Stesura Seveso Archivio Italiano di Urologia e Andrologia 2024; 96(3):12627 1 REVIEW INTRODUCTION Advancing into 3rd decade of the new millennium, progress of organ replacement care is rapidly evolving due to its promising prospect as the next definitive treat- ment for degenerative and chronic diseases. Kidney trans- plantation (KTx) is currently the state-of-art procedure to attenuate symptoms of end-stage kidney disease (ESKD), offering nearly “permanent” restoration despite requiring long-term close observation on the recipients (1, 2). The etiologies of ESKD are diverse, often resulted from multi- system damage and longstanding pathologic involvement of the kidney as observed in systemic lupus erythematosus (SLE) (3). Immune-complex deposition plus abnormal interplay of immune cells’ response in SLE may cause persistent kidney damage termed lupus nephritis (LN), which is clinically confirmed by laboratory and biopsy evaluation (4). The prevalence of SLE among the global population is estimated to be between 48 to 366.6 per 100.000 indi- viduals, with at least 50% of cases developing LN at some point, and 10-30% progressing further into ESKD (5, 6). ESKD is the most aggravating complication of LN, that primarily affects young female population (mean diagno- sis age of 31.2 years old) and has a 10-20% probability to progress into ESKD within 15 years from diagnosis (7). As a kidney replacement therapy, KTx offers major prospects on treatment’s effect longevity, although indi- viduals with SLE/LN might possess higher risk for devel- oping worse prognostic value. Although outcomes of KTx had been generally associated to other factors as ethnic/racial differences, related to the genetical suscepti- bility and local lifestyle, the apparent influence on KTx outcome of prior LN diagnosis, as the underlying etiolo- gy, remains questionable, specifically in the last couple of decades with some remarkable breakthroughs in trans- plant-molecular science (8, 9). Regardless its distinctive autoimmune origin and subse- Background: The actual prognostic impact of prior lupus nephritis (LN) diagnosis on end-stage kidney disease (ESKD) patients remains question- able, especially in relation to outcomes of kidney transplanta- tion (KTx) We aim to determine the survival of the graft and recipient after the KTx procedure among patients with ESKD due to LN in comparison to non-LN. Methods: This meta-analysis included retrospective studies from the last two decades, focusing on the KTx’s outcomes among ESKD due to LN in comparison to non-LN. We estab- lish the graft/recipient survival rate at different follow-up intervals as the primary outcome, and acute graft rejection and pooled graft failure rate as secondary outcomes. All analyses were performed with the random-effect model (REM) and were presented as odd ratio (OR; within 95% confidence interval (CI)). The protocol of this study was registered in PROSPERO: CRD42023394310. Results: A total of 1,299 KTx (368 LN patients) from 10 stud- ies with >10 years of follow-up were thoroughly reviewed. All checkpoints (at 1-, 5-, 10, and 15-year post-KTx) on graft sur- vival rate demonstrated comparable outcomes in either LN or non-LN (e.g., at 10-year follow up (OR, 1.08 [0.40, 2.91]; p = 0.88). Similar findings at all checkpoints for recipient survival rate were also observed without statistically significant differ- ence between LN and non-LN arm (e.g., at 10-year checkpoint; OR, 0.99 [0.68, 1.46]; p = 0.98). Both of our secondary analy- ses also presented insignificant differences (p = 0.70 and = 0.16, respectively). Conclusions: Our findings suggested that prognosis of ESKD due to complicated LN is equal compared to ESKD associated with non-LN etiologies, suggesting the impact of LN as the inducing cause of ESKD on KTx outcome is relatively neglec- table. KEY WORDS: Graft survival; Kidney transplantation; Lupus nephritis; Systemic lupus erythematosus; Recipient survival. Submitted 30 April 2024; Accepted 2 June 2024 Redefining kidney transplantation procedure among adult Lupus nephritis: Expedient review approach and meta-analysis from the last couple of decades Syah Mirsya Warli 1, 2, Andi Raga Ginting 3, Naufal Nandita Firsty 4, Adrian Joshua Velaro 5, Stephani Clarissa Sembiring 6, 7, Dewi Masyithah Darlan 8, Zaimah Zulkarnaini Tala 9 1 Department of Urology, Universitas Sumatera Utara Hospital, Universitas Sumatera Utara, Medan, Indonesia; 2 Division of Urology, Department of Surgery, Faculty of Medicine, Universitas Sumatera Utara - Haji Adam Malik General Hospital, Medan, Indonesia; 3 Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia; 4 General Practitioner, Putri Hijau Level II Military Hospital, Medan, Indonesia; 5 General Practitioner, Djasamen Saragih Hospital, Pematang Siantar, Indonesia; 6 General Practitioner, Sipirok Hospital, South Tapanuli Regency, Indonesia; 7 Department of Pediatrics, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia; 8 Department of Parasitology, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia; 9 Department of Nutrition, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia DOI: 10.4081/aiua.2024.12627 Summary Archivio Italiano di Urologia e Andrologia 2024; 96(3):12627 S. Mirsya Warli, A. Raga Ginting, N. Nandita Firsty, et al. 2 quent requirement of systemic management, should the general transplant care be extended to LN-related KTx? Is the outcome of KTx recipients remarkably worse than general population, hence requiring early robust observa- tion? Should the current research progress be focused on preventing SLE-related flare after KTx? This review is aimed to define the prognostic aspect of kidney-transplanted individuals after ESKD following complicated LN in comparison with non-LN etiologies, by focusing on the grafts and recipients’ survival plus the overall rejection status. MATERIALS AND METHODS Registration and protocol The protocol of this review had been approved and regis- tered in PROSPERO: International Prospective Register of Systematic Reviews under issue ID CRD42022376362. Study design, search strategy, and eligibility criteria We conducted this study based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) protocol to address our main clinical question on whether the KTx’s outcomes among individuals with LN with ESKD are different to those of ESKD due to other eti- ologies. Online electronic databases e.g., PubMed, ScienceDirect, Cochrane Library and ProQuest were thor- oughly searched to retrieve all eligible literatures (in English) until November 2022. We employed Boolean method to connect the keywords on abstract/title-based identification i.e. (“Lupus Nephritis”) AND (“Systemic Lupus Erythematosus”) AND (“Kidney Transplantation”). Each keywords derivatives or synonyms e.g., ‘renal trans- plantation’ for the ‘kidney transplantation’ phrase was also included through “OR” keywords in between. Duplicate documents were automatically identified by using Mendeley (version 1.19.8) software, and subsequently removed. The literatures were initially screened by two authors (S.M.W. and N.N.F.) through relevant abstract- to-full text identification, followed by group discussion with other co-authors for any identified discrepancies. To date, most of the studies investigating KTx were designed as either cohort or case-control analysis, consid- ering that the procedure itself is a “personalized approach” for both donor (either living or deceased) and recipient, therefore assumption to organize a trial-based investiga- tion is impractical in this case. Consequently, the reviewed literatures mainly consisted of studies with aforementioned designs (cohort and/or case-control), covering an adequate period of time (≥ 10 years of cover- age from either single- or multi-centre records) in a geo- graphical region (or nation), but not restricted to specific continent or race. Studies older than a decade are includ- ed in this review since we aimed to synthesize reliable evi- dences from previous years (or the new millennia i.e., > year 2000), capturing how the progress had evolved over time. However, we also excluded nationwide cohort, which might solely rely on medical records and were often conducted by independent investigators (outside of the KTx-eligible centres) to reduce “gap” in population size and avoid potential statistical bias. Risk of bias assessment and data extraction The risk-of-bias (RoB) were collectively assessed by three authors (N.N.F., A.J.V., and S.C.S.), using a criteria appraisal tools by Joanna Briggs Institute (JBI), each specifi- cally designed for estimating the bias level of both cohort and case-control studies (10, 11). Discrepancies between each interpretation were resolved through a re-assess- ment of respective studies in an internal discussion with the first author (S.M.W.). To systematically summarize our finding, we extracted the following information from each study: its design, region and period, diagnosis of included patients and controls, both arm’s characteristics (age, donor status, pretransplant dialysis status, and pre- transplant dialysis duration (in months)). In the quantitative analysis, we applied proportional-odds model to compare each group which focused on graft and patient survival analysis as the primary outcomes. We also secondarily investigate the acute graft rejection (< 1 month) to represent short-term graft-host interaction and overall graft-failure, accumulated throughout the full- duration of cohort and case-control studies. Effect measures and statistical analysis Variations might be observed considering both cohort and case-control studies were included in the final analy- sis (as indicated by I square (I2) value). Therefore, this meta-analysis will be conducted by a random-effect model (REM) to reduce the heterogeneity’s impact on the final estimation. The statistical analysis was performed by Review Manager (RevMan) 5.4 to capture our review model on Forest plots whilst estimating odd-ratio (OR) value in 95% confidence interval (CI; P value of < 0.05 was considered to be statistically significant). This review also attempted to conduct sub-group analysis on graft- and patient-survival based on time-point of follow-up (e.g., 1-year, 5-year, 10-year, and 15-year after KTx.). However, it should be noted that not all studies provide complete reports from the aforementioned checkpoints due to limitations in the observation period and reporting model. We prefer OR over risk ratio (RR) parameter since our review also comprised of case-control study, in which the latter study model is basically tracking the exposure from cases and controls populations (rather than identifying the exposure, then analyzing the subsequent outcomes); thus OR is more preferrable in this situation (12). Inclusion of case-control study in this review is justifi- able, considering KTx procedure among LN patients are relatively uncommon requiring an individualized care, hence we prioritize to synthesize as much evidence as possible. A meta-epidemiological study by Lanza et al. suggested that meta-analysis with both cohort and case- control studies included might possess no statistically sig- nificant difference in estimating treatment effects, which can be applied as well in our study (13). A set of sensi- tivity analysis was conducted as well by restricting the analysis to investigations which included only adult age populations (> 18 years old), performed the KTx from liv- ing donor source > 50.0% of the total, cohort-only analy- sis, and applying leave-one-out approach by removing individual studies one at a time to confirm its overall influence in pooled estimation. Archivio Italiano di Urologia e Andrologia 2024; 96(3):12627 3 Kidney transplantation in adult Lupus nephritis RESULTS After thorough identification of studies from literature (Figure 1), we included 10 studies (8 retrospective cohorts) from multiple regions with at least 10 years of investigation period (Table 1). Uncontrolled studies, nationwide investigations, studies that included general rheumatic diseases other than SLE- LNs, and those with different aims (e.g., focusing on eth- nic/race influence, re-transplantation, etc.) were excluded from the final analysis (Figure 1). All patients were diag- nosed with ESKD due to LN’s complication following SLE diagnosis, and were compared to a control group (i.e., ESKD resulting from any other disease except for LN or SLE’s kidney manifestation). All studies enlisted > 50 indi- viduals in total, though the participant’s distributions were not always in 1:1 ratio and the study population might be compared to a control group twice it size (e.g., 25 vs. 50 individuals) (14-23). A total of 368 KTx procedure from LN arm were com- pared to 931 controls, with majority of studies consisting of females (mostly > 70.0% of the total study size), except for a cohort by Pampa-Saico in 2019. The mean ages (or median) of the populations were relatively homogenous, ranging from 3rd to 5th decade of life. Though variability in population’s age occurred, inclusion of all the cohorts is still within our review scope since specific limitation on studied population’s age was not applied. The donor sta- tus of the transplanted kidney included both living (either related or unrelated donor) and deceased donor. Five studies (Ghafari et al., Horta-Baas et al., Lionaki et al., Park et al., Ramirez-Sandoval et al., and Roozbeh et al.) reported living donors to be > 50.0% of organ source. Pretransplant dialysis method and duration were also provided on Table 1 though significant difference on baseline characteristics was not observable. The RoB assessment results in Table 2 demonstrated the majority of confounding aspects in our studies were completely reported based on the JBI-based quality scoring. Figure 1. Process of identifying the eligible studies by utilizing PRISMA 2020 flow diagram. Archivio Italiano di Urologia e Andrologia 2024; 96(3):12627 S. Mirsya Warli, A. Raga Ginting, N. Nandita Firsty, et al. 4 Graft and recipients’ survival Our first primary analysis on graft survival demonstrated that there was not any statistically meaningful difference between the two arms based on the modelled propor- tional-odd estimation (Figure 2). On sub-group analysis at 1-year post-KTx, the estimated OR value was 0.79 [0.38, 1.62] in 95% CI (p > 0.05), slightly favouring LN population though statistical difference was not signifi- cant. However, analysis at the following checkpoint (5- year post-KTx) revealed a lower OR of 0.74 [0.41, 1.32] in 95% CI (p = 0.31). The latter results represent a lower possibility of longer sur- viving grafts among non-LN population despite this change does not directly translate into a significant finding upon 95% CI estimation. Further analysis on 10- and 15-year post-KTx demonstrated that the long-term follow-up of graft survival does not show any difference between the two groups. Moreover, our analysis also depicted a progressive- ly reduced graft survival rate throughout the observation period (only 46.8% vs. 28.2% of the transplanted kidney will survive after 10 years in LN vs. non-LN etiology, respectively). Comparison of those rates with those observed at earlier checkpoints (e.g., 1st year (89.7% vs. 86.9; p = 0.52, and 5th year 62.3% vs. 63.5%; p = 0.31) revealed consistent reductions on graft survival, which even lower rates at 15th year with only 42.4% (LN) vs. 38.2% (non-LN); p = 0.83. Those percentages were congregated from the Figure 2 by calculating the event-to-total rate in each arm (i.e., grafts’ survival rate per total KTx performed). Overall analysis on the recipient survival comparison demonstrated similar outcomes to the corresponding graft status after several years of follow-up (Figure 3). On 1-year Table 2. Risk of bias assessment by checklists provided by Joanna-Briggs Institute (10, 11). Table 1. Summary of the included studies of this review. LN/non-LN KTx characteristics Study Design, region, Study size (n) Age (years) Living donor (%) Pretransplant dialysis % (HD, PD) Pre-transplant dialysis and studied period and female duration (months) percentage (%) LN non-LN LN non-LN Ghafari 2008 Retrospective cohort, 23(78.2)/60(81.6) 22.5 ± 16.0 26.2 ± 18.0 (77 a/23b)/(40 a/60 b) NA NA Iran (SC; 1989-2006) Horta-Baas 2018 Retrospective cohort, 25(76.0)/50(74.0) 20.5 (10-50) (84 a/8b)/(43 a/3 b) 36/48/12 c 22/62/6 c NA Mexico (SC; 2003-2014) Lionaki 2008 Case-control, (26/26; 89.0) 34.4 ± 9.2 36.9 ± 10.5 54 a/54 a NA 30.0 ± 29.0/42.7 ± 48.7 Greece (SC; 1985-2005) Moroni 2005 Retrospective cohort, 33(78.8)/70(80.0) 34.6 ± 9.9 35.8 ± 9.8 26/26 73/27 83/17 42.0 ± 38.4/47.6 ± 45.9 Italy (SC; 1982-2004) Naranjo-Escobar 2017 Case-control, 65(85.0)/65(85.0) 34 (27-43) 31/25 48/15/31 c/6d 49/22/18 c/11 d 35 (16-62)/31 (20-49) Colombia (SC; 1996-2014) Pampa-Saico 2019 Retrospective cohort, 47(39.5)/367(36.2) 38.5 ± 13.4 44.0 ± 14.0 * NA NA 30.1 ± 27.7/30.8 ± 31.5 Mexico (SC; 1980-2014) Park 2017 Retrospective cohort, (19/18; 100.0) 43.5 ± 10.2 43.6 ± 10.5 (79 a/5b)/(39 a/6 b) * 74/21/5d 43.3 ± 47.9/50.3 ± 43.8 Korea (SC 2005-2016) Ramirez-Sandoval 2018 Retrospective cohort, 74(83.0)/148(80.0) 31.5 ± 10.2 32.1 ± 10.4 66/65 NA NA USA (SC 1979-2015) Roozbeh 2011 Case-control, 33(NA)/33(NA) 26.8 ± 8.0 26.7 ± 8.0 (18 a/45 b; both arm) NA 24.3 ± 24.0/14.3 ± 8.9 Iran (SC; 1990-2004) Yu 2008 Retrospective cohort, 23(87.3)/94(81.7) 33.7 ± 10.3 33.6 ± 11.6 4/7 70/30 78/22 29.7 ± 28.4/26.1 ± 32.2 Taiwan (SC; 1984-2007) a Living-related donor; b Living-unrelated donor; c Both HD-PD; d No pretransplant dialysis at all; * Significant baseline difference (p < 0.05). ESRD: End-stage renal disease; GN: Glomerulonephritis; LN: Lupus nephritis; NA: not available. Archivio Italiano di Urologia e Andrologia 2024; 96(3):12627 5 Kidney transplantation in adult Lupus nephritis post-KTx, the estimated OR value was 0.94 [0.26, 3.43] in 95% CI (p > 0.05). Conversely to the previous analysis, we observe that after 5 years of KTx the OR value of recipient survival is slightly favouring non-LN population (1.52 [0.72, 3.21] in 95% CI (p = 0.27)). Nevertheless, this find- ing does not possess any significance in our estimation model though the findings are interesting to be elaborated further. Further analysis on 10- and 15-year post-KTx dis- closed similar results with those observed for graft, as this analysis failed to show any difference (both p > 0.05). Additionally, we observed a remarkable challenge of trans- plantation care in relation to the progressively reduced recipient survival rate after years of observation. In com- parison, the 1st year survival rate was 96.3% vs. 95.7% (p = 0.93) in LN and non-LN arm, respectively. However, the patients’ survival rate was massively affected throughout the years with reduced values at 5th year (80.8% vs. 74.0%; p = 0.27), 10th year (69.3% vs. 59.6%; p = 0.98), and 15th year (65.1% vs. 61.8%; p = 0.75). Acute and chronic graft rejection status Secondary investigation was conducted on the recorded Figure 2. Graft survival after 1, 5, 10, and 15 years of follow-up post-kidney transplantation. Archivio Italiano di Urologia e Andrologia 2024; 96(3):12627 S. Mirsya Warli, A. Raga Ginting, N. Nandita Firsty, et al. 6 rejection rate within acute graft reaction period (< 1 month) and pooled graft failure during each complete study period (Figure 4). The estimation of acute rejection demonstrated an OR value of 1.06 [0.77, 1.47] in 95% CI (p = 0.70). The fol- lowing analysis on pooled graft failure disclosed similar outcomes which delineated insignificant difference among both groups, as represented by a OR value of 1.48 [0.86, 2.55]; 95% CI (p = 0.16). For that reason, our results concluded that the etiology of LN hardly influence the grafts’ reaction rate in both short- and long-term observation. Sensitivity analysis The influence of living-donor graft status was not observed on all analysis, since most of the sub-group estimation remain statistically insignificant. However, at 5-year post- KTx checkpoint of grafts’ survival analysis, we observe a significant finding (p < 0.05) with the OR value at 0.41 [0.24, 0.69] in 95% CI, favouring the LN arm by only including studies with > 50.0% living-donor percentage. Further sensitivity analysis on pooled rejection status also demonstrated similar outcomes to our primary report, with neither LN nor non-LN having better estimation on both acute rejection (OR 1.01 [0.61, 1.68]; p = 0.98) and graft Figure 3. Recipient survival after 1, 5, 10, and 15 years of follow-up post-kidney transplantation. Archivio Italiano di Urologia e Andrologia 2024; 96(3):12627 7 Kidney transplantation in adult Lupus nephritis Figure 4. Meta-analysis of graft’s reaction on acute- and chronic-phase post-renal transplantation after maximum follow-up period in each study. failure variable (OR 1.97 [0.84, 4.60]; p = 0.12) in 95% CI. Those sensitivity analysis draw a confounding question on LN-etiology influence; how does the population has better grafts’ survival in 5-year post-KTx checkpoint, but also possess similar pooled graft failure risk? (The Forest plot outcomes of these sensitivity analysis are available on supplementary data). DISCUSSION Current research in transplantation care is focused on improving the prognosis, by avoiding graft rejection or subsequent organ failure. The transplant procedure is a demanding task in modern medicine, and issues need to be addressed beforehand, as donor organ shortage and preservation, recipients’ compatibility, technological lim- itation, and the main issue reviewed in this study that was graft and recipient survival in a special population (2, 24, 25). The role of other renal replacement therapy (RRT) is considered to be pivotal and often deemed to be the only regular ESKD ‘treatment’ option available in remote regions. Both haemodialysis and peritoneal dialysis hold much advantages in early-cost effectiveness and are rela- tively “attainable” in short-term, yet their advantages remain controversial in continuous and long-term run (26). The patient may discontinue the dialysis and pro- ceed to KTx option since its overall outcomes are signifi- cantly better than prolonged and routine dialysis, which eventually involves pitfalls on the individuals’ quality of life (1, 27). However, transplantation may involves the risk of early (< 1 month) or longer-term host-graft reac- tion, though it is generally accepted that the patient may achieve high survival rate in case of minimal rejection event (28). Moreover, chronic graft rejection will eventu- ally lead into lower graft survival, creating the necessity to identify the outcome-influencing factors. Donor transplantation procedure requires a complex col- laboration to establish recipient eligibility and organ availability. Eligible recipients are placed on a “waiting list” and selected based on several “qualifications” related to life expectancy (26, 29). The statement “different ESKD’s etiology might manifest unique outcomes” is related to the personalized medicine program, based on the the- oretically reasonable idea that a pathology might induce a specific reaction in a specific patient. Though the recur- rence-related concern is relatively rare among LN, it was presumed to be correlated with high-titers of anti-phos- pholipid antibodies, therefore the immunosuppressive options of post-KTx care may significantly reduce its impact (30, 31). The 2020 clinical guideline by Kidney Disease Improving Global Outcomes (KDIGO) placed the recommendation “not excluding” for selection of LN patients to KTx but also assessed that minimal disease activity should be achieved prior to the procedure (32). Even though the recommended waiting time to trans- plant among LN patients is ideally as short as possible, European League Against Rheumatism and European Kidney Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) suggested that the patients should achieve controllable disease for at least 3-6 months prior Archivio Italiano di Urologia e Andrologia 2024; 96(3):12627 S. Mirsya Warli, A. Raga Ginting, N. Nandita Firsty, et al. 8 to be eligible for KTx (33). Considering its autoimmune course, combination of the underlying dysfunctional immune reaction plus expected host-graft’ reaction could theoretically drive the prognostication of much worse outcomes of RTx for LN patients. Requirements of stan- dardized induction and maintenance therapy for both LN and transplantation procedures is another issue to be resolved. Performing KTx on serologically active SLE might involve an higher risk of subsequent recurrence and lower graft/recipient survival, thus, apart from its complicated LN, the underlying lupus should be quies- cent or stable within minimal or no immunosuppressive influence (34, 35). The main objective of our study was to determine whether LN may significantly influence KTx outcomes, so we sole- ly scoped the survival-related outcomes without describ- ing much of its influencing factors from each study. To our knowledge, this is the first systematic review and meta-analysis to compare LN versus non-LN etiology among ESKD patients which received KTx. Revisiting the outcomes of this demanding procedure is unquestionably essential to establish the impact of this variable in patients who underwent KTx. This review basically concluded that there are no signifi- cant differences (p > 0.05) between LN versus non-LN arm, according to proportional-odds estimation at differ- ent timing of follow-up (1-, 5-, 10-, and 15-years post- KTx). The results are relatively consistent throughout each observation period, though the latter checkpoint only involved 3-4 studies at the most. If the analysis was aimed solely to OR values, fluctuations at each check- point, were statistically inconsistent. Throughout each checkpoint estimation, our analysis was unable to observe even a slightest suggestion to differentiate the outcomes, excluding the hypothesis that LN might nega- tively influence the graft/recipient survival. This lack of differences might be originated from diverse etiologies included in non-LN population or other factors such race/ethnicity or others, although our simplified conclu- sion is that LN might, in fact, did not involve a worse prognostic value compared to KTx procedures in general. Several controversies around possible factors influencing graft and patients’ survival after KTx had been elaborated, and yet, the most commonly described variables are the absence of induction treatment, multiple immunosup- pressant medication, pre-existing comorbidities, higher body mass index, donor/recipient of Afro-American race, non-living donor, longer dialysis time, prior dialysis Figure S1. Graft’s survival after 1, 5, 10, and 15 years of follow-up post-renal transplantation limited to studies which included 50.0% living-donor. Archivio Italiano di Urologia e Andrologia 2024; 96(3):12627 9 Kidney transplantation in adult Lupus nephritis Figure S2. Meta-analysis of recipients’ survival after 1, 5, 10, and 15 years of follow-up post-renal transplantation limited to studies which included 50.0% living-donor. Figure S3. Meta-analysis of graft’s reaction on acute- and chronic-phase post-renal transplantation after maximum follow-up period in each study; limited to studies which included 50.0% living-donor. Archivio Italiano di Urologia e Andrologia 2024; 96(3):12627 S. Mirsya Warli, A. Raga Ginting, N. Nandita Firsty, et al. 10 method, lower adherence to treatment or routine control, and delayed graft function (36-38). It is highly perceivable that the concomitant SLE might theoretically worsen outcome of KTx procedures consid- ering the similarity of risk factors between graft loss and the SLE (37, 39, 40). Specific evaluation on the causes of graft loss was not performed in this study, even though chronic graft nephropathy was the most common etiolo- gy, followed by thrombotic events which are related to anti-phospholipid antibody (APA) positivity or pregnancy. The population age was younger in LN arm, raising the hypothesis that this might affect the outcome of the pro- cedure. Did it favour the survival or early onset translat- ed into more severe course of disease? Another issue is the statistical design of the studies which estimated the prognosis by hazard-ratio (HR) value in Kaplan-Meier curve. Since not all studies provided those details, we adapted our approach to the proportional- odds model evaluating values corresponding to each checkpoint of follow-up, although this choice is our main limitation in providing more accurate estimation in sur- vival rate, Our review primarily consisted of retrospective studies that lack the advantages of randomization and all the benefits of trial-investigation. We incorporated both case-control and cohorts into the same pooling of analysis because of the scarcity of the included studies that obliged us to perform a meta-analy- sis of all the studies available at that point. Only 3 case- control studies (Lionaki et al., Naransjo-Escobar et al., and Roozbeh et al.) were included in the final analysis (16, 18, 22), however it should be underlined that differences in design compared to other retrospective cohorts may act as an important selection bias (originated from case-con- trol studies) in this review (41). Nevertheless, our pri- mary outcome was statistical confirmation of KTx out- come to justify KTx among LNs, since it might offer bet- ter quality of life or superior survival rate compared to individuals in routine dialysis schedule. We encourage future original studies on LN-ESKD-KTx subjects to be focused on identifying factors preceding grafts loss and subsequent recipient mortality in order to evaluate not only grafts rejection rate but also the best modality of control of SLE activity and prevention of LN recurrence by managing the most appropriate immuno- suppressants. CONCLUSIONS KTx procedure in ESKD with LN etiology is equally ben- eficial in short- and long-term outcomes compared to procedure in patients with non-LN etiologies since no statistically significant difference of outcomes were observed. Hence no special care was practically required on the LN population. 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Correspondence Syah Mirsya Warli, MD, PhD warli@usu.ac.id Department of Urology, Universitas Sumatera Utara Hospital, Universitas Sumatera Utara, Medan, Indonesia Division of Urology, Department of Surgery, Faculty of Medicine, Universitas Sumatera Utara - Haji Adam Malik General Hospital, Medan, Indonesia Jl. Dr. Mansyur, No.66, Medan, North Sumatera, 20154, Indonesia Andi Raga Ginting andi.raga@usu.ac.id Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia Naufal Nandita Firsty acnaufal06@gmail.com General Practitioner, Putri Hijau Level II Military Hospital, Medan, Indonesia Adrian Joshua Velaro ajoshuav@gmail.com General Practitioner, Djasamen Saragih Hospital, Pematang Siantar, Indonesia Stephani Clarissa Sembiring stephaniclarissas@gmail.com General Practitioner, Sipirok Hospital, South Tapanuli Regency, Indonesia Department of Pediatrics, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia Dewi Masyithah Darlan dewi2@usu.ac.id Department of Pediatrics, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia Zaimah Zulkarnaini Tala zaimah@usu.ac.id Department of Nutrition, Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia Conflict of interest: The authors declare no potential conflict of interest. The initial version of this study has been presented as poster presentation session of World Congress of Nephrology (WCN) 2023 by the International Society of Nephrology (ISN) from March 30th to April 2nd, 2023 in Bangkok, Thailand.