|Year : 2007 | Volume
| Issue : 4 | Page : 170-173
Immunoglobulin M nephropathy in familial Mediterranean fever
O Yavascan1, N Aksu1, K Demir2, S Sarioglu3, OD Kara1, A Bal1
1 Department of Pediatric Nephrology, Izmir Tepecik Teaching and Research Hospital, Izmir, Turkey
2 Department of Pediatrics, Dokuz Eylül University Medical Faculty, Izmir, Turkey
3 Department of Pathology, Dokuz Eylül University Medical Faculty, Izmir, Turkey
9105/14 Sokak, No: 9/5, Serdar Apartmant, Akevler 35370, Yesilyurt-Izmir
Source of Support: None, Conflict of Interest: None
Familial Mediterranean fever (FMF) is the most common periodic syndrome characterized by various clinical manifestations associated with self-limited auto-inflammatory process. Amyloidosis is its most common renal complication that can be prevented with colchicine treatment. In the last years, further clinical and histological features of FMF nephropathy have been established, such as the associations with vasculitic diseases and various types of glomerulonephritis. IgM nephropathy (IgMN) is an uncommon histological entity that is characterized by prominent diffuse mesangial deposition of IgM. Herein, we present a 10-year-old Turkish female child suffering from FMF in which non-nephrotic proteinuria is due to IgMN other than amyloidosis.
Keywords: Familial Mediterranean fever, IgM nephropathy, non-amyloid nephropathy
|How to cite this article:|
Yavascan O, Aksu N, Demir K, Sarioglu S, Kara O D, Bal A. Immunoglobulin M nephropathy in familial Mediterranean fever. Indian J Nephrol 2007;17:170-3
| Introduction|| |
Familial Mediterranean fever More Details (FMF) is a recessively inherited disorder of inflammation that commonly affects Turks, Jews, Armenians and Arabs. The classical clinical findings of FMF consist of recurrent self-limited attacks accompanied by peritonitis, arthritis and erysipel such as erythema. ,,,,,, Amyloidosis is the most common renal complication of FMF. However, in addition to amyloidosis, other renal lesions have been described in patients with FMF, and it seems that these renal lesions have been relatively neglected. ,,,,,,,, The differentiation of the underlying renal disease in FMF patients who present with proteinuria is difficult, often requiring further diagnostic studies to identify the etiology. In various reports, mesangial proliferation, immunoglobulin M nephropathy (IgMN), focal and diffuse proliferative glomerulonephritides (GN), mesangiocapillary GN and progressive GN were described in patients with FMF even in the absence of amyloidosis. ,,,, Among uncommon glomerulonephritis with FMF, few cases of immune complex GN with IgM deposition have been reported. ,,, IgM nephropathy is an idiopathic GN with mesangial IgM deposition. Patients generally present with nephrotic syndrome; however, isolated hematuria and asymptomatic proteinuria may be observed. The disease remains silent for long period, but it is progressive. However, its association with FMF is not yet elucidated.
In this study, we present a Turkish child with FMF in which non-nephrotic proteinuria is due to IgMN other than amyloidosis.
| Case Report|| |
A 10-year-old female patient suffering from familial Mediterranean fever (FMF) was referred to the department of pediatric nephrology due to microalbuminuria detected during the follow-up. Her first complaints had appeared 2 years ago as severe, non-febrile and spontaneously resolving recurrent abdominal pain with a duration of 24-48 h. She had been admitted to our hospital with a new ailment as swelling and tenderness of right ankle and arthralgia of right knee. Her past medical history had been unremarkable. Physical examination revealed normal findings, but arthritis of right ankle was observed. Complete blood count, urine analysis, biochemical markers and serum fibrinogen level were found to be in normal ranges, while the erythrocyte sedimentation rate had been slightly elevated (25 mm/h). Antinuclear antibodies (ANA), serologic tests for Brucellosis More Details, Salmonellosis More Details and EBV infection were negative. During the follow-up, the problem of arthritis was resolved with ibuprofen treatment (10 mg/kg qid); however, a few aphthous oral ulcer lesions had developed. Concerning Behηet's disease (BD), pathergy test was found to be negative; ophthalmologic evaluation excluded uveitis, but HLA B5 had been established. Among the 12 most common mutations, heterozygote M694V was detected. The complaints diminished, erythrocyte sedimentation rate returned to normal ranges following colchicine treatment (1 mg/d). On the sixth month of follow-up, a 24-h urine analysis revealed microalbuminuria (80 mg/L, normal: 0-20 mg/L) without any symptoms or findings.
Physical examination revealed the following: body weight in 75-90th percentile, height in 90-97th percentile, normotensive, but no pathologic findings. Urinalysis showed a specific gravity of 1010 and a pH value of 6.5; the urinary sediment was normal. The 24-h urine protein and microalbumin excretion was 8.35 mg/m 2 /h and 120 mg/d, respectively. Complete blood count was in normal ranges. Blood urea was 18 mg/dl; creatinine, 0.6 mg/dL; albumin, 4.8 g/dl; and other biochemical markers were in normal ranges. Renal ultrasonography was normal.
Percutaneous renal biopsy disclosed 24 glomeruli; half of them showed slightly increased mesangial matrix, one was globally sclerotic, five of them had mesangial matrix expansion and two of them revealed fibrin thrombi in some capillary. Interstitium and tubules revealed no pathological changes. Congo red staining was negative for amyloidosis [Figure - 1],[Figure - 2]. Immunofluorescent staining was positive for IgM (++) along the mesangial and capillary loops, C3 (++) in one glomerulus, but negative for IgG, IgA, C1q, fibrinogen and albumin [Figure - 3].
Therefore, the diagnosis of IgMN was established based on these findings of renal biopsy. Captopril (2 mg/kg/d) treatment was added. At present, she remained well, and no proteinuric and microalbuminuric at the 24-month follow-up.
| Discussion|| |
Among the diagnostic criteria of FMF defined by Livneh et al. ,  one major (monoarthritis), three minor (incomplete attacks of abdomen, joint/arthralgia and favorable response to colchicine) and six supportive (appropriate ethnic origin, age < 20 years at disease onset, spontaneous resolving of severe abdominal pain, symptom free interval and transient inflammatory response during arthritis consistent with erythrocyte sedimentation rate) had been present in our case, thereby establishing the presence of the disease.  Since laboratory and genetic evaluations are no more supportive, the diagnosis of FMF is based on clinical findings. Recurrent, self-limited attacks of severe abdominal pain in association with arthritis and/or arthralgia in a 10-year-old Turkish female child should recall FMF among the periodic fever syndromes. The probability of occurrence of Behcet's disease (BD) should be considered during the differential diagnosis of periodic fever syndromes in children, particularly if recurrent aphthous ulcers are evident in the follow-up. However, our patient had not experienced the diagnostic criteria other than recurrent oral ulcers required to establish BD. ,
On the sixth month of colchicine treatment, we observed microalbuminuria and mild proteinuria. Because of probability of amyloidosis, we performed renal biopsy. However, histologic studies showed no amyloid deposition, but features of IgM nephropathy [Figure - 2].
In some patients who are not under treatment, the renal involvement in FMF, usually secondary AA amyloidosis, may lead to kidney failure and other organ damage. Vasculitis, crescentic rapidly progressive GN, mesangial IgA nephropathy, IgMN, mesangial proliferative and diffuse proliferative and exudative GN have also been documented. ,,,,,,,,,,, Eliakim et al . found that 22% of 106 patients with FMF had non-amyloid renal problems, which include transient or persistent hematuria and/or albuminuria, recurrent acute pyelonephritis, typical acute poststreptococcal GN and various other types of GN. 
IgM nephropathy is an idiopathic glomerulonephritis with mesangial IgM deposition. Most reports of IgM deposition are concerned with patients having a nephrotic syndrome. IgM nephropathy is characterized by prominent diffuse mesangial deposition of IgM, either sole or predominant among other immunoglobulins, particularly accompanied by C3 deposition. Diffuse proliferation of mesangial cells and increase in extracellular mesangial matrix may also be noted on light microscopy. The major clinical picture of this uncommon disease is nephrotic syndrome; nevertheless, isolated hematuria and asymptomatic proteinuria are also associated. Various responses (good to poor) to corticosteroid treatment have been reported particularly for patients with proteinuria of nephrotic range. ,,,,
Although the range of renal syndromes in FMF is not diverse, non-amyloid glomerulopathies and FMF-associated vasculitides have been reported. ,,,,,,,,,,, Besides, can IgM deposition accompany FMF? Yes; however, it is a rare association. To the best of our knowledge, the only report of IgM nephropathy associated with FMF had been in three patients (one adolescent and two adults) with non-nephrotic proteinuria and mild hematuria. 
It is not known whether the presence of non-amyloid glomerular diseases with FMF is coincidental or causal. However, the reviews and the reported cases in the literature favor a causal relationship. ,,,,,,, However, Said et al . suggested that the presence of mesangial IgA, IgM and C 3 deposits that were observed in patients with FMF and renal involvement may represent an immunoreactant mechanism. ,,,, Another possible explanation could be the nonimmunological entrapment of these substances as a result of mesangial dysfunction in clearing.  Since FMF can be described as a disease of defective inhibition of inflammation owing to the mutations of the MEFV gene, it can be speculated that patients with FMF might have an exaggerated response to certain antigens that at times exceed the clearing and processing capacity of the glomerulus and facilitate the development of these non-amyloid glomerular diseases.  However, mesangial proliferation is a good supportive evidence for an immunological process underlying the development of non-amyloid renal lesions in patients with FMF. For this reason, it can be speculated that the possible mechanism for IgM deposition as a sign of the immune process in FMF reflects rather than a mesangial dysfunction of mesangial cells; however, this needs to be investigated further.
Colchicine treatment has been shown to ameliorate the course of FMF and to prevent the development of amyloidosis. ,,,,,, It may prevent the development of non-amyloid glomerular diseases in patients with FMF.  However, Cagdas et al .  reported a case of membranoproliferative glomerulonephritis with FMF, which remitted with colchicine treatment alone. We added an angiotensin-converting enzyme inhibitor (Captopril, 2 mg/kg/d) to colchicine treatment because of proteinuria. The frequency and severity of the patient's crises decreased with colchicine, and by the first year of follow-up, urinalysis was completely normal. After a follow-up of 24 months, she remained clinically well with no proteinuria and microalbuminuria.
In conclusion, there are no reliable epidemiological studies showing the association between non-amyloid glomerular diseases and FMF. It is not known whether these diseases are more frequent in patients with FMF than in the general population. However, it is important to emphasize that non-amyloid glomerular diseases should be considered in the differential diagnosis of FMF patients associated with renal involvement.
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[Figure - 1], [Figure - 2], [Figure - 3]