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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 1 192-195
Copyright © 2006 by The Endocrine Society

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Syndrome with Renal Failure: Impact of Posttransplant Immunosuppression on Disease Activity

Tim Ulinski, Laurence Perrin, Michael Morris, Muriel Houang, Sylvie Cabrol, Christine Grapin, Nathalie Chabbert-Buffet, Albert Bensman, Georges Deschênes and Irina Giurgea

Departments of Pediatric Nephrology (T.U., L.P., A.B., G.D.), Pediatric Endocrinology (M.H., S.C.), and Pediatric Surgery (C.G.), Hôpital Trousseau, 75571 Paris Cedex 12, France; Division of Medical Genetics (M.M.), Centre Medical Universitaire, 1121 Genève, Switzerland; Department of Endocrinology and Diabetes (N.C.-B.), Hôpital Tenon, F-75970 Paris Cedex 20, France; and Department of Genetics (I.G.), Hôpital Henri Mondor, 94010 Créteil, France

Address all correspondence and requests for reprints to: T. Ulinski, Department of Pediatric Nephrology; Hôpital Trousseau; 26, avenue du Dr. Arnold-Netter; 75571 Paris Cedex 12, France. E-mail: tim.ulinski{at}trs.aphp.fr.


   Abstract
Top
 Abstract
Introduction
 Patient and Methods
 Results and Discussion
 References
 
Context: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder caused by mutations in the gene AIRE (autoimmune regulator). APECED affects mainly endocrine organs resulting in hypoparathyroidism, adrenocortical failure, diabetes mellitus, hypogonadism, and hypothyroidism. Nonendocrine organ manifestations are autoimmune hepatitis, vitiligo, pernicious anemia, exocrine pancreatic insufficiency, and alopecia. APECED’s first manifestation generally is mucocutaneous candidiasis presumably related to T cell dysfunction.

Patient: A 5-yr-old Iranian girl presented first with pernicious anemia, exocrine pancreatic insufficiency, and nail candidiasis. She had renal dysfunction due to chronic interstitial nephritis (CIN), which progressed to end-stage renal failure. She was transplanted 1 yr later. Common causes of CIN were excluded. APECED was suspected first because she developed progressively hypoparathyroidism, adrenocortical failure, glucose intolerance, and hypothyroidism.

Results: Genetic analysis revealed a large homozygous deletion (g.424_2157del1734), spanning exons 2–4, in the AIRE gene. The predicted protein, if it is produced, has only 44 amino acids (exon 1) in common with the wild-type protein. Immunosuppression after the first renal transplant included prednisone, azathioprine, and cyclosporine A. Multiple acute rejection episodes occurred. Chronic rejection resulted in lost graft and she was retransplanted 2 yr later. Surprisingly, all APECED-related symptoms including candidiasis and autoantibody levels decreased, presumably due to the reinforced immunosuppression (tacrolimus, mycophenolate mofetil, prednisone).

Conclusions: This is the first report of an APECED patient with CIN resulting in end-stage renal failure. Clinical and biological improvement was observed under posttransplant multidrug immunosuppression including tacrolimus and mycophenolate mofetil.


   Introduction
Top
 Abstract
 Introduction
Patient and Methods
 Results and Discussion
 References
 
AUTOIMMUNE POLYENDOCRINOPATHY-candidiasis-ectodermal dystrophy (APECED) or autoimmune polyglandular syndrome type I is characterized by multiple organ damage caused by an autoimmune mechanism (1). APECED affects mainly the endocrine organs, resulting in hypoparathyroidism, adrenocortical failure, diabetes mellitus, gonadal failure, and hypothyroidism. Nonendocrine organ manifestations are autoimmune hepatitis, vitiligo, pernicious anemia, exocrine pancreatic insufficiency, and alopecia. The first manifestation of APECED generally is mucocutaneous candidiasis presumably related to T cell dysfunction (2). APECED is a rare disorder with higher frequency in Finns (1:25,000), Iranian Jews (1:9,000), and Sardinians (1:14,500) (1, 3, 4). The inheritance is autosomal recessive, caused by mutations in a gene called AIRE (autoimmune regulator) consisting of 14 exons spanning 11.9 kb, located in the 21p22.3 region (5, 6). The 55-kDa protein encoded by this gene acts as a transcription regulator. This protein is a compound of a highly conserved N-terminal 100-amino acid domain, which shows a significant homology to the homogeneously staining region dimerization domain of the speckled (Sp)100 and Sp140 proteins, a DNA binding domain, dubbed SAND [Sp100, AIRE, nuclear deformed epidermal autoregulatory factor (DEAF-1) related, and DEAF-1], four nuclear receptor-binding LXXLL, two zinc fingers of the plant homeodomain type, and a proline-rich region (7, 8, 9). AIRE is expressed in thymic medullary epithelial cells, peripheral macrophages, and dendritic cells (10, 11). To date, more than 50 different mutations of the AIRE gene have been described, with many of the APECED-causing mutations clustered within putative DNA binding and transactivation domains, suggesting the importance of these domains for the function of AIRE (4). However, the exact pathophysiological mechanism of AIRE has not yet been identified.

Treatment strategies of multiple endocrine and nonendocrine dysfunctions in APECED are based on specific supplementations. One report about lupus-like panniculitis in a patient with APECED (R257X mutation in exon 6) with rapid amelioration after systemic glucocorticoid treatment suggested immunosuppressive treatment to be beneficial (12). Clinical improvement with oral cyclosporine (5 mg/kg·d) has been reported in one case of APECED with exocrine pancreatic dysfunction and keratoretinitis (13).

We report for the first time an autoimmune interstitial nephritis resulting in end-stage renal failure in a child with APECED.


   Patient and Methods
Top
 Abstract
 Introduction
 Patient and Methods
Results and Discussion
 References
 
Case report

The patient, a 5-yr-old Iranian girl (20 kg, 105 cm), of consanguineous parents, presented first with chronic diarrhea, exocrine pancreatic insufficiency, pernicious anemia, and nail candidiasis. Intravenous vitamin B12 injections and oral pancreatic enzymes resulted in initial clinical improvement. Generalized seizures revealed hypocalcemia with ionized calcium levels of 0.82 mmol/liter. At the same time, renal failure was revealed. Renal biopsy revealed tubulointerstitial nephritis with severe glomerular sclerosis. No steroid or other immunosuppressive treatment was administered at this time.

Two years later, at the age of 7 yr, she came to France and was admitted to our hospital with end-stage renal disease and hemodialysis was initiated. Longitudinal growth failure (height SD score –5) and increasing weight loss (weight SD score –3.5) were noted. No IGF-I or GH deficiency was detected on standard stimulation tests. High-calorie diet and recombinant human GH therapy were initiated, without significant catch-up growth. Despite renal failure, serum PTH levels remained undetectable, suggesting hypoparathyroidism. She also presented alopecia, buccal, and Sicca syndrome with keratitis punctata. Hypothyroidism required thyroxin treatment. However, repeated episodes of asthenia persisted. Serum cortisol levels were low despite elevated ACTH levels, suggesting adrenal insufficiency. Hydrocortisone treatment in stress periods was initiated.

Further investigations revealed autoimmune thrombopenia (positive antiplatelet antibodies), autoimmune thyroiditis (antithyroglobulin 557 kU/liter; normal value < 60), positive antirenal tubular epithelium, antiadrenal, antijejunum, and antimitochondria type 2 antibodies. Pernicious anemia was confirmed by a positive Schilling test and positive anti intrinsic factor antibodies (3.08 kU/liter; n = < 1.30). However, no antiparathyroid antibodies were detected despite hypoparathyroidism (undetectable PTH). Antithyroperoxydase, antinuclear autoantibodies (Goujerot-Sjogren syndrome), antiendoplasmatic reticulum, antiliver cytosol, and anti-smooth muscle antibodies were negative.

The clinical follow-up was mainly marked by recurrent fever episodes with respiratory and upper airway infections. She also developed a myocardiopathy, presumably related to autoimmune vitamin B1 deficiency, responsible for recurrent episodes of pulmonary edema. Her psychomotor development was delayed. Episodes of generalized seizures persisted despite normal calcium levels, and the patient was started on valproic acid. The electroencephalograms confirmed paroxystic anomalies. Cerebral magnetic resonance imaging revealed severe cerebral atrophy and an arachnoid cyst of the posterior fossa. The pituitary gland was normal.

A first renal graft (five human leukocyte antigen mismatches, cold ischemia time 41 h) was performed at the age of 10 yr; the immunosuppressive regimen included basiliximab induction on d 0 and 4, prednisone, cyclosporine (CsA), and aziathioprine (AZA). Two months later she presented with an acute steroid-resistant rejection episode requiring OKT3, resulting in stabilization of renal function. Five more acute rejection episodes, all steroid responsive, complicated the following 3 yr. Increased steroid doses resulted in a glucose intolerance and diabetes, necessitating insulin therapy for 4 months. Antiendocrine pancreatic antibodies were negative at this time. A chronic rejection resulted in graft loss 6 yr after transplantation, and hemodialysis was performed for a period of 2 yr.

A second graft (five human leukocyte antigen mismatches, cold ischemia time 22 h) was performed 8 yr after the first transplantation. The immunosuppressive treatment included basiliximab induction, CsA, mycophenolate mofetil (MMF), and prednisone. She presented two acute rejection episodes on d 7 and 86, necessitating methylprednisolone pulses and switch from CsA to tacrolimus. The second posttransplant period was marked by a rapid clinical improvement of thyroiditis and thrombopenia correlated with normalization of autoantibody levels (antithyroid, antiplatelet). Furthermore, antiadrenal, antirenal tubular epithelium, antimitochondria, and antijejunum antibodies were not detected anymore. Clinical improvement of those endocrine and nonendocrine disorders without specific autoantibodies such as hypoparathyroidism, alopecia, candidiasis, Sicca syndrome, and cardiomyopathy has been observed. The patient required lower doses of thyroxin, hemoglobin A1c was stable, and insulin therapy could be tapered off. PTH levels increased and remained in the lower normal range with improved control of calcemia. However, the exocrine pancreatic insufficiency persisted, antiintrinsic factor antibodies remained positive, and the supplementation with pancreatic enzymes (Creon), liposoluble vitamins, and vitamin B12 was pursued.

The antiepileptic treatment was tapered off because no further seizures occurred and the electroencephalogram normalized. The patient is now 23 yr old and works as an assistant secretary in her father’s company.

Genetic analysis were performed after written informed consent of both parents and confirmed the diagnosis of APECED with the presence of a large homozygous deletion encompassing exons 2–4 (g.424_2157del1734) in the AIRE gene. Parents’ DNA was not available.


   Results and Discussion
Top
 Abstract
 Introduction
 Patient and Methods
 Results and Discussion
References
 
Despite a variety of endocrine and nonendocrine organ involvements, renal disease has never been reported in APECED patients so far. Our patient first presented with pernicious anemia, exocrine pancreatic insufficiency, and nail candidiasis. In addition to well-known APECED-related organ involvements, our patient developed chronic interstitial nephritis with severe glomerular sclerosis. End-stage renal disease was reached 2 yr later. Antiproximal tubular autoantibodies have been detected, and no other etiology of chronic interstitial nephritis was found, suggesting the involvement of APECED-related autoimmune mechanisms in interstitial nephritis.

The patient carries a homozygous mutation (g.424_2157del1734) in the gene AIRE that has been reported only once in a patient from Azerbaijan. Clinical data from this patients have not been described in detail (14). This mutation deleting exons 2–4 results in the open reading frame encoding a deduced 241-amino acid protein. The truncated protein, if it is produced, has only the first 44 amino acids (exon1) in common with the wild-type protein (545 amino acids) and failed almost all functional protein domains (the major part of homogeneously staining region dimerization domain, the SAND (Sp100, AIRE, nuclear DEAF-1 related, and DEAF-1) domain, the LXXLL motifs, the plant homeodomain-type zinc-finger motifs, and the proline-rich region). In normal mice, the ectopic production in the thymus of a number of organ-specific proteins, including some of those implicated in APECED autoimmunity, led to the deletion of the respective T cell-specific clones. In contrast, the production of these proteins is defective or absent in AIRE-deficient mice. The consequent persistence of these T cell clones results in the abrogation of the specific-central tolerance, thus leading to the specific autoimmune phenomena typical of the disease (15, 16).

Several attempts with immunosuppressive drugs such as glucocorticoids (12) or CsA (13) have been undertaken in APECED patients. The treated patients showed a transitory improvement of several APECED-related symptoms, but no experience with multidrug immunosuppression was available.

Our patient presented six acute rejection episodes in the first posttransplant period followed by a chronic rejection, resulting in lost graft 6 yr after the transplant. It can be hypothesized that renal autoantibodies could have played a role in not only the initial development of chronic interstitial nephritis but also the multiple acute rejection episodes and graft failure after chronic rejection. This phenomenon might be due to increased antigene exposure after autoimmune damage. The second posttransplant period was complicated by two acute rejection episodes on d 7 and 86, followed by an immunological stability without any further rejection episode and a stable renal function. This might be explained by a reduction of autoantibody production under immunosuppression including MMF and tacrolimus (17, 18). Preexisting autoantibodies may have been cleared after approximately 3 months. At this time a clinical improvement was noted: all APECED-related symptoms disappeared, except pernicious anemia and exocrine pancreatic insufficiency, which persisted in a less severe form. At the same time, several autoantibody levels became undetectable or decreased (Fig. 1Go). A spontaneous decrease in disease activity cannot be excluded but seems less probable.



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  		FIG. 1. Time course of renal function, treatment, and autoantibodies after the first and second renal transplantation. Those autoantibodies that remained negative throughout the whole disease course (antithyroperoxidase, antiovary, anti-Langerhans islets, anti-pancreatic protein tyrosin phosphatase, antiglutamic acid decarboxylase, antiislet cell antibody, antiinsulin, anti-smooth muscle, antiliver cytosol, antiendoplasmatic reticulum, antiparathyroid, antinuclear, antimicrosome) are not shown. {blacktriangledown}, Acute rejection episode; ESR, end-stage renal failure; FK, tacrolimus; PDN, prednisone; Creatser, serum creatinine; Co, trough level.

 
The difference between the first and second graft was the use of MMF instead of AZA in the immunosuppressive regimen and the switch from CsA to tacrolimus. Because tacrolimus trough levels were maintained at 10 ng/ml, the degree of immunosuppression was increased, compared with the first posttransplant period. A putative role of MMF and/or tacrolimus in clinical and biological improvement of APECED symptoms has to be considered. The inhibitory activity of MMF on de novo purin synthesis in activated T and B lymphocytes is more specific than that of AZA: MMF acts via inhibition of inosine monophosphate dehydrogenase expressed in activated T and B lymphocytes (more than the housekeeping isoform of the enzyme), whereas AZA has several metabolites that inhibit different enzymes (19). MMF is therefore a more potent inhibitor of lymphocyte proliferation than other cell types. MMF has been shown to be efficacious in many autoimmune disorders such as lupus erythematosus, attributed to its inhibition of B-lymphocyte proliferation and thereby autoantibody production (17, 18). The use of AZA in autoimmune disorders has also shown some efficacy; however, MMF appears to be by far superior in severe forms of lupus in large clinical trials (20). In a recent report, autoimmune hepatitis, presumably related to APECED, was successfully treated with steroids and azathioprine in one patient (21). Immunological investigations in APECED patients revealed a cell-mediated immunodeficiency with a low thymocyte helper to thymocyte suppressor cell ratio (22). The beneficial effect of MMF on APECED activity can be explained by two potential mechanisms: reduction of putative anti-T helper cell antibodies and reduction of T suppressor cells, resulting in an increase in T helper to T suppressor cell ratio. The investigation of T cell activity in any APECED patient before and under immunosuppressive treatment might further enlighten this aspect. The role and mechanisms of distinct immunosuppressive therapies on APECED activity needs further in-depth investigation.


   Footnotes
 
The authors have no conflicts of interest.

First Published Online November 1, 2005

Abbreviations: APECED, Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; AZA, aziathioprine; CsA, cyclosporine; MMF, mycophenolate mofetil; Sp, speckled.

Received July 12, 2005.

Accepted October 26, 2005.


   References
Top
 Abstract
 Introduction
 Patient and Methods
 Results and Discussion
 References
 

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