTis1 pTis High3 pTis pTis1 pTa High1 pTis Low2 pTis Low1 pTis � pTa High5 pTis —1 — pT31 — Low

1 — Low-grade

emaining 21 patients. All preoperative bladderiopsy specimens were histologically normal.In a previous study, the diagnostic value of

rinary cytological tests performed before sur-ery was assessed. Fresh voided urine samplesnd material provided by ureteral brushings wereompared with histological findings in surgicalpecimens. Specificities of cytological analysesn voided urine and brushing samples were 100%nd 96%, and sensitivities, 17% and 54%, respec-ively.18

The follow-up period resulted in the diagnosisf 15 cases of bladder cancer (cumulative inci-ence, 39.5%) distributed as follows: 12 of 17atients with a history of upper-tract UC experi-nced relapse in the bladder (urothelial CIS asso-iated with a noninvasive low-grade papillaryC of 1 ureteral stump in 1 case), whereas thisccurred in only 3 of 21 patients free of upper-ract UC at the time of ureterobinephrectomy (2ases of noninvasive low-grade papillary UC andcase of infiltrating UC, presented as a nested

ariant; Table 1). The increased incidence ofladder UC in patients with prior upper-tract UCas statistically significant (P � 0.01; Fig 1).

ristolochia Exposure andRisk ofUC inPatientsithAAN

Except for 1 case in which no tissue wasvailable, specific AA-DNA adducts were de-ected in the ureterobinephrectomy specimens ofll patients, proving prior exposure to AA.5 Meanumulative dose of Aristolochia ingested by pa-ients with AAN who developed upper-tract UC

ancers Found in Specimens of Native Kidneys andt Recipients With Aristolochic Acid Nephropathy

dder Outcome

pT1 Death from metastatic cancerDeath from metastatic cancerAlive with no evidence of disease

pT1 Alive with no evidence of diseaseAlive with no evidence of disease

pTa � pTis Alive with no evidence of diseasepTa Death from hepatocarcinomapTa Alive with no evidence of diseasepTa Alive with no evidence of disease

Alive with no evidence of diseaseDeath from metastatic cancer

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as significantly higher compared with patientsith AAN free of cancer at the time of ureteron-

phrectomy (236 � 90.8 [SD] versus 156 �0.3 g; P � 0.01). However, we were not able tohow a significant relationship between cumu-ated dose of AA and the development of bladderC (215 � 90.3 versus 177 � 86.2 g; P � 0.2;ig 2).

utcomesofUC inPatientsWithAAN

Three patients developed an infiltrating upper-ract UC (Table 1). The first patient with T3pper-tract UC received adjuvant chemotherapyonsisting of 6 cycles of paclitaxel and carbopla-in. Eleven months later, a tumor of the rightreteral meatus was discovered (high-grade pT1).espite intravesical instillations of farmorubi-

in, the patient died 73 months after transplanta-ion with metastatic bone involvement. The sec-nd patient with upper-tract UC refused systemichemotherapy. Five months later, urothelial CIS

Figure 2. Mean cumulated doses of Aristolo-hia ingested by patients according to the develop-

ent of upper-tract urothelial carcinoma (UC) and/orladder UC.

as found at the bladder dome and managedith instillations of mitomycin C and farmorubi-

in. The patient died 86 months after transplanta-ion with bone and liver metastases.

The third patient received only 3 cures ofarboplatin and paclitaxel because of neurologi-al side effects. She experienced 3 relapses ofrothelial CIS (87, 103, and 126 months afterransplantation). Despite extensive transurethralladder resections and intravesical mitomycin Cnstillations (40 mg/wk for 4 to 8 weeks, fol-owed by 40 mg/mo for 3 to 6 months), radicalystectomy with ileal conduct diversion was per-ormed. At the conclusion of data assessment theatient was alive with a functioning kidney graft.he remaining patients with noninvasive upper-

ract UC (urothelial CIS or papillary UC) arelive except for 1 patient with hepatitis C virusho died of hepatocarcinoma (Table 1).When the cystoscopy follow-up program de-

ected the presence of bladder urothelial CIS or

Figure 1. Kaplan-Meier curves show proportionsof transplant recipients with aristolochic acid nephrop-athy (AAN) free of bladder urothelial carcinoma (UC)during endoscopic follow-up. UTC�, presence ofupper-tract UC in surgical pieces of ureterobinephrec-tomy; UTC�, absence of upper-tract UC in surgicalsamples of ureterobinephrectomy. Dots, onset of blad-der UC in patients; crosses, patients without bladderUC at the end of the analysis. Abbreviation: CA,cancer.

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Bladder Cancer in Aristolochic Acid Nephropathy 475

oninvasive high-grade papillary UC, the thera-eutic approach consisted of transurethral blad-er resection of the lesion and intravesical instil-ations of mitomycin C (40 to 60 mg/wk) as arst-line therapy (same doses as described). Ba-illus Calmette-Guerin (BCG) instillations couldot be applied in these kidney recipients receiv-ng immunosuppression. Gemcitabine was usedn case of recurrence despite mitomycin C givenrst (2 g/wk for 6 weeks). One patient did notespond to this conservative treatment and neededadical cystectomy with percutaneous nephros-omy. Pathological analysis showed several focif microinvasion in the posterior wall. To date,here is no evidence of metastatic disease and theidney graft is well functioning.The patient with the nested variant of invasive

ladder UC presented with an atypical dilation ofhe renal pelvis of the graft. Opacification throughhe nephrostomy catheter confirmed completebstruction of the ureterovesical junction by annflammatory lesion of the vesical dome. Radicalystectomy was technically unfeasible becausef a walling up of the pelvis and vesicovaginalnd vesicocutaneous fistulae. The patient died 2ears later. Bladder postmortem examinationhowed pT3N1 disease.

DISCUSSION

This study reports an unusually high incidencef bladder UC (39.5%) in transplant recipientsccurring nearly 15 years after the end of expo-ure to AA. We also show that the risk of devel-ping bladder UC is significantly greater in pa-ients who previously developed upper-tract UC.hree risk factors need to be considered in thisarticular population: long-term uremia, chronicmmunosuppression, and prior exposure to AA.ompared with the general population, the rela-

ive risk of developing cancer related to uremia isreater.19-21 In kidney transplant recipients, thencidence of de novo neoplasia after transplanta-ion is reported to range from 4% to 7%, reach-ng 13% to 20% after long-term immunosuppres-ion.22,23 In addition to the most frequent cancersskin, genital tract, and lymphoproliferative dis-ases) observed in recipients of kidney trans-lants, the relative risk of kidney and bladderancers is multiplied by 8 and 5, respectively.24

onsidering kidney cancer, clear-cell carcinoma

s predominant (incidence, 4.8%).24,25 Con- i

ersely, UC of the urinary tract is rare, except inuch toxic nephropathies as analgesic abuse, theo-called Balkan endemic nephropathy, and, fi-ally, AAN.5,25-27

AAs, the main compounds of Aristolochiapecies, are nitrophenanthrene derivatives knownor their potent carcinogenic action in rodents, asell as their mutagenic properties in bacterial

nd mammalian models.28-30 They are activatedy nitroreduction to aristolactams I and II throughytochromes 1A1 and 1A2 and prostaglandin Hynthetase.31,32 These complex metabolic path-ays are believed to generate individual suscep-

ibility to AA nephrotoxicity and seem to have areferential localization in the kidney and uri-ary tract. Moreover, carcinogenicity of AA-NA adducts also was related to the mutation in

odon 61 of proto-oncogene Ha-ras in rodents, asell as mutation of tumor suppressor gene p53 inumans.11,33-35 These specific DNA adducts areot only recognized as markers of prior exposureo AA, but also have an active role in the processf tumorigenesis, as recently detailed in a com-rehensive pathophysiological review.28

The present study confirms our first report of aohort of patients with end-stage AAN whohowed a 46% prevalence of upper-tract UC inelation to the cumulative ingested dose of Aris-olochia.5 However, although the mean cumula-ive dose of Aristolochia tends to be greater inatients with bladder cancer than patients free ofhe disease, the difference does not reach statisti-al significance. This may be caused by theelatively small sample size.

The major therapeutic problem we encoun-ered with these patients is the requirement forong-term immunosuppression because of theiridney transplant. We did not use the currentold-standard therapy of intravesical instillationf BCG for superficial high-grade bladder UCnd/or urothelial CIS to avoid the risk of sys-emic BCG infection. However, this approachight be reconsidered because a recent publica-

ion reported successful treatment of immunosup-ressed patients with intravesical BCG whileeing treated with prophylactic isoniazide.36 Inractice, we thus used intravesical instillations ofitomycin C at the increased dose of 60 mg for

oninvasive bladder UC at risk of progression. Inatients who developed tumor recurrence despite

ntravesical mitomycin C, intravesical gemcitab-

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ne was administered. This last drug was mainlysed intravenously in patients with metastaticladder cancer, but recent data suggested thatntravesical instillations at a dose of 1,000 mgight prevent noninvasive bladder tumor recur-

ences, even in those with BCG-refractory high-rade noninvasive bladder cancer.37 Our experi-nce with gemcitabine has been positive, but itsfficacy is short lived and most treated patientseveloped recurrences after 1 year. Overall, inhe majority of patients with a diagnosis ofladder cancer, the close follow-up helped avoidrogression of the disease and keep a functioningladder and kidney transplant. Two patients hadvolving disease despite adequate management:he patient with the nested variant of infiltratingladder UC who could not undergo surgery andhe patient with metastases from a high-gradeT1 upper-tract UC.In conclusion, the present results emphasize the

ong-term carcinogenic potential of AA. Healthrofessionals should be aware that even 15 yearsfter long-term exposure to AA, individuals are atigh risk of developing upper-tract and/or bladderC. In patients with end-stage AAN, the poor

ensitivity of such cytological tests as upper-tractrushing samples or fresh-voided urine samplesustifies the prophylactic surgical removal of nativeidneys and ureters, as well as regular cystoscopiescheduled every 6 months.

ACKNOWLEDGEMENTSWe thank Drs N. Broeders, L. Ghisdal, and A.D. Hoang

or care of the patients and the nursing and technical staffs ofhe nephrology, urology, and pathology departments for theirontinuous cooperation.

Preliminary results of this study were presented at the “8e

éunion commune de la Société de Néphrologie et de laociété Francophone de Dialyse,” Lille, France, October 3

o 6, 2006, and the Annual Meeting of the American Societyf Nephrology, San Diego, CA, November 14 to 19, 2006.Support: None.Financial Disclosure: None.

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Bladder Cancer in Aristolochic Acid Nephropathy 477

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31. Pezzuto JM, Swanson SM, Mar W, et al: Evaluationf the mutagenic and cytostatic potential of aristolochiccid (3,4-methylene-dioxy-8-methoxy-10-nitrophenanthrene--carboxylic acid) and several of its derivatives. Mutat Res06:447-454, 198832. Stiborova M, Frei E, Wiesler M, Schmeiser HH:

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33. Stiborova M, Frei E, Breuer A, Wiessler M: Evidenceor reductive activation of carcinogenic aristolochic acids byrostaglandin H synthase–(32)P-labeling analysis of DNAdduct formation. Mutat Res 493:149-160, 2001

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ections of tumors induced by aristolochic acid in rats andice. Cancer Lett 59:139-143, 199135. Lord GM, Hollstein M, Arlt VM, et al: DNA adducts

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36. Palou J, Angerri O, Segarra J, et al: Intravesicalacillus Calmette-Guerin for the treatment of superficialladder cancer in renal transplant patients. Transplantation6:1514-1516, 200337. Dalbagni G, Russo P, Sheinfeld J, et al. Phase I trial of

ntravesical gemcitabine in bacillus Calmette-Guerin-refrac-ory transitional-cell carcinoma of the bladder. J Clin Oncol

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