http://informahealthcare.com/amy ISSN: 1350-6129 (print), 1744-2818 (electronic) Amyloid, 2014; 21(4): 231–237 ! 2014 Informa UK Ltd. DOI: 10.3109/13506129.2014.943834
ORIGINAL ARTICLE
Cystic fibrosis and AA amyloidosis: a survey in the French cystic fibrosis network Katia Stankovic Stojanovic1,2, Dominique Hubert3, Sylvie Leroy4, Stephane Dominique5, Dominique Grenet6, Magali Colombat7, Annick Clement8, Michael Fayon9, and Gilles Grateau1,2 1
Centre de Reference pour les Amyloses d’Origine Inflammatoire et de la Fie`vre Mediterraneenne Familiale, Service de Medecine Interne, Assistance Publique – Hoˆpitaux de Paris, Hoˆpital Tenon, Paris France, 2UMR 933 INSERM, Universite Pierre et Marie Curie-Paris 6, Paris, France, 3Centre de Ressources et de Competences pour la Mucoviscidose, Service de Pneumologie, Assistance Publique – Hoˆpitaux de Paris, Hoˆpital Cochin, Universite Paris Descartes, Paris, France, 4Centre de Ressources et de Competences pour la Mucoviscidose, Service de Pneumologie, Hoˆpital Pasteur, CHU de Nice, Nice, France, 5Centre de Ressources et de Competences pour la Mucoviscidose, Clinique Pneumologique, Hoˆpital Charles Nicolle, CHU de Rouen, Rouen France, 6Centre de Ressources et de Competences pour la Mucoviscidose, Service de Pneumologie, Hoˆpital Foch, Suresnes, France, 7 Service d’ Anatomie Pathologique, Hoˆpital Foch, Suresnes, France, 8Centre de Ressources et de Competences pour la Mucoviscidose, Service de Pneumologie pediatrique, Assistance Publique – Hoˆpitaux de Paris, Hoˆpital Trousseau, Paris, France, and 9Departement de Pediatrie, Centre d’Investigation Clinique (CIC 0005), CHU de Bordeaux, Bordeaux, France Abstract
Keywords
Introduction: To define the characteristics of CF patients developing AA amyloidosis. Methods: A 30-year retrospective survey conducted within the national French CF network to identify cases of CF associated with AA amyloidosis. Results: Nine cases of AA amyloidosis were identified (CF prevalence in France is approximately 6000 patients) and sufficient data were collected in six. The clinical presentation was renal disease in four cases, a compressive goiter in one case, and epigastric pain in one case. Organ involvement included kidney disease in all cases (proteinuria, with a median age at onset of 24 years, 4 cases with nephrotic syndrome, 5 with renal failure); gastrointestinal (4 cases with duodenal ulcer); thyroid (2 cases); and hepatobiliary system (3 cases). The median age at diagnosis of CF was 6.5 years. Five patients had pancreatic insufficiency. All patients had chronic respiratory infections requiring intravenous antibiotics several times a year. Five patients have died, at a median age of 29 years and a median duration of 6 years after the onset of proteinuria. Conclusion: AA amyloidosis is a rare but morbid complication of CF. Renal involvement is predominant.
AA amyloidosis, chronic renal disease, cystic fibrosis, goiter, intestinal disorders, proteinuria History Received 6 February 2014 Accepted 8 July 2014 Published online 23 July 2014
Abbreviations: ACE: angiotensin-converting enzyme; CF: cystic fibrosis; CFTR: CF transmembrane conductance regulator; FEV1: forced expiratory volume in one second; GFR: glomerular filtration rate; IV: intravenous; SAA: serum amyloid A
Introduction Cystic fibrosis (CF) is a common autosomal recessive genetic disease. It is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein which is involved in the regulation of the components of sweat, digestive juices, and mucus [1]. Major clinical manifestations include chronic lung and sinus infection, diarrhea, diabetes, poor growth, and infertility. CF lung disease is characterized by neutrophilic airway inflammation, increased expression of proinflammatory cytokines, and pulmonary infection [2]. AA (secondary) amyloidosis may complicate chronic diseases Address for correspondence: Katia Stankovic Stojanovic, Service de me´decine interne, hoˆpital Tenon, 4 rue de la Chine, 75970 Paris cedex 20, France. Tel: +33 1560 17080. Fax: +33 1560 18407. E-mail: [email protected]
associated with a sustained inflammatory response. The symptoms are caused by the extracellular deposition of insoluble abnormal fibrils derived from the acute phase reactant serum amyloid A (SAA) protein. AA amyloidosis is a systemic disease affecting primarily the kidneys, but also the gut, the thyroid gland, and the skin [3]. CF as a chronic inflammatory disease is a rare cause of AA amyloidosis [3,4]. Only small case series have been reported in the literature. Our aim was to report a series of cases of AA amyloidosis diagnosed within the last 30 years in French patients with CF.
Patients and methods Design This retrospective study was approved by the Scientific Committee of the French CF Society. In November 2008, we
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contacted the directors of all 49 French CF centers by email, asking them if they were aware of cases of AA amyloidosis in patients with CF. In January 2009, we had re-contacted by e-mail or by telephone the CF centers that had not responded in order to improve the response rate. In the meantime, data was collected either by a physician from the CF center or by the study coordinator (KS) in centers that had reported cases of AA amyloidosis. The study was approved by the Institutional Review Board ‘‘Comite´ de Protection des Personnes, Ile de France V’’ and was in accordance with the French regulations regarding clinical research. Data collection A questionnaire was developed in collaboration with both CF and AA amyloidosis specialists. It included demographic data, age at diagnosis of CF, CFTR genotype, pancreatic status (exocrine pancreatic insufficiency, diabetes), chronic bronchial bacterial colonization (defined by the presence of bacteria for at least 6 months) and pulmonary exacerbations (requiring intravenous (IV) antibiotic courses), pulmonary function (in particular, forced expiratory volume in one second FEV1) at the time of amyloidosis diagnosis. More specifically, data collected regarding AA amyloidosis included renal function, level and duration of proteinuria with or without nephrotic syndrome, extra-renal sites of amyloidosis, and histopathological proof of AA amyloidosis (with Congo red stain and immunohistochemistry). Other causes of renal disease were ruled out. Histology
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were obtained for 6 cases; for the 3 other cases, they were unavailable because the patients had died more than 15 years previously. Clinical characteristics of the patients are presented in Tables 1 and 2. Characteristics of cystic fibrosis Patients were born between 1953 and 1981. The median age at diagnosis was 6.5 years [3–11]. There were 4 male and 2 female patients (male/female sex ratio ¼ 2). CFTR genotype was homozygous F508del in 4 cases and compound heterozygous F508del/2789 + 5G-4A in 2 cases. Five patients had exocrine pancreas insufficiency, which was mild in one of them. Median FEV1 was 20% [18–37] of predicted values; 3 patients required continuous oxygen therapy. All patients were chronically infected with Pseudomonas aeruginosa, and 5 with Staphylococcus aureus. Other microorganisms were also present: Aspergillus (3 cases), Klebsiella pneumoniae (2 cases), Haemophilus (2 cases), Candida albicans (2 cases), Stenotrophomonas maltophilia (1 case), Burkholderia cenocepacia (1 case). All patients received regular IV antibiotic courses, at least 3 times per year and continuously in one. None received systemic corticosteroids. Three patients showed hepato-biliary involvement and 3 had severe malnutrition. Three patients were recipients of lung transplantation at a median age of 26 years [26–31.5], in combination with a heart transplant in one case, and a kidney transplant in 2 cases. Characteristics of AA amyloidosis
The results are expressed as median (interquartile range) and compared with the Mann–Whitney test, using XL Statistics software, Deakin University Warrnambool, Australia, Copyright Rodney Carr 1997–2008, Warrnambool, Australia. A p value 50.05 was considered significant.
AA amyloidosis was suspected by renal dysfunction and confirmed by renal biopsy in four cases. In one case, a compressive goiter was resected and amyloidosis was found histologically. In one case presenting with diarrhea, intestinal biopsy found amyloidosis. Proteinuria was present in all cases, was in the range of a nephrotic syndrome in four cases, and was associated with renal failure in five cases (of which 3 required hemodialysis). The median age at onset of proteinuria was 24 years [18-25.5]. AA amyloidosis was found in organs of the gastrointestinal system in four cases. Indications for biopsy were: diarrhea in one case, abdominal pain in one case, severe malnutrition at the time of transplantation in one case, and cirrhosis of the liver in one case. Hepatic AA amyloidosis was found on autopsy in one additional case. Among the three transplanted patients, the diagnosis of AA amyloidosis was known at the time of transplantation in two cases, and was associated with severe malnutrition and nephrotic syndrome prior to transplantation in one case; proteinuria was mild in the two other transplanted patients. CRP levels at steady state at the time of the diagnosis of AA amyloidosis were available in three cases and were respectively 9 mg/L, 2 mg/L and 2–25 mg/L in the third case (normal range510 mg/L). SAA assays were not available at that time in France.
Analysis of our case series
Outcome of the patients
All French pediatric and adult CF centers responded to the survey; 7 centers identified 9 cases of histologicallyconfirmed AA amyloidosis complicating CF. Medical files
Angiotensin-converting enzyme (ACE) inhibitor did not show efficacy in preventing progression of amyloid renal disease in most of the cases and colchicine had no effect.
Biopsy specimens for light microscopic analysis were fixed either in ethanol/formalin/acetic acid or in alcoholic Bouin solution and embedded in paraffin. The presence of amyloid was established by Congo red stain and the appearance of an apple green birefringence under polarized light. AA amyloidosis was demonstrated by positive immunohistochemical staining. In some cases, IF specimens were studied on frozen sections with fluorescein isothiocyanate (FITC)-conjugated, monospecific, anti–light chains (k and ) and reviewed by an expert amyloidosis pathologist (MC). Review of literature We searched the ‘‘MEDLINE database’’ (National Library of Medicine, Bethesda, MD) using the keywords ‘‘amyloidosis’’ and ‘‘cystic fibrosis’’ and compared the results with the present series. Statistical analysis
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45
No. of patient
[5] [6] [6] [7] [8] [9] [9] [5,10] [11] [12] [5,13] [5,13] [14 [15] [15] [15] [15] [15] [13,16] [16] [16 [16] [16] [16] [16] [16] [16] [16] [16] [17] [18] [18] [19] [19] [20] [21] [21] [22] [23] [24] [24] [25] [25] [26] [27]
Reference
M M F M M ND ND M F M M M M M F M M M F F F M M M F F M M F M M F M F F M M M M M F M M F M
Sex
22 years 9 years 5.5 years 18 months 6 years ND ND 11 years 8 years 9 years 6.5 years 9 years 7 weeks 19 years 1 year 13 years 18 years 2 years At birth 16 years 14 months 6 months ND At birth 3 years 6 months At birth 2 months ND 16 years 7 years 11.5 years 8 years 6 years 2 years 19 years 1 year 3 months 3 years 7 years ND 5 years ND ND 11 years
Age at diagnosis of CF 27 18 22 18 13 ND ND 32 15 21 25 21 15 24 12 20 20 6 ND ND ND ND ND ND ND ND ND ND ND 21 16 17 26 18 14 37 24 21 24 32 ND 27 36 14 13
Age at diagnosis of amyloidosis (years) 8 g/24 h ND 0 Intermittent proteinuria 12–19 g/L ND ND 13 g/24h 12.5 g/L ND 8g/24 h 10.2g/L ND 3.2g/24h 26g/24h 3g/24h 12g/24h 9g/24h ND ND ND ND ND ND ND ND ND ND ND 6g/24h 3g/24h 0.7g/24h 10g/24h 14.1g/24h 5g/24h 1.1g/24h 20g/24h 3.6g/24h ND 2.4g/24h ND 10.8g/24h 18g/24h Nephrotic syndrome Nephrotic syndrome
Level of proteinuria at diagnosis of renal amyloidosis Localizations of amyloidosis AG, H, IT, K, Li, Lu, M, Pc, Pr, SG, Sk, Sp AG, Br, IT, H, K, Li, LN, Pc, SG, Sp, Th AG, H, K, SG, Th IT, H, K, L, Pa, Pc, PG, Sp, Th Mesenteric LN, K, Pl, Th K K AG, K, Pa, Sp AG,H, IT, K, Li, Sk, Sp, Th, To AG, Ao, IT, K, Li, Sp, Th AG, H, IT, K, Li, Lu, Sp, Th, To AG, K, Li, mediastinal LN, Sp AG, K, Li, Sp, Th AG, IT, K, Li, Lu, Pc, SG, Sp, Th IT, K K, Th AG, H, IT, K, Li, LV, Sp, Th AG, H, IT, K, Li, Lu, Pc, SG, Sp, Th IT, K, Li, LN, Lu, Sp, U K, Li, Sp K, Li, Sp AG, K, Li, LN, Sp K, Li, Sp K, Li, Sp K, Li, Sp K, Li, Sp K, Li, Sp K, Sp K, Lu, Sp FT, IT, K K K AG, IT, K, Li, Lu, Sp, Th K K K K K BM, K, Th IT, K, Th H, IT, K, Li, Lu, Sp K K K, Lu K, Lu
Table 1. Review of cases (literature and our personal series) of cystic fibrosis associated with AA amyloidosis.
27 20 22 24 16 ND ND 32 16.5 21 25 21 17 27 13 ND 20 6 22 17 15 21 15 24 27 15 27 19 29 21 17 18 26 18 Alive at the age of 16 Alive t the age of 39 29 21 ND Alive at the age of 34 20 27 36 15 Alive 15 years later
Age at death (years)
AA amyloidosis in cystic fibrosis (continued )
Few months 17 months 0 (autospsy) 6 ans 2 mois ND ND 4 months 1.5 years 3 years 2 years 6.5 months 3 years 3 years 1 year ND Few weeks Few weeks ND ND ND ND ND ND ND ND ND ND ND 1.5 month 2 years 1 years 41 days 2 months ND ND 4 years 10 months 9 months ND ND 0 (Autopsy) 21 months 7 months 17 months ND
Time between onset of proteinuria and death
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6 years 23 1.16g/24h 19 Present series 53
4 years F
series series series series series
ND 49 years 9 years 38 years 12 years 5 months 3 years ND F M M F M M [28] [29] Present Present Present Present Present
Legends: F: Female. M: Male. ND: no data. Organs: AG: adrenal glands. Ao: aorta. BM: bone marrow. Br: bronchus. FT: fat tissue. H: heart. IT: intestinal tract. LN: lymph nods. K: kidney. Li: liver. Lu: lungs. LV: lymph vessels. M: muscles. Pa: parathyroid. Pc: pancreas. PG: pituitary gland. Pl: pleura. Pr: prostate. SG: salivary glands. Sk: skin. Sp: spleen. Th: thyroid. To: tongue. U: uterus.
2 years
ND 9.5g/24h 8.8g/24h 1.85g/24h 2.4g/24h 0.34g/24h 0.3g/24h
AG, K, Sp K IT, K, Th suspected but not confirmed IT, K, Li IT, K K, Th IT, K, Li, ‘‘diffuse amyloidosis’’ at autopsy K
25 50 29 42 30 Alive in 2014 (43 years old) 27
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46 47 48 49 50 51 52
No. of patient
Reference
Sex
ND ND 25 22 24 32 25
Age at death (years) Localizations of amyloidosis Level of proteinuria at diagnosis of renal amyloidosis Age at diagnosis of amyloidosis (years) Age at diagnosis of CF
Table 1. Continued
ND 1 year 6 years 25 years 6 years
K. Stankovic Stojanovic et al Time between onset of proteinuria and death
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Five patients died at a median age of 29 years [27–30], approximately 6 years after the identification of proteinuria. Two patients died in the context of renal failure, concomitant to respiratory distress in another one; these three patients had severe renal AA amyloidosis. One heart-and-lung-transplanted patient with mild proteinuria and normal serum creatinine at the time of transplantation died from respiratory distress and multiorgan failure 9 months after transplantation; the diagnosis of AA amyloidosis was made 6 months after transplantation due to diarrhea. One kidney-and-lung-transplanted patient who developed bronchiolitis obliterans after transplantation died from acute renal failure of multifactorial origin 4 years later, without any evidence of recurrence of AA amyloidosis in the transplanted kidney. These two patients had digestive AA amyloidosis with malnutrition. The patient with AA amyloidosis revealed by a thyroid goiter and confirmed by renal biopsy indicated by mild proteinuria prior to lung-and-kidney transplantation is still alive 6 years after transplantation.
Comparison with cases reported in the literature Totally, 47 cases of CF with AA amyloidosis have previously been reported in the literature [5–29]. Including our 6 cases, the median age at diagnosis of CF was 8.5 years (14 months11 years), and the male/female ratio was 1.9. Proteinuria was discovered at a median age of 21 years [16–25] with a median level of 7.4 g/day [3.2–14.1g]. The median delay between the diagnosis of proteinuria and death was 8 months [2–23 months]. The median age at death was 21 years [17–26.5]. The kidneys were involved in all cases and revealed AA amyloidosis when alive in all the cases but 1. On autopsy, all patients were found to have renal involvement, 26 of 53 (49%) had involvement of the spleen; 24 (45%) had involvement of the liver; 19 (36%) had involvement of the GI tract; 17 (32%) had involvement of the thyroid gland; 16 (30%) had involvement of the adrenal glands; 13 (25%) had involvement of the respiratory tract including bronchi, lungs, and pleurae; 11 (21%) had cardiac involvement; 7 (13%) had lymph node involvement; and 6 (11%) had involvement of the pancreas or salivary glands each. Involvement of skin, parathyroid glands, tongue, muscles, prostate, uterus, pituitary glands, and bone marrow was also seen, in a few cases each. Inflammatory markers have not been consistently reported in the literature. Table 3 indicates the main characteristics of cases in our series versus the cases retrieved from the literature. There is no statistical difference between the reported cases and our own series regarding the sex-ratio, age at diagnosis of CF, and age at onset of proteinuria. Proteinuria level at diagnosis of AA amyloidosis was significantly higher in the cases from literature. Age at death and the delay between the onset of proteinuria and death are significantly lower in the previous reported cases.
Discussion AA amyloidosis may be a late complication of any chronic inflammatory disease. CF is associated with chronic respiratory inflammation and infection, which may predispose to AA amyloidosis. Our series and a systematic search of the literature since 1964 (start of the MEDLINE database)
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Table 2. Summary of the review of cases of cystic fibrosis associated with AA amyloidosis. Mean level of proteinuria at Mean age at diagnosis of diagnosis of Mean age at diagnosis amyloidosis renal amyloidosis Number of Sex ratio (g/day) (years) patients (Male/Female) of CF (years) 53
1.9
8.3
21.5
7.45
Mean time between onset of proteinuria Mean age at death (years) and death (years)
Localizations of amyloidosis Number of patients (%) Kidneys 53 (100) Spleen 26 (49) Liver 24 (45) Intestinal tract 19 (36) Thyroid 17 (32) Adrenal glands 16 (30) Bronchus-Lungs-Pleura 13 (24.5) Heart 11 (21) Lymph nods 7 (13) Pancreas 6 (11) Salivary glands 6 (11) Skin 3 (6) Parathyroids 2 (4) Tongue 2 (4) Muscles 1 (2) Prostate 1 (2) Uterus 1 (2) Pituitary glands 1 (2) Bone marrow 1 (2)
23
2.5
Table 3. Comparison between the present series and cases retrieved from the literature.
n Present series Literature p value between present series and literature
6 47
Sex-ratio (Male/Female) 2 1.9 0.97
Age at diagnosis of CF (years)
Age at onset of proteinuria (years)
Age at death (years)
Delay between discovery of proteinuria and death (years)
Proteinuria level at diagnosis of amyloidosis (g/day)
6.5 ± 13.8 [3–11] 6 ± 9.2 [1–11] 0.6
24 ± 5.1 [18–25.5] 21 ± 8.6 [16–25] 0.18
29 ± 7.1 [27–30] 21 ± 7.3 [17–26.5] 0.01
6 ± 9.1 [6–6] 0.65 (8 months) ± 1.5 [2 months–2 years] 0.001
1.5 ± 3.2 [0.5–2.2] 9 ± 6.8 [3.2–14.1] 0.01
CF: cystic fibrosis. Quantitative data are expressed in medians ± standard deviation (interquartile range). Comparison used Mann-Whitney test. p value50.05 were considered significant.
identified 56 reported cases of AA amyloidosis in CF patients. While case finding is undoubtedly incomplete, these findings suggest that AA amyloidosis is a rare complication of CF. Most of our cases were diagnosed at an advanced stage of AA amyloidosis, either at a nephrotic level of proteinuria, or in some cases in the presence of overt renal failure. Milder cases of AA amyloidosis may be missed if routine screening by the annual assessment of proteinuria is not performed. AA amyloidosis did not appear to change overall mortality in our series (the mean age at death in French CF patients is 29 years [30]) but contributed to death in all cases. Awareness of this complication in CF should be enhanced to allow an earlier diagnosis [3]. The initiation of systematic screening of newborns in France for CF in 2002 and improved care of CF patients should decrease infection and inflammation, and thus decrease the incidence and severity of AA amyloidosis. Moreover, an earlier diagnosis of AA amyloidosis could modify the therapeutic strategy: intensification of antibiotic courses, avoidance of nephrotoxic drugs, and earlier consideration of lung transplantation in order to reduced suppuration and chronic inflammation of the lungs.
Renal involvement was predominant in this series, and involvement of other organs appears similar to that associated with other inflammatory and rheumatic diseases [3]. Among our three transplanted patients, two patients died: the first case was one of the first lung transplantations for CF in France (1989), and the patient died 9 months after transplantation from complications of CF disease; for this patient AA amyloidosis was diagnosed after transplantation due to diarrhea. The second patient died 4 years after transplantation from bronchiolitis obliterans and from intestinal complications of AA amyloidosis; it was noteworthy that AA amyloidosis was already diffuse and severe at the time of transplantation. There is a twenty-year time interval between the first and the third transplanted patient who is still alive 6 years after his lung-and-kidney transplantation. For the other three non-transplanted cases, AA amyloidosis was diagnosed at an advanced stage (nephrotic syndrome and/or renal failure) and contributed to complications resulting in death. Thus, from these cases, we hypothesize that better care and prevention of respiratory infection in CF and earlier diagnosis of AA amyloidosis may be correlated with a better outcome in patients that are candidates for organ transplantation.
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In auto-inflammatory diseases, elevated SAA is a predictor of AA amyloidosis [3]. In this series, unfortunately, we had no parameters to evaluate the level of inflammation. Indeed, SAA is not routinely tested in our country and only a few CRP results were available. Some genotypes of the SAA1 gene are reported to be more frequently associated with the occurrence of AA amyloidosis in patients with familial Mediterranean fever [32]. These biomarkers and genotypes should be assessed in CF in future studies with the hypothesis that patients with more frequent acute respiratory infections, higher SAA, and a specific genotype of SAA1 could be predictive factors for the occurrence of AA amyloidosis. CF genotypes of the patients in our series were as follows: homozygous F508del in 4 cases and compound heterozygous F508del/2789 + 5G-4A in 2 cases. F508del is the most common mutation in CF patients in France, present in 70% of cases (approximately 45% homozygous and 25% compound heterozygous with another mutation) whereas 2789 + 5G-4A is present in about 2% of French CF patients, all compound heterozygous F508del/2789 + 5G-4A [30]. Correlation between the CF genotype of the patients and the risk of developing AA amyloidosis was not possible in this series due to the small sample size. AA amyloidosis has been described in non-CF bronchiectasis of various origins, including severe pulmonary infections and pulmonary tuberculosis, Kartagener’s or Mounier-Kuhn’s syndrome [33–35]. Recurrent bronchial infections are the main complication of non-CF bronchiectasis, contributing to an inflammatory reaction and to the onset of AA amyloidosis. However, the median delay between the occurrence of AA amyloidosis and the first manifestations of non-CF bronchiectasis in these patients is usually greater than in AA amyloidosis associated with CF. This suggests that factors other than recurrent bronchial infections are involved in the development of AA amyloidosis in CF, such as perhaps timing and intensity of infections. Renal abnormalities in CF can be variable [29]. AA amyloidosis causes proteinuria and sometimes renal failure. Renal toxicity of treatments, complication of diabetes mellitus, and glomerulonephritis [36,37] are more common causes of renal damage in CF. In all patients in the present series, histologically-proven renal AA amyloidosis was not associated with any other cause of renal disease.
Conclusion AA amyloidosis is a complication of CF and should be suspected in patients with of renal abnormalities or intestinal disorders including malnutrition. AA can lead to significant morbidity, and should be considered in patients eligible for organ transplantation. We recommend systematic screening of CF patients for proteinuria, and renal biopsy should be performed in order to diagnose AA amyloidosis at an earlier stage. This may influence treatment strategy and provoke earlier lung transplantation.
Declaration of interest The authors report no conflicts of interest.
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32. Cazeneuve C, Ajrapetyan H, Papin S, Roudot-Thoraval F, Genevie`ve D, Mndjoyan E, Papazian M, et al. Identification of MEFV-independent modifying genetic factors for familial Mediterranean fever. Am J Hum Genet 2000;67:1136–43. 33. Akc¸ay S, Akman B, Ozdemir H, Eyu¨bog˘lu FO, Karacan O, Ozdemir N. Bronchiectasis-related amyloidosis as a cause of chronic renal failure. Ren Fail 2002;24:815–23. 34. Demir M, Kutlucan A, Sezer MT. Renal amyloidosis in a patient with Kartagener syndrome. Ren Fail 2007;29:117. 35. Youakim C, Cottin V, Juillard L, Fouque D, MacGregor B, Cordier JF. Renal AA amyloidosis secondary to bronchiectasis: a report of two cases (including one with Mounier-Kuhn syndrome). Rev Mal Respir 2004;21:821–4. 36. Stirati G, Antonelli M, Fofi C, Fierimonte S, Pecci G. IgA nephropathy in cystic fibrosis. J Nephrol 1999;12:30–1. 37. Stephens SE, Rigden SP. Cystic fibrosis and renal disease. Paediatr Respir Rev 2002;3:135–8.
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ORIGINAL ARTICLE
Cystic fibrosis and AA amyloidosis: a survey in the French cystic fibrosis network Katia Stankovic Stojanovic1,2, Dominique Hubert3, Sylvie Leroy4, Stephane Dominique5, Dominique Grenet6, Magali Colombat7, Annick Clement8, Michael Fayon9, and Gilles Grateau1,2 1
Centre de Reference pour les Amyloses d’Origine Inflammatoire et de la Fie`vre Mediterraneenne Familiale, Service de Medecine Interne, Assistance Publique – Hoˆpitaux de Paris, Hoˆpital Tenon, Paris France, 2UMR 933 INSERM, Universite Pierre et Marie Curie-Paris 6, Paris, France, 3Centre de Ressources et de Competences pour la Mucoviscidose, Service de Pneumologie, Assistance Publique – Hoˆpitaux de Paris, Hoˆpital Cochin, Universite Paris Descartes, Paris, France, 4Centre de Ressources et de Competences pour la Mucoviscidose, Service de Pneumologie, Hoˆpital Pasteur, CHU de Nice, Nice, France, 5Centre de Ressources et de Competences pour la Mucoviscidose, Clinique Pneumologique, Hoˆpital Charles Nicolle, CHU de Rouen, Rouen France, 6Centre de Ressources et de Competences pour la Mucoviscidose, Service de Pneumologie, Hoˆpital Foch, Suresnes, France, 7 Service d’ Anatomie Pathologique, Hoˆpital Foch, Suresnes, France, 8Centre de Ressources et de Competences pour la Mucoviscidose, Service de Pneumologie pediatrique, Assistance Publique – Hoˆpitaux de Paris, Hoˆpital Trousseau, Paris, France, and 9Departement de Pediatrie, Centre d’Investigation Clinique (CIC 0005), CHU de Bordeaux, Bordeaux, France Abstract
Keywords
Introduction: To define the characteristics of CF patients developing AA amyloidosis. Methods: A 30-year retrospective survey conducted within the national French CF network to identify cases of CF associated with AA amyloidosis. Results: Nine cases of AA amyloidosis were identified (CF prevalence in France is approximately 6000 patients) and sufficient data were collected in six. The clinical presentation was renal disease in four cases, a compressive goiter in one case, and epigastric pain in one case. Organ involvement included kidney disease in all cases (proteinuria, with a median age at onset of 24 years, 4 cases with nephrotic syndrome, 5 with renal failure); gastrointestinal (4 cases with duodenal ulcer); thyroid (2 cases); and hepatobiliary system (3 cases). The median age at diagnosis of CF was 6.5 years. Five patients had pancreatic insufficiency. All patients had chronic respiratory infections requiring intravenous antibiotics several times a year. Five patients have died, at a median age of 29 years and a median duration of 6 years after the onset of proteinuria. Conclusion: AA amyloidosis is a rare but morbid complication of CF. Renal involvement is predominant.
AA amyloidosis, chronic renal disease, cystic fibrosis, goiter, intestinal disorders, proteinuria History Received 6 February 2014 Accepted 8 July 2014 Published online 23 July 2014
Abbreviations: ACE: angiotensin-converting enzyme; CF: cystic fibrosis; CFTR: CF transmembrane conductance regulator; FEV1: forced expiratory volume in one second; GFR: glomerular filtration rate; IV: intravenous; SAA: serum amyloid A
Introduction Cystic fibrosis (CF) is a common autosomal recessive genetic disease. It is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein which is involved in the regulation of the components of sweat, digestive juices, and mucus [1]. Major clinical manifestations include chronic lung and sinus infection, diarrhea, diabetes, poor growth, and infertility. CF lung disease is characterized by neutrophilic airway inflammation, increased expression of proinflammatory cytokines, and pulmonary infection [2]. AA (secondary) amyloidosis may complicate chronic diseases Address for correspondence: Katia Stankovic Stojanovic, Service de me´decine interne, hoˆpital Tenon, 4 rue de la Chine, 75970 Paris cedex 20, France. Tel: +33 1560 17080. Fax: +33 1560 18407. E-mail: [email protected]
associated with a sustained inflammatory response. The symptoms are caused by the extracellular deposition of insoluble abnormal fibrils derived from the acute phase reactant serum amyloid A (SAA) protein. AA amyloidosis is a systemic disease affecting primarily the kidneys, but also the gut, the thyroid gland, and the skin [3]. CF as a chronic inflammatory disease is a rare cause of AA amyloidosis [3,4]. Only small case series have been reported in the literature. Our aim was to report a series of cases of AA amyloidosis diagnosed within the last 30 years in French patients with CF.
Patients and methods Design This retrospective study was approved by the Scientific Committee of the French CF Society. In November 2008, we
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contacted the directors of all 49 French CF centers by email, asking them if they were aware of cases of AA amyloidosis in patients with CF. In January 2009, we had re-contacted by e-mail or by telephone the CF centers that had not responded in order to improve the response rate. In the meantime, data was collected either by a physician from the CF center or by the study coordinator (KS) in centers that had reported cases of AA amyloidosis. The study was approved by the Institutional Review Board ‘‘Comite´ de Protection des Personnes, Ile de France V’’ and was in accordance with the French regulations regarding clinical research. Data collection A questionnaire was developed in collaboration with both CF and AA amyloidosis specialists. It included demographic data, age at diagnosis of CF, CFTR genotype, pancreatic status (exocrine pancreatic insufficiency, diabetes), chronic bronchial bacterial colonization (defined by the presence of bacteria for at least 6 months) and pulmonary exacerbations (requiring intravenous (IV) antibiotic courses), pulmonary function (in particular, forced expiratory volume in one second FEV1) at the time of amyloidosis diagnosis. More specifically, data collected regarding AA amyloidosis included renal function, level and duration of proteinuria with or without nephrotic syndrome, extra-renal sites of amyloidosis, and histopathological proof of AA amyloidosis (with Congo red stain and immunohistochemistry). Other causes of renal disease were ruled out. Histology
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were obtained for 6 cases; for the 3 other cases, they were unavailable because the patients had died more than 15 years previously. Clinical characteristics of the patients are presented in Tables 1 and 2. Characteristics of cystic fibrosis Patients were born between 1953 and 1981. The median age at diagnosis was 6.5 years [3–11]. There were 4 male and 2 female patients (male/female sex ratio ¼ 2). CFTR genotype was homozygous F508del in 4 cases and compound heterozygous F508del/2789 + 5G-4A in 2 cases. Five patients had exocrine pancreas insufficiency, which was mild in one of them. Median FEV1 was 20% [18–37] of predicted values; 3 patients required continuous oxygen therapy. All patients were chronically infected with Pseudomonas aeruginosa, and 5 with Staphylococcus aureus. Other microorganisms were also present: Aspergillus (3 cases), Klebsiella pneumoniae (2 cases), Haemophilus (2 cases), Candida albicans (2 cases), Stenotrophomonas maltophilia (1 case), Burkholderia cenocepacia (1 case). All patients received regular IV antibiotic courses, at least 3 times per year and continuously in one. None received systemic corticosteroids. Three patients showed hepato-biliary involvement and 3 had severe malnutrition. Three patients were recipients of lung transplantation at a median age of 26 years [26–31.5], in combination with a heart transplant in one case, and a kidney transplant in 2 cases. Characteristics of AA amyloidosis
The results are expressed as median (interquartile range) and compared with the Mann–Whitney test, using XL Statistics software, Deakin University Warrnambool, Australia, Copyright Rodney Carr 1997–2008, Warrnambool, Australia. A p value 50.05 was considered significant.
AA amyloidosis was suspected by renal dysfunction and confirmed by renal biopsy in four cases. In one case, a compressive goiter was resected and amyloidosis was found histologically. In one case presenting with diarrhea, intestinal biopsy found amyloidosis. Proteinuria was present in all cases, was in the range of a nephrotic syndrome in four cases, and was associated with renal failure in five cases (of which 3 required hemodialysis). The median age at onset of proteinuria was 24 years [18-25.5]. AA amyloidosis was found in organs of the gastrointestinal system in four cases. Indications for biopsy were: diarrhea in one case, abdominal pain in one case, severe malnutrition at the time of transplantation in one case, and cirrhosis of the liver in one case. Hepatic AA amyloidosis was found on autopsy in one additional case. Among the three transplanted patients, the diagnosis of AA amyloidosis was known at the time of transplantation in two cases, and was associated with severe malnutrition and nephrotic syndrome prior to transplantation in one case; proteinuria was mild in the two other transplanted patients. CRP levels at steady state at the time of the diagnosis of AA amyloidosis were available in three cases and were respectively 9 mg/L, 2 mg/L and 2–25 mg/L in the third case (normal range510 mg/L). SAA assays were not available at that time in France.
Analysis of our case series
Outcome of the patients
All French pediatric and adult CF centers responded to the survey; 7 centers identified 9 cases of histologicallyconfirmed AA amyloidosis complicating CF. Medical files
Angiotensin-converting enzyme (ACE) inhibitor did not show efficacy in preventing progression of amyloid renal disease in most of the cases and colchicine had no effect.
Biopsy specimens for light microscopic analysis were fixed either in ethanol/formalin/acetic acid or in alcoholic Bouin solution and embedded in paraffin. The presence of amyloid was established by Congo red stain and the appearance of an apple green birefringence under polarized light. AA amyloidosis was demonstrated by positive immunohistochemical staining. In some cases, IF specimens were studied on frozen sections with fluorescein isothiocyanate (FITC)-conjugated, monospecific, anti–light chains (k and ) and reviewed by an expert amyloidosis pathologist (MC). Review of literature We searched the ‘‘MEDLINE database’’ (National Library of Medicine, Bethesda, MD) using the keywords ‘‘amyloidosis’’ and ‘‘cystic fibrosis’’ and compared the results with the present series. Statistical analysis
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45
No. of patient
[5] [6] [6] [7] [8] [9] [9] [5,10] [11] [12] [5,13] [5,13] [14 [15] [15] [15] [15] [15] [13,16] [16] [16 [16] [16] [16] [16] [16] [16] [16] [16] [17] [18] [18] [19] [19] [20] [21] [21] [22] [23] [24] [24] [25] [25] [26] [27]
Reference
M M F M M ND ND M F M M M M M F M M M F F F M M M F F M M F M M F M F F M M M M M F M M F M
Sex
22 years 9 years 5.5 years 18 months 6 years ND ND 11 years 8 years 9 years 6.5 years 9 years 7 weeks 19 years 1 year 13 years 18 years 2 years At birth 16 years 14 months 6 months ND At birth 3 years 6 months At birth 2 months ND 16 years 7 years 11.5 years 8 years 6 years 2 years 19 years 1 year 3 months 3 years 7 years ND 5 years ND ND 11 years
Age at diagnosis of CF 27 18 22 18 13 ND ND 32 15 21 25 21 15 24 12 20 20 6 ND ND ND ND ND ND ND ND ND ND ND 21 16 17 26 18 14 37 24 21 24 32 ND 27 36 14 13
Age at diagnosis of amyloidosis (years) 8 g/24 h ND 0 Intermittent proteinuria 12–19 g/L ND ND 13 g/24h 12.5 g/L ND 8g/24 h 10.2g/L ND 3.2g/24h 26g/24h 3g/24h 12g/24h 9g/24h ND ND ND ND ND ND ND ND ND ND ND 6g/24h 3g/24h 0.7g/24h 10g/24h 14.1g/24h 5g/24h 1.1g/24h 20g/24h 3.6g/24h ND 2.4g/24h ND 10.8g/24h 18g/24h Nephrotic syndrome Nephrotic syndrome
Level of proteinuria at diagnosis of renal amyloidosis Localizations of amyloidosis AG, H, IT, K, Li, Lu, M, Pc, Pr, SG, Sk, Sp AG, Br, IT, H, K, Li, LN, Pc, SG, Sp, Th AG, H, K, SG, Th IT, H, K, L, Pa, Pc, PG, Sp, Th Mesenteric LN, K, Pl, Th K K AG, K, Pa, Sp AG,H, IT, K, Li, Sk, Sp, Th, To AG, Ao, IT, K, Li, Sp, Th AG, H, IT, K, Li, Lu, Sp, Th, To AG, K, Li, mediastinal LN, Sp AG, K, Li, Sp, Th AG, IT, K, Li, Lu, Pc, SG, Sp, Th IT, K K, Th AG, H, IT, K, Li, LV, Sp, Th AG, H, IT, K, Li, Lu, Pc, SG, Sp, Th IT, K, Li, LN, Lu, Sp, U K, Li, Sp K, Li, Sp AG, K, Li, LN, Sp K, Li, Sp K, Li, Sp K, Li, Sp K, Li, Sp K, Li, Sp K, Sp K, Lu, Sp FT, IT, K K K AG, IT, K, Li, Lu, Sp, Th K K K K K BM, K, Th IT, K, Th H, IT, K, Li, Lu, Sp K K K, Lu K, Lu
Table 1. Review of cases (literature and our personal series) of cystic fibrosis associated with AA amyloidosis.
27 20 22 24 16 ND ND 32 16.5 21 25 21 17 27 13 ND 20 6 22 17 15 21 15 24 27 15 27 19 29 21 17 18 26 18 Alive at the age of 16 Alive t the age of 39 29 21 ND Alive at the age of 34 20 27 36 15 Alive 15 years later
Age at death (years)
AA amyloidosis in cystic fibrosis (continued )
Few months 17 months 0 (autospsy) 6 ans 2 mois ND ND 4 months 1.5 years 3 years 2 years 6.5 months 3 years 3 years 1 year ND Few weeks Few weeks ND ND ND ND ND ND ND ND ND ND ND 1.5 month 2 years 1 years 41 days 2 months ND ND 4 years 10 months 9 months ND ND 0 (Autopsy) 21 months 7 months 17 months ND
Time between onset of proteinuria and death
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6 years 23 1.16g/24h 19 Present series 53
4 years F
series series series series series
ND 49 years 9 years 38 years 12 years 5 months 3 years ND F M M F M M [28] [29] Present Present Present Present Present
Legends: F: Female. M: Male. ND: no data. Organs: AG: adrenal glands. Ao: aorta. BM: bone marrow. Br: bronchus. FT: fat tissue. H: heart. IT: intestinal tract. LN: lymph nods. K: kidney. Li: liver. Lu: lungs. LV: lymph vessels. M: muscles. Pa: parathyroid. Pc: pancreas. PG: pituitary gland. Pl: pleura. Pr: prostate. SG: salivary glands. Sk: skin. Sp: spleen. Th: thyroid. To: tongue. U: uterus.
2 years
ND 9.5g/24h 8.8g/24h 1.85g/24h 2.4g/24h 0.34g/24h 0.3g/24h
AG, K, Sp K IT, K, Th suspected but not confirmed IT, K, Li IT, K K, Th IT, K, Li, ‘‘diffuse amyloidosis’’ at autopsy K
25 50 29 42 30 Alive in 2014 (43 years old) 27
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46 47 48 49 50 51 52
No. of patient
Reference
Sex
ND ND 25 22 24 32 25
Age at death (years) Localizations of amyloidosis Level of proteinuria at diagnosis of renal amyloidosis Age at diagnosis of amyloidosis (years) Age at diagnosis of CF
Table 1. Continued
ND 1 year 6 years 25 years 6 years
K. Stankovic Stojanovic et al Time between onset of proteinuria and death
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Five patients died at a median age of 29 years [27–30], approximately 6 years after the identification of proteinuria. Two patients died in the context of renal failure, concomitant to respiratory distress in another one; these three patients had severe renal AA amyloidosis. One heart-and-lung-transplanted patient with mild proteinuria and normal serum creatinine at the time of transplantation died from respiratory distress and multiorgan failure 9 months after transplantation; the diagnosis of AA amyloidosis was made 6 months after transplantation due to diarrhea. One kidney-and-lung-transplanted patient who developed bronchiolitis obliterans after transplantation died from acute renal failure of multifactorial origin 4 years later, without any evidence of recurrence of AA amyloidosis in the transplanted kidney. These two patients had digestive AA amyloidosis with malnutrition. The patient with AA amyloidosis revealed by a thyroid goiter and confirmed by renal biopsy indicated by mild proteinuria prior to lung-and-kidney transplantation is still alive 6 years after transplantation.
Comparison with cases reported in the literature Totally, 47 cases of CF with AA amyloidosis have previously been reported in the literature [5–29]. Including our 6 cases, the median age at diagnosis of CF was 8.5 years (14 months11 years), and the male/female ratio was 1.9. Proteinuria was discovered at a median age of 21 years [16–25] with a median level of 7.4 g/day [3.2–14.1g]. The median delay between the diagnosis of proteinuria and death was 8 months [2–23 months]. The median age at death was 21 years [17–26.5]. The kidneys were involved in all cases and revealed AA amyloidosis when alive in all the cases but 1. On autopsy, all patients were found to have renal involvement, 26 of 53 (49%) had involvement of the spleen; 24 (45%) had involvement of the liver; 19 (36%) had involvement of the GI tract; 17 (32%) had involvement of the thyroid gland; 16 (30%) had involvement of the adrenal glands; 13 (25%) had involvement of the respiratory tract including bronchi, lungs, and pleurae; 11 (21%) had cardiac involvement; 7 (13%) had lymph node involvement; and 6 (11%) had involvement of the pancreas or salivary glands each. Involvement of skin, parathyroid glands, tongue, muscles, prostate, uterus, pituitary glands, and bone marrow was also seen, in a few cases each. Inflammatory markers have not been consistently reported in the literature. Table 3 indicates the main characteristics of cases in our series versus the cases retrieved from the literature. There is no statistical difference between the reported cases and our own series regarding the sex-ratio, age at diagnosis of CF, and age at onset of proteinuria. Proteinuria level at diagnosis of AA amyloidosis was significantly higher in the cases from literature. Age at death and the delay between the onset of proteinuria and death are significantly lower in the previous reported cases.
Discussion AA amyloidosis may be a late complication of any chronic inflammatory disease. CF is associated with chronic respiratory inflammation and infection, which may predispose to AA amyloidosis. Our series and a systematic search of the literature since 1964 (start of the MEDLINE database)
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Table 2. Summary of the review of cases of cystic fibrosis associated with AA amyloidosis. Mean level of proteinuria at Mean age at diagnosis of diagnosis of Mean age at diagnosis amyloidosis renal amyloidosis Number of Sex ratio (g/day) (years) patients (Male/Female) of CF (years) 53
1.9
8.3
21.5
7.45
Mean time between onset of proteinuria Mean age at death (years) and death (years)
Localizations of amyloidosis Number of patients (%) Kidneys 53 (100) Spleen 26 (49) Liver 24 (45) Intestinal tract 19 (36) Thyroid 17 (32) Adrenal glands 16 (30) Bronchus-Lungs-Pleura 13 (24.5) Heart 11 (21) Lymph nods 7 (13) Pancreas 6 (11) Salivary glands 6 (11) Skin 3 (6) Parathyroids 2 (4) Tongue 2 (4) Muscles 1 (2) Prostate 1 (2) Uterus 1 (2) Pituitary glands 1 (2) Bone marrow 1 (2)
23
2.5
Table 3. Comparison between the present series and cases retrieved from the literature.
n Present series Literature p value between present series and literature
6 47
Sex-ratio (Male/Female) 2 1.9 0.97
Age at diagnosis of CF (years)
Age at onset of proteinuria (years)
Age at death (years)
Delay between discovery of proteinuria and death (years)
Proteinuria level at diagnosis of amyloidosis (g/day)
6.5 ± 13.8 [3–11] 6 ± 9.2 [1–11] 0.6
24 ± 5.1 [18–25.5] 21 ± 8.6 [16–25] 0.18
29 ± 7.1 [27–30] 21 ± 7.3 [17–26.5] 0.01
6 ± 9.1 [6–6] 0.65 (8 months) ± 1.5 [2 months–2 years] 0.001
1.5 ± 3.2 [0.5–2.2] 9 ± 6.8 [3.2–14.1] 0.01
CF: cystic fibrosis. Quantitative data are expressed in medians ± standard deviation (interquartile range). Comparison used Mann-Whitney test. p value50.05 were considered significant.
identified 56 reported cases of AA amyloidosis in CF patients. While case finding is undoubtedly incomplete, these findings suggest that AA amyloidosis is a rare complication of CF. Most of our cases were diagnosed at an advanced stage of AA amyloidosis, either at a nephrotic level of proteinuria, or in some cases in the presence of overt renal failure. Milder cases of AA amyloidosis may be missed if routine screening by the annual assessment of proteinuria is not performed. AA amyloidosis did not appear to change overall mortality in our series (the mean age at death in French CF patients is 29 years [30]) but contributed to death in all cases. Awareness of this complication in CF should be enhanced to allow an earlier diagnosis [3]. The initiation of systematic screening of newborns in France for CF in 2002 and improved care of CF patients should decrease infection and inflammation, and thus decrease the incidence and severity of AA amyloidosis. Moreover, an earlier diagnosis of AA amyloidosis could modify the therapeutic strategy: intensification of antibiotic courses, avoidance of nephrotoxic drugs, and earlier consideration of lung transplantation in order to reduced suppuration and chronic inflammation of the lungs.
Renal involvement was predominant in this series, and involvement of other organs appears similar to that associated with other inflammatory and rheumatic diseases [3]. Among our three transplanted patients, two patients died: the first case was one of the first lung transplantations for CF in France (1989), and the patient died 9 months after transplantation from complications of CF disease; for this patient AA amyloidosis was diagnosed after transplantation due to diarrhea. The second patient died 4 years after transplantation from bronchiolitis obliterans and from intestinal complications of AA amyloidosis; it was noteworthy that AA amyloidosis was already diffuse and severe at the time of transplantation. There is a twenty-year time interval between the first and the third transplanted patient who is still alive 6 years after his lung-and-kidney transplantation. For the other three non-transplanted cases, AA amyloidosis was diagnosed at an advanced stage (nephrotic syndrome and/or renal failure) and contributed to complications resulting in death. Thus, from these cases, we hypothesize that better care and prevention of respiratory infection in CF and earlier diagnosis of AA amyloidosis may be correlated with a better outcome in patients that are candidates for organ transplantation.
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In auto-inflammatory diseases, elevated SAA is a predictor of AA amyloidosis [3]. In this series, unfortunately, we had no parameters to evaluate the level of inflammation. Indeed, SAA is not routinely tested in our country and only a few CRP results were available. Some genotypes of the SAA1 gene are reported to be more frequently associated with the occurrence of AA amyloidosis in patients with familial Mediterranean fever [32]. These biomarkers and genotypes should be assessed in CF in future studies with the hypothesis that patients with more frequent acute respiratory infections, higher SAA, and a specific genotype of SAA1 could be predictive factors for the occurrence of AA amyloidosis. CF genotypes of the patients in our series were as follows: homozygous F508del in 4 cases and compound heterozygous F508del/2789 + 5G-4A in 2 cases. F508del is the most common mutation in CF patients in France, present in 70% of cases (approximately 45% homozygous and 25% compound heterozygous with another mutation) whereas 2789 + 5G-4A is present in about 2% of French CF patients, all compound heterozygous F508del/2789 + 5G-4A [30]. Correlation between the CF genotype of the patients and the risk of developing AA amyloidosis was not possible in this series due to the small sample size. AA amyloidosis has been described in non-CF bronchiectasis of various origins, including severe pulmonary infections and pulmonary tuberculosis, Kartagener’s or Mounier-Kuhn’s syndrome [33–35]. Recurrent bronchial infections are the main complication of non-CF bronchiectasis, contributing to an inflammatory reaction and to the onset of AA amyloidosis. However, the median delay between the occurrence of AA amyloidosis and the first manifestations of non-CF bronchiectasis in these patients is usually greater than in AA amyloidosis associated with CF. This suggests that factors other than recurrent bronchial infections are involved in the development of AA amyloidosis in CF, such as perhaps timing and intensity of infections. Renal abnormalities in CF can be variable [29]. AA amyloidosis causes proteinuria and sometimes renal failure. Renal toxicity of treatments, complication of diabetes mellitus, and glomerulonephritis [36,37] are more common causes of renal damage in CF. In all patients in the present series, histologically-proven renal AA amyloidosis was not associated with any other cause of renal disease.
Conclusion AA amyloidosis is a complication of CF and should be suspected in patients with of renal abnormalities or intestinal disorders including malnutrition. AA can lead to significant morbidity, and should be considered in patients eligible for organ transplantation. We recommend systematic screening of CF patients for proteinuria, and renal biopsy should be performed in order to diagnose AA amyloidosis at an earlier stage. This may influence treatment strategy and provoke earlier lung transplantation.
Declaration of interest The authors report no conflicts of interest.
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