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Renal disorders in Autoimmune Polyendocrinopathy Candidiasis Ectodermal dystrophy (APECED): a systematic review

BMC Pediatrics volume 25, Article number: 139 (2025) Cite this article

Abstract

Background

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), also known as autoimmune polyendocrine syndrome type I (APS-I) is an inborn error of immunity (IEI) with an immune dysregulation phenotype, mainly characterized by endocrine and non-endocrine manifestations including adrenal insufficiency, chronic mucocutaneous candidiasis, and ectodermal dystrophy. Renal disorders seem to be a significant morbidity in APECED patients, requiring further investigations.

Methods

The literature search was conducted in PubMed, Web of Science, and Scopus databases using relevant keywords, and included articles were systematically reviewed regarding the clinical and immunological features. APECED patients with at least one nephrological complication were included.

Results

Ninety-three APECED patients from 30 studies were identified. More than half of the patients (38,52%) presented nephrocalcinosis. The second and third most prevalent renal complications were tubulointerstitial nephritis (TIN) (23,31%), and hypertension (13,18%), respectively. Other less frequent renal disorders including renal tubular acidosis (RTA) glomerulonephritis were also reported among patients. Additionally urinary tract infections (UTI), were also common among cases (15,20.5%).

Conclusions

Renal complications in APECED represent a significant issue that should be monitored and considered in managing these patients to preserve renal function and improve patients’ outcomes.

Peer Review reports

Introduction

Autoimmune polyglandular syndrome type 1 (APS-1), also known as Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a systemic autoimmune disease that involves endocrine and non-endocrine organs [1]. Mutations in the Autoimmune Regulator (AIRE) gene are causative for APECED development [2]. The AIRE is located at chromosome position 21q22.3, comprising 14 coding exons that produces a transcription regulator of 545 amino acids, weighing 58 kDa [3]. AIRE plays a role in regulating the expression of tissue-specific antigens (TSAs), which are crucial for the process of negative selection by ensuring the presentation of the full range of self-antigens at the site of negative selection, leading to the removal of any self-reactive T cells, therefore, mutations in AIRE impair self-tolerance and increase autoreactive immune cells that target multiple tissues [4].

The clinical features of APECED are characterized by a triad of chronic mucocutaneous candidiasis (CMC), adrenal insufficiency (AI), and hypoparathyroidism (HP) [5]. Besides the classic triad, patients also suffer from other endocrine and non-endocrine manifestations. Based on recent estimations up to 10% of APECED patients experience at least one type of renal disorder [6]. Renal complications are caused by T-cell infiltration in renal tubules and the development of anti-proximal tubular and anti-collecting duct-specific autoantibodies in some APECED patients. Renal disorders range from mild renal impairment in patients with nephrocalcinosis to a rapidly progressive renal failure requiring kidney transplantation followed by tubulointerstitial nephritis (TIN) [1, 6, 7]. Early administration of immunosuppressive therapies to APECED patients with kidney complications led to the cessation of TIN progression in some patients, therefore, detection of renal involvement by monitoring renal function may improve patients’ outcomes [8]. Although more than 80% of patients with APECED have hypoparathyroidism, nephrocalcinosis is observed in some patients, suggesting that iatrogenic impaired calcium homeostasis may deteriorate patients’ condition [8, 9].

Regardless of previous investigations, estimations regarding the prevalence of renal complications in these patients are controversial, and the mechanism underlying the renal pathologies is not fully understood. In this study, we reviewed the characteristics of renal disorders and their correlation with genetic changes and polymorphisms and tried to better define the mechanism underlying renal pathologies of APECED patients. The result of this study may provide a better prognostic feature of involved individuals and impede inaccurate therapeutics that deteriorate renal function and patients’ prognosis.

Methods

We adhered to the Preferred Reporting Items for systematic Reviews and Meta-Analyses (PRISMA) guidelines to ensure transparency and rigor in the study design, literature search, selection, and reporting processes.

Search strategy

A comprehensive search was conducted using several databases including PubMed, and Web of Science up to January 1st, 2023, applying different terms: “Autoimmune polyendocrine syndrome type 1” OR “Polyglandular Autoimmune Syndrome type 1” OR “Autoimmune Polyglandular Syndrome type 1” OR “APS1” OR “Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy” OR “APECED” OR “Autoimmune polyendocrinopathy type 1” OR “Autoimmune regulator gene” OR “AIRE gene” AND “Renal Insufficiency” OR “Renal Failure” OR “Kidney” OR “Renal Disease” OR “ESRD” OR “kidney diseases” OR “Hypercalcemia” AND “Hypercalciuria” OR “Hypertension” OR “Nephrotic Syndrome” OR “Nephritic Syndrome” OR “Glomerulonephritis” OR “Hydronephrosis” OR “Hyperoxaluria” OR “Nephritis” OR “Nephrocalcinosis” OR “Renal Tubular Transport” OR “Renal Tubular Acidosis” OR “Nephrolithiasis”. Patients reported in screened articles were further assessed for renal complications. We also identified potentially relevant literature by a manual search in references of all included studies.

Study selection

The initial screening of articles was performed by two independent investigation teams, who reviewed titles/abstracts to include relevant studies according to the inclusion criteria.

The literature search was limited to articles written in the English language, and articles reporting at least one APECED patient with renal disorder were considered to be included. We excluded Studies using animal models, reviews and meta-analyses, and any types of secondary studies, conference abstracts, and articles in other languages. Further screening was performed by reviewing full texts.

Data extraction

Two independent investigation teams collected the following data: publication year and author, age, gender, country, gene defect, the number of participants, and renal and non-renal disorders and other abnormalities. Duplicate data was removed, and a third researcher resolved discrepancies between the two investigators.

Results

Study characteristics

After the removal of duplicates, a total of 1144 articles were assessed based on title and abstract. Of these, 1017 articles were excluded; 127 remaining articles were further reviewed by reviewing the full text. Data was extracted from 30 articles fulfilling the inclusion criteria. A total of 93 patients were finally enrolled in our study. The Prisma diagram is shown in Fig. 1. The list of extracted data including articles and patients is shown in Table 1.

Fig. 1
figure 1

PRISMA diagram summarizing the selection of eligible studies based on the PRISMA guideline

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Table 1 Summary of renal disorders in patients with APECED
Full size table

Case characteristics

A total of 73 patients were evaluated (42 males, 17 females, and 14 patients of unknown sex). At the time of the study, 10 patients were alive (live status only for 13 of a total of 73 patients were available). The median age of patients at the diagnosis of the disease, and at the study was 9.7, and 30.7 years, respectively (from available cases). Most patients were from Finland (41,44%), the United States (23,25%), Italy (6,6.5%), Iran (6,6.5%), Brazil (3,32%), and Turkey (2,21%). Other cases were reported in diverse countries including Portugal, Austria, Ireland, Lebanon, Canada, Japan, China, Netherlands, Saudi Arabia, and Poland. Only the genetic data of 33 patients were available. For thirty-five patients, at least one type of gene defect was described. AIRE mutations c.967-979del13bp (p. L323Sfs*51) in 7 patients (22%) was the most repeated mutation, followed by c.769 C > T (p.R257*) mutation in 6 patients (19%) and 11 Alleles.

Clinical features

The classical triad of APECED comprises CMC, HP, and adrenal insufficiency (AI). Of these, HP was the most prevalent with presentation in 90% (53 of 59) of patients, pursued by CMC (86%, 30 of 35) and AI (44%, 26 of 59).

Most of the patients (59, 80.8%) had at least one type of endocrinopathy, 16 patients (21.9%) had two types of endocrinopathy, 9 patients (12.3%) had three types of endocrinopathy, and 6 patients (8.2%) had four types of endocrinopathy.

Hypoparathyroidism (90%, 53 of 59 reported) was the most common complication among endocrinopathies, followed by primary adrenal insufficiency (PAI) (44%, 26 of 59), hypogonadism (8.5%, 5 of 59), hypothyroidism (27%, 16 of 59), primary ovarian insufficiency (8.5%, 5 of 59). Diabetes mellitus (3%, 2 of 59), subclinical thyroiditis (3%, 2 of 59), growth hormone deficiency (3%, 2 of 59), single occurrence of chronic thyroiditis, and ovarian atrophy.

Ectodermal dystrophy occurred as the most prevalent non-triad manifestation in APECED patients 37% (27 of 73). In addition, two patients showed more than two types of ectodermal dystrophy. Among patients with ectodermal dystrophy, the most prevalent form of ectodermal dystrophy was alopecia (18, 66.6%), with enamel hypoplasia (10, 37%), cataract (6, 22.2%), keratitis (2, 7.4%) and nail dystrophy (3,11.1%) following behind. Other ectodermal dystrophies such as onychomycosis, nail dysplasia, corneal keratopathy, superior corneal vascularization, tear reduction, and glaucoma were among other complications.

Besides routine clinical manifestations in APECED patients including autoimmune endocrinopathy, mucocutaneous candidiasis, and ectodermal dystrophy, about 44% of patients (32 of 73) showed a wide spectrum of other abnormalities, including more than seventy different diseases or symptoms (Table 1).

The spectrum of renal disorders

APECED patients suffer from various types of renal disorders including nephrocalcinosis, hypertension, end-stage renal disease (ESRD), renal tubular acidosis (RTA), diabetic nephropathy, multicystic kidney disease, vasculitis, glomerulonephritis, and hypercalciuria. In this study, more than half of patients (38,52%) presented nephrocalcinosis which was severe in 5 cases and moderate in 3 cases. Besides nephrocalcinosis, four patients had nephrolithiasis, and one patient had mild hypercalciuria. The second most prevalent renal complication among patients was TIN (23, 31.5%); one of the TIN cases had chronic renal failure related to TIN. Hypertension was the third most prevalent (13,18%) renovascular involvement among patients. Autoimmune renal disorders were also prevalent among patients; three patients (4%) had glomerulonephritis (one of them had ANCA-mediated crescentic glomerulonephritis), and three cases (4%) had renal tubular acidosis (RTA). One case had positive LKM antibody but not any other diseases. In addition to the renal disorders, urinary tract complications including urinary tract infections (UTI), were common among cases (15,20.5%).

At the time of this study, in patients with available life status, three patients were alive (at the ages of 19, 33, and 54) with a functioning kidney graft, and three patients deceased at the ages of 19, 56, and 58 with a functioning graft. Two patients were under dialysis and one patient had a progressive worsening of kidney function. The graft was removed one year after kidney transplantation for one patient.

Therapeutic strategies

Multiple therapeutic strategies were used to ameliorate patients’ symptoms and outcomes. About 32% of all patients had received one type of Ca/vit D/PTH replacement therapy. Of 24 cases who received Ca/vit D/PTH replacement therapy, 19 were under treatment with 25-OH-rhpTH1-34, 3 patients were under treatment with elemental calcium and calcitriol, one case was under treatment with high dose therapy with oral calcium, alfacalcidol (analogue of vitamin D), and recombinant PTH. Another case was under treatment with calcium supplementation and 1-alpha hydroxycholecalciferol administration.

Patients also received diverse medications which might cause or affect renal complications including sodium bicarbonate, intravenous immunoglobulin (IVIG), rituximab, and prophylactic antibacterial or antifungal therapy. Twenty-one patients (29%) were under treatment with immunosuppressive agents, of these, six patients received Mycophenolate mofetil (MMF), two patients were under treatment with steroids, three patients were under treatment with the combination of cyclosporine A (CSA), azathioprine, and steroids, three patients were under treatment with azathioprine, two patients were under treatment with CSA + MMF + steroids, and single cases were under treatment with basiliximab + CSA + MMF + steroids, basiliximab + MMF + Tacrolimus + steroids, Tacrolimus + MMF + steroids, cyclosporine, and azathioprine.

Other therapeutic and prophylactic agents used to improve the conditions and outcomes of patients are presented in Table 1.

Discussion

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) or Autoimmune Polyendocrine Syndrome type 1 (APS type 1) is a rare genetic syndrome diagnosed typically in childhood and late adolescence [9]. Renal disorders have recently been reported in 6.3–10% of APECED patients [36]. APECED patients suffer from a variety of renal diseases, which include renal tubular acidosis, nephrocalcinosis, tubulointerstitial nephritis, acute tubular necrosis, cystitis, pyelonephritis, nephrolithiasis, persistent proteinuria, diabetic nephropathy, microalbuminuria, and in later stages chronic renal failure. In the present study, we evaluated the incidence of renal complications and their association with genetic variations.

The most common mutation in APECED patients with renal disorders is consistent with previous reports and is the same as other APECED patients (35.8% of APECED patients had c.967-979del13bp (p. L323Sfs*51) mutation, which is also the most common mutation in included patients in our study). A study showed that while 3% of mutation-positive probands had tubulointerstitial nephritis, none of mutation-negative probands showed this renal complication, suggesting a potential high impact of genetic mutations in this renal involvement [37]. Several unique mutations have been reported in the included studies. However, it is not fully understood how genetic mutations could affect renal complications, and future studies should be carried out to find the associations between mutations and renal complications in APECED.

In this review, the most common cause of renal involvement in APECED patients is nephrocalcinosis. The prevalence of nephrocalcinosis in this review was 52%.

Several clinical conditions may induce nephrocalcinosis during the course of the disease, such as vitamin D replacement, congenital hypothyroidism, inherited tubulopathies, and RTA; hypoparathyroidism-induced hypercalciuria seems to be the most common cause as the fractional excretion of calcium increases and the tubular absorption of calcium decreases due to the lack of PTH. Nephrocalcinosis occurs through hypercalciuria with hypercalcemia or hypercalciuria with no hypercalcemia [38]. A study by Laakso and colleagues showed that APECED patients suffered from lower serum calcium, higher serum phosphate, and higher urine calcium secretion [39]. Therefore, hypercalciuria-induced without hypercalcemia nephrocalcinosis in APECED patients is probably the most among these patients. Based on clinical and laboratory findings in APECED patients; to elucidate the underlying mechanism of nephrocalcinosis in APCED patients, we suggested two theories. First, mutations in calcium-sensing receptors (CASR) can suppress PTH levels and exert a hypercalciuric hypocalcemia condition. Circulating autoantibodies against CASR in APECED patients, particularly activating antibodies, consolidate this theory [40, 41]. Second, vitamin D therapy may cause iatrogenic hypercalciuria at the initiation of treatment, therefore ongoing assessment of nephrocalcinosis is warranted [42]. It is suggested that calcium should be maintained just below or within the lower normal range to prevent nephrocalcinosis, nephrolithiasis, and renal failure [43]. Novel therapies such as recombinant PTH could maintain serum calcium levels without requiring intravenous calcium injection, which may exacerbate nephrocalcinosis [10].

In this study, the second form of renal involvement in patients with APECED was TIN, with a 32% prevalence. TIN is a severe complication of APECED that might ultimately lead to renal failure. Its prevalence in Finnish APECED patients is about 10% [8]. Severe pediatric cases of renal failure associated with TIN result in dialysis and kidney transplantation [1, 44]. In APECED, the only clinical sign of TIN may be impaired renal function without any urinalysis abnormalities [8]. Recently, the role of circulating circulating metabolites and antibodies and their prognostic value in nephritis have been shown [45]. Circulating antibodies against the proximal and distal parts of the nephron are present in TIN patients, with kidney biopsies showing lymphocyte infiltration and complement components deposition. Autoantibodies against proximal renal tubules in some cases indicate involvement of autoimmune pathogenic mechanisms in the development of renal complications in some patients [8]. The treatment of TIN is not clearly defined, but early initiation of immunosuppressive therapy such as MMF reduces the formation of fibrosis in the kidney via reducing circulating antibodies and diminishing T cell activity [29, 46].

The mechanism underlying kidney injuries could vary from metabolites dysfunctions, mitochondrial dysfunction, impaired autophagy, and activation of cell death pathways to immunologic processes such as infiltration of inflammatory cells, activation of inflammatory cytokines, and accumulation of macrophages [47, 48]. As mentioned above, renal complications are caused by T-cell infiltration in renal tubules and the development of anti-proximal tubular and anti-collecting duct-specific autoantibodies in the case of APECED.

The role of autoantibodies in the pathogenesis of kidney disorders in APECED is a matter of controversy. While some studies suggest that autoantibodies can rarely cause renal injury, the presence of these autoantibodies in some cases advocates the involvement of autoimmune pathogenic mechanisms in the development of renal complications in some patients, even though the main immunopathogenesis of APECED is the manipulated T-cell tolerance [7]. Hence, this could be a potential underlying mechanism of kidney involvement in APECED. Nevertheless, there are several types of autoantibodies against tissues, interferons, and interleukins in APECED patients. It is of not to say there were several autoantibodies in patients in this study such as anti tubular epithelium that were not reported in the previous comprehensive review of APECED patients [9]. These specific autoantibodies could also be used to predict renal involvement, as a previous study suggested that the measurement of autoantibodies produced against the cytokines could be used for early diagnosis of APECED [49].

No anti-proximal tubular and anti-collecting duct-specific autoantibodies were reported in the mentioned review. Therefore, other antibodies such as liver-kidney microsomal (LKM) or Anti-nuclear Ab (ANA), could also participate in the renal disorders’ development, particularly TIN.

The prevalence of other renal complications is inconsistent between our findings and previous reports. Hypertension was reported in 18% of included patients in this study, whereas the prevalence of hypertension was 36% in a Finnish cohort [8]. Since proteinuria and hypertension diminish renal function, early detection and management of these conditions seem to be necessary to preserve renal function in these patients, and screening for hypertension, proteinuria, and other renal function indicators should be considered in the examination of these patients. Since the onset of hypertension occurs during childhood in these patients, secondary screening tests such as plasma aldosteronism-to-renin ratio (ARR) test should be done to rule out other causes of hypertension and avoid cardiovascular damage [50]. Our study revealed that the occurrence of RTA was found to be 4% among renal complications in APECED, however, a previous Finnish study reported a higher prevalence of RTA at 6% among 30 cases [8]. In the context of APECED, autoantibodies predominantly target specific intracellular enzymes within organs. These autoantibodies are typically not pathogenic but rather signify ongoing T-cell activity within the affected tissue. A plausible hypothesis suggests a potential association between the presence of ductal cell antibodies and the development of distal renal tubular acidosis (type 1) observed in a subset of patients [51]. This rationale could be extended to APECED, even though future investigations are required to clarify the underlying mechanisms.

It is noteworthy to declare that while in the study by Sharifinejad and colleagues, 92% of patients were alive, our study showed that about 77% were alive (of reported cases) at the time of the study. This might show higher mortality in patients with kidney involvement, even though there is a lack of reported data on the living status of patients with kidney disorders is an obstacle to accurate estimation. Most of the cases included in our study were from Finland followed by the United States, Italy, Iran, Brazil, and Turkey. Whereas the Sharifinejad and colleagues, Italian cases were the second reported cases (followed by finish people), which suggest lower renal manifestations in Italian patients. The frequency of AIRE mutations was as same as the previous reports. The clinical presentation of APECED patients with kidney involvement is relatively different from all cases.

The prevalence of hyperparathyroidism is slightly higher in patients with renal involvement (reported in our studies with 90% prevalence) than previous comprehensive report (84.2%).

A screening for hypertension, UTI, microalbuminuria, metabolic acidosis, nephrocalcinosis, nephrolithiasis, and other renal function (particularly tubular) indicators is recommended to be considered in the examination of APECED patients (Table 2).

Table 2 Suggested screening test to detect renal involvement in APECED patients. This suggestion should be further completed by other clinicians and studies
Full size table

Limitation

This study has also some limitations. Since APECED is relatively a rare disorder, the number of included patients in studies was limited, and most of the included studies were case reports. The results of this study should be confirmed by future studies, especially cohorts and case controls which could enhance our understanding and knowledge of this disease. Furthermore, since APECED is a rare disorder, most of the included studies were case series, case reports studies. Therefore, we were unable to prefom an appropriate and solid statical analysis. There is a lack of investigations, especially cohort studies on APECED and renal involvement. Future studies, particularly cohort studies is warranted to update our understanding regarding this rare condition.

Conclusion

Taken together, renal complications in APECED represent a significant issue that should be monitored and considered in managing these patients to preserve renal function and improve patients’ outcomes. This is the first study reviewing renal involvement in patients with APECED. The results of this study could enhance our understanding of the impact of this disease on patients.

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Ferre EMN, Schmitt MM, Lionakis MS. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Front Pediatr. 2021;9:723532.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006;91(8):2843–50.

    Article  CAS  PubMed  Google Scholar 

  3. Peterson P, Org T, Rebane A. Transcriptional regulation by AIRE: molecular mechanisms of central tolerance. Nat Rev Immunol. 2008;8(12):948–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Besnard M, Padonou F, Provin N, Giraud M, Guillonneau C. AIRE deficiency, from preclinical models to human APECED disease. Dis Model Mech. 2021;14(2). https://doiorg.publicaciones.saludcastillayleon.es/10.1242/dmm.046359.

  5. Bousfiha A, Jeddane L, Picard C, Al-Herz W, Ailal F, Chatila T, et al. Human inborn errors of immunity: 2019 update of the IUIS Phenotypical classification. J Clin Immunol. 2020;40(1):66–81.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Aytekin ES, Cagdas D. APECED and the place of AIRE in the puzzle of the immune network associated with autoimmunity. Scand J Immunol. 2023;98(2):e13299.

    Article  CAS  PubMed  Google Scholar 

  7. Shajari A, Zare Ahmadabadi A, Ashrafi MM, Mahdavi T, Mirzaee M, Mohkam M, et al. Inborn errors of immunity with kidney and urinary tract disorders: a review. Int Urol Nephrol. 2024;56(6):1965–72.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Kluger N, Kataja J, Aho H, Ronn AM, Krohn K, Ranki A. Kidney involvement in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy in a Finnish cohort. Nephrol Dial Transpl. 2014;29(9):1750–7.

    Article  CAS  Google Scholar 

  9. Sharifinejad N, Zaki-Dizaji M, Tebyanian S, Zainaldain H, Jamee M, Rizvi FS, et al. Clinical, immunological, and genetic features in 938 patients with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED): a systematic review. Expert Rev Clin Immunol. 2021;17(8):807–17.

    Article  CAS  PubMed  Google Scholar 

  10. Winer KK, Schmitt MM, Ferre EMN, Fennelly KP, Olivier KN, Heller T, et al. Impact of periprocedural subcutaneous parathyroid hormone on control of hypocalcaemia in APS-1/APECED patients undergoing invasive procedures. Clin Endocrinol (Oxf). 2021;94(3):377–83.

    Article  CAS  PubMed  Google Scholar 

  11. Soyak Aytekin E, Serin O, Cagdas D, Tan C, Aksu T, Unsal Y, et al. A patient with AIRE Mutation who presented with severe diarrhea and Lung Abscess. Pediatr Infect Dis J. 2021;40(1):66–9.

    Article  PubMed  Google Scholar 

  12. Lima Ferreira J, Simoes de Carvalho F, Marques AP, Principe RM. Hypoparathyroidism as the single major component for decades of autoimmune polyglandular syndrome type 1. Endocrinol Diabetes Metab Case Rep. 2020;2020. https://doiorg.publicaciones.saludcastillayleon.es/10.1530/EDM-20-0083.

  13. Chascsa DM, Ferre EMN, Hadjiyannis Y, Alao H, Natarajan M, Quinones M, et al. APECED-Associated Hepatitis: clinical, biochemical, histological and Treatment Data from a large, predominantly American Cohort. Hepatology. 2021;73(3):1088–104.

    Article  CAS  PubMed  Google Scholar 

  14. Laurer E, Grunberger J, Naidoo U, Lanzersdorfer R, Wimleitner M, Tischlinger K, et al. Recombinant human parathyroid hormone (1–84) replacement therapy in a child with hypoparathyroidism. Bone. 2021;144:115834.

    Article  CAS  PubMed  Google Scholar 

  15. Schmitt MM, Ferre EMN, De Melo MS, Cooper MA, Quezado MM, Heller T et al. Mycophenolate-Induced Colitis in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal dystrophy patients. JPGN Rep. 2021;2(4). https://doiorg.publicaciones.saludcastillayleon.es/10.1097/pg9.0000000000000131.

  16. Radetti G, Puel A, Franceschi R, Longhi S, Gallo N, Betterle C. A non-classical presentation of APECED in a family with heterozygous R203X AIRE gene mutation. J Endocrinol Invest. 2022. https://doiorg.publicaciones.saludcastillayleon.es/10.1007/s40618-022-01937-w.

  17. Bruserud O, Costea DE, Laakso S, Garty BZ, Mathisen E, Makitie A, et al. Oral Tongue malignancies in Autoimmune Polyendocrine syndrome type 1. Front Endocrinol (Lausanne). 2018;9:463.

    Article  PubMed  Google Scholar 

  18. Weiler FG, Dias-da-Silva MR, Lazaretti-Castro M. Autoimmune polyendocrine syndrome type 1: case report and review of literature. Arq Bras Endocrinol Metabol. 2012;56(1):54–66.

    Article  PubMed  Google Scholar 

  19. Chang B, Brosnahan D, McCreery K, Dominguez M, Costigan C. Ocular complications of autoimmune polyendocrinopathy syndrome type 1. J AAPOS. 2006;10(6):515–20.

    Article  PubMed  Google Scholar 

  20. Weiler FG, Peterson P, Costa-Carvalho BT, de Barros Dorna M, Correia-Deur JE, Sader SL, et al. The heterogeneity of autoimmune polyendocrine syndrome type 1: clinical features, new mutations and cytokine autoantibodies in a Brazilian cohort from tertiary care centers. Clin Immunol. 2018;197:231–8.

    Article  CAS  PubMed  Google Scholar 

  21. Meloni A, Perniola R, Faa V, Corvaglia E, Cao A, Rosatelli MC. Delineation of the molecular defects in the AIRE gene in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients from Southern Italy. J Clin Endocrinol Metab. 2002;87(2):841–6.

    Article  CAS  PubMed  Google Scholar 

  22. Akesson LS, Francis D, GdS M, Cole T, Simm P, Oliver M, et al. Microarray diagnosis of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy caused by a novel homozygous intragenic AIRE deletion. J Paediatr Child Health. 2021;57(7):1109–12.

    Article  PubMed  Google Scholar 

  23. Cervato S, Mariniello B, Lazzarotto F, Morlin L, Zanchetta R, Radetti G, et al. Evaluation of the autoimmune regulator (AIRE) gene mutations in a cohort of Italian patients with autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) and in their relatives. Clin Endocrinol (Oxf). 2009;70(3):421–8.

    Article  PubMed  Google Scholar 

  24. Alkhammash S, Saumet J, Genest G. Infertility and pregnancy in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy: more than just primary ovarian failure? Am J Reprod Immunol. 2019;82(4):e13169.

    Article  PubMed  Google Scholar 

  25. Faiyaz-Ul-Haque M, Bin-Abbas B, Al-Abdullatif A, Abdullah Abalkhail H, Toulimat M, Al-Gazlan S, et al. Novel and recurrent mutations in the AIRE gene of autoimmune polyendocrinopathy syndrome type 1 (APS1) patients. Clin Genet. 2009;76(5):431–40.

    Article  CAS  PubMed  Google Scholar 

  26. Yildiz EH, Saad CG, Eagle R, Ayres BD, Cohen EJ. The Boston keratoprosthesis in 2 patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Cornea. 2010;29(3):354–6.

    Article  PubMed  Google Scholar 

  27. Rautemaa R, Hietanen J, Niissalo S, Pirinen S, Perheentupa J. Oral and oesophageal squamous cell carcinoma–a complication or component of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, APS-I). Oral Oncol. 2007;43(6):607–13.

    Article  PubMed  Google Scholar 

  28. Chida N, Kobayashi I, Takezaki S, Ueki M, Yamazaki Y, Garelli S, et al. Disease specificity of anti-tryptophan hydroxylase-1 and anti-AIE-75 autoantibodies in APECED and IPEX syndrome. Clin Immunol. 2015;156(1):36–42.

    Article  CAS  PubMed  Google Scholar 

  29. Ulinski T, Perrin L, Morris M, Houang M, Cabrol S, Grapin C, et al. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome with renal failure: impact of posttransplant immunosuppression on disease activity. J Clin Endocrinol Metab. 2006;91(1):192–5.

    Article  CAS  PubMed  Google Scholar 

  30. Podkrajsek KT, Milenkovic T, Odink RJ, Claasen-van der Grinten HL, Bratanic N, Hovnik T, et al. Detection of a complete autoimmune regulator gene deletion and two additional novel mutations in a cohort of patients with atypical phenotypic variants of autoimmune polyglandular syndrome type 1. Eur J Endocrinol. 2008;159(5):633–9.

    Article  CAS  PubMed  Google Scholar 

  31. Al-Owain M, Kaya N, Al-Zaidan H, Bin Hussain I, Al-Manea H, Al-Hindi H, et al. Renal failure associated with APECED and terminal 4q deletion: evidence of autoimmune nephropathy. Clin Dev Immunol. 2010;2010:586342.

    PubMed  PubMed Central  Google Scholar 

  32. Zhu F, Willette-Brown J, Song NY, Lomada D, Song Y, Xue L, et al. Autoreactive T cells and chronic fungal infection drive esophageal carcinogenesis. Cell Host Microbe. 2017;21(4):478–93. e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Laakso S, Kaijansinkko H, Raisanen-Sokolowski A, Jahnukainen T, Kataja J, Makitie O, et al. Long-term outcome of kidney transplantation in 6 patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Transplantation. 2022;106(4):e244–6.

    Article  CAS  PubMed  Google Scholar 

  34. Bjanid O, Adamczyk P, Stojewska M, Roszkowska-Bjanid D, Paszyna-Grzeskowiak M, Jedzura A, et al. Rare case of nephrocalcinosis in a 14-year-old girl: questions. Pediatr Nephrol. 2017;32(4):607–8.

    Article  PubMed  Google Scholar 

  35. Bjanid O, Adamczyk P, Stojewska M, Roszkowska-Bjanid D, Paszyna-Grzeskowiak M, Jedzura A, et al. Rare case of nephrocalcinosis in a 14-year-old girl: answers. Pediatr Nephrol. 2017;32(4):609–13.

    Article  PubMed  Google Scholar 

  36. Perheentupa J. Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED). Horm Metab Res. 1996;28(7):353–6.

    Article  CAS  PubMed  Google Scholar 

  37. Cranston T, Boon H, Olesen MK, Ryan FJ, Shears D, London R, et al. Spectrum of germline AIRE mutations causing APS-1 and familial hypoparathyroidism. Eur J Endocrinol. 2022;187(1):111–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Vaidya SR, Yarrarapu SNS, Aeddula NR. Nephrocalcinosis. Treasure Island: StatPearls; 2024. PMID: 30725890

  39. Laakso S, Borchers J, Toiviainen-Salo S, Pekkinen M, Makitie O. Severe phenotype of APECED (APS1) increases risk for structural bone alterations. Front Endocrinol (Lausanne). 2020;11:109.

    Article  PubMed  Google Scholar 

  40. Kemp EH, Gavalas NG, Krohn KJ, Brown EM, Watson PF, Weetman AP. Activating autoantibodies against the calcium-sensing receptor detected in two patients with autoimmune polyendocrine syndrome type 1. J Clin Endocrinol Metab. 2009;94(12):4749–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gavalas NG, Kemp EH, Krohn KJ, Brown EM, Watson PF, Weetman AP. The calcium-sensing receptor is a target of autoantibodies in patients with autoimmune polyendocrine syndrome type 1. J Clin Endocrinol Metab. 2007;92(6):2107–14.

    Article  CAS  PubMed  Google Scholar 

  42. Hendy GN, Cole DEC, Bastepe M et al. Hypoparathyroidism and Pseudohypoparathyroidism. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, editors. South Dartmouth: Endotext; 2000. PMID: 25905388

  43. Winer KK, Ye S, Ferre EMN, Schmitt MM, Zhang B, Cutler GB Jr., et al. Therapy with PTH 1–34 or calcitriol and calcium in diverse etiologies of hypoparathyroidism over 27 years at a single tertiary care center. Bone. 2021;149:115977.

    Article  CAS  PubMed  Google Scholar 

  44. Constantine GM, Lionakis MS. Lessons from primary immunodeficiencies: autoimmune regulator and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Immunol Rev. 2019;287(1):103–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Causal association of plasma circulating metabolites with nephritis: a Mendelian randomization study. https://doiorg.publicaciones.saludcastillayleon.es/10.3389/fnut.2024.1364841.

  46. Braden GL, O’Shea MH, Mulhern JG. Tubulointerstitial diseases. Am J Kidney Dis. 2005;46(3):560–72.

    Article  PubMed  Google Scholar 

  47. Zeng YF, Li JY, Wei XY, Ma SQ, Wang QG, Qi Z, et al. Preclinical evidence of reno-protective effect of quercetin on acute kidney injury: a meta-analysis of animal studies. Front Pharmacol. 2023;14:1310023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Shao F, Yao Y, Weng D, Wang R, Liu R, Zhang Y, et al. Causal association of plasma circulating metabolites with nephritis: a mendelian randomization study. Front Nutr. 2024;11:1364841.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Jamee M, Mahdaviani SA, Mansouri D, Azizi G, Joneidi N, Ghaffaripour H, et al. Delay in the diagnosis of APECED: a Case Report and Review of Literature from Iran. Immunol Invest. 2020;49(3):299–306.

    Article  PubMed  Google Scholar 

  50. Li X, Liang J, Hu J, Ma L, Yang J, Zhang A, et al. Screening for primary aldosteronism on and off interfering medications. Endocrine. 2024;83(1):178–87.

    Article  CAS  PubMed  Google Scholar 

  51. Gaarder PI, Heier HE. A human autoantibody to renal collecting duct cells associated with thyroid and gastric autoimmunity and possibly renal tubular acidosis. Clin Exp Immunol. 1983;51(1):29–37.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Mahnaz Jamee holds the 2023 European Society for Immunodeficiencies (ESID) Juniors Bridge Grant.

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Authors and Affiliations

  1. Student Research Committee, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran

    Mohammadreza Shafiei, Solale Hosseini, Mohammadamin Keikhah & Nastaran Ardalan

  2. School of Medicine, Azad University of Medical Sciences, Tehran, Iran

    Soodeh Ghadimi

  3. Pediatric Nephrology Research Center, Research Institute for Children’s Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Mahbubeh Mirzaee, Masoumeh Mohkam & Mahnaz Jamee

  4. Department of Computer Science, Rice University, Houston, TX, USA

    Mehrdad Tamiji

Authors
  1. Mohammadreza Shafiei
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  2. Solale Hosseini
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Contributions

Mohammadreza Shafiei: Writing – review & editing, Writing – original draft, Supervision, Methodology, Data curation, conceptualization. Soodeh Ghadimi: Writing – original, Data curation Mahbubeh Mirzaee: Writing – original draft. Solaleh Hosseini: Methodology, Investigation, Data curation. Mohammadamin keikhah and Nastaran Ardalan : Methodology, Investigation, Mahnaz Jamee: conceptualization , Writing – review & editing Masoumeh Mohkam Mehrdad Tamiji : Writing – review & editing. All authors reviewed and approved the final manuscript.

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Correspondence to Mohammadreza Shafiei.

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Shafiei, M., Hosseini, S., Ghadimi, S. et al. Renal disorders in Autoimmune Polyendocrinopathy Candidiasis Ectodermal dystrophy (APECED): a systematic review. BMC Pediatr 25, 139 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12887-025-05458-2

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Keywords

BMC Pediatrics

ISSN: 1471-2431

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