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International Journal of Urology (2014) 21, 797–802

doi: 10.1111/iju.12455

Original Article: Clinical Investigation

Impact of graft nephrectomy on outcomes of second kidney transplantation Saâd Ed-Dine Fadli,1 Vincent Pernin,2 Erika Nogue,3 Valérie Macioce,3 Marie-Christine Picot,3,4 Annie Ramounau-Pigot,5 Valérie Garrigue,2 François Iborra,1 Georges Mourad2 and Rodolphe Thuret1 Departments of 1Urology and Transplantation, 2Nephrology and 5Immunology, University Hospital of Montpellier, 3Unit of Clinical Research and Epidemiology, Department of Medical Information, CHU Montpellier, and 4Clinical Investigation Center, Montpellier, France

Abbreviations & Acronyms CMV = cytomegalovirus CRP = C-reactive protein DGF = delayed graft function DSA = donor-specific antibodies ESRD = end-stage renal disease GFR = glomerular filtration rate HLA = human leukocyte antigen IQR = interquartile range LCT = microlymphocytotoxicity MDRD = modified diet and renal disease MHC = major histocompatibility complex MMF = mycophenolate mofetil MP = methylprednisolone MPA = mycophenolic acid PNF = primary non-function PRA = panel reactive antibody SD = standard deviation Correspondence: Saâd Ed-Dine Fadli M.D., Department of Urology and Transplantation, Lapeyronie University Hospital, 371 avenue du Doyen Gaston Giraud, 34295 Montpellier cedex 5, France. Email: [email protected] Received 6 September 2013; accepted 7 March 2014. Online publication 13 April 2014

© 2014 The Japanese Urological Association

Objectives: To determine the impact of renal graft nephrectomy on second kidney transplantation survival. Methods: We carried out a retrospective single-center study by analyzing cases performed from January 2000 to December 2011. Retransplanted patients who underwent previous allograft nephrectomy more than 3 months post-transplantation (group 1) were compared with those who did not (group 2) in terms of graft survival, incidences of acute rejection and delayed graft function. Multivariate Cox proportional hazard models were used to assess risk factors of graft loss after retransplantation. Results: Overall, 146 patients were analyzed, including 52 (35.6%) in group 1 and 94 (64.4%) in group 2. Group 1 patients presented a significantly shorter first graft survival (0.8 vs 8.6 years, P < 0.001) and more anti-class I antibodies (90.5% vs 74.2%, P = 0.03). A total of 10 patients (19%) in group 1 and 16 patients (17%) in group 2 had at least one acute rejection episode (P = 0.74). Delayed graft function was observed in 13 patients (25%) in group 1 and 17 patients (18%) in group 2 (P = 0.32). Graft survival at 1, 5 and 10 years was, respectively, 94%, 81% and 58% in group 1, and 99%, 93% and 66% in group 2 (P = 0.10). Graft survival was decreased by increased donor age and serum creatinine, and tended to be associated with post-transplantation presence of anti-class I and II antibodies. Graft nephrectomy was not associated with graft survival in multivariate analysis. Conclusions: Graft nephrectomy, probably a marker of high immunological risk patients, is not a risk factor of increased retransplant failure.

Key words:

acute renal failure, graft nephrectomy, graft survival, kidney transplantation.

Introduction Kidney transplantation improves survival of patients with ESRD, compared with remaining on the transplant waiting list.1 Survival is also improved in the case of retransplantation; Ojo et al. found that retransplantation reduced mortality by 23–45%, mainly in type I diabetes mellitus ESRD.2 The survival benefit of retransplantation was also supported by data from Canada.3 In France, 14% of renal transplantations carried out in 2011 were retransplantations.4 The rate of failed graft nephrectomy carried out before retransplantation varies greatly from 0.5% to 43%,5 depending on transplantation centers. In fact, indication of graft nephrectomy is a matter of debate; while in many centers the failed allograft is removed only in patients with graft-related symptoms, such as acute rejection or graft intolerance syndrome (hematuria, abdominal pain, anemia, fever and chronic inflammation), others advise systematic failed allograft nephrectomy. Lopez-Gomez et al. reported that patients with failed allografts require more erythropoietin, have an increased incidence of malnutrition and elevated levels of inflammatory markers. These alterations were reversible 6 months after graft nephrectomy.6 Graft nephrectomy can improve patient survival even when retransplantation is not planned.7 The non-functional graft plays a role in regulating the immune response to donor MHC antigens by absorbing a part of anti-HLA antibodies.8 Graft nephrectomy allows the identification of DSA present in the patient and not detectable in the blood;9–11 in addition, it increases the PRA levels, especially pronounced within 6 months of transplantation,12 which could be detrimental to the new transplant. A few retrospective studies evaluated the effects of failed graft nephrectomy on retransplantation, with contradictory results. Some of them showed that nephrectomy of the 797

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failed graft did not affect the outcome of a subsequent kidney transplant.5,13–15 Others found that nephrectomy might have a negative influence on the retransplant outcome in all patients studied16 or only in those who underwent at least two retransplantations, or who received a graft from a donor aged older than 65 years.17 The aim of the present retrospective, single-center study was to compare graft survival after a second transplantation in patients with and without a prior failed graft nephrectomy.

Methods Patients Among the 1269 kidney transplantations carried out in our center between 1 January 2000 and 31 December 2011, a total of 199 (15.7%) were retransplantations. Patients with incomplete medical records, those who had an early allograft nephrectomy (50%, regrafts), whereas cyclosporine was generally preferred if risk factors of post-transplant diabetes mellitus (obesity, presence of hepatitis C virus infection, family history of diabetes) were present. Acute rejection episodes, suspected in cases of acute graft dysfunction and confirmed by graft biopsy, were treated with three boluses of intravenous MP. Steroid-resistant rejections were treated with plasma exchanges and switch to tacrolimus in patients receiving cyclosporine. Maintenance immunosuppression usually included a dual therapy with MMF or MPA associated with cyclosporine or tacrolimus. In cases of graft failure, maintenance therapy was rapidly withdrawn. MMF or MPA were stopped immediately, while CNI were maintained at a low dose over 3–6 months. In the few patients having steroids as maintenance therapy, prednisolone was progressively tapered and stopped at 6 months. If signs of graft intolerance appeared after cessation of immunosuppression, graft nephrectomy was carried out.

Statistical analysis Patients’ characteristics were presented using median and IQR or mean and SD for continuous variables, and frequencies and proportions for categorical variables. Graft nephrectomy groups were compared using Student or Wilcoxon Mann– Whitney test for continuous variables and χ2-test or Fisher’s test for categorical variables. Univariate and multivariate associations with second graft failure were evaluated using Cox regression analysis, and summarized with hazard ratios and 95% confidence intervals. For calculation, all patients lost to follow up or who died were considered as failures. Adjustment variables and all variables associated with graft failure with P < 0.15 in the univariate analysis were entered in the multivariate model. All statistical analyses were carried out using the SAS software package (SAS Institute, Cary, NC, USA). All tests were two-sided, and P ≤ 0.05 was considered statistically significant.

Results Patients and donors characteristics Of the 146 patients with kidney retransplantation, 52 (35.6%) underwent graft nephrectomy (group 1) and 94 patients (64.4%) did not (group 2). In our center, graft nephrectomy was carried out only in case of hematuria, fever, pain and chronic inflammation syndrome. Patient and donor characteristics of each group are summarized in Table 1. The mean age was 48.2 years (SD 13.9) in group 1 and 45.3 years (SD 11.1) in group 2 (P = 0.17). The donor age was significantly higher in group 1 (median 51.0, IQR 33.0–58.5) © 2014 The Japanese Urological Association

Impact of graft nephrectomy

Table 1

Baseline characteristics of patients and donors

Patient’s characteristics Mean age (years) Male, n (%) Mean hemoglobin (SD) Mean albumin (SD) Median CRP (IQR) Median first graft survival, years (IQR) Donor’s characteristics Median age, years (IQR) Male, n (%) Living donor, n (%) Median serum creatinine (IQR) Retransplantation characteristics Median duration of dialysis, years (IQR) Median no. graft arteries (IQR) Median vascular anastomoses time, min (IQR) Median cold ischemia time, min (IQR) HLA compatibility, n (%) 0 1 2 3 4 5 6 Median compatibility (IQR) Current PRA (LCT), n (%) ≤20% 20–80% >80% Presence of anti-HLA antibodies, n (%) Pretransplantation Class I Class II

Group 1 (n = 52) (graft nephrectomy)

Group 2 (n = 94) (no graft nephrectomy)

P

48.2 (13.9) 33 (64) 11.9 (1.9) 42.5 (4.7) 2.4 (0.8–6.4) 0.8 (0.02–6.6)

45.3 (11.1) 56 (61) 11.7 (1.8) 40.9 (4.6) 2.5 (1.3–8.0) 8.6 (4.3–15.6)

0.17 0.74 0.65 0.05 0.43 46 years First graft survival (years) Albumin CRP Donor age >45 years Donor creatinine Duration of dialysis (years) Cold ischemia time (min) PRA Compatibility Antibodies presence Pretransplantation class I Pretransplantation class II Post-transplantation class I Post-transplantation class II

HR (95% CI)

P

HR (95% CI)

P

1.9 (0.9–3.7) 0.73 (0.34–1.54) 0.98 (0.92–1.03) 1.04 (0.96–1.12) 0.98 (0.92–1.04) 2.94 (1.34–6.48) 1.01 (1.00–1.01) 0.98 (0.91–1.06) 1.00 (1.00–1.00) 0.99 (0.98–1.01) 1.13 (0.88–1.46)

0.10 0.40 0.39 0.33 0.49 0.007 0.03 0.60 0.90 0.33 0.34

1.67 (0.72–3.88)

0.23

2.53 (1.07–6.0) 1.01 (1.00–1.01)

0.04 0.04

1.02 (0.92–1.14) 1.02 (0.92–1.13) 1.10 (0.97–1.25) 1.12 (0.97–1.29)

0.66 0.71 0.12 0.11

1.05 (0.92–1.20) 1.11 (0.95–1.30)

0.47 0.18

retransplantations or who received a graft from a donor aged older than 65 years, but not in patients with none of these risk factors.17 The present study clearly shows that although graft nephrectomy is a strong marker of high immunological risk patients, it does not significantly influence the outcome of retransplantation. In fact, graft nephrectomy was carried out in patients who rapidly lost their first graft (median survival of 0.8 years), probably as a result of severe rejection, and who developed large sensitization (78% of patients with graft nephrectomy had the presence of anti-class I antibodies), both markers of high immunological risk patients. In the present series, as in many previous reports,5,13–15,28 graft survival after second transplantation was similar in patients with or without previous nephrectomy (Fig. 1). This finding was confirmed by our multivariate analysis, where graft nephrectomy was not associated with second graft loss (Table 3). In our cohort, only the quality of the second graft was associated with the risk of graft failure. The creatinine clearance (MDRD) at the first year after transplantation was statistically different between the two groups because of the difference in donor age. In fact, donor age >45 years was a strong predictor of graft failure, even after adjustment for potential confounders, as already reported by Abouljoud. Some authors reported that high PRA level was an independent predictive factor of graft loss.5,17 Sumrani also reported increased PRA levels after graft nephrectomy. In the present study, PRA level was not associated with retransplantation outcomes, as also reported by Surga et al. This could be attributed to the relatively small sample size of our cohort. Some authors found that longer duration of dialysis before the second transplantation,13,29 longer time interval between the first and second transplantations,16,29 longer duration between graft nephrectomy and retransplantation,16 and shorter first graft survival16,29 were associated with worse graft outcome. However, none of these durations were associated with graft outcome in the present study. © 2014 The Japanese Urological Association

Multivariate Cox model

We recognize that the present study had several limitations. First, it was a monocentric and restrospective study, which might introduce several bias. Second, the techniques used for the detection of anti-HLA antibodies greatly changed over the study period, which could have influenced the role of immunization and DSA in the outcome of retransplantation. Finally, the fact that graft nephrectomy was only carried out for clinical indication resulted in the selection of a specific high immunological risk group. Our analysis suggests that transplant nephrectomy is not a risk factor of increased retransplant failure. Future prospective studies regarding the consequences of graft nephrectomy on subsequent graft outcome are required, particularly to determine the ideal timing of the surgical procedure, its effects on formation of DSA or anti-HLA antibodies and its influence on subsequent patient and graft outcome.

Acknowledgment We thank Ghalib Albadaai, Abdullah Alessimi and Aziz El Majdoub for collecting the data.

Conflict of interest None declared.

References 1 Ojo AO, Hanson JA, Meier-Kriesche HU et al. Survival in recipients of marginal cadaveric donor kidneys compared with other recipients and wait-listed transplant candidates. J. Am. Soc. Nephrol. 2001; 12: 589–97. 2 Ojo A, Wolfe RA, Agodoa LY et al. Prognosis after primary renal transplant failure and the beneficial effects of repeat transplantation: multivariate analyses from the United States Renal Data System. Transplantation 1998; 66: 1651–9. 3 Rao PS, Schaubel DE, Wei G, Fenton SS. Evaluating the survival benefit of kidney retransplantation. Transplantation 2006; 82: 669–74. 4 Agence de biomédecine, Medical and scientific report. rapport_rein 2011. [Cited 7 Apr 2014.] Available from URL: http://www.agence-biomedecine .fr/IMG/pdf/rapport_reinvdef.pdf

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5 Ahmad N, Ahmed K, Mamode N. Does nephrectomy of failed allograft influence graft survival after re-transplantation? . Nephrol. Dial. Transplant. 2009; 24: 639–42. 6 López-Gómez JM, Pérez-Flores I, Jofré R et al. Presence of a failed kidney transplant in patients who are on hemodialysis is associated with chronic inflammatory state and erythropoietin resistance. J. Am. Soc. Nephrol. 2004; 15: 2494–501. 7 Ayus JC, Achinger SG, Lee S, Sayegh MH, Go AS. Transplant nephrectomy improves survival following a failed renal allograft. J. Am. Soc. Nephrol. 2010; 21: 374–80. 8 Barocci S, Valente U, Nocera A. Detection and analysis of HLA class I and class II specific alloantibodies in the sera of dialysis recipients waiting for a renal retransplantation. Clin. Transplant. 2007; 21: 47–56. 9 Del Bello A, Congy-Jolivet N, Sallusto F et al. Donor-specific antibodies after ceasing immunosuppressive therapy, with or without an allograft nephrectomy. Clin. J. Am. Soc. Nephrol. 2012; 7: 1310–19. 10 Billen EV, Christiaans MH, Lee J, van den Berg-Loonen EM. Donor-directed HLA antibodies before and after transplantectomy detected by the luminex single antigen assay. Transplantation 2009; 87: 563–9. 11 Marrari M, Duquesnoy RJ. Detection of donor-specific HLA antibodies before and after removal of a rejected kidney transplant. Transpl. Immunol. 2010; 22: 105–9. 12 Khakhar AK, Shahinian VB, House AA et al. The impact of allograft nephrectomy on percent panel reactive antibody and clinical outcome. Transplant. Proc. 2003; 35: 862–3. 13 Yagmurdur MC, Emirog˘lu R, Ayvaz I, Sozen H, Karakayali H, Haberal M. The effect of graft nephrectomy on long-term graft function and survival in kidney retransplantation. Transplant. Proc. 2005; 37: 2957–61. 14 Surga N, Viart L, Wetzstein M, Mazouz H, Collon S, Tillou X. Impact of renal graft nephrectomy on second kidney transplant survival. Int. Urol. Nephrol. 2013; 45: 87–92. 15 Lucarelli G, Vavallo A, Bettocchi C et al. Impact of transplant nephrectomy on retransplantation: a single-center retrospective study. World J. Urol. 2013; 31: 959–63. 16 Abouljoud MS, Deierhoi MH, Hudson SL, Diethelm AG. Risk factors affecting second renal transplant outcome, with special reference to primary allograft nephrectomy. Transplantation 1995; 60: 138–44.

17 Schleicher C, Wolters H, Kebschull L et al. Impact of failed allograft nephrectomy on initial function and graft survival after kidney retransplantation. Transpl. Int. 2011; 24: 284–91. 18 Mourad G, Rostaing L, Legendre C, Garrigue V, Thervet E, Durand D. Sequential protocols using basiliximab versus antithymocyte globulins in renal-transplant patients receiving mycophenolate mofetil and steroids. Transplantation 2004; 78: 584–90. 19 Coppolino G, Criseo M, Nostro L et al. Management of patients after renal graft loss: an open question for nephrologists. Ren. Fail. 2006; 28: 203–10. 20 Ayus JC, Achinger SG. At the peril of dialysis patients: ignoring the failed transplant. Semin. Dial. 2005; 18: 180–4. 21 Langone AJ, Chuang P. The management of the failed renal allograft: an enigma with potential consequences. Semin. Dial. 2005; 18: 185–7. 22 Mazzucchi E, Nahas WC, Antonopoulos IM, Piovesan AC, Ianhez LE, Arap S. Surgical complications of graft nephrectomy in the modern transplant era. J. Urol. 2003; 170: 734–7. 23 Alberts VP, Minnee RC, Bemelman FJ, van Donselaar-van der Pant KA, Idu MM. Transplant nephrectomy: what are the surgical risks? . Ann. Transplant. 2013; 16: 174–81. 24 Rosenthal JT, Peaster ML, Laub D. The challenge of kidney transplant nephrectomy. J. Urol. 1993; 149: 1395–7. 25 Toledo-Pereyra LH, Gordon C, Kaufmann R, Whitten JI, Mittal VK. Role of immediate versus delayed nephrectomy of failed renal transplants. Am. Surg. 1987; 53: 534–6. 26 Hansen BL, Rohr N, Starklint H, Svendsen V, Birkeland SA. Indications for and timing of removal of non-functioning kidney transplant. Scand. J. Urol. Nephrol. 1986; 20: 217–20. 27 Delgado P, Diaz F, Gonzalez A et al. Intolerance syndrome in failed renal allografts: incidence and efficacy of percutaneous embolization. Am. J. Kidney Dis. 2005; 46: 339–44. 28 Lair D, Coupel S, Giral M et al. The effect of a first kidney transplant on a subsequent transplant outcome: an experimental and clinical study. Kidney Int. 2005; 67: 2368–75. 29 Goldfarb-Rumyantzev AS, Smith L, Shihab FS et al. Role of maintenance immunosuppressive regimen in kidney transplant outcome. Clin. J. Am. Soc. Nephrol. 2006; 1: 563–74.

Editorial Comment Editorial Comment from Dr Lucarelli and Dr Ditonno to Impact of graft nephrectomy on outcomes of second kidney transplantation In recent years, the incidence of acute rejection and early graft failure has declined progressively as a result of better immunosuppressive protocols. However, the rate of graft failure and return to dialysis remains at10% in the first year and 2–4% per year thereafter. Therefore, the number of patients with a failed kidney transplant is growing and represents 15–20% of patients on the waiting list, even if the prospect of a second kidney transplant is low, because returning to hemodialysis increases morbidity that could compromise a potential retransplantation. However, retransplantation should always be pursued, because it offers a significant survival benefit compared with patients remaining on dialysis. Should this population of patients returning to dialysis be treated in the same way of patients with de novo end-stage renal disease? Many questions arise. What is the influence of a non-functional graft on the outcome of a subsequent transplantation? Should a failed graft be removed? Which is the best technique of removal, and what are the right indications? What is the effect of retransplantation on patient outcome? Unfortunately, to date, we do not have definitive 802

answers to these questions. Although there is a common agreement on graft nephrectomy in case of hyperacute rejection or technical complications, the management of an asymptomatic failed allograft remains controversial. Fadli et al. add another piece to this puzzle with their study. In accordance to other studies, these authors did not find a significant difference in graft and patient survival between patients with or without graft nephrectomy before retransplantation.1 In our experience, we found that patients who did not undergo graft nephrectomy before a second transplant had significantly better renal function.2 These findings seem to suggest that graft nephrectomy should be carried out only in a particular clinical condition, considering the risks associated with this procedure.3 Even though a non-functioning graft can act as a trap for anti-human leukocyte antigen antibodies against a new graft, there is evidence that shows how a failed graft can be the site of persistent immune-mediated reactivity inducing a chronic inflammation. Clotted arteriovenous grafts with subclinical infection in patients on hemodialysis can contribute to a condition © 2014 The Japanese Urological Association

Impact of graft nephrectomy on outcomes of second kidney transplantation.

To determine the impact of renal graft nephrectomy on second kidney transplantation survival...
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