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Table of Contents
Year : 2020  |  Volume : 3  |  Issue : 1  |  Page : 21-23

Immunoglobulin A nephropathy associated with familial mediterranean fever

1 Department of Pediatric Nephrology, Chronic Kidney Disease Research Center, Tehran University of Medical Science, Tehran, Iran
2 Department of Pediatrics, Children Medical Center; Department of Rheumatology Research Center, Tehran University of Medical Science, Tehran, Iran

Date of Submission12-Mar-2020
Date of Decision03-Apr-2020
Date of Acceptance04-Jun-2020
Date of Web Publication27-Jun-2020

Correspondence Address:
Mastaneh Moghtaderi
Department of Pediatric Nephrology, Chronic Kidney Disease Research Center, Children Medical Center, Tehran University of Medical Science, Tehran
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/AJPN.AJPN_6_20

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Familial Mediterranean fever (FMF) is a rare autosomal recessive autoinflammatory disorder, characterized by recurrent episodes of transient fever and polyserositis. Nonamyloid renal involvement has been reported rarely in patients with FMF, such as immunoglobulin A (IgA)nephropathy, in childhood. We report a 7-year-old girl, who was first seen at 1.5 years of age with nephrotic range proteinuria and edema. Based on renal histological demonstration of mesangial proliferation and mesangial IgA deposits, a diagnosis of IgA nephropathy was made. Following recurrent episodes of fever, abdominal pain, and bone pain, a diagnosis of periodic fever was suspected. A known homozygous mutation (p. P369S) was detected in exon 3 of MEPV, the gene encoding pyrin, indicating the diagnosis of FMF. Hence, FMF and IgA nephropathy might coexist. Kidney biopsy is indicated in patients with FMF and early onset of proteinuria to rule out renal involvement with amyloidosis or glomerulonephritis to enable decisions on management.

Keywords: Periodic fever, immunoglobulin A nephropathy, glomerulonephritis

How to cite this article:
Moghtaderi M, Talaipour S, Esfahani ST, Ziaee V. Immunoglobulin A nephropathy associated with familial mediterranean fever. Asian J Pediatr Nephrol 2020;3:21-3

How to cite this URL:
Moghtaderi M, Talaipour S, Esfahani ST, Ziaee V. Immunoglobulin A nephropathy associated with familial mediterranean fever. Asian J Pediatr Nephrol [serial online] 2020 [cited 2022 Jul 7];3:21-3. Available from: https://www.ajpn-online.org/text.asp?2020/3/1/21/288153

  Introduction Top

Familial  Mediterranean fever More Details (FMF) is a rare autosomal recessive disease most commonly reported in individuals of Armenian, Turkish, Arabic, and Jewish ethnicity, with overall incidence of 1:3000. The disease is characterized by recurrent episodes of self-limited fever, pleurisy, peritonitis, synovitis, pericarditis, and an erysipelas-like erythematosus rash.[1] FMF is caused by mutations in the MEFV gene, that encodes pyrin, an inflammatory component that recognizes bacterial modifications in Rho GTPases, and leads to an increase of the production of interleukin-1 β (IL-1 β). More than 300 mutations are reported in MEFV.[2] Colchicine, the chief therapy for FMF, reduces inflammation, and therefore, flares, in most patients, and decreases the long-term risk of amyloidosis.[3] Anti-IL-1 drugs are emerging as promising options for specific therapy for FMF, particularly in patients who do not respond to, or tolerate, colchicine. Compliance to therapy is a major determinant of responsiveness.[4]

Proteinuria in patients with FMF is usually caused by renal amyloidosis (AA variant), which presents with nephrotic syndrome, and often progresses to kidney failure. This complication was seen chiefly in boys, and in the presence of arthritis, delayed diagnosis, family history of amyloidosis, and in homozygous M694V mutation, and is the leading cause of FMF-related mortality in untreated patients.[4],[5] Uncommon etiologies of proteinuria include IgM nephropathy, IgA nephropathy, rapidly progressive glomerulonephritis (GN), diffuse proliferative GN, minimal change disease, and membranoproliferative GN.[6] IgA nephropathy, defined immunohistologically by the presence of glomerular mesangial IgA deposits and variable histopathological changes, chiefly mesangial proliferation, usually presents with gross or microscopic hematuria with subnephrotic proteinuria, and uncommonly with rapidly progressive GN, nephrotic syndrome with hematuria, or malignant hypertension.[7] Nonamyloid kidney diseases, such as IgA nephropathy, have a variable prevalence in patients with FMF.[8] Kidney biopsy is recommended for patients with proteinuria exceeding 0.5 g/day.[9]

We present a rare case of IgA nephropathy that presented with nephrotic syndrome and preceded the diagnosis of FMF.

  Case Report Top

An Iranian 7-year-old girl was admitted for the evaluation of nephrotic range proteinuria without macroscopic or microscopic hematuria. The past history was significant for features suggestive of nephrotic syndrome (hypoalbuminemia, edema, and nephrotic range proteinuria) at 19 months of age. Family history was noncontributory, and parental consanguinity was absent. During the current admission, serum protein and creatinine were within the normal range; the estimated glomerular filtration rate was 99 mL/min per 1.73 m 2. Echocardiography revealed mild pericardial effusion, mild left ventricular hypertrophy, and preserved ejection fraction (55%). Following no response to therapy with prednisolone, kidney biopsy was performed. Light microscopy revealed mesangial hypercellularity, without glomerular sclerosis, endocapillary proliferation, interstitial fibrosis, arteriolar thrombosis, or necrosis [Figure 1]. Immunofluorescence indicated intense (3+) mesangial deposition of IgA, and a diagnosis of IgA nephropathy was made.
Figure 1: Mesangial cell proliferation and mild matrix expansion, H and E, ×400

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Proteinuria declined but persisted in nephrotic range despite therapy with angiotensin-converting enzyme inhibitors along with prednisolone and sequentially, calcineurin inhibitors (tacrolimus and cyclosporine), cyclophosphamide, mycophenolate mofetil, and rituximab, administered in adequate doses and for an appropriate duration. Three years later, the child developed recurrent episodes of fever along with abdominal and bone pain. Rash, arthritis, or myalgia was not reported. Viral and bacterial infections were ruled out. Antinuclear antigen was weakly positive (1: 80); complement C3 was 116 mg/dl, complement C4 was 20 mg/dl, and CH50 was 140 units (all values were within the normal range). Wright ( Brucellosis More Details) and Widal (typhoid) tests were negative. Bone marrow biopsy was normal.

Based on clinical suspicion of diagnosis of FMF, genetic analysis was performed using polymerase chain reaction and reverse hybridization, to cover the following common mutations in MEFV gene: E148Q, P369S, F479l, M6801 (G/C), M6801 (G/A), 1692del, M694V, M694I, K695R, V726A, A744S, and R761H. Testing revealed the presence of the homozygous P369S mutation. Therapy with colchicine, initiated at 0.5 mg daily, resulted in a decrease in the frequency, duration, and intensity of febrile episodes. In view of persistent proteinuria, kidney biopsy was repeated. Biopsy indicated mesangial proliferation and matrix expansion in all glomeruli and periglomerular fibrosis in two glomeruli, without thickening of the capillary wall or crescent formation [Figure 2]. Congo red staining did not show evidence of amyloid deposits. At the last follow-up, at 5 years of therapy, serum creatinine was in the normal range (estimated glomerular filtration rate 91 mL/min per 1.73 m 2), and low-grade proteinuria was present.
Figure 2: (a) Segmental glomerulosclerosis (thick arrows), H and E, ×400. (b) Segmental sclerosis (thick arrows), and interstitial fibrosis with tubular atrophy (thin arrow), Masson trichrome ×400

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  Discussion Top

We report a case of FMF in which typical clinical features were preceded by nephrotic syndrome, caused by IgA nephropathy, presenting in early childhood. FMF was diagnosed based on history and evaluation and confirmed by genetic testing that revealed a mutation in MEFV that is commonly associated with FMF. Renal biopsy findings were typical of IgA nephropathy.

The concomitant occurrence of FMF and IgA nephropathy is described infrequently.[10] In most cases, therapy with colchicine led to the resolution of proteinuria.[10] The most common mutation reported to be associated with FMF in Iranian individuals is M694V, and the most common compound genotype was M694V–V726A.[2] Said et al. reported mesangial deposits of IgA in two adult patients with FMF who showed proteinuria and microscopic hematuria during febrile attacks.[11] Akpolat et al. described a 25-year-old patient with FMF whose proteinuria, associated with membranoproliferative GN, remitted partially with prednisolone and azathioprine.[12] Concomitant amyloidosis was ruled out by two biopsies 3 years apart. Further, amyloidosis in FMF typically develops after long-standing disease with frequent inflammatory episodes and is usually ameliorated by compliance to colchicine therapy.

Colchicine, which is used to control flares of FMF, inhibits neutrophil chemotaxis, reduces expression of adhesion molecules, and also has antioxidant and antifibrotic properties, all of which may contribute to the remission of proteinuria in these case reports.[5] However, therapy with colchicine or various immunosuppressive agents was unsuccessful in inducing remission in our patient, but might have contributed to preventing a decline in renal function.

To conclude, proteinuria and nephrotic syndrome in patients with FMF may be associated with IgA nephropathy. Kidney biopsy is essential in children with FMF presenting with proteinuria in the early stages of the disease.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Jalkh N, Génin E, Chouery E, Delague V, Medlej-Hashim M, Idrac CA, et al. Familial Mediterranean fever in Lebanon: Founder effects for different MEFV mutations. Ann Hum Genet 2008;72:41-7.  Back to cited text no. 1
Salehzadeh F. Familial Mediterranean fever in Iran: A report from FMF registration Center. Int J Rheumatol 2015;2015:912137.  Back to cited text no. 2
Özen S, Batu ED, Demir S. Familial Mediterranean fever: Recent developments in pathogenesis and new recommendations for management. Front Immunol 2017;8:253.  Back to cited text no. 3
Ben-Zvi I, Livneh A. Colchicine failure in familial Mediterranean fever and potential alternatives: Embarking on the anakinra trial. Isr Med Assoc J 2014;16:271-3.  Back to cited text no. 4
Kukuy O, Livneh A, Ben-David A, Kopolovic J, Volkov A, Shinar Y, et al. Familial Mediterranean fever (FMF) with proteinuria: Clinical features, histology, predictors, and prognosis in a cohort of 25 patients. J Rheumatol 2013;40:2083-7.  Back to cited text no. 5
Tekin M, Yalçinkaya F, Tümer N, Akar N, Misirlioǧlu M, Cakar N. Clinical, laboratory and molecular characteristics of children with Familial Mediterranean Fever-associated vasculitis. Acta Paediatr 2000;89:177-82.  Back to cited text no. 6
Papazyan M, Nazaryan H, Sanamyan A, Mkrtchyan N, Amaryan G. Renal biopsy findings in children with FMF in Armenia: Trends over the study period. Pediatr Rheumatol 2015;13:88.  Back to cited text no. 7
Ceri M, Unverdi S, Altay M, Unverdi H, Ensari A, Duranay M. Familial Mediterranean fever and membranous glomerulonephritis: Report of a case. Ren Fail 2010;32:401-3.  Back to cited text no. 8
Shen H, Gu W, Mao J, Zhu X, Jin X, Fu H, et al. Clinical characteristics of concomitant nephrotic IgA nephropathy and minimal change disease in children. Nephron 2015;130:21-8.  Back to cited text no. 9
Chbihi M, Dumaine C, Deschênes G, Couderc A, Monteiro RC, Hogan J, et al. A pediatric case of IgA nephropathy associated with familial Mediterranean fever. Arch Clin Med Case Rep 2020;4:218-25.  Back to cited text no. 10
Said R, Nasrallah N, Hamzah Y, Tarawneh M, Al-Khatib M. IgA nephropathy in patients with FMF. Am J Nephrol 1988;8:417-20.  Back to cited text no. 11
Akpolat T, Akpolat I, Karagoz F, Yilmaz E, Kandemir B, Ozen S. Familial Mediterranean fever and glomerulonephritis and review of the literature. Rheumatol Int 2004;24:43-5.  Back to cited text no. 12


  [Figure 1], [Figure 2]


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