Abstract

Kidney allograft failure is a significant complication in kidney transplant recipients, and the surgical decision to perform allograft nephrectomy poses a strong dilemma because it is associated with significant morbidity and mortality. There is a debate over the effect of allograft nephrectomy on the development
of allosensitization and the impact on potential retransplantation. Moreover, the use of immunosup-pression may contribute to antibody allosensitization as allograft nephrectomy and immunosuppression
act jointly and interdependently toward antibody formation. Because more and more patients with kidney allograft failure are entering wait lists for repeat transplant procedures, a review of available evidence on the field is required. Here, we performed a literature search using multiple medical databases to identify relevant studies that assessed the effects of allograft nephrectomy on important retransplant endpoints such as allograft and patient survival; furthermore, secondary outcomes such as alloantibody sensitization were also evaluated. A total of 15 studies were identified; all were retrospective, single-center studies. The rate of allograft nephrectomy in patients with retransplant varied widely (from 20% to 80%). The average allograft nephrectomy rate in included studies was 43% (allograft nephrectomy number/number of repeat transplantations: 2351/5431). Most studies
did not observe an allograft survival benefit after retransplant for patients with allograft nephrectomy with the exception of 4 studies that found worse allograft survival after allograft nephrectomy. Interestingly, 1 study found that, in the patient subgroup with early kidney allograft failure (<12 months posttransplant), allograft nephrectomy may be associated with better allograft survival. Available data suggested that allograft nephrectomy may be associated with a higher risk of increasing anti-HLA antibody levels. The quality of the included studies suffered from nonrandomized design, potential confounding, and small sample size. To conclude, further randomized controlled trials are required to delineate the role of allograft nephrectomy on retransplant outcomes.

Key words : Allograft nephrectomy, Immunosuppression minimization, Kidney allograft failure, Kidney transplantation, Retransplantation

Introduction

Although kidney transplant (KT) remains the therapy of choice for patients with end-stage renal disease (ESRD), long-term allograft survival (AS) remains moderate and has not dramatically improved despite successful management of acute rejection with modern immunosuppression.^1-3 As a result, many KT recipients face the inevitable decline of allograft function to a point where homeostasis cannot be maintained without return to dialysis.⁴ Kidney allograft failure (KAF) can be a traumatic experience for patients because it results in loss of a quasi-normal mode of living and potential return to the undesired lifestyle of dialysis.^5,6 The incidence of KAF is ever increasing because of the rise of the absolute number of KTs and the relative increase in survival of KT recipients. In the United States, the KAF rate among deceased donor KT recipients exceeded 20% between 2000 and 2015 and the percentage of KAF patients who relisted for a second KT remained well above 10% among ESRD patients on wait lists.⁷ The long-term prognosis for KAF patients returning to dialysis is poor; using data from the Scientific Registry of Transplant Recipients, Rao and colleagues found a significantly greater mortality of 78% (hazard ratio [HR] of 1.78; P < .0001) for these patients compared with prevalent ESRD patients on wait lists.⁸ Less than 40% of KAF patients are still alive 10 years after return to dialysis; thus, the option of retransplant seems highly preferable and should be further explored.⁹

The issue of allograft nephrectomy (AN) before retransplant is highly debatable. Published AN rates have ranged from 9% to 74%, with individual center strategies dictating the decision to perform AN.10,11 Standard indications for AN are illustrated in Table 1. When allograft loss occurs, it is widely accepted that the allograft must be removed within the first 3 months after KT because it is often associated with imminent life-threatening risk (such as the risk for allograft rupture in acute arterial thrombosis or the risk for severe urosepsis). As a result, the AN rate in these patients is twice as much as those who have later loss.12 The indications for AN are less well-defined when allograft loss occurs later on, since clinical symptoms are often absent or mild.13 Symptomatic patients present with graft intolerance syndrome, which mimics acute rejection (allograft tenderness, fever, and hematuria), or signs of chronic inflammation (such as anemia with resistance to erythropoiesis-stimulating agents and malnutrition). According to Lopez-Gomez and colleagues, the removal of the failed transplant in symptomatic KAF patients was associated with amelioration of markers of chronic inflammation.14 The advantages and disadvantages of AN are shown in Table 2. The impact of AN on subsequent allosensitization has not yet been fully explained. The “sponge” theory suggests that the retained failed allograft traps preformed anti-HLA antibodies and that AN results in release of these antibodies in the circulation. Early retrospective studies found that panel reactive antibody (PRA) levels were much higher in KAF patients who had undergone AN than in those who had not.^15,16 Furthermore, eluates derived from excised allografts were found to contain anti-HLA antibodies at very high rates, whereas those antibodies were not consistently found in the serum at the same time.^17,18 Another theory proposes that AN causes severe tissue damage that triggers alloimmune response, leading to accelerated cytotoxic antibody formation. Finally, it has been speculated that it is not AN that is responsible for the emergence of anti-HLA antibodies but the immunosuppression cessation that follows AN; the management of immunosuppression following KAF is of particular importance.

The possibility of a preemptive retransplant may avert the need for complete immunosuppression withdrawal, and reduced immunosuppression may be used to bridge the gap to retransplant (as suggested by the British Transplantation Society guidelines for management of the failing KT).¹⁹ In all other cases, there has been no universal agreement on whether immunosuppression should be discontinued. Both approaches are in use, and advocates of each one have argued about their risks and benefits (Table 3). The intention to preserve residual diuresis from the failed allograft (as a means to control hypervolemia) may lead to slow or no immunosuppression tapering at all (but at the expense of increased susceptibility to infections). On the other hand, immunosuppression weaning may result in graft intolerance syndrome, which typically presents within 1 year after KAF; in a retrospective study of 186 KAF patients, it necessitated AN in 81% of patients.^20,21

In the Eurotransplant geographical area, about 14% of deceased donor KTs are repeat KTs; similar rates have been reported in the United States, where retransplants represented 12.4% of KTs performed in 2005.^22,23 Retransplantation has been strongly associated with a survival benefit over dialysis. In a study of 3067 patients from the Canadian Organ Replacement Register, Rao and colleagues found that retransplant is associated with a covariate-adjusted 50% reduction in mortality versus remaining on dialysis (HR of 0.50; P < .0001).²⁴ The exact influence of AN on retransplant remains unclear.

In this literature review, our aim was to evaluate the effects of AN on the hard endpoints of AS and patient survival (PS) after retransplant. We performed a thorough literature search and identified relevant studies that compared patients with and without AN before retransplant. We systematically assessed and reported the studied endpoints of AS, PS, and donor-specific antibody (DSA) development, since these are the most important determinants of retransplant outcomes. We analyzed the results and compared the included studies using qualitative synthesis.

Materials and Methods

The overall literature search strategy was based on the PRISMA Statement guidelines.25 The following sources of literature were used: the MEDLINE-PubMed electronic databases (US National Library of Medicine, National Institutes of Health), the Cochrane Central Register for Controlled Trials-The Cochrane Library, and the international trials database (www.clinicaltrials.gov). Two different search themes combined with the Boolean operator “AND” were used to perform the literature search up to October 2020. The first theme involved terms relative to AN (ie, “allograft nephrectomy” and “kidney [or renal] transplantectomy”), and the second theme involved terms relative to KAF. These were truncated as needed because terms such as failing or failed transplant are commonly used interchangeably (ie, “fail* kidney [or renal] transplant* and “fail* kidney [or renal] allograft”). Combinations of these themes with “retransplantation” or “second transplantation” were also used. The inclusion criteria included articles that were written in English language, were published in indexed scientific journals, and were relevant to adult transplantation. Accordingly, articles that were written in non-English language, were relevant to pediatric transplantation, and did not involve studies but were letters to editors or conference proceedings were excluded. Although filters relative to the inclusion and exclusion criteria were used when available by the database software, eligible full-text articles were further scrutinized to ensure they met inclusion and exclusion criteria. No limitations regarding study design were used; literature searches were aimed to find both randomized controlled trials (RCT) and observational studies on the topic and to evaluate them during the qualitative synthesis stage. The search process was divided into 4 stages: (1) identification of available articles, (2) screening for satisfaction of inclusion and exclusion criteria, (3) checking full-text articles for eligibility, and (4) compiling articles for qualitative synthesis. Of 508 manuscripts initially identified, 499 were from database searches and 9 were gathered from reference lists. After removal of 37 duplicate manuscripts, the titles and abstracts of the remaining 471 manuscripts were viewed to exclude studies that did not examine AN in the setting of KAF and potential retransplant. In the next step, the full text of 24 manuscripts was thoroughly reviewed for eligibility. Of these, 9 manuscripts were excluded26-34: 3 described retrospective cohort studies that did not evaluate the outcomes of PS and AS after retransplant^26,28,33 and 5 involved case series of AN without a control group.^27,29-32 The remaining study of the 9 excluded, by Ayus and colleagues,³⁴ deserves a special mention. It was a nation-wide US retrospective study that identified all adults who received a KT and returned to long-term dialysis after KAF in a 10-year period. Among 10 951 patients who returned to dialysis, 3451 (31.5%) received AN during follow-up. Although this study found that patients with AN were more than twice as likely to receive a second transplant during the follow-up period versus those who did not undergo nephrectomy of the initial failed allograft (10.0% vs 4.1%; P < .001), it did not assess the AS and PS rates after retransplant; therefore, it was deemed not eligible. The remaining 15 manuscripts were included in the qualitative synthesis (Figure 1).^12,15,35-47

Both AS and PS were set as the primary outcomes; where available, survival was estimated at specific time points such as 1-year, 3-year, 5-year, or 10-year survival. Secondary perioperative outcomes were also assessed, such as the occurrence of delayed graft function (DGF), defined as the need for dialysis within the first week after retransplant (except for treatment of hyperkalemia) and acute rejection. Moreover, eligible studies were evaluated regarding the indications for AN. Finally, identified studies were examined for the question of anti-HLA antibody sensitization after AN, since this is a highly debatable issue. Quality of included studies was assessed by the Critical Appraisal Skills Programme (CASP) tool.⁴⁸ The CASP Cohort Study Checklist contains a 12-piece set of questions that facilitate answers to 3 broad issues: (1) whether the results of the study are valid, (2) what the results are, and (3) whether the results can be generalizable. The corresponding level of evidence was assessed with the universally accepted Center of Evidence-Based Medicine (CEBM) level of evidence checklist to determine their strength of evidence on a 1 to 5 scale.⁴⁹

Results

Characteristics of the 15 included studies are depicted in Table 4. All were single-center retrospective cohort studies and not RCTs. All of the studies reported AS outcomes; however, PS was reported in only 60% (9/15) of the studies. The rate of AN in patients with retransplant varied widely (20% to 80%) among different centers, reflecting the variation and uncertainty on the indication for AN, as discussed below. The average AN rate of all included studies was 43% (number of AN/number of repeat transplants: 2351/5431). The decision to perform AN was uniformly based on clinical reasons, most commonly for graft intolerance syndrome (Table 1); however, most studies did not provide the exact rate of each indication. Four studies did not report at all whether AN was done for clinical indications or electively.^12,35,40,46 Sumrani and colleagues¹⁵ reported that 81% (35/41) of AN were performed on clinical indications; the remaining 19% were done electively shortly before retransplant to make space for the new allograft. Ahmad and colleagues⁴⁴ reported that 60% (53/89) of AN were performed on clinical indications and 40% were done electively shortly before retransplant. Schachtner and colleagues³⁶ reported that 76% (39/51) of AN were performed on clinical indications and 24% were done electively shortly before retransplant. It is impressive that only 4 of the 15 studies reported details about the immunosup-pression weaning protocol used after KAF^15,36,39,40; thus, it is difficult to draw conclusions on the relation between immunosuppression weaning and emergence of clinical symptoms, as well as the subsequent need for AN.

Perioperative outcomes and complications
The impact of AN on the occurrence of both DGF and acute rejection has attracted the interest of researchers because both are the result of DSA emergence. Twelve of the 15 studies assessed the association between patients with AN and patients without AN regarding DGF; of these, 8 found no significant difference (Table 5). Of note, Lair and colleagues⁴⁵ used a slightly modified definition of DGF (number of days required to reach a Cockcroft-calculated creatinine clearance of at least 10 mL/min) but reached the same conclusion. Four studies demonstrated that performing AN before retransplant may lead to DGF.^15,37,12,47 Sumrani and colleagues¹⁵ divided their study population into 3 subgroups; therefore, their findings could not be represented in Table 5. However, the investigators clearly reported that, in patients who received AN for clinical indications, DGF was more common compared with that shown in patients without AN and patients with elective AN at the time of retransplant (P < .01). Similar results were reported regarding the association between AN and acute rejection. Nine studies did not find any statistical significance between patients with AN and without AN regarding acute rejection.^{15,35,37,39,41,42,44,45,47} Data from Abouljoud and colleagues⁴⁷ and Sumrani and colleagues¹⁵ were not shown or could not be retrieved, respectively, and are missing from Table 5. Four studies found that acute rejection rates were higher in patients with AN.^36,38,43,46

Impact on allosensitization

Fourteen of the 15 included studies evaluated the association between AN and anti-HLA antibodies.^{12,15,35-45,47} Nevertheless, there exists much heterogeneity among these studies because the methods used to identify anti-HLA antibodies have changed dramatically over the past 15 years, with the advent of the single-antigen bead technology (Luminex) allowing much more precise charac-terization of DSA.⁵⁰ As a result, some recent studies have reported data on DSA identification with Luminex, whereas older studies only relied on measurement of PRA levels. Direct comparisons between the latter studies cannot be made because they used different PRA level cutoffs to divide subgroups according to immunological risk. Overall, PRA levels were significantly increased before retransplant in patients with AN versus those without AN in 7 studies.^{12,37-39,43,45,47} Six studies did not find a statistically significant difference,^{35,36,40-42,44} and the study by Sumrani and colleagues¹⁵ found that patients with AN for clinical indications had significantly increased PRA levels compared with those with elective AN or those without AN. Muramatsu and colleagues investigated the presence of preformed DSA before retransplant with Luminex technology and found that there was no significant difference in DSA between patients with or without AN,³⁵ with 39% of patients with AN having either class I or II DSAs versus 29% of patients without AN (P = .24). In contrast, Fadli and colleagues³⁹ found that a statistically significant 78% of patients with AN had class I DSA versus 60% of patients without AN (P = .02); no difference was found for class II DSA (73% in patients with AN vs 64% in patients without AN; P = .29).

Allograft survival
All studies included in the qualitative synthesis assessed second AS after retransplant (Table 4). No difference in the induction immunosuppression protocol was observed for patients with AN versus those without AN. Seven studies reported survival rates at specific time points (Table 6).^{35,38-40,42,44,45} One-year AS varied from 77% to 97% in patients with AN and from 67% to 99% in patients without AN. Three-year AS in patients with AN and patients without AN ranged from 69% to 91% and from 82% to 87%, respectively. Five-year AS ranged from 62% to 91% in patients with AN and from 59% to 93% in patients without AN. Ten-year AS ranged from 46% to 85% in patients with AN and from 30% to 69% in patients without AN. Only Muramatsu and colleagues³⁵ reported that AN was associated with significantly worse 1-, 3-, and 5-year AS; the remaining 6 studies found no significant differences in AS between patients with and without AN; this same result was obtained when the analysis was censored for death with a functioning graft (in 5 of the 6 studies). In the other 8 studies, exact survival rates were not reported or different metrics were used (such as HR for the risk of death); 3 of these 8 studies found that AN was significantly associated with worse AS.^36,43,47 Schleicher and colleagues⁴³ reported that mean AS time was 81.9 ± 4.5 months in patients with AN versus 98.9 ± 5.7 months in patients without AN (P = .03). The study by Johnston and colleagues¹² deserves a special mention because it was the only one that did find an AS benefit for patients with AN; the group only found a benefit with “early” KAF, that is, when first allograft loss occurred less than 12 months after KT (HR of 0.72; 95% CI, 0.56-0.94). This is an interesting observation because it may have implications for clinical practice should it be confirmed. Unfortunately, other studies from the qualitative synthesis excluded patients with early allograft loss from their analysis; as such, results from Johnston and colleagues were not comparable to any other included study.

Patient survival
The role of AN on PS after retransplant was assessed in 9 studies (Table 4). Four of these studies reported data on 1-, 3-, 5-, and 10-year PS (Table 6).^35,38,40,44 One-year PS varied from 93% to 94% in patients with AN and from 79% to 96% in patients without AN. Five-year PS ranged from 86% to 91% in patients with AN and from 73% to 92% in patients without AN. The study by Tittelbach-Helmrich and colleagues⁴⁰ found that PS was better in patients with AN versus patients without AN (P < .01). In particular, 1-year PS was 94% in patients with AN versus 79% in patients without AN, 5-year PS in patients with AN was 86% versus 73% in patients without AN, and 10-year PS was 72% versus 44%, respectively. However, all other studies did not find statistically significant associations between AN and PS. As a result, no definite answer could be drawn, and the issue of patient mortality after retransplant remains indeterminate.

Study quality: level of evidence
The CASP checklist was applied to included retrospective cohort studies to evaluate individual study properties in a qualitative way. The research question was addressed in a clearly focused manner in most of the studies; patient population (KAF patients), intervention and comparison (patients with AN vs those without), and outcomes (AS and PS, allosensitization level) were all well-described and measured. However, the possibility of selection bias cannot be excluded. Patient selection was done retrospectively, and patients who should have been included in a particular study could have been ultimately excluded (ie, due to incomplete medical records³⁹). It is worth mentioning that cases (patients with AN) and controls (patients without AN) may not have been treated equally in all studies because data on immunosuppression weaning after KAF are lacking in most of the studies. Moreover, none of the studies identified potential confounding factors. Follow-up was generally long and complete enough. Study design and statistical analysis were not optimal in included studies; methods to control or adjust for confounding factors (such as stratification, regression, or sensitivity analyses) were undertaken in only 60% of the studies. Although outcomes were measured accurately, study results must be viewed with caution since the possibility of bias was not appropriately excluded. As a result, study results cannot be extrapolated to KT candidates without further confirmation in the form of an RCT. The level of evidence of all included studies, according to the CEBM level of evidence checklist, corresponded to level 3 (on a scale from 1 to 5); all studies were retrospective cohort studies. None of them exerted results with dramatic effects to justify level upgrading.

Discussion

The present literature review collected data from 15 retrospective cohort studies that included 5431 patients in total and assessed the role of AN after KAF on retransplant outcomes. The indications for AN and the efficacy and harms of AN following KAF were described. It was found that there was broad variation in the number of AN that were done and in the timing that they were performed. The findings imply that AN may be associated with increased anti-HLA antibody formation. However, this finding was the result from older studies that did not use the single-antigen bead Luminex method. As such, confirmation with studies using state-of-the-art technology is required to reproduce this finding and to clarify whether AN is associated with DSA formation or nonspecific activation of the immune system and non-DSA formation. In most of the studies, results for AS and PS did not show statistically significant differences between patients with AN and patients without AN. As a result, the impact of AN on retransplant outcomes is neither beneficial nor harmful, and AN does not seem to offer an advantage in patients with KAF. However, suboptimal quality of included studies calls for further research.

Most of the included studies did not find a statistically significant association between DGF or acute rejection and AN (8 of 12 and 9 of 13 studies, respectively). However, 4 studies^12,15,37,47 found that DGF rates were higher in the AN group, and another 4 studies found that acute rejection rates were also higher after AN.^36,38,43,46 These results should be viewed with caution and are not adequate to drive changes in clinical practice; it cannot be concluded that AN could lead to DGF or acute rejection, but it is alarming that a potential relation over them is suggested. Results in the studies were neither controlled nor adjusted for the presence of anti-HLA antibodies to explain the higher rates of DGF or acute rejection that were shown; if results were corrected for the presence of increased anti-HLA antibody levels, then the significant association may have disappeared. Allograft nephrectomy is commonly performed for allograft inflammation (graft intolerance syndrome), and it is not clear whether anti-HLA antibodies are causing allograft inflammation or whether inflam-mation acts as a triggering event to stimulate the production of anti-HLA antibodies. In the former case, a type of indication bias may occur, and removal of the failed allograft would not necessarily have an effect on the level of preexisting anti-HLA antibodies.

The impact of AN on the development of anti-HLA antibodies seems to be either neutral or harmful; 6 studies^{35,36,40-42,44} did not find a statistically significant difference on PRA levels between patients with or without AN, and 7 studies^{12,37-39,43,45,47} found that PRA levels were significantly increased before retransplant in patients with AN versus those without AN. Moreover, 1 recent study³⁹ found that patients with AN had higher class I DSA versus those without AN. However, it should be noted that only the most recent study used Luminex technology to identify DSA instead of the PRA method used in older studies. The study by Muramatsu and colleagues³⁵ failed to detect any significant difference in DSA between patients with or without AN. As such, confirmation with more studies using Luminex technology is needed to reach a definite conclusion. Overall, these results seem to support the “sponge” theory that removal of a failed allograft (which has previously absorbed anti-HLA antibodies) leads to release of these antibodies into the circulation. The study by Milongo and colleagues⁵¹ compared the simultaneous presence of anti-HLA antibodies in the serum and in the graft at the time of an AN using solid-phase assays. They surprisingly found that all anti-HLA antibodies that were detected in grafts were also detected in the serum, thus providing evidence that anti-HLA antibodies are not entirely absorbed by a retained failed allograft and partially refuting the sponge theory. Because the sponge theory cannot exclusively explain the increase in anti-HLA antibodies after AN, an alternative theory must be sought. It has been proposed that AN produces severe tissue damage that leads to nonspecific stimulation of the immune system and overproduction of anti-HLA antibodies; this needs examination in future research.

However, the fact that immunosuppression cessation, which follows AN, is involved in allosensitization should not be overlooked. It has been observed that development of anti-HLA antibodies may occur after KAF and immunosup-pression cessation not only in the absence of AN but even in the absence of other triggering events (eg, pregnancy, transfusions). It is not easy to detect which of the 2 concurrent therapeutic strategies (AN or immunosuppression cessation) contributes more to allosensitization; some form of synergy between them is more likely. In fact, in a study of 69 KAF patients with DSA measurement using the Luminex method by Del Bello and colleagues, DSA increased after ceasing immunosuppression in both patients with AN and patients without AN; however, DSA increase was more pronounced in patients with AN (81.0% vs 52.4%; P = .02).⁵² Prolonged immunosup-pression administration may preserve nonsensitization status after KAF, especially if an early retransplant is planned. Vigilance for adverse reactions to immuno-suppression such as infections and malignancies is required. Partial immunosuppression withdrawal or small dose maintenance immunosuppression may offer an alternative solution; specific corticosteroid minimization protocols have gained popularity over the past decade. Nevertheless, only patients at low immunological risk are considered as optimal candidates for such protocols.⁵³

The results of AN on AS after retransplant are largely inconclusive. Ten studies showed that there was no difference in AS for patients with AN versus those without AN, and 4 studies found worse AS for patients with AN. The heterogeneity of results reflects the heterogeneity of the studies themselves. Throughout the included patient populations, AN was performed at different time points: some studies did not report timing of AN at all, some excluded patients with AN for early KAF, and in the study by Sumrani and colleagues AN was performed at the time of retransplant in a patient subgroup.¹⁵ In the latter case, it is evident that the impact of AN on development of anti-HLA antibodies, and in turn on AS, cannot be determined since exposure (AN) and outcome (retransplant) occur simultaneously. The study by Johnston and colleagues¹² was the only one that found AN as beneficial in KAF when performed early, that is, at less than 12 months after KT (lower risk of repeat transplant failure; HR of 0.72; 95% CI, 0.56-0.94). These researchers also proved that the opposite occurs: among patients with late transplant failure (>12 months from KT), AN was associated with a higher risk of repeat transplant failure (HR of 1.20; 95% CI, 1.02-1.41). Although current evidence argues against a presumed benefit of AN on AS after retransplant, a well-designed, adequately powered RCT could clarify the impact of AN on retransplant based on the results by Johnston and colleagues. As such, selection of proper comparison (eg, early elective AN group vs small-dose, maintenance immunosuppression without AN group) would be greatly important.

The meta-analysis by Wang and colleagues, which included 8 studies that involved 1008 patients, also assessed the efficacy and safety of AN versus no AN for renal retransplant.⁵⁴ The reason for the lower yield of eligible studies is that inclusion criteria were much more restrictive. For example, the authors had decided to include studies that reported data on the outcomes of serum creatinine at 1 year after retransplant and the time interval to retransplant (among other studied outcomes). Results were consistent with findings of the present review. No significant differences were found in 1-year AS rate (odds ratio [OR] of 0.74; 95% CI, 0.31-1.72; P = .48), 1-year PS rate (OR of 1.60; 95% CI, 0.57-4.46; P = .37), acute rejection rate (OR of 1.30; 95% CI, 0.89-1.91; P = .17), postoperative complications (OR of 1.51; 95% CI, 0.24-9.43; P = .66), and serum creatinine 1 year after retransplant (weighted mean difference of -0.25; 95% CI, -0.52 to 0.03; P = .08). Patients with AN were found to have an extended time interval from allograft loss to retransplant (weighted mean difference of 11.23; 95% CI, 2.47-19.99; P = .01) and higher rates of PRA >10% before retransplant (OR of 1.62, 95% CI, 1.17-2.23; P = .003). By all means, the higher PRA rates and the longer time to retransplant did not seem to affect hard outcomes such as AS and PS after retransplant, just as it was found for most of the studies included in this review. The authors of the meta-analysis concluded that AN before retransplant appears to be safe and tolerated, but it is not associated with a significant benefit.

After thorough assessment of available literature in the field, no clear benefits on AS and PS were found when AN is followed by retransplant. Therefore, no change in current clinical practice is suggested since no definite advantage of AN has been so far proved. The lack of good quality evidence calls for better designed studies. The interesting finding in one study that, in early KAF, AN may be associated with an AS benefit requires further research and could be the theme of a future RCT. Available evidence has shown a trend toward increased anti-HLA antibody levels after AN. Irrespective of whether that occurs due to the “sponge” theory or whether AN in itself acts as a sensitizing effect, that is alarming and the decision to proceed to AN should be done with great caution. Especially in sensitized patients, who are considered to be at high immunological risk, the performance of routine AN and immunosup-pression withdrawal should be discouraged if those patients are asymptomatic and potential candidates for retransplant. There is circumstantial evidence that AN may hold a survival benefit after retransplant even if it is associated with an increase in anti-HLA antibody levels; that possibility is intriguing, and the assessment of pathophysiologic mechanisms and confirmation should be the focus of future studies.

References:

1. Coemans M, Susal C, Dohler B, et al. Analyses of the short- and long-term graft survival after kidney transplantation in Europe between 1986 and 2015. Kidney Int. 2018;94(5):964-973. doi:10.1016/j.kint.2018.05.018
   CrossRef - PubMed
   
2. Hart A, Smith JM, Skeans MA, et al. OPTN/SRTR 2015 Annual Data Report: Kidney. Am J Transplant. 2017;17 Suppl 1(Suppl 1):21-116. doi:10.1111/ajt.14124
   CrossRef - PubMed
   
3. Lamb KE, Lodhi S, Meier-Kriesche HU. Long-term renal allograft survival in the United States: a critical reappraisal. Am J Transplant. 2011;11(3):450-462. doi:10.1111/j.1600-6143.2010.03283.x
   CrossRef - PubMed
   
4. Gill JS, Abichandani R, Khan S, Kausz AT, Pereira BJ. Opportunities to improve the care of patients with kidney transplant failure. Kidney Int. 2002;61(6):2193-2200. doi:10.1046/j.1523-1755.2002.00373.x
   CrossRef - PubMed
   
5. Jana AK, Sircar D, Waikhom R, et al. Depression and anxiety as potential correlates of post-transplantation renal function and quality of life. Indian J Nephrol. 2014;24(5):286-290. doi:10.4103/0971-4065.132996
   CrossRef - PubMed
   
6. Szeifert L, Molnar MZ, Ambrus C, et al. Symptoms of depression in kidney transplant recipients: a cross-sectional study. Am J Kidney Dis. 2010;55(1):132-140. doi:10.1053/j.ajkd.2009.09.022
   CrossRef - PubMed
   
7. Hart A, Smith JM, Skeans MA, et al. OPTN/SRTR 2018 Annual Data Report: Kidney. Am J Transplant. 2020;20 Suppl s1:20-130. doi:10.1111/ajt.15672
   CrossRef - PubMed
   
8. Rao PS, Schaubel DE, Jia X, Li S, Port FK, Saran R. Survival on dialysis post-kidney transplant failure: results from the Scientific Registry of Transplant Recipients. Am J Kidney Dis. 2007;49(2):294-300. doi:10.1053/j.ajkd.2006.11.022
   CrossRef - PubMed
   
9. Kaplan B, Meier-Kriesche HU. Death after graft loss: an important late study endpoint in kidney transplantation. Am J Transplant. 2002;2(10):970-974. doi:10.1034/j.1600-6143.2002.21015.x
   CrossRef - PubMed
   
10. 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(3):734-737. doi:10.1097/01.ju.0000080566.42381.94
    CrossRef - PubMed
    
11. Secin FP, Rovegno AR, del Rosario Brunet M, Marrugat RE, Davalos Michel M, Fernandez H. Cumulative incidence, indications, morbidity and mortality of transplant nephrectomy and the most appropriate time for graft removal: only nonfunctioning transplants that cause intractable complications should be excised. J Urol. 2003;169(4):1242-1246. doi:10.1097/01.ju.0000050658.94353.24
    CrossRef - PubMed
    
12. Johnston O, Rose C, Landsberg D, Gourlay WA, Gill JS. Nephrectomy after transplant failure: current practice and outcomes. Am J Transplant. 2007;7(8):1961-1967. doi:10.1111/j.1600-6143.2007.01884.x
    CrossRef - PubMed
    
13. DiSesa VJ, Tilney NL. Conservative management of the failed renal allograft: indications for transplant nephrectomy. Curr Surg. 1982;39(6):417-418.
    CrossRef - PubMed
    
14. Lopez-Gomez JM, Perez-Flores I, Jofre 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(9):2494-2501. doi:10.1097/01.ASN.0000137879.97445.6E
    CrossRef - PubMed
    
15. Sumrani N, Delaney V, Hong JH, Daskalakis P, Sommer BG. The influence of nephrectomy of the primary allograft on retransplant graft outcome in the cyclosporine era. Transplantation. 1992;53(1):52-55. doi:10.1097/00007890-199201000-00009
    CrossRef - PubMed
    
16. Douzdjian V, Rice JC, Carson RW, Gugliuzza KK, Fish JC. Renal retransplants: effect of primary allograft nephrectomy on early function, acute rejection and outcome. Clin Transplant. 1996;10(2):203-208.
    CrossRef - PubMed
    
17. Martin L, Guignier F, Mousson C, Rageot D, Justrabo E, Rifle G. Detection of donor-specific anti-HLA antibodies with flow cytometry in eluates and sera from renal transplant recipients with chronic allograft nephropathy. Transplantation. 2003;76(2):395-400. doi:10.1097/01.TP.0000078895.24606.45
    CrossRef - PubMed
    
18. Bocrie O, Hussein Aly AA, Guignier F, et al. Distribution of donor-specific antibodies in the cortex and the medulla of renal transplants with chronic allograft nephropathy. Transpl Immunol. 2007;17(3):227-229. doi:10.1016/j.trim.2007.01.001
    CrossRef - PubMed
    
19. Andrews PA; Standards Committee of the British Transplantation Society. Summary of the British Transplantation Society Guidelines for Management of the Failing Kidney Transplant. Transplantation. 2014;98(11):1130-1133. doi:10.1097/TP.0000000000000426
    CrossRef - PubMed
    
20. Woodside KJ, Schirm ZW, Noon KA, et al. Fever, infection, and rejection after kidney transplant failure. Transplantation. 2014;97(6):648-653. doi:10.1097/01.TP.0000437558.75574.9c
    CrossRef - PubMed
    
21. Singh P, Feld RI, Colombe BW, et al. Sensitization, pathologic, and imaging findings comparing symptomatic and quiescent failed renal allografts. Clin Transplant. 2014;28(12):1424-1432. doi:10.1111/ctr.12474
    CrossRef - PubMed
    
22. Branger P, Samuel U. Eurotransplant Annual Report; 2015. https://www.eurotransplant.org/wp-content/uploads/2019/12/AR2015.pdf
    CrossRef - PubMed
    
23. Magee JC, Barr ML, Basadonna GP, et al. Repeat organ transplantation in the United States, 1996-2005. Am J Transplant. 2007;7(5 Pt 2):1424-1433. doi:10.1111/j.1600-6143.2007.01786.x
    CrossRef - PubMed
    
24. Rao PS, Schaubel DE, Wei G, Fenton SS. Evaluating the survival benefit of kidney retransplantation. Transplantation. 2006;82(5):669-674. doi:10.1097/01.tp.0000235434.13327.11
    CrossRef - PubMed
    
25. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264-269, W64. doi:10.7326/0003-4819-151-4-200908180-00135
    CrossRef - PubMed
    
26. Lucisano G, Brookes P, Santos-Nunez E, et al. Allosensitization after transplant failure: the role of graft nephrectomy and immunosuppression - a retrospective study. Transpl Int. 2019;32(9):949-959. doi:10.1111/tri.13442
    CrossRef - PubMed
    
27. Chowaniec Y, Luyckx F, Karam G, et al. Transplant nephrectomy after graft failure: is it so risky? Impact on morbidity, mortality and alloimmunization. Int Urol Nephrol. 2018;50(10):1787-1793. doi:10.1007/s11255-018-1960-4
    CrossRef - PubMed
    
28. Nimmo A, McIntyre S, Turner DM, Henderson LK, Battle RK. The impact of withdrawal of maintenance immunosuppression and graft nephrectomy on HLA sensitization and calculated chance of future transplant. Transplant Direct. 2018;4(12):e409. doi:10.1097/TXD.0000000000000848
    CrossRef - PubMed
    
29. Toth F, Zadori G, Fedor R, et al. A single-center experience of allograft nephrectomies following kidney transplantation. Transplant Proc. 2016;48(7):2552-2554. doi:10.1016/j.transproceed.2016.08.002
    CrossRef - PubMed
    
30. Bonilla AJ, Alfaro AG, Henandez JP, et al. Review of a transplantectomy series. Transplant Proc. 2015;47(1):81-83. doi:10.1016/j.transproceed.2014.11.014
    CrossRef - PubMed
    
31. Ariyarathenam A, Bamford A, Akoh JA. Transplant nephrectomy - A single-center experience. Saudi J Kidney Dis Transpl. 2015;26(6):1108-1112. doi:10.4103/1319-2442.168557
    CrossRef - PubMed
    
32. Knight MG, Tiong HY, Li J, Pidwell D, Goldfarb D. Transplant nephrectomy after allograft failure is associated with allosensitization. Urology. 2011;78(2):314-318. doi:10.1016/j.urology.2011.02.068
    CrossRef - PubMed
    
33. Sener A, Khakhar AK, Nguan CY, House AA, Jevnikar AM, Luke PP. Early but not late allograft nephrectomy reduces allosensitization after transplant failure. Can Urol Assoc J. 2011;5(6):E142-E147. doi:10.5489/cuaj.10032
    CrossRef - PubMed
    
34. 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(2):374-380. doi:10.1681/ASN.2009050480
    CrossRef - PubMed
    
35. Muramatsu M, Hyodo Y, Sheaff M, et al. Impact of allograft nephrectomy on second renal transplant outcome. Exp Clin Transplant. 2018;16(3):259-265. doi:10.6002/ect.2018.0046
    CrossRef - PubMed
    
36. Schachtner T, Otto NM, Stein M, Reinke P. Transplantectomy is associated with presensitization with donor-reactive T cells and graft failure after kidney retransplantation: a cohort study. Nephrol Dial Transplant. 2018;33(5):889-896. doi:10.1093/ndt/gfy002
    CrossRef - PubMed
    
37. Sanchez-Gonzalez A, Carrasco-Valiente J, Arenas-Bonilla AJ, et al. Graft survival in patients who received second allograft, comparing those with or without previous failed allograft nephrectomy. Transplant Proc. 2016;48(9):2895-2898. doi:10.1016/j.transproceed.2016.09.016
    CrossRef - PubMed
    
38. Dinis P, Nunes P, Marconi L, et al. Kidney retransplantation: removal or persistence of the previous failed allograft? Transplant Proc. 2014;46(6):1730-1734. doi:10.1016/j.transproceed.2014.05.029
    CrossRef - PubMed
    
39. Fadli SE, Pernin V, Nogue E, et al. Impact of graft nephrectomy on outcomes of second kidney transplantation. Int J Urol. 2014;21(8):797-802. doi:10.1111/iju.12455
    CrossRef - PubMed
    
40. Tittelbach-Helmrich D, Pisarski P, Offermann G, et al. Impact of transplant nephrectomy on peak PRA levels and outcome after kidney re-transplantation. World J Transplant. 2014;4(2):141-147. doi:10.5500/wjt.v4.i2.141
    CrossRef - PubMed
    
41. Lucarelli G, Vavallo A, Bettocchi C, et al. Impact of transplant nephrectomy on retransplantation: a single-center retrospective study. World J Urol. 2013;31(4):959-963. doi:10.1007/s00345-012-0986-y
    CrossRef - PubMed
    
42. 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(1):87-92. doi:10.1007/s11255-012-0369-8
    CrossRef - PubMed
    
43. 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(3):284-291. doi:10.1111/j.1432-2277.2010.01197.x
    CrossRef - PubMed
    
44. Ahmad N, Ahmed K, Mamode N. Does nephrectomy of failed allograft influence graft survival after re-transplantation? Nephrol Dial Transplant. 2009;24(2):639-642. doi:10.1093/ndt/gfn567
    CrossRef - PubMed
    
45. 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(6):2368-2375. doi:10.1111/j.1523-1755.2005.00343.x
    CrossRef - PubMed
    
46. Yagmurdur MC, Emiroglu 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(7):2957-2961. doi:10.1016/j.transproceed.2005.07.022
    CrossRef - PubMed
    
47. 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(2):138-144.
    CrossRef - PubMed
    
48. Critical Appraisal Skills Programme. CASP Cohort Study Checklist online; 2018. Accessed January 3, 2020. https://casp-uk.net/casp-tools-checklists
    CrossRef - PubMed
    
49. OCEBM Levels of Evidence Working Group. The Oxford Levels of Evidence 2. https://www.cebm.net/index.aspx?o=5653
    CrossRef - PubMed
    
50. Pei R, Lee JH, Shih NJ, Chen M, Terasaki PI. Single human leukocyte antigen flow cytometry beads for accurate identification of human leukocyte antigen antibody specificities. Transplantation. 2003;75(1):43-49. doi:10.1097/00007890-200301150-00008
    CrossRef - PubMed
    
51. Milongo D, Kamar N, Del Bello A, et al. Allelic and epitopic characterization of intra-kidney allograft anti-HLA antibodies at allograft nephrectomy. Am J Transplant. 2017;17(2):420-431. doi:10.1111/ajt.13958
    CrossRef - PubMed
    
52. 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(8):1310-1319. doi:10.2215/CJN.00260112
    CrossRef - PubMed
    
53. Vlachopanos G, Bridson JM, Sharma A, Halawa A. Corticosteroid minimization in renal transplantation: Careful patient selection enables feasibility. World J Transplant. 2016;6(4):759-766. doi:10.5500/wjt.v6.i4.759
    CrossRef - PubMed
    
54. Wang K, Xu X, Fan M, Qianfeng Z. Allograft nephrectomy vs. no-allograft nephrectomy for renal transplantation: a meta-analysis. Clin Transplant. 2016;30(1):33-43. doi:10.1111/ctr.12654
    CrossRef - PubMed