- Email: [email protected]
Native Nephrectomy in Renal Transplant Recipients With Autosomal Dominant Polycystic Kidney Disease
Accepted Manuscript Native Nephrectomy in Renal Transplant Recipients with Autosomal Dominant Polycystic Kidney Disease Magdalena Jankowska, Izabella Kuźmiuk-Glembin, Piotr Skonieczny, Alicja DębskaŚlizień PII:
S0041-1345(18)30286-0
DOI:
10.1016/j.transproceed.2018.02.100
Reference:
TPS 28267
To appear in:
Transplantation Proceedings
Received Date: 28 December 2017 Accepted Date: 6 February 2018
Please cite this article as: Jankowska M, Kuźmiuk-Glembin I, Skonieczny P, Dębska-Ślizień A, Native Nephrectomy in Renal Transplant Recipients with Autosomal Dominant Polycystic Kidney Disease, Transplantation Proceedings (2018), doi: 10.1016/j.transproceed.2018.02.100. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Native Nephrectomy in Renal Transplant Recipients with Autosomal Dominant Polycystic Kidney Disease My manuscript is submitted for the following meeting: XIII Congress of Polish Transplantation
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Society, Warsaw, Oct 12-14, 2017. Magdalena Jankowska, Izabella Kuźmiuk-Glembin, Piotr Skonieczny, Alicja Dębska-Ślizień Department of Nephrology, Transplantology and Internal Medicine,
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Medical University of Gdańsk, Poland
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Email addresses of authors:
Magdalena Jankowska [email protected], Izabella Kuźmiuk-Glembin [email protected] Piotr Skonieczny [email protected] , Alicja Dębska-Ślizień [email protected] Corresponding author: Magdalena Jankowska, Medical University of Gdańsk, 3a M. Skłodowskiej-
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Curie Street, 80-210, Gdańsk, Poland; Email: [email protected], Telephone + 48 58 3492505, Fax + 48 58 3492551
Grant information: The paper was supported by educational grant ST 02-0004/07/122 of Medical
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University of Gdańsk
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Key words: polycystic kidney, nephrectomy, transplantation, dialysis Abbreviations: ADPKD- autosomal dominant polycystic kidney disease; AR- acute rejection; CMV – cytomegalovirus; DGF – delayed graft function; KT – kidney transplantation; KTR – kidney transplant recipient; NKN – native kidney nephrectomy; NODAT – new onset diabetes after transplantation; TKV – total kidney volume Tables: 3 Figures: 1 (color: No)
ACCEPTED MANUSCRIPT Abstract Introduction: Patients with autosomal dominant polycystic kidney disease (ADPKD) represent about 10% of kidney transplant recipients (KTR) and have unique needs as regards acceptance for this procedure. Whether native kidney nephrectomy (NKN) impacts on kidney transplantation (KT)
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outcomes remains a matter of debate, and more data is needed to establish a standard approach to KTR with ADPKD.
of ADPKD recipients in a single institution.
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Method: Retrospective, observational study.
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Aim: To analyze the prevalence, timing, as well as short and long-term outcomes of NKN in a cohort
Results: In years 1993-2016 we identified 162 KTR with ADPKD, out of them, 149 with known NKN status. A high proportion of ADPKD KTR (n = 72) underwent NKN, the majority of which (69.4%) were performed before KT. There was no difference in short-term and long-term transplantation outcomes
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(including death, graft loss, delayed graft function, acute rejection, bacterial and CMV infection and post-transplant diabetes mellitus) between NKN and Non-NKN groups in a median of 98 months of follow-up. However, we found a significant difference in time on a waiting list, which was longer in
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the NKN group versus Non-NKN.
Conclusions: There is a need for a consensus regarding indications and timing for NKN in recipients
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with ADPKD. A systematic acquisition, sharing, and analyzing accessible data on NKN between institutions is an important step towards meeting this need. In our cohort, we found no impact of the NKN procedure on KT impact. However, undergoing NKN importantly prolonged the time on the waiting list.
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Introduction Autosomal dominant polycystic kidney disease (ADPKD) is a most common hereditary disorder of the
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kidney. The continued cysts growth leads to progressive loss of kidney function in affected individuals. At age of 50, approximately 50% of ADPKD patients require renal replacement therapy. ADPKD constitutes the fourth most common cause of end-stage renal disease (ESRD) and renal replacement therapy
worldwide. ADPKD patients have the best life expectancy on dialysis as compared to other primary
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causes of ESRD [1,2]. Also, this group of patients is disproportionally more likely to get enlisted on a transplant list [3]. As a consequence, a high proportion of ADPKD patients (up to 40%) are treated with
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kidney transplantation (KT), mostly from a deceased donor [4]. ADPKD patients represent about 10% of kidney transplant recipients (KTR). Due to many complications of the disease, including the massive size of kidneys, recurrent hematuria, cyst infection, aneurysms, colon diverticulosis, hernias and pain, KTR with ADPKD may have unique needs as regards qualification to the procedure of transplantation. Also,
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the risk of post-transplant complications may importantly differ in this group of patients [5]. One of the controversial issues remains the timing, and indications to native kidney nephrectomy (NKN), as no consensus exists on this medical problem. NKN is considered before transplantation when patients suffer
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from recurrent urinary tract infections, gross hematuria, untreatable loin pain, suspicion of renal carcinoma, or when there is limited space for a placement of the renal graft. NKN after transplantation is
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performed in the case of occurrence of infectious complications, increased intraabdominal pressure or when renal carcinoma is suspected. Nevertheless, different transplant centers show various attitudes towards acceptance of ADPKD candidates to KT. Especially, indication and timing of the NKN and its impact on KT outcome remains a matter of debate, and more data is needed to establish some consensus to this dilemma. The aim of our study was to analyze the prevalence, timing, as well as short and long-term outcomes of NKN in a cohort of ADPKD recipients in a single institution.
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Methods The study design was retrospective – observational. The clinical and research activities being reported are consistent with the “Declaration of Istanbul on Organ Trafficking and Transplant Tourism”. The
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database of patients that underwent KT at our institution between January 1992 and January 2016 was searched to identify individuals with ADPKD as the primary kidney disease. In the next step, medical histories of all identified ADPKD patients were surveyed. Demographic and clinical data, that were
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retrieved from patient’s records, included the incidence and timing of NKN and outcome of KT. Primary outcomes of our interest included death, graft loss, delayed graft function (DGF) and acute rejection
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(AR). Secondary outcomes included serum creatinine (at week 6, and month 12 post-transplantation), new onset diabetes mellitus after transplantation (NODAT), as well as an incidence of bacterial and cytomegalovirus (CMV) infection. Graft loss was defined as a return to dialysis. Delayed graft function was defined as a need for dialysis in the first week post-transplantation. Acute rejection included biopsy-
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proven cases as well as clinically diagnosed and improved after empirical treatment. The time of follow-up was defined as the time until death, graft loss, or November 11, 2017.
analysis.
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Statistical analysis
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Due to the high rate of missing data on indications to the procedure of NKN, they were excluded from
Continuous data are reported as medians and interquartile ranges (IQR). Rates are expressed as a percentage. Comparisons between groups were assessed with the nonparametric U Mann Whitney Test for continuous variables, and χ2 test for nominal variables. Statistical significance was set at the level of P < 0.05. Statistical analyses were performed using statistical software STATISTICA 12, StatSoft. Results
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Between January 1992 and January 2016 we identified 162 KTR with ADPKD. The vast majority of KTs were the deceased donor procedures, and only a single one was from a living donor. 72 patients (44%) underwent NKN (uni- or bilateral), 77 were not nephrectomized (Non-NKN), in 13 cases the status of the
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patients was undetermined and they were excluded from the further analysis. A total of 149 patients were included in the study. Among 72 NKN patients, 36 underwent bilateral nephrectomy. In 50 cases kidney was removed before transplantation, in 16 after transplantation and in 6 one kidney before and
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one after transplantation (‘sandwich’ technique). There was no case of simultaneous nephrectomy and transplantation at our center. In 18 cases KT was performed preemptively and 9 NKN occurred in this
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sub-group, in all cases post-transplantation. In the consecutive clusters of years (between 1992 and 2000, 2001-2005, 2006-2010 and 2011-2015) we did not observe a trend towards a decreased number of NKN procedures. Also, pre-transplantation NKN was the preferred option in each time period (Figure 1). The baseline characteristics of the patients’ cohorts are summarized in Table 1. There were no statistical
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differences between groups NKN and Non-NKN in respect of age, sex, re-transplantation rate or immunosuppressive regimen (regimens with a use of azathioprine and anti-IL2 were more, but not significantly, frequent in the Non-NKN group). Also, there was a trend, although statistically non-
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significant, towards a higher number of re-transplantations in the Non-NKN group. However, a significant difference occurred in time on waiting list. NKN cohort waited for KT longer, a median of 8 months. The
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average time of follow-up was above 8 years. There were no significant differences in analyzed primary outcomes between NKN and Non-NKN groups (Table 2). In comparison between pre- and posttransplantation NKN, again we found no significant differences in primary outcomes, but the time on the waiting list, that was significantly longer in the pre-transplantation NKN cohort (Table 3). Discussion
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In this study, we have described the prevalence and timing of NKN as well as outcomes of KT in a cohort of ADPKD patients from a single institution. In comparison to previously published data, the number of patients in our cohort was among the largest, and with a sound period of follow-up. The need and timing
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of NKN in KTR inflicted with ADPKD is a long controversy and only joint efforts towards the acquisition, sharing and analyzing of accessible data may change this situation and improve patients’ management.
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Prevalence of NKN
It is believed that approximately 40% ADPKD patients with ESRD requiring KT also require NKN [6]. The
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prevalence of NKN in KTR with ADPKD reported in our study was 44% and confirmed this notion. However, our rate of NKN was apparently higher as compared to recent retrospective studies from other individual institutions [7-9]. In general, NKN prevalence in KTR with ADPKD observed in recent studies was lower, ranging from 20% to 30% and most probably reflected a trend towards limiting indications to NKN [10]. Of note, both ours and the literature’s rates of NKNs could be underreported as not all ADPKD
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patients with a history of NKN became KTR and, as such, were not included in the studied cohorts. It seems that our institution’s approach towards surgical treatment of kidney-derived complications of ADPKD is not changing with time because the number of NKN is not decreasing in the consecutive years
Timing of NKN
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as is shown in Figure 1.
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The majority of NKNs in our cohort were performed pre-transplant. What is more, we may observe a trend to an increasing proportion of NKN performed before KT in recent years (Figure 1). There is some justification to such an approach; because, besides a threat of infection, enlarged, polycystic kidneys may cause a compression to the transplanted kidney, contributing to disturbances of urine flow, vascular thrombosis or technical complications during surgery. It is very difficult to contradict such a belief on the basis of our data, as we did not manage to acquire data on indications to NKN. This issue might be reliably settled only in a prospective study assessing total kidney volume (TKV). Our reluctance to
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perform simultaneous NKN and KT seems to be well-founded, in view of the mounting evidence that such a procedure imposes an increased risk of postoperative complications when compared to KT alone and should be discouraged. Especially, the extremely high (up to 100%) need for blood transfusion was
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reported [11]. Existing data points to post-transplant NKN as the most recommended option [8,11]. However, this recommendation is motivated mostly by the center’s experiences with pretransplant immunization resulting from surgery associated blood transfusions or unfavourable outcomes of
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simultaneous NKN and KT. Still, in symptomatic cases, when the surgery is performed to alleviate
symptoms or is necessary as the preparation to KT, pretransplant NKN seems the only possible option.
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Outcomes of KT
Our results are consistent with other, albeit much smaller, series published previously [9,12]. We did not find any difference in KT outcomes between the NKN and Non- NKN groups. However, most previous studies concentrated on perioperative complications associated with NKN or compared various surgery
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techniques with the highest interest in simultaneous NKN and KT, a technique not performed at our center [11,13,14]. While comparing KT outcomes in pre- and post-transplant groups of KTR with ADPKD, we also did not identify any difference. Despite a relatively long time of follow-up, the number of end-
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points in our cohort was low, which precludes sound conclusions. Nevertheless, conclusions on primary outcomes drawn from one larger cohort are consistent with ours [8]. The secondary outcomes analyzed
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in our study, that were also not different, are difficult to compare with other cohorts due to a lack of such data. In fact, we could only confirm our findings as regards DGF and creatinine, that were not different between NKN and Non-NKN cohorts [9]. We found no previous information regarding CMV infection or NODAT rates in NKN and Non-NKN groups. Time on the waiting list NKN significantly extended the time from enlisting to KT. Patients with NKN waited for a median of 8 months longer. As our study was focused mainly on KT outcome, it is difficult to infer about definite
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reasons for such a discrepancy in waiting time. As the difference was maintained while comparing preand post-transplant NKN, it seems that it was the pre-transplant NKN that was responsible for prolonging the waiting time. We may hypothesize, that a need for a surgery ‘per se’, especially while triggered by
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severe complications, such as generalized infection or massive bleeding, when the patient has been already enlisted, most plausibly explains this finding. Nevertheless, the need for blood transfusion and the risk of immunization could not be excluded either, given the limited data. Regardless of what the
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explanation might be, it seems recommendable to perform NKN early, if indicated. The time of
postsurgical recovery could be then employed for procedures necessary before enlisting. This approach,
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together with well-considered indications for NKN, could plausibly counteract the delay of KT that was observed in the NKN group. Limitations
Despite apparent strengths, including a relatively large number of participants and long-time of
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observation, our study has several limitations, mostly inherent to its retrospective design. The most important drawback is the lack of definite indications to NKN and TKV data. Also, in most cases, we have
Conclusions
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no access to the histopathological evaluation of resected kidneys.
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In summary, we would like to underline that there is an urgent need for establishing a consensus regarding indications and timing for NKN in recipients with ADPKD. Systematic acquisition, sharing and analyzing of accessible data on NKN between institutions is an important step towards meeting this need and towards improving management of ADPKD. The analysis of data from our institution showed a high prevalence of NKN, with a preference of pre-transplant procedure. Clinical outcomes of KT were not different between the NKN and Non-NKN groups as well as between pre-and post-transplant NKN. The
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only difference found between groups was time on waiting list favouring the Non-NKN group, and posttransplant NKN group. References Jankowska M, Qureshi AR, Barany P, Heimburger O, Stenvinkel P, Lindholm B: Do metabolic
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derangements in end-stage polycystic kidney disease differ versus other primary kidney diseases? Nephrology (Carlton) 2018;23:31-36.
Mosconi G, Persici E, Cuna V, Pedone M, Tonioli M, Conte D, Ricci A, Feliciangeli G, La Manna G,
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Transplant Proc 2013;45:2635-2640. 3
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Nanni Costa A, Stefoni S: Renal transplant in patients with polycystic disease: the Italian experience.
Jankowska M, Chmielewski M, Lichodziejewska-Niemierko M, Jagodziński P, Rutkowski B:
Peritoneal dialysis as a treatment option in autosomal dominant polycystic kidney disease. Int Urol Nephrol 2015;47:1739-1744.
Spithoven EM, Kramer A, Meijer E, Orskov B, Wanner C, Abad JM, Aresté N, de la Torre RA,
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Caskey F, Couchoud C, Finne P, Heaf J, Hoitsma A, de Meester J, Pascual J, Postorino M, Ravani P, Zurriaga O, Jager KJ, Gansevoort RT, Registry E-E, Consortium E, WGIKD: Renal replacement therapy for
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autosomal dominant polycystic kidney disease (ADPKD) in Europe: prevalence and survival--an analysis of data from the ERA-EDTA Registry. Nephrol Dial Transplant 2014;29 Suppl 4:iv15-25. Jankowska M, Dębska-Ślizień A, Imko-Walczuk B, Piesiaków ML, Lizakowski S, Czarnacka K,
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Rutkowski B: Skin cancer in kidney transplant recipients affected with autosomal dominant polycystic kidney disease. Clin Transplant 2016;30:339-343. 6
Kanaan N, Devuyst O, Pirson Y: Renal transplantation in autosomal dominant polycystic kidney
disease. Nat Rev Nephrol 2014;10:455-465.
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Patel P, Horsfield C, Compton F, Taylor J, Koffman G, Olsburgh J: Native nephrectomy in
transplant patients with autosomal dominant polycystic kidney disease. Ann R Coll Surg Engl 2011;93:391-395. Chebib FT, Prieto M, Jung Y, Irazabal MV, Kremers WK, Dean PG, Rea DJ, Cosio FG, Torres VE, El-
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Zoghby ZM: Native Nephrectomy in Renal Transplant Recipients with Autosomal Dominant Polycystic Kidney Disease. Transplant Direct 2015;1:e43.
García-Rubio JH, Carrasco Valiente J, Campos Hernández JP, Ruiz García J, Márquez López J,
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Regueiro López JC, Cano Castiñeira R, Pendón Ruiz de Mier MV, Requena Tapia MJ: Graft Survival in
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Patients With Polycystic Kidney Disease With Nephrectomy of Native Kidney Pretransplant. Transplant Proc 2015;47:2615-2617. 10
Argyrou C, Moris D, Vernadakis S: Tailoring the 'Perfect Fit' for Renal Transplant Recipients with
End-stage Polycystic Kidney Disease: Indications and Timing of Native Nephrectomy. In Vivo
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2017;31:307-312.
Jean RA, Alexandre M, Yoo PS: Kidney Transplant With and Without Native Nephrectomy for
Polycystic Kidney Disease: Results of the National Inpatient Sample and the Rationale for a 2-Staged
12
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Procedure. J Am Coll Surg 2017; DOI: 10.1016/j.jamcollsurg.2017.11.021 Kirkman MA, van Dellen D, Mehra S, Campbell BA, Tavakoli A, Pararajasingam R, Parrott NR, Riad
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HN, McWilliam L, Augustine T: Native nephrectomy for autosomal dominant polycystic kidney disease: before or after kidney transplantation? BJU Int 2011;108:590-594. 13
Kim JH, Chae SY, Bae HJ, Kim JI, Moon IS, Choi BS, Park CW, Yang CW, Kim YS, Chung BH: Clinical
Outcome of Simultaneous Native Nephrectomy and Kidney Transplantation in Patients With Autosomal Dominant Polycystic Kidney Disease. Transplant Proc 2016;48:840-843. 14
Sulikowski T, Tejchman K, Zietek Z, Rózański J, Domański L, Kamiński M, Sieńko J, Romanowski M,
Nowacki M, Pabisiak K, Kaczmarczyk M, Ciechanowski K, Ciechanowicz A, Ostrowski M: Experience with
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autosomal dominant polycystic kidney disease in patients before and after renal transplantation: a 7-
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year observation. Transplant Proc 2009;41:177-180.
ACCEPTED MANUSCRIPT Figure 1
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Trends in prevalence of native kidney nephrectomies (pre- and post-transplant) between 1992 and 2015
ACCEPTED MANUSCRIPT Table 1 Patients characteristics according to native kidney nephrectomy (NKN) status
All
NKN
(n = 149)
(n = 72)
Non-NKN
P
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Variables
(n = 77)
NKN vs.
Non-NKN
62 (56 -67) 81 (54)
Months on waiting list (IQR)
37 (48)
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Male (%)
62 (57-68)
63 (56-67)
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Age at transplantation, years (IQR)
0.81
44 (57)
0.21
20 (13-35)
23 (15 -38)
15 (9-32)
<0.01
12 (8)
1 (1.3)
11 (14.3)
0.09
4 (2.7)
1 (1.4)
3 (3.8)
0.11
17 (11.4)
5 (6.9)
12 (15.6)
0.05
147 (98)
72 (100)
75 (97.4)
0.41
25 (16.8)
5 (6.9)
20 (2.6)
0.05
111 (74.5)
57 (79.4)
54 (70.1)
0.42
74 (49.6)
34 (45.9)
40 (54.1)
0.25
Tacrolimus (%)
72
41 (56.9)
31 (43.1)
0.12
Target of rapamycine inhibitors (mTOR) (%)
12
7
5
0.29
Re-transplantation (%)
Induction with a-IL2 (%)
Azathioprine (%)
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Steroids (%)
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Induction with ATG/Thymoglobulin (%)
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Mycophenolate mofetil (%) Cyclosporine (%)
ACCEPTED MANUSCRIPT Table 2 Clinical outcome according to native kidney nephrectomy (NKN) status
NKN (n = 72)
Months of follow-up (IQR)
98 (67 – 156) 6 (8.3) 14 (19.7)
99 (69-149)
0.54
7 (9.1)
0.79
9 (11.7)
0.26
23 (31.9)
23 (29.9)
0.82
13 (18.1)
9 (11.7)
0.41
1.29 (1.08-1.63)
1.44 (1.19-1.79)
0.11
1.29 (1.10-1.54)
1.34 (1.25-1.81)
0.14
Posttransplant diabetes mellitus (%)
14 (19.4)
10 (13)
0.12
Bacterial infection (%)
37 (51.4)
31 (40.3)
0.60
8 (11)
10 (13)
0.79
Delayed graft function (%) Acute rejection (%) Creatinine at 6 week post-transplant
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(mg/dL)(IQR)
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Graft loss (%)
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(n = 77)
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Death (%)
Non-NKN
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Variables
Creatinine at 1 year post-transplant (mg/dL)
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(IQR)
CMV infection (%)
ACCEPTED MANUSCRIPT Table 3 Clinical outcome according to time of native kidney nephrectomy (NKN)
Post – transplant NKN
n = 50
n = 16
Months of follow -up (IQR)
98 (69 -162)
98 (68 -148)
0.72
Months on waiting list (IQR)
20 (17-41)
13 (1-19)
0.007
6 (11.5)
Graft loss (%)
3 (5.76)
0
-
2 (12.5)
0.41
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Death (%)
P
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Pre – transplant NKN
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Variables
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Native nephrectomy in ADPKD kidney transplant recipients was analyzed Native nephrectomy extended time from enlisting to kidney transplantation Outcomes of kidney transplantation were not influenced by history of nephrectomy Consensus on indications and timing for nephrectomy in ADPKD should be established
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• • • •
S0041-1345(18)30286-0
DOI:
10.1016/j.transproceed.2018.02.100
Reference:
TPS 28267
To appear in:
Transplantation Proceedings
Received Date: 28 December 2017 Accepted Date: 6 February 2018
Please cite this article as: Jankowska M, Kuźmiuk-Glembin I, Skonieczny P, Dębska-Ślizień A, Native Nephrectomy in Renal Transplant Recipients with Autosomal Dominant Polycystic Kidney Disease, Transplantation Proceedings (2018), doi: 10.1016/j.transproceed.2018.02.100. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Native Nephrectomy in Renal Transplant Recipients with Autosomal Dominant Polycystic Kidney Disease My manuscript is submitted for the following meeting: XIII Congress of Polish Transplantation
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Society, Warsaw, Oct 12-14, 2017. Magdalena Jankowska, Izabella Kuźmiuk-Glembin, Piotr Skonieczny, Alicja Dębska-Ślizień Department of Nephrology, Transplantology and Internal Medicine,
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Medical University of Gdańsk, Poland
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Email addresses of authors:
Magdalena Jankowska [email protected], Izabella Kuźmiuk-Glembin [email protected] Piotr Skonieczny [email protected] , Alicja Dębska-Ślizień [email protected] Corresponding author: Magdalena Jankowska, Medical University of Gdańsk, 3a M. Skłodowskiej-
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Curie Street, 80-210, Gdańsk, Poland; Email: [email protected], Telephone + 48 58 3492505, Fax + 48 58 3492551
Grant information: The paper was supported by educational grant ST 02-0004/07/122 of Medical
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University of Gdańsk
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Key words: polycystic kidney, nephrectomy, transplantation, dialysis Abbreviations: ADPKD- autosomal dominant polycystic kidney disease; AR- acute rejection; CMV – cytomegalovirus; DGF – delayed graft function; KT – kidney transplantation; KTR – kidney transplant recipient; NKN – native kidney nephrectomy; NODAT – new onset diabetes after transplantation; TKV – total kidney volume Tables: 3 Figures: 1 (color: No)
ACCEPTED MANUSCRIPT Abstract Introduction: Patients with autosomal dominant polycystic kidney disease (ADPKD) represent about 10% of kidney transplant recipients (KTR) and have unique needs as regards acceptance for this procedure. Whether native kidney nephrectomy (NKN) impacts on kidney transplantation (KT)
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outcomes remains a matter of debate, and more data is needed to establish a standard approach to KTR with ADPKD.
of ADPKD recipients in a single institution.
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Method: Retrospective, observational study.
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Aim: To analyze the prevalence, timing, as well as short and long-term outcomes of NKN in a cohort
Results: In years 1993-2016 we identified 162 KTR with ADPKD, out of them, 149 with known NKN status. A high proportion of ADPKD KTR (n = 72) underwent NKN, the majority of which (69.4%) were performed before KT. There was no difference in short-term and long-term transplantation outcomes
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(including death, graft loss, delayed graft function, acute rejection, bacterial and CMV infection and post-transplant diabetes mellitus) between NKN and Non-NKN groups in a median of 98 months of follow-up. However, we found a significant difference in time on a waiting list, which was longer in
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the NKN group versus Non-NKN.
Conclusions: There is a need for a consensus regarding indications and timing for NKN in recipients
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with ADPKD. A systematic acquisition, sharing, and analyzing accessible data on NKN between institutions is an important step towards meeting this need. In our cohort, we found no impact of the NKN procedure on KT impact. However, undergoing NKN importantly prolonged the time on the waiting list.
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Introduction Autosomal dominant polycystic kidney disease (ADPKD) is a most common hereditary disorder of the
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kidney. The continued cysts growth leads to progressive loss of kidney function in affected individuals. At age of 50, approximately 50% of ADPKD patients require renal replacement therapy. ADPKD constitutes the fourth most common cause of end-stage renal disease (ESRD) and renal replacement therapy
worldwide. ADPKD patients have the best life expectancy on dialysis as compared to other primary
SC
causes of ESRD [1,2]. Also, this group of patients is disproportionally more likely to get enlisted on a transplant list [3]. As a consequence, a high proportion of ADPKD patients (up to 40%) are treated with
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kidney transplantation (KT), mostly from a deceased donor [4]. ADPKD patients represent about 10% of kidney transplant recipients (KTR). Due to many complications of the disease, including the massive size of kidneys, recurrent hematuria, cyst infection, aneurysms, colon diverticulosis, hernias and pain, KTR with ADPKD may have unique needs as regards qualification to the procedure of transplantation. Also,
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the risk of post-transplant complications may importantly differ in this group of patients [5]. One of the controversial issues remains the timing, and indications to native kidney nephrectomy (NKN), as no consensus exists on this medical problem. NKN is considered before transplantation when patients suffer
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from recurrent urinary tract infections, gross hematuria, untreatable loin pain, suspicion of renal carcinoma, or when there is limited space for a placement of the renal graft. NKN after transplantation is
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performed in the case of occurrence of infectious complications, increased intraabdominal pressure or when renal carcinoma is suspected. Nevertheless, different transplant centers show various attitudes towards acceptance of ADPKD candidates to KT. Especially, indication and timing of the NKN and its impact on KT outcome remains a matter of debate, and more data is needed to establish some consensus to this dilemma. The aim of our study was to analyze the prevalence, timing, as well as short and long-term outcomes of NKN in a cohort of ADPKD recipients in a single institution.
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Methods The study design was retrospective – observational. The clinical and research activities being reported are consistent with the “Declaration of Istanbul on Organ Trafficking and Transplant Tourism”. The
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database of patients that underwent KT at our institution between January 1992 and January 2016 was searched to identify individuals with ADPKD as the primary kidney disease. In the next step, medical histories of all identified ADPKD patients were surveyed. Demographic and clinical data, that were
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retrieved from patient’s records, included the incidence and timing of NKN and outcome of KT. Primary outcomes of our interest included death, graft loss, delayed graft function (DGF) and acute rejection
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(AR). Secondary outcomes included serum creatinine (at week 6, and month 12 post-transplantation), new onset diabetes mellitus after transplantation (NODAT), as well as an incidence of bacterial and cytomegalovirus (CMV) infection. Graft loss was defined as a return to dialysis. Delayed graft function was defined as a need for dialysis in the first week post-transplantation. Acute rejection included biopsy-
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proven cases as well as clinically diagnosed and improved after empirical treatment. The time of follow-up was defined as the time until death, graft loss, or November 11, 2017.
analysis.
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Statistical analysis
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Due to the high rate of missing data on indications to the procedure of NKN, they were excluded from
Continuous data are reported as medians and interquartile ranges (IQR). Rates are expressed as a percentage. Comparisons between groups were assessed with the nonparametric U Mann Whitney Test for continuous variables, and χ2 test for nominal variables. Statistical significance was set at the level of P < 0.05. Statistical analyses were performed using statistical software STATISTICA 12, StatSoft. Results
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Between January 1992 and January 2016 we identified 162 KTR with ADPKD. The vast majority of KTs were the deceased donor procedures, and only a single one was from a living donor. 72 patients (44%) underwent NKN (uni- or bilateral), 77 were not nephrectomized (Non-NKN), in 13 cases the status of the
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patients was undetermined and they were excluded from the further analysis. A total of 149 patients were included in the study. Among 72 NKN patients, 36 underwent bilateral nephrectomy. In 50 cases kidney was removed before transplantation, in 16 after transplantation and in 6 one kidney before and
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one after transplantation (‘sandwich’ technique). There was no case of simultaneous nephrectomy and transplantation at our center. In 18 cases KT was performed preemptively and 9 NKN occurred in this
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sub-group, in all cases post-transplantation. In the consecutive clusters of years (between 1992 and 2000, 2001-2005, 2006-2010 and 2011-2015) we did not observe a trend towards a decreased number of NKN procedures. Also, pre-transplantation NKN was the preferred option in each time period (Figure 1). The baseline characteristics of the patients’ cohorts are summarized in Table 1. There were no statistical
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differences between groups NKN and Non-NKN in respect of age, sex, re-transplantation rate or immunosuppressive regimen (regimens with a use of azathioprine and anti-IL2 were more, but not significantly, frequent in the Non-NKN group). Also, there was a trend, although statistically non-
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significant, towards a higher number of re-transplantations in the Non-NKN group. However, a significant difference occurred in time on waiting list. NKN cohort waited for KT longer, a median of 8 months. The
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average time of follow-up was above 8 years. There were no significant differences in analyzed primary outcomes between NKN and Non-NKN groups (Table 2). In comparison between pre- and posttransplantation NKN, again we found no significant differences in primary outcomes, but the time on the waiting list, that was significantly longer in the pre-transplantation NKN cohort (Table 3). Discussion
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In this study, we have described the prevalence and timing of NKN as well as outcomes of KT in a cohort of ADPKD patients from a single institution. In comparison to previously published data, the number of patients in our cohort was among the largest, and with a sound period of follow-up. The need and timing
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of NKN in KTR inflicted with ADPKD is a long controversy and only joint efforts towards the acquisition, sharing and analyzing of accessible data may change this situation and improve patients’ management.
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Prevalence of NKN
It is believed that approximately 40% ADPKD patients with ESRD requiring KT also require NKN [6]. The
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prevalence of NKN in KTR with ADPKD reported in our study was 44% and confirmed this notion. However, our rate of NKN was apparently higher as compared to recent retrospective studies from other individual institutions [7-9]. In general, NKN prevalence in KTR with ADPKD observed in recent studies was lower, ranging from 20% to 30% and most probably reflected a trend towards limiting indications to NKN [10]. Of note, both ours and the literature’s rates of NKNs could be underreported as not all ADPKD
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patients with a history of NKN became KTR and, as such, were not included in the studied cohorts. It seems that our institution’s approach towards surgical treatment of kidney-derived complications of ADPKD is not changing with time because the number of NKN is not decreasing in the consecutive years
Timing of NKN
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as is shown in Figure 1.
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The majority of NKNs in our cohort were performed pre-transplant. What is more, we may observe a trend to an increasing proportion of NKN performed before KT in recent years (Figure 1). There is some justification to such an approach; because, besides a threat of infection, enlarged, polycystic kidneys may cause a compression to the transplanted kidney, contributing to disturbances of urine flow, vascular thrombosis or technical complications during surgery. It is very difficult to contradict such a belief on the basis of our data, as we did not manage to acquire data on indications to NKN. This issue might be reliably settled only in a prospective study assessing total kidney volume (TKV). Our reluctance to
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perform simultaneous NKN and KT seems to be well-founded, in view of the mounting evidence that such a procedure imposes an increased risk of postoperative complications when compared to KT alone and should be discouraged. Especially, the extremely high (up to 100%) need for blood transfusion was
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reported [11]. Existing data points to post-transplant NKN as the most recommended option [8,11]. However, this recommendation is motivated mostly by the center’s experiences with pretransplant immunization resulting from surgery associated blood transfusions or unfavourable outcomes of
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simultaneous NKN and KT. Still, in symptomatic cases, when the surgery is performed to alleviate
symptoms or is necessary as the preparation to KT, pretransplant NKN seems the only possible option.
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Outcomes of KT
Our results are consistent with other, albeit much smaller, series published previously [9,12]. We did not find any difference in KT outcomes between the NKN and Non- NKN groups. However, most previous studies concentrated on perioperative complications associated with NKN or compared various surgery
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techniques with the highest interest in simultaneous NKN and KT, a technique not performed at our center [11,13,14]. While comparing KT outcomes in pre- and post-transplant groups of KTR with ADPKD, we also did not identify any difference. Despite a relatively long time of follow-up, the number of end-
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points in our cohort was low, which precludes sound conclusions. Nevertheless, conclusions on primary outcomes drawn from one larger cohort are consistent with ours [8]. The secondary outcomes analyzed
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in our study, that were also not different, are difficult to compare with other cohorts due to a lack of such data. In fact, we could only confirm our findings as regards DGF and creatinine, that were not different between NKN and Non-NKN cohorts [9]. We found no previous information regarding CMV infection or NODAT rates in NKN and Non-NKN groups. Time on the waiting list NKN significantly extended the time from enlisting to KT. Patients with NKN waited for a median of 8 months longer. As our study was focused mainly on KT outcome, it is difficult to infer about definite
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reasons for such a discrepancy in waiting time. As the difference was maintained while comparing preand post-transplant NKN, it seems that it was the pre-transplant NKN that was responsible for prolonging the waiting time. We may hypothesize, that a need for a surgery ‘per se’, especially while triggered by
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severe complications, such as generalized infection or massive bleeding, when the patient has been already enlisted, most plausibly explains this finding. Nevertheless, the need for blood transfusion and the risk of immunization could not be excluded either, given the limited data. Regardless of what the
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explanation might be, it seems recommendable to perform NKN early, if indicated. The time of
postsurgical recovery could be then employed for procedures necessary before enlisting. This approach,
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together with well-considered indications for NKN, could plausibly counteract the delay of KT that was observed in the NKN group. Limitations
Despite apparent strengths, including a relatively large number of participants and long-time of
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observation, our study has several limitations, mostly inherent to its retrospective design. The most important drawback is the lack of definite indications to NKN and TKV data. Also, in most cases, we have
Conclusions
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no access to the histopathological evaluation of resected kidneys.
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In summary, we would like to underline that there is an urgent need for establishing a consensus regarding indications and timing for NKN in recipients with ADPKD. Systematic acquisition, sharing and analyzing of accessible data on NKN between institutions is an important step towards meeting this need and towards improving management of ADPKD. The analysis of data from our institution showed a high prevalence of NKN, with a preference of pre-transplant procedure. Clinical outcomes of KT were not different between the NKN and Non-NKN groups as well as between pre-and post-transplant NKN. The
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only difference found between groups was time on waiting list favouring the Non-NKN group, and posttransplant NKN group. References Jankowska M, Qureshi AR, Barany P, Heimburger O, Stenvinkel P, Lindholm B: Do metabolic
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derangements in end-stage polycystic kidney disease differ versus other primary kidney diseases? Nephrology (Carlton) 2018;23:31-36.
Mosconi G, Persici E, Cuna V, Pedone M, Tonioli M, Conte D, Ricci A, Feliciangeli G, La Manna G,
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Transplant Proc 2013;45:2635-2640. 3
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Nanni Costa A, Stefoni S: Renal transplant in patients with polycystic disease: the Italian experience.
Jankowska M, Chmielewski M, Lichodziejewska-Niemierko M, Jagodziński P, Rutkowski B:
Peritoneal dialysis as a treatment option in autosomal dominant polycystic kidney disease. Int Urol Nephrol 2015;47:1739-1744.
Spithoven EM, Kramer A, Meijer E, Orskov B, Wanner C, Abad JM, Aresté N, de la Torre RA,
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Caskey F, Couchoud C, Finne P, Heaf J, Hoitsma A, de Meester J, Pascual J, Postorino M, Ravani P, Zurriaga O, Jager KJ, Gansevoort RT, Registry E-E, Consortium E, WGIKD: Renal replacement therapy for
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autosomal dominant polycystic kidney disease (ADPKD) in Europe: prevalence and survival--an analysis of data from the ERA-EDTA Registry. Nephrol Dial Transplant 2014;29 Suppl 4:iv15-25. Jankowska M, Dębska-Ślizień A, Imko-Walczuk B, Piesiaków ML, Lizakowski S, Czarnacka K,
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Rutkowski B: Skin cancer in kidney transplant recipients affected with autosomal dominant polycystic kidney disease. Clin Transplant 2016;30:339-343. 6
Kanaan N, Devuyst O, Pirson Y: Renal transplantation in autosomal dominant polycystic kidney
disease. Nat Rev Nephrol 2014;10:455-465.
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Patel P, Horsfield C, Compton F, Taylor J, Koffman G, Olsburgh J: Native nephrectomy in
transplant patients with autosomal dominant polycystic kidney disease. Ann R Coll Surg Engl 2011;93:391-395. Chebib FT, Prieto M, Jung Y, Irazabal MV, Kremers WK, Dean PG, Rea DJ, Cosio FG, Torres VE, El-
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Zoghby ZM: Native Nephrectomy in Renal Transplant Recipients with Autosomal Dominant Polycystic Kidney Disease. Transplant Direct 2015;1:e43.
García-Rubio JH, Carrasco Valiente J, Campos Hernández JP, Ruiz García J, Márquez López J,
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Regueiro López JC, Cano Castiñeira R, Pendón Ruiz de Mier MV, Requena Tapia MJ: Graft Survival in
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Patients With Polycystic Kidney Disease With Nephrectomy of Native Kidney Pretransplant. Transplant Proc 2015;47:2615-2617. 10
Argyrou C, Moris D, Vernadakis S: Tailoring the 'Perfect Fit' for Renal Transplant Recipients with
End-stage Polycystic Kidney Disease: Indications and Timing of Native Nephrectomy. In Vivo
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2017;31:307-312.
Jean RA, Alexandre M, Yoo PS: Kidney Transplant With and Without Native Nephrectomy for
Polycystic Kidney Disease: Results of the National Inpatient Sample and the Rationale for a 2-Staged
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Procedure. J Am Coll Surg 2017; DOI: 10.1016/j.jamcollsurg.2017.11.021 Kirkman MA, van Dellen D, Mehra S, Campbell BA, Tavakoli A, Pararajasingam R, Parrott NR, Riad
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HN, McWilliam L, Augustine T: Native nephrectomy for autosomal dominant polycystic kidney disease: before or after kidney transplantation? BJU Int 2011;108:590-594. 13
Kim JH, Chae SY, Bae HJ, Kim JI, Moon IS, Choi BS, Park CW, Yang CW, Kim YS, Chung BH: Clinical
Outcome of Simultaneous Native Nephrectomy and Kidney Transplantation in Patients With Autosomal Dominant Polycystic Kidney Disease. Transplant Proc 2016;48:840-843. 14
Sulikowski T, Tejchman K, Zietek Z, Rózański J, Domański L, Kamiński M, Sieńko J, Romanowski M,
Nowacki M, Pabisiak K, Kaczmarczyk M, Ciechanowski K, Ciechanowicz A, Ostrowski M: Experience with
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autosomal dominant polycystic kidney disease in patients before and after renal transplantation: a 7-
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year observation. Transplant Proc 2009;41:177-180.
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Trends in prevalence of native kidney nephrectomies (pre- and post-transplant) between 1992 and 2015
ACCEPTED MANUSCRIPT Table 1 Patients characteristics according to native kidney nephrectomy (NKN) status
All
NKN
(n = 149)
(n = 72)
Non-NKN
P
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Variables
(n = 77)
NKN vs.
Non-NKN
62 (56 -67) 81 (54)
Months on waiting list (IQR)
37 (48)
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Male (%)
62 (57-68)
63 (56-67)
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Age at transplantation, years (IQR)
0.81
44 (57)
0.21
20 (13-35)
23 (15 -38)
15 (9-32)
<0.01
12 (8)
1 (1.3)
11 (14.3)
0.09
4 (2.7)
1 (1.4)
3 (3.8)
0.11
17 (11.4)
5 (6.9)
12 (15.6)
0.05
147 (98)
72 (100)
75 (97.4)
0.41
25 (16.8)
5 (6.9)
20 (2.6)
0.05
111 (74.5)
57 (79.4)
54 (70.1)
0.42
74 (49.6)
34 (45.9)
40 (54.1)
0.25
Tacrolimus (%)
72
41 (56.9)
31 (43.1)
0.12
Target of rapamycine inhibitors (mTOR) (%)
12
7
5
0.29
Re-transplantation (%)
Induction with a-IL2 (%)
Azathioprine (%)
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Steroids (%)
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Induction with ATG/Thymoglobulin (%)
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Mycophenolate mofetil (%) Cyclosporine (%)
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NKN (n = 72)
Months of follow-up (IQR)
98 (67 – 156) 6 (8.3) 14 (19.7)
99 (69-149)
0.54
7 (9.1)
0.79
9 (11.7)
0.26
23 (31.9)
23 (29.9)
0.82
13 (18.1)
9 (11.7)
0.41
1.29 (1.08-1.63)
1.44 (1.19-1.79)
0.11
1.29 (1.10-1.54)
1.34 (1.25-1.81)
0.14
Posttransplant diabetes mellitus (%)
14 (19.4)
10 (13)
0.12
Bacterial infection (%)
37 (51.4)
31 (40.3)
0.60
8 (11)
10 (13)
0.79
Delayed graft function (%) Acute rejection (%) Creatinine at 6 week post-transplant
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(mg/dL)(IQR)
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Graft loss (%)
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Death (%)
Non-NKN
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Variables
Creatinine at 1 year post-transplant (mg/dL)
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(IQR)
CMV infection (%)
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Post – transplant NKN
n = 50
n = 16
Months of follow -up (IQR)
98 (69 -162)
98 (68 -148)
0.72
Months on waiting list (IQR)
20 (17-41)
13 (1-19)
0.007
6 (11.5)
Graft loss (%)
3 (5.76)
0
-
2 (12.5)
0.41
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Death (%)
P
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Pre – transplant NKN
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Variables
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Native nephrectomy in ADPKD kidney transplant recipients was analyzed Native nephrectomy extended time from enlisting to kidney transplantation Outcomes of kidney transplantation were not influenced by history of nephrectomy Consensus on indications and timing for nephrectomy in ADPKD should be established
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