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Review Article *Corresponding author Keith C. Meyer, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Safety of Transplantion Section of , Pulmonary and Critical Care Medicine, USA, Tel: 608-263-6363; 608-263-3035; Fax: 608- 263-3104; Email: for Transplant Recipients Submitted: 11 August 2016 Accepted: 03 October 2016 with End-Stage Renal Failure Published: 05 October 2016 Copyright 1 2 2 Theodore J. McMenomy , Mehgan Holland , Nilto C. de Oliveira , © 2016 Meyer et al. James D. Maloney2, Richard D. Cornwell1, and Keith C. Meyer1* OPEN ACCESS 1Department of Medicine, University of Wisconsin School of Medicine and Public Health, USA Keywords 2Department of , University of Wisconsin School of Medicine and Public Health, • Transplant USA • • Abstract • Renal failure Lung transplant recipients may develop profound renal dysfunction due to Stage IV following successful lung transplantation (LTX). A comprehensive medical record review was performed for all LTX recipients transplanted from 1988 to 2012 to identify patients who subsequently underwent renal transplantation (RTX) for end-stage renal insufficiency. Sixteen LTX recipients underwent subsequent RTX (6 males, 10 females) at an average of 8.3 years (median 8, range 3-15) following LTX. Forced expiratory volume in 1 second (FEV1) obtained 6-12 months following RTX declined by more than 10% versus stable pre-RTX FEV1 values in only 4 recipients, and no recipients experienced new onset of BOS post-RTX. We conclude that RTX should be considered for those LTX recipients who develop chronic, end-stage renal failure, and that RTXcan be performed safely in LTX recipients without significant impact on lung allograft function.

ABBREVIATIONS hemodynamic instability or concomitant use of other drugs that can cause and (CKD). BOS: Bronchiolitis Obliterans Syndrome; CKD: Chronic Other factors such as mellitus or systemic hypertension Kidney Disease; CLAD: Chronic Lung Allograft Dysfunction; COPD: Chronic Obstructive Pulmonary Disease; FEV1: Forced Expiratory Volume in One Second; GFR: Glomerular Filtration (HTN), if present, can also cause or contribute significantly to Rate; HTN: Systemic Hypertension; IPF: Idiopathic Pulmonary progressiveUp to 65% renal of lunginsufficiency. transplant recipients have been reported Fibrosis; LTX: Lung Transplantation; RTX: Renal Transplantation to have at least one episode of within the

INTRODUCTION of patients can develop CKD that progresses to end-stage kidney first weeks following transplant [7,8], and a substantial number Lung transplantation (LTX) is a treatment that is being increasingly used worldwide for end-stage pulmonary disorders end-stage kidney disease was found to be especially increased fordisease pediatric requiring patients who received [8-13].The lung transplants risk of developing versus a and chronic obstructive pulmonary disease (COPD). Lifelong immunosuppressivesuch as medications(CF), idiopathic are pulmonary required afterfibrosis LTX (IPF), to significantly lower risk for heart or liver recipients [10]. Mason prevent acute rejection and chronic lung allograft dysfunction et al., [12] reported a prevalence of renal failure requiring (CLAD)due tobronchiolitis obliterans syndrome (BOS) or post-transplant chronic kidney injury has been associated with of 13% in a lung transplant cohort of 425 patients, and other forms of CLAD that may lead to progressive loss of increased mortality after LTX [13-15]. A CKD prevalence in immunosuppressive regimens usually include a calcineurin allograft function over time and recipient death [1,2]. Typical lung transplant recipients of 15.8% at 5 years using a definition of glomerular filtration rate (GFR) <30 ml/min has been can have adverse effects on renal tubular function and lead to inhibitor ( or cyclosporine A), and these agents reported, and treatment of end-stage renal disease with renal transplantation was associated with significantly improved survival versus dialysis [16]. Risk factors for developing post-LTX nephrotoxicitynephrotoxicity, ofwhich calcineurin is a well-recognized inhibitors can side be effect accentuated of chronic by calcineurin inhibitor administration [3-6]. Additionally, the renal insufficiency other than an episode of acute kidney injury include renal function impairment at the time of transplant, Cite this article: McMenomy TJ, Holland M, de Oliveira NC, Maloney JD, Cornwell RD, et al. (2016) Safety of Kidney Transplantion for Lung Transplant Re- cipients with End-Stage Renal Failure. JSM Renal Med 1(1): 1004. Meyer et al. (2016) Email:

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higher age, pre-transplant systemic or , of the 16renal transplant recipients had >10% (12%, 13%, 15%, Transplant centers must determine whether patients who and low center transplant volume [4,8,11-13,15]. ofand RTX 43%) yet decline survived in FEV1for 3 followingmore years RTX, following and the RTX recipient (Table with 1). develop CKD that requires renal replacement therapy should be the 43% decline in FEV1 had established Stage 2 BOS at the time the number candidates being placed on the kidney transplant Additionally, 3 other recipients with Stage 2 BOS and 2 recipients considered as candidates for renal transplantation (RTX), and decline in FEV1. waiting list for CKD that develops after successful LTX is with Stage 1 BOS at the time of RTX had no significant post-RTX No major complications of RTX occurred in any patient with of RTX on the function of the transplanted lung allograft(s) and the exception of one patient who had immediate thrombosis of the thegradually risk of increasing calcineurin [6,17,18]. inhibitor-associated Given the potential recurrent consequences injury to transplanted kidney that required kidney retransplantation 5 days later. Following RTX all patients received the transplanted clinical course kidney, of our questions center’s remain lung transplant regarding recipientsthe safety whoof RTX subsequently in lung transplant received recipients. kidney Therefore,transplants we for examined chronic with prednisone, mycophenolate, and a calcineurin inhibitor renal failure at our center to evaluate the impact of RTX on lung (cyclosporine in 5, tacrolimus in 11). All recipients survived allograft function when performed following previous LTX. delayedbeyond one recurrence year post-RTX of end-stage (Table 1), renal and failure serum requiringcreatinine renal at 1 replacementyear post-RTX therapy was 1.30 or kidney± 0.10 retransplantation.mg/dL. None of the patients had METHODS This investigation was approved by the University of DISCUSSION Wisconsin Human Subjects Committee (approval number Risk factors for developing CKD following solid include the pre-transplant level of kidney performed for all lung transplant recipients who underwent LTX M-2009-1308). A comprehensive medical record review was the outcomes of patients who underwent RTX for end-stage function, and reliance on serum only as a measure at the University of Wisconsin from 1988 to 2012to evaluate of renal status may overestimate renal function [19]. Other risk factors include advancing age, female gender, diabetes mellitus, renal insufficiency that developed following successful LTX. We systemic hypertension, peri-operative renal insults, requirement whosought received to determine LTX and safety subsequently and efficacy developed of RTX renal in this failure patient and for prolonged , renal vasoconstriction cohort and to identify significant complications. Sixteen patients caused by calcineurin inhibitor exposure, and a pulmonary diagnosis other than COPD [19,20]. underwent RTX at our institution were identified (6 males, 10 of pulmonary function over time before and after RTX and renal Although RTX did not appear to have a significant deleterious functionfemales). followingCharts were successful then analyzed RTX. Secondaryfor the primary data end-points that were recipients.effect on lung This function lack of improvement for the majority may of be our consistent patients, with lung a priorfunction study also that did showed not improve that the significantlynegative effects in anyof chronic of our renal RTX failure requiring hemodialysis on lung function are not fully andanalyzed survival included and ultimatecomorbidities, cause time of death to RTX, (if deceased).whether BOS Forced was expiratorypresent at the volume time inof oneRTX, second initiation (FEV1) of hemodialysis was used as prior the primary to RTX, occurred at the time of RTX was an acute thrombus inreversed one patient following that RTX necessitated [21]. The only emergent serious retransplantation.complication that was used as the primary measure of change in renal function. measure of lung function and BOS stage, and serum creatinine Adequate renal function was sustained despite post-operative RESULTS maintenance immunosuppression that included a calcineurin inhibitor in all renal transplant recipients. The cause of death for those patients who expired was not related to their kidney Age at time of LTX (Table 1) ranged from 26 to 63 years (mean safely in lung transplant recipients and should be considered ± SEM = 45 ± 3.4 yrs). Indications for LTX were cystic fibrosis transplant. These findings suggest that RTX can be performed (N=6), emphysema (N=9), and radiation fibrosis (N=1). All for those who develop renal failure. This is consistent with patients received post-LTX immunosuppresion with prednisone, a calcineurin inhibitor (cyclosporinein 8, tacrolimusin 8), and previous reports [22-24], although the reports authored by either (N=7) or mycophenolate (N=9). recipient and renal allograft survival and did not report whether Number of days on the renal transplant waiting list ranged from Lonzo et al., [23] and Tarnow et al., [24] focused entirely on Time from LTX to RTX ranged from 3 to 15 years (8.3 ± 0.8 yrs). their lung recipients experienced any significant impact on lung Conditions0-1278 (mean associated 385 and with median renal 191). dysfunction Type of RTXthat waswere deceased present inallograft patients function with end-stage once recipients lung disease had stabilized has been followingconsidered RTX. by donor (N=9), living-related (N=4), or living-unrelated (N=3). Additionally, although the presence of advanced kidney disease dual transplantations (simultaneously performed lung and RTX) prior to RTX.RTX included diabetes mellitus (N=8), HTN (N=12), and most centers to be a contraindication to LTX, reports of successful polycystic kidney disease (N=1). Ten patients received dialysis exist [22,25-27], and further investigation into the risks and benefitOne of obvious such operations limitation is warranted. of our study is the small number Forced expiratory volume in 1 second (FEV1) obtained 6-12 months following renal transplant (2.26 ± 0.32 L) changed little versus pre-RTX values (2.37 ± 0.36 L) for the entire group; only 4 reviewed of LTX recipients who underwent RTX (n=16). While JSM Renal Med 1(1): 1004 (2016) 2/5 Meyer et al. (2016) Email:

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Cause of death Metastatic carci noma to stomach & liver Bacterial Viral Lymphoproliferative disorder Lung Survival post-LTX (years) post-LTX Survival

4 -- 12 15 13 16 11 11 13 17

9.7 16.5 19.5 22.5 19.5 12.5 10.5 Post-RTX survival (years) survival Post-RTX

5 6 3 1 3 3 6 4 -- 11

1.5 9.5 2.7 6.5 3.5 12.5 11.5 Status

A A A A A A A A A D D D D D -- D D

ery to 1 year post-RTX) year 1 to ery

- Change in Cr (post-RTX recov (post-RTX Cr in Change 0 0 0.7 0.1 0.3 0.3 0.4 0.4 0.1 0.1 0.1 0.2 0.3

0.85 0.26 0.03

0.3±0.1

(gm/dl) Post-RTX Cr (at 1 year) 1 (at Cr Post-RTX 1.7 1.3 1.6 1.2 1.9 1.6 0.9 1.3 1.0 1.2 0.8 1.4 0.9

1.45 1.46 1.33

1.3±0.1

(gm/dl) Post-RTX Cr (early) Cr Post-RTX 1.0 1.2 0.6 1.2 1.3 1.3 0.9 1.5 1.2 0.9 1.3 0.9 1.0 0.7 1.2 0.6

1.1±0.1 ΔFEV1>10%?

--

No No No No No No No No No No No No Yes Yes Yes Yes

6-12 months post-RTX (Liters) post-RTX months 6-12 FEV1 post-RTX performed performed post-RTX FEV1 1.68 3.27 1.97 4.42 2.22 2.07 1.17 2.33 2.21 0.98 0.89 3.22 2.67 1.16 5.07 0.79

2.26±0.32 FEV1 pre-RTX (Liters) pre-RTX FEV1 1.53 3.29 5.18 2.43 1.89 1.77 2.05 2.23 2.55 0.91 0.94 3.67 2.37 0.93 5.29 0.84

2.37±0.36 Type of RTX (Source) RTX of Type

--

LR LR LR LR DD DD DD DD DD DD DD DD DD LUR LUR LUR BOS Stage at RTX at Stage BOS 0 0 0 0 0 2 2 0 0 2 1 0 1 2 0 0

-- Dialysis?

--

No No No No No No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Years to RTX (post-LTX) RTX to Years 9 3 5 8 8 7 6 7 8 7 7 15 10 10 10 13

8.3±0.8y DM (Pre/Post) DM

--

No No No No No No No No Yes Yes Yes Yes Yes Yes Yes Yes Gender

F F F F F F F F F F M M M M M M Age (at time of LTX) in years in LTX) of time (at Age 55 39 26 40 42 56 61 30 45 51 29 28 55 63 61 38

45±3.4 LTX Type LTX --

BIL BIL BIL BIL BIL SLL SLL BIL BIL BIL BIL BIL SLR SLL SLL BIL LTX Indication LTX -- E CF PF CF E E E CF E E CF CF E E E CF

Subject data. Subject # Subject 1 7 8 9 2 3 4 5 6 16 13 14 15 10 12 11 Abbreviations: A: Alive; BIL: Bilateral Lung Transplant; BOS: Bronchiolitis Obliterans Syndrome; CF: Cystic Fibrosis; Cr: Serum Creatinine; D: Dead; DD: Deceased Donor; DM: Emphysema; Diabetes FEV1: Forced Mellitus; Expiratory Volume E: In One Second; LR: Living-Related; LTX: Lung Transplant LUR: Living-Unrelated; NA: Not Applicable; PF: ; RTX: Renal Transplant; SEM: Standard Error Of The Mean; SLL: Left Single Lung Transplant; SLR: Right Transplant Mean ± SEM Table 1:

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Central Bringing Excellence in Open Access calcineurin inhibitor toxicity was the presumed major cause of composition. changes consistent with calcineurin inhibitor toxicity were not collection, statistical analysis, data interpretation, and manuscript renal failure in all of the patients in our study, renal pathologic Dr. Maloney: contributed to the study design, data collection, routinely verified by or autopsy. Eight of 16 recipients which could have been independent causes of renal failure rather data interpretation, and manusc ript composition. thanhad diabetes merely contributing mellitus, and factors. many Atalso least had one systemic study that hypertension, attempted to distinguish renal failure etiologies via biopsy in lung transplant Dr. Cornwell: contributed to the study data collection, data recipients showed that only 35.5% showed predominant features interpretation, and manuscript composition. manuscriptDr. Meyer: composition. conceived of and contributed to the study design, As the number of patients who undergo LTX gradually data collection, statistical analysis, data interpretation, and of chronic calcineurin inhibitor nephrotoxicity [28]. Funding Sources calcineurinincreases, more inhibitor-based recipients are chronic likely immunosuppression.to develop severe CKD Given that requires renal replacement therapy, especially when receiving Fund.This research was supported, in part, by unrestricted funds with hemodialysis (especially in already immunosuppressed provided by the George and Julie Mosher Pulmonary Research the significant costs, inconvenience, and complications associated REFERENCES 1. lungpatients), transplant RTX recipients will remain can do an very attractive well if RTX option is performed and can significantly improve quality of life. Our experience suggests that Verleden GM, Raghu G, Meyer KC, Glanville AR, Corris P. A new classification system for chronic lung allograft dysfunction. J Heart therapies. for delayed-onset, severe CKD that is unresponsive to medical Lung Transplant. 2014; 33: 127-133. ACKNOWLEDGMENTS 2. Meyer KC. Bronchiolitis obliterans syndrome. Curr Respir Care Rep. 3. 2012; 1: 147-156. æ ørtuft

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Dr. De Oliveira: contributed to the study design, data George TJ, Arnaoutakis GJ, Beaty CA, Pipeling MR, Merlo CA, Conte JV, et JSM Renal Med 1(1): 1004 (2016) 4/5 Meyer et al. (2016) Email:

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Cite this article McMenomy TJ, Holland M, de Oliveira NC, Maloney JD, Cornwell RD, et al. (2016) Safety of Kidney Transplantion for Lung Transplant Recipients with End-Stage Renal Failure. JSM Renal Med 1(1): 1004.

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