A Simultaneous Liver-Kidney Transplant Recipient With IgA Nephropathy Limited to Native Kidneys and BK Virus Nephropathy Limited to the Transplant Kidney

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<ul><li><p>Case Report</p><p>ranivetherry,</p><p>nd D</p><p>neysenig</p><p>ephroe kidhol-re</p><p>livertationof theportee bioction</p><p>l Kid</p><p>nt; im</p><p>Sdiskid90gemune system, IgA complexes being shunted directlyto the systemic circulation due to portal hypertension,antheea50soThsimlimpa</p><p>atibudeurheprofprhapa</p><p>creof</p><p>kidne</p><p>1%frone</p><p>ofdescribed in patients who underwent lung, pancreas,bone marrow, or heart transplantation.9 The preva-</p><p>Amd defective liver IgA clearance all may contribute todevelopment of IgAN in patients with liver dis-</p><p>se.5 Pooled biopsy and autopsy data suggest that%-100% of patients with alcoholic cirrhosis haveme glomerular abnormalities on light microscopy.6e light microscopic features of hepatic IgAN areilar to those of primary IgAN. Precise data areited due to the paucity of kidney biopsies in</p><p>tients with cirrhosis.Patients with hepatic IgAN often are asymptom-c. Secondary IgAN usually is thought to be benign,t hematuria and proteinuria in this setting are wellscribed. As with primary IgAN, the most commonine abnormality in secondary IgAN is microscopicmaturia. Nakamoto et al3 reported hematuria oroteinuria in 9.6% and nephrotic syndrome in 1.6%a series of 752 patients with cirrhosis. The risk of</p><p>ogressive chronic kidney disease in hepatic IgANs been reported to be low,6 but clearly some of thesetients progress to chronic kidney failure.5During the last decade, BK virus nephropathy in-asingly has been recognized as an important causedecreased kidney function and transplant loss after</p><p>lence of BK viremia is lower in liver transplantrecipients compared with other solid-organ transplantrecipients, possibly due to the lower level of immuno-suppression used for livers.9</p><p>We report the case of a 60-year-old man whoreceived a simultaneous liver-kidney transplant andexperienced decreasing kidney function. Biopsy speci-mens of the native kidneys showed IgAN, but no BKvirus nephropathy. The transplant kidney biopsy speci-men showed BK virus nephropathy, but no IgAN. Toour knowledge, this is the first reported case of simul-taneous liver-kidney transplantation wherein both func-</p><p>From 1The Transplant Institute and 2Department of Pathology,Beth Israel Deaconess Medical Center, Boston, MA.</p><p>Received June 26, 2012. Accepted in revised form December 17,2012. Originally published online March 13, 2013.</p><p>Address correspondence to Didier A. Mandelbrot, MD, TheTransplant Institute, 110 Francis St, Boston, MA 02215. E-mail:dmandelb@bidmc.harvard.edu</p><p> 2013 by the National Kidney Foundation, Inc.0272-6386/$36.00http://dx.doi.org/10.1053/j.ajkd.2012.12.031A Simultaneous Liver-Kidney TNephropathy Limited to Nat</p><p>Nephropathy Limited toManasa P. Ujire, MD,1 Michael P. Cu</p><p>Douglas W. Hanto, MD, PhD,1 a</p><p>Immunoglobulin A (IgA) deposition in the native kidSecondary IgA nephropathy usually is thought to be bfunction have been reported in this context. BK virus nloss; however, BK virus nephropathy is rare in the nativother organs. We report the case of a patient with alcodisease with hematuria who underwent simultaneouscreased over the course of several weeks posttransplannephropathy, but no IgA deposits. In contrast, biopsyvirus nephropathy. To our knowledge, this is the first retion wherein both the native and transplant kidneys werdifferent pathologies. These findings confirm the predilenative kidneys.Am J Kidney Dis. 62(2):331-334. 2013 by the Nationa</p><p>INDEX WORDS: Simultaneous liver-kidney transplanephropathy.</p><p>econdary immunoglobulin A (IgA) nephropathy(IgAN) is a well-known complication of liver</p><p>ease. Since it was first reported in the 1970s,1,2ney IgA deposition has been described in 33%-</p><p>% of patients with cirrhosis.3,4 Portosystemic anti-n overload, intrinsic abnormalities of the IgA im-J Kidney Dis. 2013;62(2):331-334splant Recipient With IgAKidneys and BK VirusTransplant KidneyMD,1 Isaac E. Stillman, MD,2idier A. Mandelbrot, MD1</p><p>of patients with liver disease is well described.n, but hematuria, proteinuria, and loss of kidneypathy is an important cause of kidney transplant</p><p>neys of patients who underwent transplantation oflated end-stage liver disease and chronic kidney-kidney transplantation. His kidney function de-. Biopsy of the transplant kidney showed BK virusnative kidneys showed IgA deposits, but no BK</p><p>d case of a simultaneous liver-kidney transplanta-psied posttransplantation and showed exclusivelyof BK virus nephropathy for transplant rather than</p><p>ney Foundation, Inc.</p><p>munoglobulin A (IgA) nephropathy; BK virus</p><p>ney transplantation. The prevalence of BK virusphropathy in kidney transplantation ranges from-10%.7 Reported rates of transplant loss rangem 10%-80%.7,8 Although most cases of BK virusphropathy occur in transplant kidneys, a few casesBK virus nephropathy in native kidneys has been331</p></li><li><p>tiopoThlimkid</p><p>whing1.7[MhavUrdysbil1.7rigKibuinca c</p><p>toSChediano</p><p>0.9im</p><p>ng/pretiomo</p><p>52%rigwhthemg15po(Fivirwiim</p><p>mytio5mgtrarec</p><p>incperneu</p><p>tox</p><p>SCeGSe</p><p>(UriOth</p><p>N;tion:8%</p><p>A merulin trans</p><p>a ined</p><p>33</p><p>Ujire et alning native and transplant kidneys were biopsiedsttransplantation and showed different pathologies.is case also illustrates that BK virus nephropathy isited to the transplant kidney and spares the nativeneys.</p><p>CASE REPORTA 60-year-old man with end-stage liver disease from alcoholismo had a serum creatinine (SCr) level of 1.1 mg/dL (correspond-to estimated glomerular filtration rate [eGFR] of 68 mL/min/</p><p>3 m2 using the 4-variable Modification of Diet in Renal DiseaseDRD] Study equation) 2 weeks prior to evaluation was found toe an SCr level of 2.9 mg/dL (eGFR, 22 mL/min/1.73 m2).</p><p>inalysis showed 20-50 red blood cells, many of which weremorphic, and a urine protein-creatinine ratio of 0.4. Total</p><p>irubin level was 2.9 mg/dL, international normalized ratio was, and platelets were 113103/L. Ultrasound showed a 10.8-cmht kidney, 11.0-cm left kidney, and no other abnormalities.dney biopsy was not performed because of the risk of bleeding,t a presumptive diagnosis of IgAN was made. Medical historyluded hypertension, hypercholesterolemia, aortic stenosis, andhronic stable abdominal aortic aneurysm.During the next 4 months, the patients bilirubin level increased6.9 mg/dL, international normalized ratio increased to 2.6, andr level increased to 4.1 mg/dL (eGFR, 15 mL/min/1.73 m2), andunderwent simultaneous liver-kidney transplantation. The imme-te posttransplantation course was uncomplicated, with rapidrmalization of liver function test results and a SCr level nadir of</p><p>mg/dL (eGFR, 86 mL/min/1.73 m2; Table 1). The initialmunosuppressive regimen was tacrolimus (target level 10-15</p><p>Table 1. Laboratory Value</p><p>Pre-tx2 wk</p><p>Post-tx 4-6 wk Post-</p><p>r (mg/dL) 4.1 0.9 2.2FR (mL/min/1.73 m2) 15 86 31rum BK viral loadcopies/mL)</p><p> 500 15,000</p><p>ne RBC count/hpf 20 20 20er findings Presumptive</p><p>diagnosis:IgAN</p><p> Tx Kidney bioBKN, no IgAkidney func52% (Tx), 4(native)a</p><p>bbreviations: BKN, BK virus nephropathy; eGFR, estimated gloA nephropathy; RBC, red blood cells; SCr, serum creatinine; Tx,The relative function of transplant and native kidneys was determ2mL), mycophenolate mofetil (1,000 mg twice a day), anddnisone (tapered to 10 mg/day). One month posttransplanta-n, screening serum BK viral load was 1,200 copies/mL. Adified renal MAG3 (mercaptuacetyltriglycine) scan10 showed</p><p>function from the transplant kidney, 24% function from theht native kidney, and 24% function from the left native kidney,ich suggested substantial recovery of native kidney function. In</p><p>following weeks, the patients SCr level increased to 2.2/dL (eGFR, 31 mL/min/1.73 m2) and BK viral load increased to</p><p>,000 copies/mL. Transplant kidney biopsy performed 6 weekssttransplantation showed mild tubulitis, atypical tubular cellsg 1A), and a positive signal upon immunostaining for simianus 40 (SV40) T antigen (the anti-SV40 antibody cross-reactsth the T antigen of the BK polyomavirus; Fig 1B). Results ofmunofluorescence studies were all negative.The tacrolimus target level was decreased to 5-7 ng/mL, andcophenolate therapy was discontinued 6 weeks posttranplanta-n. However, the BK viral load continued to increase, reaching0,000 copies/mL, so the patient was started on cidofovir, 0.5/kg, weekly. Two months posttransplantation, he developednsaminitis and liver biopsy showed mild cellular rejection. Heeived high-dose steroids and the tacrolimus target level wasreased to 10 ng/mL. Repeat liver biopsy was performed due tosistent transaminitis and showed bile duct proliferation andtrophilic infiltration. This biopsy was consistent with drugicity and possible biliary obstruction, so cidofovir therapy wascontinued. Endoscopic retrograde cholangiopancreatographys performed and a stent was placed in the common bile duct,ich led to subsequent normalization of liver function testults. Gradually, the BK viral load increased to 134,000 and SCrel increased to 4.0 mg/dL (eGFR, 15 mL/min/1.73 m2). Repeat</p><p>Findings Over Time</p><p>10 wk Post-tx 3 mo Post-tx 7 mo Post-tx</p><p>4.0 4.0 2.515 15 26134,000 22,000 500</p><p>2 2 2Tx kidney biopsy:</p><p>BKN, no IgANNative kidney</p><p>biopsy:IgAN, noBKN</p><p>Native kidney biopsy:IgAN, no BKN;Kidney function:42% (Tx), 58%(native)a</p><p>lar filtration rate; hpf, high-powered field; IgAN, immunoglobu-plantation.by renal MAG3 (mercaptuacetyltriglycine) scan.</p><p>Figure 1. Biopsy specimenfrom transplant kidney. (A) Lightmicroscopy (original magnifica-tion,40) shows focal tubulitis andepithelial cells with viral cytopathicchanges (arrow). (B) Positive sim-ian virus 40 staining. (Immunoper-oxidase; original magnification,diswa</p><p>whres</p><p>levs and</p><p>tx</p><p>psy:40.)</p><p>Am J Kidney Dis. 2013;62(2):331-334</p></li><li><p>trashosta</p><p>an</p><p>forperiscoffluloavirpre</p><p>bec(eGgavsigtec</p><p>realittralivclufirwewithaafffinstaagBKprdisrartraemnoph</p><p>Liur</p><p>poshtiotheco</p><p>biohecotiooftheIgtheintratreIgtrakidhisSisoplalivfopamoitsindresna</p><p>Ffrocrooriglomecowricoglo(O</p><p>Am</p><p>Posttransplantation IgA and BK Virus Nephropathynsplant kidney biopsy performed 10 weeks posttransplantationwed increased tubulitis, nuclear atypia, and positive SV40</p><p>ining. By this time, hematuria had resolved and did not recur.The cause of such an increase in SCr level was unclear becauseearly renal scan showed good native kidney function. There-e, 3 months posttransplantation, a native kidney biopsy wasformed. Light microscopy showed mesangial prominence andhemic changes (Fig 2A). Staining for SV40 in extensive amountscortical and medullary tissue gave negative results, and immuno-orescence results were positive for IgA only (Fig 2B). BK virald was 22,000 copies/mL. For ongoing management of BKus nephropathy, tacrolimus was switched to sirolimus anddnisone was tapered to 5 mg daily.</p><p>Seven months posttransplantation, the patients BK viral loadame undetectable and SCr level stabilized around 2.5 mg/dLFR, 26 mL/min/1.73 m2). Repeat native kidney biopsy againe negative results for SV40 immunostaining, but positive</p><p>nal for IgA immunofluorescence. BK viral load remained unde-table at the time of writing this report.</p><p>DISCUSSION</p><p>We believe that our case is unique for severalsons. To our knowledge, this is the only case in the</p><p>erature in which both the functioning native and thensplant kidneys were biopsied after simultaneouser-kidney transplantation and showed mutually ex-sive pathologies. In addition, this appears to be the</p><p>st case in which sequential native kidney biopsiesre performed after liver transplantation in a patientth hepatic IgAN. This case also confirms by biopsyt BK virus nephropathy is a disease more likely toect transplant kidneys than native kidneys. Thisding likely is due to the 2-hit hypothesis, whichtes that both immunosuppression and kidney dam-e related to transplantation surgery are required for</p><p>virus nephropathy to develop.11,12 Immunosup-ession alone, whether used to treat autoimmuneeases or nonkidney solid-organ transplantation,ely causes BK virus nephropathy.12 In addition,nsplantation between identical twins involves isch-ic damage and denervation of the kidney, but doest require immunosuppression, and BK virus ne-ropathy has not been reported in this context.There is no specific treatment for hepatic IgAN.ver transplantation has been reported to improve</p><p>13,14</p><p>igure 2. Biopsy specimenm native kidney. (A) Light mi-scopy (hematoxylin and eosin;</p><p>ginal magnification,40) showsmeruli with mildly expandedsangium together with capillary</p><p>llapse, basement membranenkling, and occasional doublentours. (B) Positive immuno-bulin A immunofluorescence.riginal magnification,40.)inary abnormalities. After liver transplantation, on</p><p>J Kidney Dis. 2013;62(2):331-334rtosystemic shunting disappears and IgA clearanceould improve, which possibly leads to the resolu-n of kidney IgA deposits, but to our knowledge,re are no reported cases with sequential biopsies to</p><p>nfirm this.We did not perform a pretransplantation kidneypsy, but we believe that our patient developed</p><p>patic IgAN before transplant surgery and that thisndition remained apparent in the posttransplanta-n biopsy specimens of the native kidney. The lackIgA deposits in the transplant kidney suggests that</p><p>transplanted liver cured the primary cause ofAN, thereby preventing further IgA deposition in</p><p>transplant kidney. Of note, recurrent IgA depositsthe transplant kidney are extremely common innsplant recipents who receive a kidney alone toat end-stage renal disease caused by primary</p><p>AN.15 The absence of IgA deposits on multiplensplant biopsy specimens after simultaneous liver-ney transplantation in our patient is consistent withhaving secondary IgAN rather than primary IgAN.</p><p>milar to prior reports, our patients hematuria re-lved 2 months after simultaneous liver-kidney trans-ntation, which is consistent with the successfuler transplant having removed the primary stimulusr IgAN. The persistence of IgA deposits in ourtients repeat native kidney biopsy specimen at 7nths posttransplantation suggests that these depos-will either take longer to resolve or will remainefinitely. In addition, despite the relatively rapidolution of hematuria, significant scarring of thetive kidneys remained.Liver transplants are unique among organ trans-nts in that some recipients of simultaneous liver-ney transplantation show substantial recovery of</p><p>tive kidney function after combined organ transplan-ion.16 Our patient provided an unusual opportunitycause we were able to demonstrate recovery of thetive kidneys, and then biopsies of both the natived transplant kidneys were clinically indicated. Inrforming these biopsies, we provide a unique ex-ple in which BK virus nephropathy was present inplakidnatatbenaanpeamly the transplant kidney, but not in the native</p><p>333</p></li><li><p>kidneys, despite prolonged viremia. These findingsconfirm the previously postulated predilection of BKvirus nephropathy for transplant over native kidneys.</p><p>ACKNOWLEDGEMENTSSupport: This work was supported by the Julie Henry Research</p><p>Fund in the Transplant Institute at Beth Israel Deaconess MedicalCenter.</p><p>Financial Disclosure: The authors declare that they have norelevant financial interests.</p><p>REFERENCES1. Callard P, Feldman G, Prandi P, et al. Immune complex type</p><p>glomerulonephritis in cirrhos...</p></li></ul>