A systematic literature search was performed in PubMed/MEDLINE® to identify reports (in French or English) on allograft nephrectomy, published between January 2000 and March 2026, in accordance with PRISMA criteria. The full search strategy is provided in Supplementary Table S1. Study selection was based on the PICOS criteria: Population (P): patients with graft failure after a first kidney transplantation, regardless of severity or age; Intervention (I): allograft transplantectomy (transplant nephrectomy), encompassing different surgical techniques; Comparator (C): other surgical approaches, immunosuppression management strategies, dialysis, or embolization; Outcomes (O): morbidity and mortality (including cardiovascular and immunological impact), adverse events (myocardial infarction, congestive heart failure, sepsis, etc.), time or access to retransplantation, anatomical feasibility for retransplantation, quality of life, and acceptability; and Study design (S): meta-analyses, randomized controlled trials, non-randomized prospective studies, or retrospective studies. Bibliographic data were complemented by literature monitoring (up to June 2024), consultation of international society websites (European Association of Urology, American Urological Association, British Transplantation Society, UK Kidney Association, and American Society of Transplantation), a search for systematic reviews in the Cochrane Library database, and suggestions from the working group. The search strategy was designed to address four predefined clinical questions: (1) the indications for kidney allograft transplantectomy and its optimal timing; (2) the immunological impact of transplantectomy and the management of immunosuppression before, during, and after the procedure; (3) surgical techniques for transplantectomy; and (4) alternatives to transplantectomy, including conservative management strategies. The present article reports the results of the literature selection and evidence synthesis related to question 2, focusing on immunological impact and management of immunosuppressants before, during, and after the allograft nephrectomy.

Inclusion and exclusion criteria were predefined prior to the study. Only studies addressing the immunological impact and management of immunosuppressants before, during, and after the allograft nephrectomy were included. Publications deemed ineligible were (i) health economic studies, as they largely depend on country-specific healthcare systems; (ii) case reports, narrative reviews, editorials, letters, or commentaries; (iii) experimental animal or in vitro studies; (iv) studies focusing on laboratory technology aspects; (v) studies on clinical practice patterns; and (vi) out-of-scope studies (e.g., not kidney-specific, public health topics not specific to kidney transplantation, immunosuppressive therapy efficacy, transplantation technique, donor nephrectomy techniques in living donors, dialysis modality, retransplantation, or primary non-function related to cancer).

Study selection was initially performed by the methodologist (DK) based on these criteria after abstract screenings. The selection was independently validated by the steering committee (TC, AF, AG, TP, and ADB) and subsequently by the full working group. Full texts of selected publications were then reviewed. Following an initial data extraction by the steering committee, the final set of included studies was confirmed by the steering committee, and any disagreements were resolved through discussion with the working group.

The methodological quality of the included studies was evaluated using validated critical appraisal tools appropriate to each study design (e.g., randomized, prospective non-randomized, or retrospective studies), combining criteria derived from the Haute Autorité de Santé (HAS) evidence appraisal framework [20], the STARD (Standards for Reporting Diagnostic Accuracy Studies) checklist [21], and the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2) tool [22], when applicable. These assessments considered the clinical relevance of the study objectives, representativeness of the selected patients, appropriateness of inclusion and exclusion criteria, relevance of the recruitment period, independence between cohorts, blinding of outcome assessment, identification and adjustment for potential confounding factors, clinical relevance of the compared methods, validity and definition of outcomes, as well as funding sources and conflicts of interest. The level of evidence (LoE) was attributed to each study after taking into account the protocol design and the risk of bias (Supplementary Table S2). The classification of conclusions by LoE (LoE1 is the highest; LoE4 the lowest) was based on the grid proposed by HAS [20]. The risk of bias was assessed independently by two reviewers, and discrepancies were solved by consensus. Randomized and prospective non-randomized studies were prioritized in the analysis, and retrospective studies were included but interpreted with caution. This work was then reviewed by 33 independent experts from all medical and surgical specialties involved in the management of patients with renal graft failure (10 urologists, 4 nephrologists, 4 pediatric nephrologists, 3 immunologists, 3 vascular surgeons, 2 pediatric urologists, 1 pediatric surgeon, 1 infectiologist, and 6 patient representatives). A summary of the methodological analysis of included studies is presented in Supplementary Table S2.

The failed graft constitutes a reservoir of donor antigens. In the absence of immunosuppression, ongoing antigen presentation by infiltrating recipient antigen-presenting cells (mainly after late allograft failure) or resident donor-derived cells (in case of early allograft failure) may promote recipient immune activation, leading to antibody formation. The inflammatory milieu surrounding the failing graft may amplify antigen presentation and costimulatory signaling [46–48].

Histopathological data support the role of inflammation. Goral et al [6] reported extensive inflammatory infiltrates in explanted grafts, including plasma cells and tertiary lymphoid structures, which may sustain local antibody production. In such contexts, graft nephrectomy may exacerbate antigen release, immune activation, and de novo DSA formation [14, 33].

It was also suggested that the failed graft could adsorb (or regulate) anti-HLA antibody specificities and prevent detection of some anti-HLA antibodies (the so-called “sponge effect”) despite the use of highly sensitive tests [43]. According to this hypothesis, removal of the antigen source could lead to an apparent increase in circulating anti-donor antibodies, as antibodies previously sequestered within the allograft become detectable following graft removal [16, 36]. However, this hypothesis has not been substantiated by direct experimental evidence and is instead supported by indirect clinical observations, including the rapid development of donor-specific antibodies following allograft nephrectomy [16]. However, it should be noted that sera considered as pre-allograft nephrectomy were collected several weeks before the surgery, which could represent a major bias. Recent studies have demonstrated that this effect is probably limited. Indeed, Milongo and colleagues [49] investigated the presence of anti-HLA DSA in both the blood and nephrectomy eluates in 17 patients. They observed that all anti-HLA DSA detected in the nephrectomy eluates were also detected in blood at the time of nephrectomy [49].

While graft nephrectomy has long been considered a major driver of alloimmunization, accumulating evidence suggests that its immunological impact is largely mediated by the management of immunosuppressive therapy rather than by the surgical removal of the graft itself (Table 3). Several studies consistently demonstrated that cessation of immunosuppressive therapy after graft failure is associated with a rapid and marked increase in anti-HLA antibodies, preceding nephrectomy. In a retrospective comparison study involving 69 patients who returned to dialysis and stopped their immunosuppression, Del Bello and colleagues [28] showed that discontinuation of immunosuppression led to a sharp rise in anti-HLA antibodies detection, regardless of whether nephrectomy was subsequently performed (anti-HLA DSA detected in 52% patients without a history of nephrectomy and 81% in those with nephrectomy). Augustine et al [34] further reinforced this concept by demonstrating in a cohort of 119 patients who returned to dialysis that late sensitization after kidney transplant failure was independently associated with immunosuppression weaning, even in the absence of nephrectomy. Patients who discontinued calcineurin inhibitors and antiproliferative agents experienced a significant increase in panel reactive antibodies (PRA) (Median PRA rose from 0% before transplantation to 57% in class I and 63% in class II, 6–24 months post graft failure), indicating broad alloimmune activation. Similar findings were reported by Nimmo et al. [29], who showed that withdrawal of maintenance immunosuppression was the dominant factor influencing the calculated chance of future transplantation, with nephrectomy exerting only a secondary effect. They observed in 41 patients that immunization (expressed by calculated reaction frequency, cRF) rose from 13% pre-immunosuppression weaning to 62% post immunosuppression withdrawal. In the subgroup of 17 patients who underwent graft nephrectomy, the mean cRF rose similarly to others, from 31% pre-immunosuppression wean to 69%. Kosmoliaptsis and colleagues [45] observed that the development of anti-HLA antibodies after return to dialysis in patients listed for another transplantation was independent of graft nephrectomy but associated with waitlist time and maintenance on dual immunosuppression.

The higher allosensitization observed after graft nephrectomy in comparison with immunosuppression weaning only could be related to the surgical intervention in inflammatory conditions and to the high rate of blood transfusion required during or immediately after the surgery [28, 29, 43]. Lucisano et al [33] conducted a retrospective study evaluating the relative contributions of transplantectomy and immunosuppression management to allosensitization in 109 patients. They found that continued immunosuppression (with tacrolimus levels ≥3 ng/mL) was associated with lower rates of de novo anti-HLA antibody formation, irrespective of whether transplantectomy was performed. Schachtner et al [31] extended this concept by demonstrating that graft nephrectomy was associated not only with humoral sensitization but also with presensitization at the T-cell level. They investigated the donor-reactive T cell response by using an IFN-γ ELISPOT assay in a cohort of 111 patients who returned to dialysis (51 with a history of graft removal and 60 without). They observed increased frequencies of donor-reactive T cells responses and inferior outcomes after retransplantation in patients with a history of graft removal in comparison with patients without.

Studies focusing on early graft nephrectomy (performed while immunosuppression is ongoing) highlight that sensitization could occur even if the graft nephrectomy is performed only a few minutes after the transplantation. Lenaers et al [35] reported an important (50% of patients) donor-specific alloimmunisation in 32 patients who lost their graft and underwent a nephrectomy during the first 4 months post transplantation. Similarly, Del Bello et al. [14] specifically examined early allograft nephrectomy (<3 months post transplantation) performed under immunosuppression and observed significant anti-HLA immunization (57% of patients after 9 months post nephrectomy). Similarly, when immunosuppression is maintained until nephrectomy in patients with late graft failure, allosensitization is frequent. In a retrospective study of 41 patients (17 with graft nephrectomy, all of whom were maintaining immunosuppression until the surgery), Nimmo and colleagues [29] found high allosensitization (the cRF rose from 31% pre-immunosuppression wean to 69% post-immunosuppression wean and 89% post-immunosuppression cessation). Similarly, Lachmann and colleagues [30] retrospectively compared the allosensitization rate in 28 patients who received a nephrectomy after immunosuppression discontinuation, in 14 patients who received a nephrectomy under immunosuppression (stopped immediately after), and 12 patients who stopped their immunosuppression without nephrectomy. They observed similar allosensitization rates (100% of patients after nephrectomy post immunosuppression withdrawal, 100% of patients after nephrectomy under immunosuppression, and 92% of patients who underwent an immunosuppression only). Matignon and colleagues observed that immunosuppression tapering in the month after the nephrectomy had limited impact on the development of allosensitization, as well as the use of high doses of intravenous immunoglobulins [27]. This could be explained by the persistence of some donor tissue after nephrectomy (in vascular patches). Alloimmunisation could then occur in patients who stop their immunosuppression after the surgery due to these residues [28]. Freist and colleagues [15] observed a lower rate of DSA in patients who maintained a calcineurin inhibitor-based immunosuppression (30/52 (57.7%) vs. 52/67 (77.6%), p = 0.02), as well as a lower rate of non-DSA allo-sensitization (17% vs. 38%, p = 0.03) regardless of the need for an allograft nephrectomy.

As expected, the number of HLA mismatches is an important factor leading to allo-sensitization [28, 40, 45]. All mismatched loci contribute to allosensitization in a similar way [45].

Beyond the formation of anti-HLA DSA, a broad allosensitization is frequently observed after immunosuppression tapering/discontinuation. By using HLA matchmaker™ [28, 41] or recombinant single HLA allele–expressing cell lines [30], several authors demonstrated that a majority of these anti-HLA non-DSA antibodies were directed against donor’s epitopes at the molecular level.

The impact of graft nephrectomy on subsequent retransplantation remains a matter of ongoing debate, as its clinical consequences are closely intertwined with alloimmunization and immunosuppression management. In a recent USRDS-based study, Achinger and colleagues observed that patients who underwent an allograft nephrectomy had higher chances of receiving a second transplant (subdistribution HR: 1.21, 95%CI[1.15–1.28, p < 0.001) [50]. When nephrectomy is performed under continued immunosuppression, its independent effect on retransplantation rates appeared limited (Table 2). In an initial meta-analysis of eight studies (1,008 patients), Wang and colleagues [51] did not observe a difference regarding the retransplant outcome (1 year graft survival: OR = 0.74; 95%IC [0.31–1.72]; p = 0.48, 1 year patient survival: OR = 1.60; 95%IC [0.57–4.46]; p = 0.37), acute rejection rate (OR = 1.30; 95%IC [0.89–1.91]; p = 0.17), post-operative complications (OR = 1.51; 95%IC [0.24–9.43]; p = 0.66), or graft function at 1 year (mean ponderate difference: -0.25; 95%IC [-0.52 à 0.03]). Nonetheless, patients with a history of graft nephrectomy present a prolonged time between dialysis and retransplantation (mean ponderate difference in months 11.23; 95%IC [2.47–19.99]; p = 0.01) and increased PRA of more than >10% (OR = 1.62; 95%IC [1.17–2.23]; p = 0.003). Another meta-analysis [13] that included 16 retrospective studies (2,256 patients) reported similar 5-year graft (HR = 1.11, 95%IC [0.89–1.38]; p = 0.37) and patient survival (HR = 0.70; 95%IC [0.45–1.10]; p = 0.12). Nonetheless, patients who underwent graft nephrectomy presented high PRA at retransplantation (%PRA: 39% vs. 35%; OR = 1.83; 95%IC [1.20–2.78]; p = 0.005), delayed graft function (39% vs. 30%; OR = 1.86; 95%IC [1.16–2.98]; p = 0.01), acute rejection (33% vs. 28%; OR = 1.70; 95%IC [1.31–2.22]; p = 0.001), and primary non-function (8% vs. 1.7%; OR = 3.41; 95%IC [1.31–8.89]; p = 0.001).

Collectively, these data suggest that graft nephrectomy in itself does not seem to have a detrimental effect on the outcomes of retransplantation.