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Volume: 15 Issue: 1 February 2017 - Supplement - 1


Late Diagnosis of E148Q Mutation–Positive Familial Mediterranean Fever in a Kidney Transplant Patient With Fever of Unknown Origin: A Case Report

Fever of unknown origin is a rare condition after solid-organ transplant and is generally associated with atypical infections (eg, tuberculosis, fungal infections) and/or lymphoproliferative disorders. Here, we present a kidney transplant patient with a late diagnosis of E148Q mutation-positive familial Mediterranean fever as the cause of fever of unknown origin. A 22-year-old female patient with a previous history of 4 years of hemodialysis and unknown primary renal disease received a deceased-donor kidney transplant at our center 5 years previously. She had an uneventful course in the first 3 years following transplant. After this period, she was hospitalized 3 times during a 4-month period with fever, nausea, vomiting, and atypical abdominal pain. At that time, hemogram results were unremarkable, except for mild leukocytosis and slightly elevated acute-phase reactants; blood, urine, and throat cultures were negative, and there were no remarkable findings on imaging tests. Fever was controlled within 48 hours by administering empiric ampicillin-sulbactam therapy and discon­tinuing immunosuppressive treatment except steroids. Three successive hospital admissions owing to similar complaints suggested periodic fever syndrome, and therapy with 1 g/day colchicine led to an excellent clinical response with no recurrence of fever or other symptoms. An FMF gene mutation analysis revealed heterozygous E148Q mutation positivity. Continuing the current treatment regimen, the patient did well during at approximately 1.5 years of follow-up. In the Mediterranean region population, familial Mediterranean fever should be considered in the diagnosis of fever of unknown origin in patients who have undergone renal transplant. E148Q mutation-positive familial Mediterranean fever has a subclinical course and renal manifestations that differ from AA amyloidosis during childhood and may be responsible for de novo familial Mediterranean fever after renal transplantation.

Key words : AA amyloidosis, FMF gene mutation, Renal transplantation


Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease. The MEFV gene mutation responsible for its pathogenesis is located on chromosome 16p13.3 encoding 10 exons and 781 codons.1-3 Familial Mediterranean fever is especially prevalent in communities living in the Middle East (eg, Ashkenazi and Iraqi Jews, Armenians, Arabs, and Turks), and common disease mutations vary according to ethnicity.1 The M694V mutation, which has a close relationship with AA amyloidosis, is seen frequently in the Turkish population.2,3 Studies in Turkish populations identified E148Q as one of the most frequent FMF mutations (3%-10%), with hetero­geneous clinical features such as nonamyloidosis renal involvement manifesting as mesangiopro­liferative or crescentic glomerulonephritis and vasculitis.2-6 In clinical practice, patients with FMF often present with AA amyloidosis-mediated end-stage renal disease (ESRD) but generally recover after kidney transplant.7-10 Fever is a common feature in patients who undergo transplant and is commonly associated with infectious diseases, but less often with lymphoproliferative disorders, cancer or graft rejection.11-13 However, fever of unknown origin (FUO) is a rare condition after solid-organ transplant and is generally associated with atypical infections (eg, tuberculosis, fungal infections) and/or lympho­proliferative disorders.13

Here, we present a deceased-donor kidney transplant patient who was admitted to the hospital 3 times within a 4-month period owing to recurrent fever, abdominal pain, and nausea of unknown cause and was diagnosed with FMF. She responded well to empiric colchicine treatment and was diagnosed with FMF after genetic analysis detected positivity for FMF gene mutations. Written informed consent was obtained from the patient featured in this case report.

Case Report

Approximately 58 months previously, a 22-year-old female patient had a deceased-donor kidney trans­plant from a 27-year-old donor with traumatic intracranial hemorrhage. She had been receiving hemodialysis treatment for 4 years before transplant, and her primary kidney disease diagnosis was likely chronic glomerulonephritis. The early stages after transplant were uneventful. The implantation biopsy findings had no remarkable features. She received a total dose of 850 mg antithymocyte globulin as induction therapy immediately posttransplant. The maintenance immunosuppression regimen consisted of prednisolone (10 mg/d), mycophenolate sodium (720 mg/d), and cyclosporine (250 mg/d). Baseline serum creatinine level was 0.9 mg/dL after transplant. During the first 3 years after transplant, cytomegalovirus and polyoma BK virus surveillance was negative, and no medical problems occurred except for a single urinary tract infection.

At 36 months after transplant, the patient was hospitalized 3 times over a 4-month period with fever, nausea, vomiting, and atypical acute ab­dominal pain. On initial admission, a physical examination showed a body temperature of 38.3ºC with a pulse rate of 96 beats per minute, 100/60 mm Hg blood pressure, and diffuse abdominal pain consistent with peritonitis. The oropharyngeal, cervical lymph node chain, and cardiovascular and respiratory system examinations were unremarkable. Thoracoabdominal computed tomography and abdominal and pelvic ultra­sonography results were normal, and urine and blood cultures as well as urinary acid-fast bacteria staining and myco­bacterium tuberculosis culture were negative. Serum agglutination and enzyme-linked immunosorbent assay tests for Salmonella and Brucella species, markers of acute hepatitis, antibody tests for autoimmune diseases, and tumor markers also were negative. Protein electrophoresis showed polyclonal gammopathy. The most obvious signs during the febrile period were leukocytosis (22 000/mm3), left shift in the peripheral blood smear (with an 88% predominance of neutrophils), and high C-reactive protein levels (≤ 28.3 mg/dL). These findings are shown in Table 1. Immunosuppressive therapy was reduced during the hospitalization period, except for steroids, and the patient was initially treated with empiric ampicillin-sulbactam.

The patient’s febrile periods and complaints resolved within 48 hours of treatment. The C-reactive protein level and white blood cell count decreased from 28.3 mg/dL to 3.71 mg/dL and from 20 100/mm3 to 9610/mm3. Despite this positive clinical response, however, the patient was admitted to the hospital with the same complaints 2 more times within a 4-month period. By the third admission, she had responded well clinically to empiric colchicine (1 mg/d) treatment, and simultaneous FMF gene mutation analysis revealed heterozygous E148Q positivity. After being free of similar episodes during the subsequent 1-year period, her follow-up was uneventful and she continued with a treatment protocol comprising colchicine (1 mg/d), pred­nisolone (5 mg/d), azathioprine (50 mg/d), and cyclosporine (125 mg/d).


In this case report, we presented a patient with recurrent fever of unknown cause in the late stage after kidney transplant. The patient was sub­sequently diagnosed with FMF through genetic analysis. Clinicians generally encounter FMF patients as kidney transplant recipients who have been diagnosed with AA amyloidosis-associated ESRD.7 Kidney transplant is often uneventful in these patients and does not differ in terms of patient outcomes from recipients with primary renal disease of a different cause.7-10 There are insufficient data in the literature about primary disease recurrence in FMF patients after renal transplant. In 2 small-scale studies from Turkey8 and Iran9 that evaluated the long-term consequences of FMF after kidney transplant, the investigators detected relapses in 2 of 17 patients8 and 1 of 18 patients.9 In an Israeli study of 16 kidney-transplanted FMF amyloidosis patients, FMF recurrence was investigated, and the period for emergence of typical serosal attacks was reported to occur 6 years (2214 days) after renal transplant.10 These relapses were observed in patients with FMF amyloidosis who carried the M694V mutation.

It is notable that, in our patient, FMF-like episodes were accompanied by E148Q gene mutation positivity; however, our patient lacked a history of fever and serosal attacks during early childhood or the pretransplant chronic kidney disease period. Although the E148Q mutation in FMF may display differences among ethnicities, it is the fourth most frequent mutation of the FMF gene in the Turkish population, after the M694V, M680I, and V726A mutations.2,3 Many studies have found a positive association with a variety of nonamyloidosis renal diseases in patients with E148Q mutation-positive FMF.2-6 For example, Topaloglu and colleagues evaluated 44 patients with E148Q-positive FMF disease.14 They did not detect AA amyloidosis in any of these cases, approximately 15% of which had subclinical progression. Our patient likewise remained asymptomatic both before kidney transplant and during the first 3 years after kidney transplant and had ESRD of nonamyloidosis cause; thus, both studies found possible associations with E148Q positivity. Patients with ESRD and delayed FMF diagnosis after renal replacement therapy are rare in the medical literature.6,15 As an example, Pateinakis and colleagues15 identified homozygous R202Q mutation–positive FMF disease in a patient with FUO who was receiving hemodialysis treatment for the previous 5 months. Similar to our case study, Mahmoodpoor and colleagues6 diagnosed a case of heterozygous E148Q-positive FMF disease via genetic analysis performed in response to graft dysfunction and episodes of FUO that occurred 11 years after kidney transplant. In considering these reports, we suggest that E148Q positivity does not have the specific features of the homozygous M694V mutation, such as an established clinical outcome and increased risk of AA amyloidosis.16 Instead, E148Q positivity has heterogeneous clinical features and relatively subclinical progression in childhood and early adulthood, leading to late diagnosis after renal replacement therapy.


In the Mediterranean region population, FMF should be considered in the differential diagnosis of FUO in patients who have undergone kidney transplant. In addition, the E148Q mutation of the FMF gene, whose phenotype shows a relatively subclinical course in childhood and various renal manifestations unrelated to AA amyloidosis, may be responsible for de novo cases of FMF after kidney transplant.


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Volume : 15
Issue : 1
Pages : 261 - 264
DOI : 10.6002/ect.mesot2016.P131

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From the 1Department of Nephrology, the 2Department of General Surgery, the 3Department of Biochemistry, and the 4Department of Radiology, Izmir Bozyaka Education and Research Hospital, Izmir, Turkey
Acknowledgements: The authors declare that they have no sources of funding for this study, and they have no conflicts of interest to declare.
Corresponding author: Erhan Tatar, Izmir Bozyaka Education and Research Hospital, Division of Nephrology, 35170, Karabaglar, Izmir, Turkey
Phone: +90 232 250 5050