Aebersold, Franziska

Bird, Patricia

Corsenca, Alf

Hofbauer, Günther

Moch, Holger

Serra, Andreas L.

Weber, Markus

Wüthrich, Rudolf P.

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Case ReportSee http://www.oxfordjournals.org/our_journals/ndtplus/Combined nephrectomy and pre-emptive renal transplantation ina tuberous sclerosis patient with angiomyolipoma, renal carcinomaand life-threatening abdominal haemorrhagesAlf Corsenca1, Franziska Aebersold2, Holger Moch2, Patricia Bird3, Markus Weber4,Gu¨nther Hofbauer5, Rudolf P. Wu¨thrich1 and Andreas L. Serra11Clinic for Nephrology, 2Institute of Surgical Pathology, Department of Pathology, 3Surgical Intensive Care Unit,4Department of Visceral and Transplant Surgery and 5Department of Dermatology, University Hospital, Zurich,SwitzerlandKeywords: abdominal haemorrhage; angiomyolipoma;renal carcinoma; renal transplantation; tuberoussclerosis complexIntroductionTuberous sclerosis complex (TSC) is an autosomaldominant disorder, with an incidence of approximately1 in 6000. It arises from a genetic abnormalityinvolving either the TSC1 gene on chromosome 9, orthe TSC2 gene on chromosome 16. The proteinproduct of the TSC1 gene is hamartin and that ofTSC2 is tuberin. In cells, hamartin and tuberin form acomplex, which inhibits the mammalian target ofrapamycin (mTOR), a central controller of cellgrowth and proliferation [1].Renal angiomyolipomas (AML) occur in 80% ofpatients with TSC. These lesions are composed ofabnormal blood vessels, smooth muscle and fat cellsand they have a tendency to bleed spontaneously,which can lead to life-threatening haemorrhagic shock[2]. Here we report on a patient with TSC sufferingfrom recurrent severe haemorrhage from both kidneysdue to extensive AML formation. Because of massivehaemorrhage the patient was nephrectomized on theright side. One year later, the remaining left kidney wasremoved and a pre-emptive living renal transplantationwas performed at the same time to prevent furtherrenal haemorrhage.CaseA 15-year-old, and till then a healthy young womanwas evaluated in the year 2000 for abdominal painafter an injury which occurred while playing soccer. Onclinical evaluation, small blisters (facial angiofibromas)were noted in her face and urine examination revealedmicrohaematuria. Kidney function was in the normalrange and no proteinuria was detected. Computerizedtomography (CT) scan of the abdomen showedenlargement of both kidneys with diffuse hypodenseareas corresponding to multiple AMLs and isolatedhaematomas. A magnetic resonance imaging (MRI)scan revealed subependymal nodules in the brain. Asthe mother also showed facial angiofibromas and thebrother was known to have diffuse bilateral AMLs inthe kidneys, a clinical diagnosis of TSC was made.A genetic examination (Institute of Human Genetics,University Heidelberg, Germany) of the patient andher mother revealed a novel nonsense mutation(c. 408C>A, Y130X) in the TSC2 gene, confirmingthe clinical diagnosis.At the age of 17 years, the patient presented with alow haemoglobin level and a large spontaneoussubcapsular haematoma was found in the left kidney(Figure 1A). This was treated conservatively but 1 yearlater, spontaneous bleeding recurred in the samekidney, with a drop in the haemoglobin concentrationto 66 g/l. The estimated glomerular filtration rate(GFR) according to the Cockcroft–Gault formula was78ml/min. An abdominal CT scan revealed persistenceof the extensive subcapsular haematoma in the leftkidney. A catheter embolization of the left upper poleartery was performed to stop bleeding. Despite arterialembolization, repeated spontaneous bleeding occurredin the left kidney, necessitating numerous bloodtransfusions to correct anaemia in the following 2 years.Correspondence to: Andreas L. Serra, Clinic for Nephrology,University Hospital, CH-8091 Zurich, Switzerland.Email: andreas.serra@usz.chNephrol Dial Transplant (2007) 22: 3330–3333doi:10.1093/ndt/gfm552Advance Access publication 23 August 2007 The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.For Permissions, please email: journals.permissions@oxfordjournals.orgIn January 2005, bleeding occurred for the first timein the right kidney, causing a profound drop of thehaemoglobin level. The serum creatinine increased to210 mmol/l (MDRD GFR 28ml/min). A transarterialright kidney embolization was performed to stop thebleeding. During embolization extensive retroperito-neal bleeding occurred and the patient was admitted tothe intensive care unit (ICU) for haemodynamicand respiratory stabilization. In the following days,the patient developed an abdominal compartmentsyndrome, sepsis and acute respiratory distress syn-drome (ARDS). Kidney function declined rapidly andthe patient became anuric. After 28 days in the ICU, anabdominal CT scan identified gas in the right-sidedhaematoma. An infection with anaerobic bacteria wassuspected and the haematoma was evacuated and theright kidney removed. Following this intervention,clinical improvement occurred quickly and the patientwas discharged with an estimated GFR (MDRDformula) of 34ml/min. Thirty-three units of packedred blood cells and 14 units of fresh frozen plasma(FFP) were transfused during the stay in the ICU tostabilize cardiovascular function.Kidney function subsequently remained stable andthe patient felt well, except for intermittent left lowerback pain. Since the patient lived in a remote area andsince there was a high risk for a new life-threateningbleeding in the left kidney, a decision was made toremove the remaining left kidney and to perform aliving kidney transplantation from her 50-year-oldhealthy aunt.The post-transplant course was uneventful and renalallograft function was excellent with a standardimmunosuppressive regime consisting of tacrolimus,mycophenolate mofetil and prednisone. An allograftbiopsy performed 3 months after transplantationshowed no signs of rejection or calcineurin inhibitortoxicity. It has been reported that treatment withmTOR inhibitors has a favourable effect on extrarenalmanifestation of TSC. MRI scan of the cortex revealedseveral subependymal nodules and cortical tubers witha maximal diameter of 10mm in our patient.Subependymal giant cell tumours (SGCTs) arise frompre-existing subependymal nodules and can showmassive haemorrhage, rapid growth and malignanttransformation in adult patients. In a preliminaryclinical trial, rapamycin was associated with regressionof SGCT and in one patient, regrowth of SGCT afterinterruption of rapamycin treatment [3]. These promis-ing results encouraged us to switch the immunosup-pression from tacrolimus to rapamycin, in anattempt to prevent neurological complications in ourpatient. An MRI scan of the brain 6 months intotreatment with rapamycin showed no progressionof the subependymal nodules and cortical tubers,suggesting that rapamycin stabilized disease progres-sion. Furthermore, after switching to rapamycin,the MDRD GFR increased from 40 to 48ml/min,which is in line with the known beneficial effect of acalcineurin-free immunosuppression on graft function.Pathological examination of left kidneyMacroscopic examination of the resected left kidneyshowed a replacement of virtually the entire renaltissue by a huge AML (Figure 1B). Careful micro-scopical examination of the kidney (diametre 15 cm)unexpectedly revealed the presence of a renal cellcarcinoma (RCC) within the AML (Figure 2A). ThisRCC was sharply demarcated with a diametre of1.9 cm. It was classified as stage pT1a cN0 cM0,Fuhrman grade III. The tumour consisted of epithe-lioid cells with granular cytoplasm and perinuclearhalo (Figure 2B). Hale’s colloidal iron staining wasA B Fig. 1. Renal Manifestations of TSC. (A) CT scan of the abdomen in the year 2002, which shows large kidneys with multipleangiomyolipomas and a subcapsular haematoma (double asterisk) in the left kidney. (B) Macroscopic view of the left kidney afternephrectomy; co-existence of RCC (arrows) and angiomyolipomatous tissue.Combined nephrectomy and pre-emptive renal transplantation 3331only focally positive. Immunohistochemically, theRCC showed absence of HMB-45 and actin, whereasthe surrounding AML was HMB-45 and actin positive(Figure 2C). The RCC also showed expressionof vimentin and cytokeratin, but was negative for aRCC-specific antibody (RCC marker) and epithelialmembrane antigen (EMA). This unusual histologywas neither characteristic for a clear cell RCC(granular cytoplasm) nor a chromophobe RCC(vimentin expression). Therefore, this RCC could notbe definitively classified.DiscussionHere we report on a case of a young patient with TSCand severe bleeding from AML in both kidneys, whowas nephrectomized and pre-emptively transplantedwith success.Renal pathologies in patients with TSC includeAML, renal cysts and epithelial neoplasms [2]. RenalAML are fat-containing tumours, which are associatedwith a strong risk of haemorrhage due to the presenceof abnormal vessels and pseudoaneurysms. AMLoccur in up to 80% of patients with TSC and are thecause of substantial morbidity. AML associated withTSC tend to be larger, bilateral, multifocal and presentat a younger age compared with sporadic forms [4].They can be diagnosed from a characteristic radi-ological pattern with the demonstration of fatty tissuein CT or MRI scans. A novel mutation, C>Atransversion at c.408 in exon 4 of TSC2 (Y130X) wasfound in the patient and her mother. This nonsensemutation will truncate the gene product of TSC2.Compared with TSC1, mutations in TSC2 are knownto cause a more severe clinical phenotype, which isconsistent with our case [5]. Thus, in our patient, renalAMLs with a diameter of >4 cm were found in bothkidneys, a finding which is very rare or not seen at allin TSC1 patients.The risk of spontaneous bleeding is roughly corre-lated with the size of the AML, though there issubstantial variation [6]. In our patient, the risk for therecurrence of life-threatening bleeding was very high.The remaining left kidney caused repetitive seriousbleeding episodes originating from numerous largeAML, some of them with a diameter >4 cm. AMLmore than 4 cm in diameter are associated with a highrisk for symptomatic bleeding.The therapeutic options to prevent bleeding fromrenal AML are limited. It has been suggested that largeAML need to be surgically reduced or resected, orshould be managed by catheter embolization to deprivethe AML of its blood supply [7]. Bleeding complica-tions from angiographic and surgical interventionsoften necessitate the removal of the entire kidney tocontrol bleeding, as also occurred in our patient.Retroperitoneal bleeding is a well-known complicationof AML, sometimes leading to death (‘Wunderlichsyndrome’). The nephrectomy of both kidneys repre-sents a definitive treatment, but it implies subsequenthaemodialysis treatment.Up to now, 38 renal transplantations have beenreported in TSC patients. In general patient outcomewas good, with functioning allografts in 32 of 38patients with a follow-up of up to 14 years [8]. It hasbeen recommended that renal transplantation shouldbe accompanied by nephrectomy of both kidneys, toremove the risk of malignant transformation andtumour growth associated with immunosuppression.Given the high risk for a recurrence of serious renalbleeding, the psychological burden for the patient andthe family and the availability of a living kidney donor,the decision was made for our patient to remove theremaining left kidney, in combination with a livingrenal transplantation. A B CFig. 2. Histology of renal AML and RCC. (A) The typical histomorphological characteristics of AML with smooth muscle and vessels (H &E stain, original magnification 15). (B) histological presentation of the incidentally diagnosed RCC. Epithelioid tumour cells with granularcytoplasm (chromophobe-like) (original magnification 400). (C) HMB-45 expression of the AML (on the right) and lack of expression in theRCC (on the left) (original magnification 15).3332 A. Corsenca et al.The occurrence of RCC is a rare but well-knowncomplication of TSC, that occurs in 1–2% of patients[2]. However, some of the previously reported RCC intuberous sclerosis were later diagnosed as epithelioidAML, suggesting that the incidence of tuberoussclerosis-associated RCC is lower than some havesuggested. Epithelioid AML represent an unusualsubtype of AML, which is characterized by prolifera-tion of predominantly epithelioid cells. In contrast tothe triphasic (classic) AML, epithelioid AML can showa malignant behaviour. These tumours have a strikingresemblance to RCC and often have high-gradehistological features. Recently, it was shown thatAML are associated with melanosome-associatedprotein (HMB-45) immunoreactivity, and that theHMB-45 expression is useful in differential diagnosisbetween AML and other tumours [9]. In our case,negative HMB-45 immunoreactivity was diagnostic foran RCC. The co-existence of AML and renal epithelialneoplasia is uncommon, with slightly more than 50reported cases in the literature [10]. Pathologicalanalysis of these case reports is difficult, becausemost have been published as clinical cases, lacking adetailed pathological description or exact histologicaltyping. In addition, most of these cases were publishedbefore epithelioid AML was recognized as a separateentity. Few of the cases reported as clear-cell RCCwere later reclassified as epithelioid AML.According to the literature, in sporadic cases as wellas in the setting of tuberous sclerosis, the mostcommon renal cell neoplasm is clear-cell RCC. Inpatients with tuberous sclerosis, there is also a highfrequency of oncocytomas. In a previous study, a largenumber of chromophobe-like RCC was detected inpatients with tuberous sclerosis. Similarly, in previousreported cases in the literature of co-existing AMLsand renal epithelial neoplasia, an unusually highincidence of oncocytomas associated with AMLs isalso seen (12%). The RCC in our patient could not beassigned to one of the 2004 WHO categories. Also inour case, the tumour showed chromophobe-likefeatures. The granular cytoplasm was suggestive of achromophobe-like RCC, but the vimentin expressionexcluded this diagnosis. All previously reported casesof co-existent AMLs and renal cell neoplasia inpatients with tuberous sclerosis have been oncocyto-mas, or were of the clear-cell RCC, chromophobe-likeor unclassified type.The TSC1–TSC2 protein complex tunnels signalsfrom growth factors, cell cycle and nutrients toregulate the activity of the downstream kinasesmTOR, p70S kinase, 4E-BP1 and ribosomal S6proteins. In tumour cells of TSC patients the mTORpathway is aberrantly activated. In a mouse model forTSC, tumour size in the kidneys regressed with thetreatment of the mTOR-specific inhibitor rapamycin[11]. Recent studies in humans demonstratedregression of renal AMLs during the administrationof rapamycin to a patient with TSC and a regrowthwhen rapamycin was withdrawn [12]. Rapamycin istherefore a potential therapeutic agent and clinicaltrials of rapamycin in patients with TSC and AML areongoing. Because of the history of repetitive renalbleeding necessitating nephrectomy, our patient wouldnot have qualified for these clinical trials.In summary, in patients with TSC, large renal AMLcan cause life-threatening abdominal bleeding.Combined nephrectomy and living renal transplanta-tion removes the risk of severe bleeding, and representsdefinitive treatment in our patient.Conflict of interest statement. None declared.References1. Tee AR, Fingar DC, Manning BD, Kwiatkowski DJ,Cantley LC, Blenis J. Tuberous sclerosis complex-1 and -2gene products function together to inhibit mammalian target ofrapamycin (mTOR)-mediated downstream signaling. Proc NatlAcad Sci USA 2002; 99: 13571–135762. Rakowski SK, Winterkorn EB, Paul E, Steele DJ, Halpern EF,Thiele EA. Renal manifestations of tuberous sclerosis complex:incidence, prognosis, and predictive factors. Kidney Int 2006; 70:1777–17823. Franz DN, Leonard J, Tudor C et al. Rapamycin causesregression of astrocytomas in tuberous sclerosis complex. AnnNeurol 2006; 59: 490–4984. Nelson CP, Sanda MG. Contemporary diagnosis and manage-ment of renal angiomyolipoma. J Urol 2002; 168: 1315–13255. Au KS, Williams AT, Roach ES et al. Genotype/phenotypecorrelation in 325 individuals referred for a diagnosis oftuberous sclerosis complex in the United States. Genet Med2007; 9: 88–1006. Yamakado K, Tanaka N, Nakagawa T, Kobayashi S,Yanagawa M, Takeda K. Renal angiomyolipoma: relationshipsbetween tumor size, aneurysm formation, and rupture.Radiology 2002; 225: 78–827. Harabayashi T, Shinohara N, Katano H, Nonomura K,Shimizu T, Koyanagi T. Management of renal angiomyolipomasassociated with tuberous sclerosis complex. J Urol 2004; 171:102–1058. Schillinger F, Montagnac R. Chronic renal failure and itstreatment in tuberous sclerosis. Nephrol Dial Transplant 1996;11: 481–4859. Jungbluth AA, Iversen K, Coplan K et al. Expression ofmelanocyte-associated markers gp-100 and Melan-A/MART-1in angiomyolipomas. An immunohistochemical and rt-PCRanalysis. Virchows Arch 1999; 434: 429–43510. Jimenez RE, Eble JN, Reuter VE et al. Concurrent angiomyo-lipoma and renal cell neoplasia: a study of 36 cases. Mod Pathol2001; 14: 157–16311. Lee L, Sudentas P, Donohue B, Asrican K et al. Efficacy of arapamycin analog (CCI-779) and IFN-gamma in tuberoussclerosis mouse models. Genes Chromosomes Cancer 2005; 42:213–22712. Wienecke R, Fackler I, Linsenmaier U, Mayer K, Licht T,Kretzler M. Antitumoral activity of rapamycin in renalangiomyolipoma associated with tuberous sclerosis complex.Am J Kidney Dis 2006; 48: e27–e29Received for publication: 25.6.07Accepted in revised form: 18.7.07Combined nephrectomy and pre-emptive renal transplantation 3333

Combined nephrectomy and pre-emptive renal transplantation in a tuberous sclerosis patient with angiomyolipoma, renal carcinoma and life-threatening abdominal haemorrhages

Combined nephrectomy and pre-emptive renal transplantation in a tuberous sclerosis patient with angiomyolipoma, renal carcinoma and life-threatening abdominal haemorrhages

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