Composition Vendor Newgen KnowledgeWorks (P) Ltd. PLoS One plos plosone PLOS One 1932-6203 Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0353887 PONE-D-25-66090 Research Article Medicine and health sciencesEpidemiologyMedical risk factors Medicine and health sciencesSurgical and invasive medical proceduresTransplantationOrgan transplantationRenal transplantation Medicine and health sciencesSurgical and invasive medical proceduresUrinary system proceduresRenal transplantation Biology and life sciencesAnatomyRenal systemKidneys Medicine and health sciencesAnatomyRenal systemKidneys Medicine and health sciencesSurgical and invasive medical proceduresBiopsy Physical sciencesChemistryChemical compoundsOrganic compoundsSteroids Physical sciencesChemistryOrganic chemistryOrganic compoundsSteroids Medicine and health sciencesClinical medicineClinical immunologyTransplantation immunology Biology and life sciencesImmunologyClinical immunologyTransplantation immunology Medicine and health sciencesImmunologyClinical immunologyTransplantation immunology Medicine and health sciencesPharmacologyDrugsImmunosuppressives Biology and life sciencesImmunologyImmune suppression Medicine and health sciencesImmunologyImmune suppression Medicine and health sciencesClinical medicineSigns and symptomsImmune suppression Incidence and risk factors for recurrent IgA nephropathy after kidney transplantation: A multicenter cohort study from Denmark Recurrent IgA nephropathy after kidney transplantation https://orcid.org/0000-0002-8570-1513 Øhrstrøm Mette Thrane Conceptualization Data curation Formal analysis Funding acquisition Investigation Methodology Project administration Validation Visualization Writing – original draft Writing – review & editing 1 * Schultz Michael Dyrehauge Data curation Investigation 2 Bistrup Claus Conceptualization Investigation Methodology Project administration Supervision Writing – review & editing 2 3 Birn Henrik Conceptualization Methodology Project administration Supervision Writing – review & editing 1 4 Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark Department of Nephrology, Odense University Hospital, Odense, Denmark Department of Clinical Research, University of Southern Denmark, Odense, Denmark Department of Clinical Medicine, Aarhus University, Aarhus, Denmark Alwahaibi Nasar Editor Sultan Qaboos University College of Medicine and Health Science, OMAN

HB declares consultancy and/or advisory board participation for NOVO Nordisk, Astra-Zeneca, Boehringer Ingelheim, Bayer, Alexion, Vifor Pharma, Otsuka, Galapagos; speakers honorarium from Astra-Zeneca, Astellas, Novartis and MSD; as well as research grants from Vifor Pharma, GSK, NOVO-foundation, Karen Elise Jensen Foundation and Augustinus Foundation. The other authors declare that they have no competing interests.

 * E-mail: mette.oehrstroem@midt.rm.dk 2072026 2026 21 7 e0353887 22122025 3062026 2026 Øhrstrøm et al This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background

Recurrent immunoglobulin A nephropathy after kidney transplantation remains a major clinical challenge, but risk factors are not fully defined. This study aimed to evaluate the incidence of biopsy-proven recurrent IgAN and identify risk factors for recurrence in a contemporary Scandinavian cohort.

 Methods

We conducted a multicenter cohort study including adult patients with biopsy-proven immunoglobulin A nephropathy who received a first kidney-only transplantation between 1990 and 2020 across two Danish transplantation centers. Recurrence incidence and associations with clinical and donor-related characteristics were assessed during follow-up.

 Results

A total of 118 recipients were followed for a median of 5.5 years. Biopsy-confirmed recurrence occurred in 14% of patients, corresponding to a cumulative incidence of 16% at 10 years post-transplantation. Younger age at immunoglobulin A nephropathy diagnosis, faster progression to kidney failure, and receipt of a kidney from a living or genetically related donor were independently associated with an increased risk of recurrence. Maintenance post-transplant steroid use was not associated with recurrence. Recurrent immunoglobulin A nephropathy was associated with an increased risk of graft failure compared with non-recurrent disease (unadjusted HR 3.8; adjusted HR 6.7).

 Conclusions

Recurrence of IgAN after kidney transplantation remains a clinically significant challenge, associated with younger age, rapid progression to KF, and transplantation from living or genetically related donors. Maintenance post-transplant steroid use was not associated with recurrence risk in this cohort. Larger and more diverse cohorts are warranted to clarify donor-related risk, strengthen the evidence on immunosuppressive protocols and guide strategies to improve graft outcomes.

 http://dx.doi.org/10.13039/501100004915 Nyreforeningen https://orcid.org/0000-0002-8570-1513 Øhrstrøm Mette Thrane http://dx.doi.org/10.13039/501100004824 Dansk Nefrologisk Selskab https://orcid.org/0000-0002-8570-1513 Øhrstrøm Mette Thrane Department of Renal Medicine, Aarhus University Hospital https://orcid.org/0000-0002-8570-1513 Øhrstrøm Mette Thrane MØ received funding from the Danish Kidney Association (https://www.nyre.dk/, no grant number applicable), the Danish Society of Nephrology (https://nephrology.dk/, no grant number applicable), and the Department of Renal Medicine at Aarhus University Hospital (https://www.en.auh.dk/departments/department-of-renal-medicine/, no grant number applicable). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data Availability The data underlying this study contain sensitive patient information obtained from medical records. According to Danish legislation, including §46(2) of the Danish Health Care Act, access to such data requires specific approval. In this study, data access was approved by the Region of Southern Denmark, which acts as the competent authority for disclosure of patient data under Danish law. Data disclosed for this project may only be shared for further scientific purposes upon prior approval from the Region of Southern Denmark. Due to the relatively small and well-defined cohort, there remains a risk of re-identification even after de-identification; therefore, the data cannot be made publicly available. De-identified data may be made available for scientific purposes upon reasonable request and with approval from the Region of Southern Denmark. Requests for data access should be directed to OPEN, Open Patient data Explorative Network, Region of Southern Denmark (email: ouh.projektjura@rsyd.dk), which can facilitate data access requests to the Region of Southern Denmark. Introduction

Immunoglobulin A nephropathy (IgAN) is the most common glomerulopathy worldwide and progresses to kidney failure (KF) in 30–50% of affected individuals [1–3].

Most patients are diagnosed before age 40, making many eligible for kidney transplantation during their lifetime [3,4]. IgAN accounts for 7–14% of all kidney transplants [5,6].

IgAN recurs in 9–52% of kidney allografts, partly depending on biopsy strategies [7]. Although not all recurrences lead to graft loss, a large retrospective registry study including 9,690 patients from the OPTN/UNOS database reported recurrent IgAN as the third most common cause of graft failure in patients with IgAN as the primary disease [8]. No effective treatment exists for recurrent IgAN, which makes the identification of risk factors crucial for prevention and improved outcomes [9].

Several factors have been associated with increased risk of IgAN recurrence, including donor type, young age, higher HLA-mismatch, and immunosuppressive regimens [10–12]. The potential role of donor type, particularly living and genetically related donors remains uncertain, as some studies have reported an increased risk of recurrence in these subgroups, while others have found no clear association [11,13–15]. The impact of maintenance post-transplant steroid use is also debated: some studies suggest a protective effect, whereas others report no association with recurrence risk [8,12,16–18]. These discrepancies may reflect differences in study populations and immunosuppressive protocols beyond steroid use. Geographical variation may also contribute, as IgAN is more prevalent in East Asia than in Europe and North America, which may influence recurrence patterns [19]. Also, and importantly, the rationale for choosing a post-transplant steroid-free immunosuppressive protocol is often unclear in previous studies, potentially leading to indication bias.

Further studies in diverse cohorts are needed to identify risk factors for IgAN recurrence after transplantation. Contemporary Scandinavian data remain limited, as earlier studies were small and conducted in earlier eras of immunosuppression [20,21].

In this Danish multicenter cohort study, we report the incidence of biopsy-proven recurrent IgAN after kidney transplantation, identify potential risk factors associated with recurrence, including the role of maintenance post-transplant steroids, and examine the association between recurrence and graft survival.

 Materials and methods Study design

An observational, cohort study, including all adult patients (≥ 18 years) with biopsy-proven IgAN and first kidney-only transplantation from 1990 to 2020 at Aarhus University Hospital or Odense University Hospital. The standard immunosuppression protocol at Aarhus University Hospital included maintenance prednisolone 5 mg/day from month 6; Odense used a steroid-free protocol until 2017. At both centers tacrolimus and mycophenolate were used as standard immunosuppressive therapy, and the choice of induction therapy was consistent, with either anti-thymocyte globulin (Thymogobuline) or anti-CD25 antibody (Basilixumab) being primarily used. The study was approved by the Regional Authority of the Region of South Denmark on behalf of the involved Danish regions (approval number: 21/21623). The requirement for individual informed consent, written or verbal, was waived in accordance with the Danish Health Care Act (§ 46, subsection 2).

 Study population

The study population enrollment is shown in Fig 1.

10.1371/journal.pone.0353887.g001The study population enrollment.

Flow diagram showing the inclusion of kidney transplant recipients with IgA nephropathy in the present study. ERA-EDTA, European Renal Association – European Dialysis and Transplant Association.

The patients were identified from the National Danish Renal Registry (Dansk Nefrologisk Selskabs Landsregister (DNSL), The Danish Clinical Quality Program, www.rkkp.dk) which includes all Danish kidney transplants since 1990. We initially identified first time renal transplant patients from 1990 to 2020 with one of the following ERA-EDTA (European Renal Association – European Dialysis and Transplant Association) codes for primary renal disease: IgA nephropathy, mesangial proliferative glomerulonephritis, focal and segmental proliferative glomerulonephritis, glomerulonephritis – secondary to systemic disease and Henoch-Schönlein purpura. The diagnosis of IgAN was verified by examination of all pathology reports and only kidney recipients with biopsy-proven IgAN in native kidneys were included. The study population was followed until graft failure, death, loss to follow-up or June 1, 2022.

 Definitions

Biopsy-proven IgAN was defined as predominant mesangial IgA deposition on immunofluorescence and/or as a mesangioproliferative glomerulonephritis with immune complex deposits identified by electron microscopy. The evaluation was performed by two authors and later by consensus among all authors before inclusion in the study. Recurrent IgAN was defined by the same criteria when identified in a kidney graft biopsy at any time. The date of the graft biopsy defined the time of recurrence. All kidney biopsies (native or graft) were clinically indicated; no protocol biopsies were performed. The Oxford MEST classification was not systematically reported in the pathology records throughout the study period and was therefore not available for consistent analysis in this cohort.

Kidney failure (KF) refers to the stage of native kidney disease requiring kidney replacement therapy (dialysis or transplantation). Graft failure was defined as time of re-transplantation, start of dialysis or death with a functioning graft.

Donor type was examined in two ways: by donor status (living vs. deceased) and by genetic relation (genetically related vs. non-related). The non-related group included both living unrelated and deceased donors.

 Data collection and outcome

Baseline data and outcome were extracted from DNSL and electronic patient records. Variables included demographics, smoking, comorbidity, dialysis history, age at IgAN diagnosis, death, HLA mismatch (A, B, DR), ABO compatibility, donor type, cold ischemia time, induction therapy, maintenance steroid use, biopsy-proven rejection and recurrence, and time/cause of graft failure. Steroid use was assessed annually after transplantation and quantitated as total time of steroid treatment in years.

The data were accessed for research purposes from June 2022 onwards. During data collection, only the authors involved in data extraction had access to identifiable patient information within secure hospital system, in accordance with the ethics approval. Other authors did not have access to identifiable data.

The primary outcome of the study was biopsy-proven recurrent IgAN, while secondary outcomes were graft failure, death and rejections.

 Statistics

Baseline categorical data are presented as frequencies and percentages. Continuous variables are presented as medians with interquartile range (IQR) or means with standard deviations (SD) as appropriate.

Risk factors for recurrence were analyzed using univariable and multivariable cox regression and expressed as hazard ratios (HR) with 95% confidence interval (95% CI). The multivariable model adjusted for sex and age at KF.

Cumulative risks for recurrence by donor type are presented as Aalen-Johansen plots.

The risk of graft failure was analyzed using cox regression, with recurrent IgAN treated as a time-varying covariate, and results reported as HR with 95% CI. 5- and 10-year death censored graft survival were also calculated.

The statistical analyses were performed using the statistical software Stata version 18.0 for Windows (StataCorp LLC), while Aalen-Johansen plots were generated using RStudio (v. 2023.12.1 + 402).

 Results Study population

A total of 118 recipients with IgAN as primary cause of KF underwent a first-time kidney transplantation during the study-period at the two transplantation centers in Denmark. 17/118 (14%) recipients were diagnosed with biopsy-proven recurrent IgAN, and 101/118 (86%) recipients were not. The median follow-up time was 5.52 years (IQR 2.83−9.33) equivalent to 798 patient-years.

 Baseline characteristics

Baseline demographics and clinical characteristics are shown in Table 1.

10.1371/journal.pone.0353887.t001Baseline demographics and clinical characteristics of kidney transplant recipients with IgAN.
N = 118 All patients(N = 118) Recurrent IgAN(N = 17) Non-recurrent IgAN (N = 101) p-valueb
Baseline characteristics
Male sex (%) 81 (69%) 11 (65%) 70 (69%) 0.705
Follow-up time, years (median (IQR)) 5.52 (2.83-9.33) 6.04 (3.20-10.37) 5.37 (2.80-9.27) 0.4664
Age at time of Kidney failure, years (mean ±SD) 40.90 ± 13.84 30.65 ± 8.75 42.62 ± 13.83 0.0008
Time from diagnosis to Kidney failure, years (median (IQR)) 3.53 (1.64−6.59) 1.88 (0.94−2.45) 3.66 (1.85−7.63) 0.0135
Pretransplant comorbidity
Hypertension (%) 111/112 (99%) 17/17 (100%) 94/95 (99%) 0.535
Diabetes (%) 4/115 (3%) 1/17 (6%) 3/98 (3%) 0.648
Heart failure 3/114 (3%) 1/17 (6%) 2/97(2%) 0.462
Ischemic heart disease 6/115 /5%) 0/17 (0%) 6/98 (6%) 0.440
Primary IgA-nephropathy, baseline characteristics
Age at time of diagnosis, years (mean ±SD) 35.80 ± 13.59 28.65 ± 9.01 37.00 ± 13.89 0.0184
Histological findings
Crescents 33/118 (28%) 6/17 (35%) 27/101 (26%) 0.467
Mesangial proliferation 97/118 (82%) 14/17 (82%) 83/101 (82%) 0.986
Deposition of IgA on immunflourescence 109/118 (92%) 16/17 (94%) 93/101 (92%) 0.770
Immunodeposits on electron microscopy 74/118 (63%) 12/17 (71%) 62/101 (61%) 0.468
Transplant characteristics
Living donor 58/118 (49%) 14/17 (82%) 44/101 (44%) 0.003
Living genetically related donor 47/118 (40%) 12/17 (71%) 35/101 (35%) 0.005
Living non-genetically related donor 11/118 (9%) 2/17 (12%) 9/101 (9%) 0.608
Pre-emptive transplantation, yes 94/118 (80%) 14/17 (82%) 80/101 (79%) 0.766
AB0-compability 104/118 (88%) 14/17 (82%) 90/101 (89%) 0.425
Donor specific antibodies positivity 5/118 (4%) 1/17 (6%) 4/101 (4%) 0.936
HLA zero mismatch 9/101 (8%) 1/16 (6%) 8/94 (9%) 0.760
Median number of HLA mismatch (min;max) 3 (0;6) 2.5 (0;5) 3 (0;6) 0.490
Cold ischemia time, hours (median (IQR)) 8.22 (3.92−14.00) 3.82 (3.22−5.00) 9.12 (4.10−14.48) 0.0280
Induction therapy 0.660
 Basiliximab 80/111 (72%) 12/16 (75%) 68/95 (72%)
 Thymoglobulin 17/111 (15%) 1/16 (6%) 16/95 (17%)
 Rituximab 5/111 (5%) 1/16 (6%) 4/95 (4%)
 Othera 9/111 (8%) 2/16 (13%) 7/95 (7%)
Steroid, part of maintenance immunosuppression
 Yes 101/118 (85%) 16/17 (94%) 85/101 (84%) 0.279
 Treatment years (median (IQR)) 4.0 (1.0-8.0) 6.0 (2.0−12.0) 4.0 (1.0−8.0) 0.1107
Post transplantation
Delayed graft function 9/118 (8%) 0/17 (0%) 9/101 (9%) 0.200
Acute rejection, humoral or cellular 24/118 (20%) 4/17 (24%) 20/101 (20%) 0.724
Time to biopsy-proven recurrent IgAN, years (median (IQR)) 2.92 (0.89-5.60)
Graft-failure 28/118 (24%) 10/17 (59%) 18/101 (18%) 0.000
Time to graft-failure, years (median (IQR)) 5.06 (1.79−8.98) 4.13 (1.86−6.04) 5.22 (1.55−10.00) 0.9998
Death, yes / no 10/118 (9%) 1/17 (6%) 9/101 (9%) 0.678

Data are presented for the total cohort (N = 118) and stratified by recurrence status (recurrent vs. non-recurrent IgAN). Values are presented as n (%), mean ±SD, or median (interquartile range).

aOther induction therapy includes thymoglobulin plus rituximab (n = 4) and basiliximab plus rituximab (n = 5).

bP-values were calculated using the Pearson chi-square test for categorical variables and the Student’s t-test for continuous variables.

In the total cohort, 69% were male, and the mean age at the time of diagnosis was 35.8 years ± 13.6.

No major difference was found between patients with and without recurrent IgAN in terms of sex, comorbidities or histological findings on native kidney biopsy. However, the patients with recurrent IgAN were younger at time of IgAN diagnosis (recurrent IgAN: 28.7 years ± 9.0 vs non-recurrent IgAN 37.0 years ± 13.9, p = 0.0184), younger at KF (recurrent IgAN: 30.7 years ± 8.75 vs non-recurrent IgAN 42.6 years ± 13.8, p = 0.0008), and progressed faster from primary diagnosis to KF (recurrent IgAN: 1.9 years (IQR 0.9–2.5) vs non-recurrent IgAN 3.7 years (IQR 1.9–7.6), p = 0.0135).

 Transplant and immunosuppression characteristics

Of the 118 recipients, 58 (49%) received a kidney from a living donor. This included 47 (40%) with a living genetically related donor and 11 (9%) with a living non-genetically related donor. Living donor transplantation was more common in the recurrence group, where 14/17 (82%) received a kidney from a living donor, compared to 44/101 (44%) in the non-recurrence group. Living genetically related donors accounted for 12/17 (71%) of the recurrence group, compared to 35/101 (35%) in the non-recurrence group.

Most transplants were AB0-compatible. Pre-emptive transplantation was performed in 94/118 recipients (80%), and donor-specific antibodies at the time of transplantation were present in 5/120 recipients (4%). The median cold ischemia time was 8.2 hours (IQR 3.9–14.0) for all patients, 3.8 hours (IQR 3.2–5.0) in the recurrence group, and 9.1 hours (IQR 4.1–14.5) in the non-recurrence group.

A total of 101/118 recipients (85%) were on steroid-containing immunosuppression protocols with 16/17 (94%) in the recurrence group and 85/101 (84%) in the non-recurrence group. There was no difference in the use of induction therapy between groups.

 Incidence

The median time from transplantation to the biopsy defining recurrence of IgAN was 2.9 years (IQR 0.9−5.6).

The cumulative incidence of biopsy-proven recurrent IgAN at 1-, 5-, and 10-years post-transplantation was 4% (95% CI 1.8–9.8), 12% (95% CI 6.8–19.9), and 16% (95% CI 9.2–25.9), respectively (Fig 2A).

10.1371/journal.pone.0353887.g002Time to event analysis from time of transplantation to recurrent IgAN.

(A) Cumulative risk for recurrent IgAN for the whole study population 10 years post transplantation. (B + C) Cumulative risk for recurrent IgAN comparing donor type, B) genetically related donor vs. non-genetically related and (C) living vs. deceased donor, respectively.

 Risk factors for recurrence

In unadjusted analyses, younger age at KF (HR 0,93 per year increase; 95% CI 0.89−0.98), shorter time from diagnosis to KF (HR 0.70 per year; 95% CI 0.54−0.91), donor type, and shorter cold ischemia time (HR 0.85 per hour increase; 95% CI 0.73−0.99) were all associated with a higher risk of recurrence. When adjusted for sex and age at KF, the association with cold ischemia time was no longer significant (Table 2).

10.1371/journal.pone.0353887.t002Risk factors of recurrent IgAN by cox regression mode.
Univariable Multivariable
Risk factors Hazard ratio 95% CI Hazard ratio 95% CI
Pre-transplantation-factors
Sex, female (vs male) 0.99 0.37-2.72
Active smoking 0.92 0.21-4.06 1.10 0.24-5.03
Age at time of KFa (per yearly increase in age) 0.93 0.89-0.98
Prescence of crescents in native kidney biopsy 2.00 0.71-5.61 1.44 0.49-4.19
Mesangial proliferation in native kidney biopsy 0.85 0.24-2.99 0.83 0.23-2.99
Time from diagnosis to KF (per year) 0.70 0.54-0.92 0.70 0.54-0.91
Transplantation-factors
Induction therapy (basiliximab vs thymoglobulin) 1.85 0.24-14.55 3.20 0.39-26.50
Pre-emptive transplantation, yes (vs no) 1.41 0.40-4.99 1.34 0.38-4.75
Donortype:
 Genetically related (vs non-genetically related) 3.92 1.38-11.17 2.53 0.86-7.32
 Living (vs deceased) 5.15 1.48-17.94 3.75 1.06-13.20
AB0 combability (vs incompability) 2.26 0.64-8.02 2.23 0.62-8.01
Donor specific antibodies positivity at time of transplantation 1.02 0.13-7.84 0.60 0.66-5.41
HLA zero-mismatch 0.53 0.07-4.12 0.76 0.10-5.90
Cold ischemia time (per hour increase in time) 0.85 0.73-0.99 0.87 0.76-1.01
Post-Transplantation-factors
Acute rejection 1.32 0.43-4.01 1.60 0.51-4.99
Steroid, yes (vs no) 3.53 0.47-26.70 3.85 0.50-29.58
Steroid, post-transplant treatment years (per yearly increase) 1.02 0.93-1.12 1.02 0.93-1.13

Hazard ratios (HR) with 95% confidence intervals (CI) are presented from univariable and multivariable Cox regression analyses. The multivariable model was adjusted for sex and age at kidney failure.

aKidney Failure.

Transplantation with a living donor was associated with an increased risk of recurrent IgAN compared with deceased donors (unadjusted HR 5.1; 95% CI 1.5−17.9; Table 2, Fig 2C).

A similar association was observed for genetically related donors compared with non-genetically related donors (unadjusted HR 3.9; 95% CI 1.4−11.1; Table 2, Fig 2B).

Both associations were attenuated after adjustment for sex and age at KF (Table 2).

There was no significant difference in recurrence risk between patients on steroid-free and steroid-containing immunosuppression protocols (unadjusted HR 3.5; 95% CI 0.5−26.7; adjusted HR 3.9; 95%CI 0.5−29.6, Table 2). Similarly, years on steroid treatment after transplantation did not affect recurrence risk (unadjusted HR 1.02; 95% CI 0.93−1.12, adjusted HR 1.02; 95% CI 0.93−1.13, Table 2).

No associations were found between the risk of recurrent IgAN and sex, smoking status, type of induction therapy, pre-emptive transplantation, AB0-compatibility, donor specific antibodies at the time of transplantation, HLA-zero mismatch, baseline histology, or rejection history (Table 2).

 Graft outcome and survival

In total, 28/118 recipients (24%) experienced graft failure during follow-up. Graft failure occurred in 10/17 (59%) recipients in the recurrent IgAN group and 18/101 (18%) in the non-recurrent IgAN group. Median time from recurrent IgAN to graft failure was 2.1 years (IQR 0.82−5.03). Among ten recipients with recurrent IgAN and graft failure, five failures were due to recurrence. In four cases, recurrence contributed together with infection and rejection, and in one case the cause was unknown.

A cox regression analysis examining the risk of graft failure, treating recurrent IgAN as a time-varying covariate, revealed an unadjusted HR 3.8 (95%CI 1.1−13.2) of graft failure in patients with recurrent IgAN compared with patients without. After adjusting for age at time of KF and sex the HR remained higher for patients with recurrent IgAN compared to those without (6.7, 95% CI 1.7−26.8). These findings suggest that recurrent IgAN is independently associated with graft failure.

5- and 10 years death-censored graft survival were 70% and 51% in the recurrent IgAN group and 91% and 77% in the non-recurrent IgAN group.

Death was rare in both groups: one patient with recurrent IgAN and nine without recurrence died during follow-up, five patients died with a functioning graft.

There were no differences in delayed graft function, rejections, or death comparing patients with and without recurrent IgAN (Table 1).

 Discussion

In this Danish cohort study the recurrence rate of IgAN was 14% during a median follow-up of 5.5 years, with a cumulative incidence of 16% at 10 years post-transplantation. Transplantation with a living donor, particularly a genetically related donor, was a potential risk factor for recurrence. Furthermore, recipients with recurrent IgAN were more likely to be younger at the time of diagnosis and at KF, and to have experienced shorter time interval form primary diagnosis to KF compared to those without recurrence, while post-transplant steroid use did not influence the risk of IgAN recurrence.

The recurrence rate of IgAN in this Danish cohort is consistent with similar studies based on indication biopsies to diagnose recurrent IgAN (9.9%−35.4%) [7]. In particular, the two largest published cohorts, with 2,393 and 504 patients from Europe, North and South America, and Australia and New Zealand, reported recurrence rates of 9.7% and 15% at median follow-up times of 6.1 and 8.7 years, respectively [18,22].

In the present study, the cumulative incidence of biopsy-proven recurrent IgAN was 16% at 10 years. This is consistent with a registry-based study from Australia and New Zealand including 225 IgAN recipients that reported a cumulative incidence of 10.1% at 10 years post transplantation [5], while the cohort study of 504 transplant recipients from Europe, North and South America reported incidences of 19% at 10 years and 23% at 15 years post-transplantation. Notably, when recurrence analysis in the latter study was limited to patients who underwent any post-transplant biopsy, the rate increased to 42% at 10 years [18]. Similarly, protocol biopsies in 165 recipients at the Mayo Clinic revealed recurrence rates of 12.5%, 42%, and 51% at 1, 3, and 5 years, respectively [23]. This underscores the impact of the biopsy strategy on recurrence estimates

In our cohort, as in many similar studies, allograft biopsies were performed only on clinical indication [16,24,25]. Thus, variation in reported rates and cumulative incidence across studies most likely reflects differences in biopsy practices, follow-up duration, and geographical variation in the prevalence of IgAN.

Several studies, including the present cohort, observed that recipients younger at the time of KF and progressing more rapidly to KF appear to have a higher risk of recurrence after transplantation [6,14,26,27]. In our study, each additional year of age at KF was associated with a 7% reduction in recurrence risk, consistent with data from Australia and New Zealand reporting a similar risk reduction [5]. A recent meta-analysis also indicated that patients with more rapid progression of primary disease are more susceptible to recurrence after transplantation [28]. This association may reflect a more aggressive IgAN phenotype, where rapid progression in the native kidneys predicts both earlier need for transplantation and a higher likelihood of recurrence. Potential explanations include a stronger or more persistent systemic autoimmune response, as well as age-related changes in immune function and autoantibody production [29].

The association between a living related donor and the recurrence of IgAN is controversial. Our Danish data suggest an increased risk of recurrent IgAN, when receiving a kidney from a living donor. Similar results were reported in a recent meta-analysis including 952 living related donors, a large register-based study from Australia and New Zealand including 557 living related donors and other observational studies comparable to ours [10,11,15,20]. In contrast, a multicenter study involving three centers in the USA and Portugal with 97 living and related donors found no association between living and related donors and the risk of recurrent IgAN [13]. Similarly, two studies from North America with 62 related living donors, and from Greece with 42 living related donors, respectively, did not identify any association between living and related donors and the risk of recurrent IgAN [14,24]. Potential explanations for the divergent findings include differences in indication for kidney biopsies, sample sizes, as well as racial and geographical variations among the study populations. It has been speculated that the greater risk of recurrent IgAN with living and genetically related donors may be related to a higher degree of HLA matching between donors and recipients, leading to lower immunosuppression, or to a genetically associated risk of recurrent IgAN [15]. However, we found no association between HLA matching and IgAN recurrence in our study. Larger and prospective studies are warranted to clarify this question further.

We did not identify a significant association between post-transplant steroid use and the risk of recurrent IgAN in our cohort. This is consistent with a large multicenter international study including 520 patients, 76 of whom were on steroid-free/early steroid withdrawal immunosuppressive protocol [18]. In contrast, a cohort study including 171 patients with 10 on a steroid-free protocol reported that steroid maintenance protocol was associated with a lower risk of recurrence (HR 0.37; 95% CI 0.19–0.73) [14]. This study is comparable to ours in terms of population size, but different in methodology since patients with recurrent IgAN were included from five centers, whereas patients without recurrence were only included from one center. Additionally, five protocol biopsies were included while our study did not include this. Furthermore, in both the mentioned studies and several others the indication for use of post-transplant steroid-free immunosuppression protocol is not specified [12–14,18,21]. In our study the use of steroids was determined by the prespecified immunosuppressive protocols at the two included centers, which may have reduced indication bias for the use of steroids compared to other studies in which this was solely up to the treating physician. However, the limited number of recurrence events in our cohort results in wide confidence intervals and uncertainty in the effect estimates. Therefore, the absence of a significant association should be interpreted with caution and cannot exclude a potential effect of maintenance post-transplant steroids.

We identified an increased risk of graft failure among patients with recurrent IgAN compared with those without recurrence, consistent with previous studies [18,22,27]. However, graft failure in recipients with recurrent IgAN was, often multifactorial and occurred in the context of additional processes such as rejection or infection. As graft biopsies were performed only on clinical indication, recurrent IgAN was sometimes identified during evaluation of graft dysfunction attributed to other causes. Moreover, since recurrent IgAN may be diagnosed many years post-transplant, death censored graft survival and comparisons between recurrent and non-recurrent groups are susceptible to immortal time-bias and should be interpreted with caution [30].

Strength of the present study include systematic data collection and the use of patient record review, ensuring accurate assessment of both inclusion criteria and outcomes. Furthermore, we applied strict criteria for biopsy-proven IgAN both as primary and recurrent disease. Finally, steroid use was determined by the prespecified immunosuppressive protocols, limiting indication bias, and the two transplantation centers were otherwise similar concerning ethnicity, socio-economic status, and other aspects of treatment differing only by regional residency. Some limitations need to be acknowledged. First, due to the retrospective design of the study, we cannot exclude potential selection bias and confounders. Secondly, the relatively small cohort and the limited number of recurrence events limit the conclusions, especially concerning potential weak associations. Thirdly, biopsies were performed only on clinical indications, implying that the recurrence rate of IgAN may have been underestimated, and although histopathological criteria were applied and uncertain cases re-evaluated, some degree of misclassification cannot be excluded. Finally, the Oxford MEST classification was not systematically available, as many biopsies were performed before its widespread implementation.

 Conclusions

In conclusion, recurrence of IgAN after kidney transplantation remains a clinically significant challenge, associated with younger age, rapid progression to KF, and transplantation from living or genetically related donors. Maintenance post-transplant steroid use was not associated with recurrence risk in this cohort.

Future studies with prospective designs are warranted to better define risk factors and guide post-transplant immunosuppressive strategies.

The authors would like to thank the Danish Clinical Quality Program – National Clinical Registries (RKKP) and the Danish Nephrology Registry (DNSL) for providing access to data. We are also grateful to Louis Nygaard Pedersen and Marie Bodilsen Nielsen for their valuable statistical support, which made this study feasible.

This study was supported by the Danish Kidney Association, the Danish Society of Nephrology, and the Department of Renal Medicine at Aarhus University Hospital.

 References McGrogan A, Franssen CFM, de Vries CS. The incidence of primary glomerulonephritis worldwide: a systematic review of the literature. Nephrol Dial Transplant. 2011;26(2):414–30. doi: 10.1093/ndt/gfq665 21068142 Pitcher D, Braddon F, Hendry B, Mercer A, Osmaston K, Saleem MA, et al. Long-Term Outcomes in IgA Nephropathy. Clin J Am Soc Nephrol. 2023;18(6):727–38. doi: 10.2215/CJN.0000000000000135 37055195 Le W, Liang S, Hu Y, Deng K, Bao H, Zeng C, et al. Long-term renal survival and related risk factors in patients with IgA nephropathy: results from a cohort of 1155 cases in a Chinese adult population. Nephrol Dial Transplant. 2012;27(4):1479–85. doi: 10.1093/ndt/gfr527 21965586 Hastings MC, Bursac Z, Julian BA, Villa Baca E, Featherston J, Woodford SY, et al. Life Expectancy for Patients From the Southeastern United States With IgA Nephropathy. Kidney Int Rep. 2017;3(1):99–104. doi: 10.1016/j.ekir.2017.08.008 29340319 Allen PJ, Chadban SJ, Craig JC, Lim WH, Allen RDM, Clayton PA, et al. Recurrent glomerulonephritis after kidney transplantation: risk factors and allograft outcomes. Kidney Int. 2017;92(2):461–9. doi: 10.1016/j.kint.2017.03.015 28601198 Jäger C, Stampf S, Molyneux K, Barratt J, Golshayan D, Hadaya K, et al. Recurrence of IgA nephropathy after kidney transplantation: experience from the Swiss transplant cohort study. BMC Nephrol. 2022;23(1):178. doi: 10.1186/s12882-022-02802-x 35538438 Moroni G, Belingheri M, Frontini G, Tamborini F, Messa P. Immunoglobulin A Nephropathy. Recurrence After Renal Transplantation. Front Immunol. 2019;10:1332. doi: 10.3389/fimmu.2019.01332 Leeaphorn N, Garg N, Khankin EV, Cardarelli F, Pavlakis M. Recurrence of IgA nephropathy after kidney transplantation in steroid continuation versus early steroid-withdrawal regimens: a retrospective analysis of the UNOS/OPTN database. Transpl Int. 2018;31(2):175–86. doi: 10.1111/tri.13075 28926143 Han HS, Lubetzky ML, Anandasivam NS, Cox RA, Lee BK. Recurrent Immunoglobulin A Nephropathy after Kidney Transplant—An Updated Review. Transplantology. 2023;4(3):161–77. doi: 10.3390/transplantology4030016 Chukwu CA, Holmberg C, Storrar J, Middleton R, Sinha S, Kalra PA, et al. Clinical and histopathologic predictors of recurrent glomerulonephritis after kidney transplantation. Clin Transplant. 2023;37(6):e14970. doi: 10.1111/ctr.14970 36950848 Kennard AL, Jiang SH, Walters GD. Increased glomerulonephritis recurrence after living related donation. BMC Nephrol. 2017;18(1):25. doi: 10.1186/s12882-016-0435-z 28095803 Di Vico MC, Messina M, Fop F, Barreca A, Segoloni GP, Biancone L. Recurrent IgA nephropathy after renal transplantation and steroid withdrawal. Clin Transplant. 2018;32(4):e13207. doi: 10.1111/ctr.13207 29345747 Kavanagh CR, Zanoni F, Leal R, Jain NG, Stack MN, Vasilescu E-R, et al. Clinical Predictors and Prognosis of Recurrent IgA Nephropathy in the Kidney Allograft. Glomerular Dis. 2022;2(1):42–53. doi: 10.1159/000519834 35450416 Alachkar N, Delsante M, Greenberg RS, Koirala A, Alhamad T, Abdalla B, et al. Evaluation of the Modified Oxford Score in Recurrent IgA Nephropathy in North American Kidney Transplant Recipients: The Banff Recurrent Glomerulonephritis Working Group Report. Transplantation. 2023;107(9):2055–63. doi: 10.1097/TP.0000000000004640 Bai J, Wu Q, Chen J, Zheng Z, Chang J, Wang L, et al. Risk factors for recurrent IgA nephropathy after renal transplantation: A meta-analysis. Biomol Biomed. 2023;23(3):364–75. doi: 10.17305/bjbms.2022.8369 36475355 Von Visger JR, Gunay Y, Andreoni KA, Bhatt UY, Nori US, Pesavento TE, et al. The risk of recurrent IgA nephropathy in a steroid-free protocol and other modifying immunosuppression. Clin Transplant. 2014;28(8):845–54. doi: 10.1111/ctr.12389 24869763 Clayton P, McDonald S, Chadban S. Steroids and recurrent IgA nephropathy after kidney transplantation. Am J Transplant. 2011;11(8):1645–9. doi: 10.1111/j.1600-6143.2011.03667.x 21797974 Uffing A, Pérez-Saéz MJ, Jouve T, Bugnazet M, Malvezzi P, Muhsin SA, et al. Recurrence of IgA Nephropathy after Kidney Transplantation in Adults. Clin J Am Soc Nephrol. 2021;16(8):1247–55. doi: 10.2215/CJN.00910121 34362788 Stamellou E, Seikrit C, Tang SCW, Boor P, Tesař V, Floege J, et al. IgA nephropathy. Nat Rev Dis Primers. 2023;9(1):67. doi: 10.1038/s41572-023-00476-9 38036542 Freese P, Svalander C, Nordén G, Nyberg G. Clinical risk factors for recurrence of IgA nephropathy. Clin Transplant. 1999;13(4):313–7. doi: 10.1034/j.1399-0012.1999.130406.x 10485372 Ortiz F, Gelpi R, Koskinen P, Manonelles A, Räisänen-Sokolowski A, Carrera M, et al. IgA nephropathy recurs early in the graft when assessed by protocol biopsy. Nephrol Dial Transplant. 2012;27(6):2553–8. doi: 10.1093/ndt/gfr664 22167589 Jiang SH, Kennard AL, Walters GD. Recurrent glomerulonephritis following renal transplantation and impact on graft survival. BMC Nephrol. 2018;19(1):344. doi: 10.1186/s12882-018-1135-7 30509213 Cosio FG, Cattran DC. Recent advances in our understanding of recurrent primary glomerulonephritis after kidney transplantation. Kidney Int. 2017;91(2):304–14. doi: 10.1016/j.kint.2016.08.030 Lionaki S, Makropoulos I, Panagiotellis K, Vlachopanos G, Gavalas I, Marinaki S, et al. Kidney transplantation outcomes in patients with IgA nephropathy and other glomerular and non-glomerular primary diseases in the new era of immunosuppression. PLoS One. 2021;16(8):e0253337. doi: 10.1371/journal.pone.0253337 34403416 Moroni G, Longhi S, Quaglini S, Gallelli B, Banfi G, Montagnino G, et al. The long-term outcome of renal transplantation of IgA nephropathy and the impact of recurrence on graft survival. Nephrol Dial Transplant. 2013;28(5):1305–14. doi: 10.1093/ndt/gfs472 23229925 Bednarova K, Mjøen G, Hruba P, Modos I, Voska L, Kollar M, et al. A novel prognostic nomogram predicts premature failure of kidney allografts with IgA nephropathy recurrence. Nephrol Dial Transplant. 2023;38(11):2627–36. doi: 10.1093/ndt/gfad097 37202220 Han SS, Huh W, Park SK, Ahn C, Han JS, Kim S, et al. Impact of recurrent disease and chronic allograft nephropathy on the long-term allograft outcome in patients with IgA nephropathy. Transpl Int. 2010;23(2):169–75. doi: 10.1111/j.1432-2277.2009.00966.x 19761553 Li Y, Tang Y, Lin T, Song T. Risk factors and outcomes of IgA nephropathy recurrence after kidney transplantation: a systematic review and meta-analysis. Front Immunol. 2023;14:1277017. doi: 10.3389/fimmu.2023.1277017 38090563 Kanbay M, Ozbek L, Guldan M, Copur S, Barratt J. Post-transplant IgA nephropathy: a rapidly evolving field of kidney transplant medicine. J Nephrol. 2025;38(4):1143–52. doi: 10.1007/s40620-024-02149-6 39565563 Gleiss A, Oberbauer R, Heinze G. An unjustified benefit: immortal time bias in the analysis of time-dependent events. Transpl Int. 2018;31(2):125–30. doi: 10.1111/tri.13081 29024071 10.1371/journal.pone.0353887.r001 Decision Letter 0 Elango Jeevithan Academic Editor 2026 Jeevithan Elango This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 0

11 Feb 2026

-->PONE-D-25-66090-->-->Incidence and risk factors for recurrent IgA nephropathy after kidney transplantation: a multicenter cohort study from Denmark-->-->PLOS One

Dear Dr. Øhrstrøm,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

ACADEMIC EDITOR: -->-->The manuscript is novel and provides new insights to the field. However, there are major concerns as raised by the reviewers. Hence, i request to revise the MS based on the reviewers comments and resubmit for further consideration. -->-->==============================

Please submit your revised manuscript by Mar 28 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:-->

A letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Jeevithan Elango, PhD

Academic Editor

PLOS One

Journal requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. We note that you have indicated that there are restrictions to data sharing for this study. For studies involving human research participant data or other sensitive data, we encourage authors to share de-identified or anonymized data. However, when data cannot be publicly shared for ethical reasons, we allow authors to make their data sets available upon request. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

Before we proceed with your manuscript, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., a Research Ethics Committee or Institutional Review Board, etc.). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of recommended repositories, please see https://journals.plos.org/plosone/s/recommended-repositories. You also have the option of uploading the data as Supporting Information files, but we would recommend depositing data directly to a data repository if possible.

Please update your Data Availability statement in the submission form accordingly.

3. We notice that your supplementary figures are uploaded with the file type 'Figure'. Please amend the file type to 'Supporting Information'. Please ensure that each Supporting Information file has a legend listed in the manuscript after the references list.

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

Additional Editor Comments:

Dear Author,

Please revise your MS based on the reviewers' comments and resubmit.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. -->

Reviewer #1: Partly

Reviewer #2: Yes

**********

-->2. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: Yes

Reviewer #2: Yes

**********

-->3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.-->

Reviewer #1: Yes

Reviewer #2: Yes

**********

-->4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.-->

Reviewer #1: Yes

Reviewer #2: Yes

**********

-->5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: Thank you for the opportunity to review this manuscript regarding the incidence and risk factors for recurrent IgA nephropathy after kidney transplantation in a multicenter cohort study from Denmark. This is an interesting small retrospective multicenter analysis about recurrent IgA nephropathy after kidney transplantation in 120 recipients between 1990 and 2020. Seventeen of 120 patients had IgA nephropathy recurrence on for cause biopsies. I suggest that the analysis raises some issues in its present form and request some modifications to improve its impact and generalizability.

1. Can you show the changes in the Oxford classification between the first biopsy and the recurrence? It is unclear whether treatment was changed after the IgA nephropathy recurrence, and the possible impact of that in terms of time to graft failure and death.

2. Four out of ten who developed graft failure presented IgA nephropathy recurrence in combination with infection and rejection. How many of them have graft loss due to IgA or rejection/infection? It would be more appropriate to perform an analysis excluding these patients if the primary cause was not IgA recurrence. Additionally, in Uffing et al. (ref#18, 10.2215/CJN.00910121), IgA nephropathy recurrence rates were higher in patients with de novo DSA and pre-emptive. Can the authors comment on that and report their data about DSAs in their population?

3. Data about IgA recurrence treatment should at least be presented in supplementary material and commented on.

4. Complement activation is acquiring greater importance in IgA nephropathy, and some new drugs targeting complement pathways (e.g., iptacopan, pegcetacoplan) showed promising results. Recent findings suggest that complement deposition could be abrogated in post-treatment biopsies (see 10.1016/j.ajt.2025.08.015). Could complement deposition (at least C3, ideally C5b-9) be evaluated in the patient and commented on the eventual differences or changes between the steroid-free group and the steroid group?

5. I do not fully understand if the differences among patients with recurrent IgAN (younger at time of IgAN diagnosis, younger at KF, faster progression from primary diagnosis to KF were significant or only trends. Please include the p-value in the text and tables.

6. Other induction therapy refers to no induction, steroids only, or alemtuzumab? Please specify.

7. Minor point: Correct typos in table 1 (e.g., Immunodeposits on electron microscopy 74(120) 62%)

Reviewer #2: Major comments

1. Disease definition and potential misclassification (IgA nephropathy)

The definition of IgA nephropathy requires clarification. In addition to cases with predominant mesangial IgA deposition on immunofluorescence, the manuscript includes patients described as having “mesangioproliferative glomerulonephritis where IgAN was most likely.” As mesangioproliferative GN represents a histopathological pattern rather than a specific diagnosis, this definition may lack specificity. In particular, other conditions such as fibrillary glomerulonephritis can present with a mesangioproliferative pattern and may occasionally show IgA or mixed immunoglobulin deposition. The use of the term “most likely IgAN” is subjective and may reduce reproducibility, especially when the same criteria are applied to define recurrent disease in allograft biopsies, where mesangioproliferative changes are often non-specific.

The authors are encouraged to clarify the exact histopathological criteria used to define both primary and recurrent IgAN, including whether electron microscopy was systematically performed and whether fibrillary or other non-IgA immune complex glomerulopathies were explicitly excluded. Clarifying these points would strengthen confidence in the reported recurrence rates and subsequent risk factor analyses.

2. Interpretation of steroid analysis and statistical considerations

The analysis of maintenance steroid use is limited by the small number of recurrence events, resulting in wide confidence intervals and limited statistical precision. Although the lack of statistical significance is appropriately reported, the discussion currently presents the steroid findings in a relatively definitive manner. Given the imprecision of the estimates, the absence of a statistically significant association should be interpreted with caution and should not be equated with evidence of no effect.

This issue would benefit from being addressed explicitly in the discussion, rather than only as a general limitation, by emphasizing limited power and uncertainty in the effect estimates. A more cautious wording would better reflect the statistical constraints of the dataset.

Minor comments

Figure 1 contains a labeling error in which the recurrent and non-recurrent IgAN groups appear to be inverted, which conflicts with the text and Table 1 and should be corrected. Figure 2 is of suboptimal visual quality and appears blurred; higher-resolution images would improve readability. In addition, the tables contain a small number of typographical and formatting issues that should be corrected for clarity and consistency.

**********

-->6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review?  For information about this choice, including consent withdrawal, please see our Privacy Policy.-->

Reviewer #1: No

Reviewer #2: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures

You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation.

NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications.

 10.1371/journal.pone.0353887.r002 Author response to Decision Letter 1 Submission Version 1

12 Apr 2026

We thank the editor and reviewers for their constructive and insightful comments. We have carefully revised the manuscript accordingly and believe that these changes have improved the clarity and robustness of the study.

In particular, we have clarified the definition of IgA nephropathy, re-evaluated selected cases leading to an updated cohort (N=118). Figures have been updated to meet journal requirements, and the Data Availability statement has been revised to clarify data access in accordance with Danish legislation and the study approval by the Region of Southern Denmark.

All reviewer comments have been addressed point-by-point in the accompanying response-to-reviewers document, and all requested revisions have been incorporated into the manuscript.

Submitted filename: Response to Reviewers.docx

 10.1371/journal.pone.0353887.r003 Decision Letter 1 Alwahaibi Nasar Academic Editor 2026 Nasar Alwahaibi This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 1

30 Jun 2026

Incidence and risk factors for recurrent IgA nephropathy after kidney transplantation: a multicenter cohort study from Denmark

PONE-D-25-66090R1

Dear Dr. Øhrstrøm,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. For questions related to billing, please contact billing support.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Nasar Alwahaibi, PhD

Academic Editor

PLOS One

Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.-->

Reviewer #1: All comments have been addressed

**********

-->2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. -->

Reviewer #1: Partly

**********

-->3. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: Yes

**********

-->4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.-->

Reviewer #1: Yes

**********

-->5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.-->

Reviewer #1: Yes

**********

-->6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: No further revisions are required. However, the manuscript's overall impact is low due to intrinsic limitations (i.e., no evaluation of the Oxford classification and complement deposition on kidney biopsies).

**********

-->7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review?  For information about this choice, including consent withdrawal, please see our Privacy Policy.-->

Reviewer #1: No

**********

 10.1371/journal.pone.0353887.r004 Acceptance letter Alwahaibi Nasar Academic Editor 2026 Nasar Alwahaibi This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PONE-D-25-66090R1

PLOS One

Dear Dr. Øhrstrøm,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS One. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

* All references, tables, and figures are properly cited

* All relevant supporting information is included in the manuscript submission,

* There are no issues that prevent the paper from being properly typeset

You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps.

Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

You will receive an invoice from PLOS for your publication fee after your manuscript has reached the completed accept phase. If you receive an email requesting payment before acceptance or for any other service, this may be a phishing scheme. Learn how to identify phishing emails and protect your accounts at https://explore.plos.org/phishing.

If we can help with anything else, please email us at customercare@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Nasar Alwahaibi

Academic Editor

PLOS One