Association between basal proteinuria levels and pregnancy outcomes in familial Mediterranean fever.

We aimed to investigate whether proteinuria in the first trimester of pregnancy in Familial Mediterranean fever (FMF) patients has an impact on pregnancy outcome and perinatal and neonatal outcome of pregnancies. A total of 66 pregnant with FMF were compared with healthy controls at the same gestational weeks. Patients with FMF had a higher antenatal hospitalisation rate (34.8% vs. 6.1%, respectively, p < .01) and higher rate of 2 or more miscarriages. FMF patients with or without obstetric complications also had a similar amount of 24-h urine proteinuria in the first trimester. Patients on colchicine therapy during pregnancy had more frequent attacks in pregnancy (59.3% vs. 18.2%, respectively, p: .012). The rates of preeclampsia, preterm delivery, foetal anomalies, small for gestation age neonates and primary caesarean rate were similar between groups. In conclusion; FMF had no significant impact on pregnancy. Neither attacks in pregnancy nor basal proteinuria were associated with adverse outcomes.Impact statementWhat is already known on this subject? Familial Mediterranean fever (FMF) is an autosomal recessive disease characterised by inflammation of the serosal, synovial and cutaneous tissues with recurrent attacks. One of the most serious complications of FMF is amyloidosis that can cause end-stage renal disease. Outcomes of FMF on pregnancy have been analysed by only few studies. Amyloidosis based on the initial renal function may adversely affect pregnancies. It has been reported that FMF patients with renal amyloidosis may suffer pregnancy complications to a greater extent.What do the results of this study add? There have been few studies on the correlation between FMF, proteinuria and pregnancy outcomes. In our study we found that FMF had no significant impact on pregnancy. Neither attacks in pregnancy nor basal proteinuria were associated with adverse outcomes.What are the implications of these findings for clinical practice and/or further research? Our study suggested that FMF had no relationship between pregnancy outcomes. However, our study population is relatively small. It will contribute to comprehensive studies involving a larger population. Future studies should be performed to investigate the effects of basal proteinuria in pregnancy with FMF.

The significance of urinary beta-2 microglobulin level for differential diagnosis of familial Mediterranean fever and acute appendicitis.

The clinical and laboratory parameters widely used are not specific to discriminate the abdominal pain due to FMF attack from that of acute appendicitis. The present study aims to investigate the urinary beta-2 microglobulin (U-ß2M) level as a potential parameter to identify these two diseases mimicking each other. A total of 51 patients with established FMF diagnosis due to Tel Hashomer criteria on colchicine treatment (1-1.5 mg/day), 15 patients with acute appendicitis who had appropriate clinical picture and were also supported pathologically after the surgery, and 20 healthy controls were enrolled in the study. Of the 51 patients with FMF, 25 were at an attack period, while remaining 26 were not. For the diagnosis of acute attack, as well as physical examination, laboratory tests including white blood cell count, C-reactive protein, and erythrocyte sedimentation rate were performed. From urine specimens U-ß2M, microalbumin, and N-acetyl glucosaminidase (U-NAG) were measured. U-ß2M levels were significantly higher in acute appendicitis group compared to FMF attack, FMF non-attack, and control groups (p < 0.001, p < 0.001, and p < 0.001, respectively). U-NAG and microalbuminuria were significantly higher in acute appendicitis, FMF attack, and FMF non-attack groups compared to controls (U-NAG p < 0.001, p = 0.016, p = 0.004, microalbuminuria p < 0.001, p < 0.001, p < 0.001, respectively). Microalbuminuria was significantly higher in acute appendicitis group compared to the FMF attack group (p = 0.004). Determination of U-ß2M levels may be helpful for differential diagnosis of peritonitis attacks of FMF patients on colchicine treatment and acute appendicitis. However, this finding should be substantiated with other studies.

Do neutrophil gelatinase-associated lipocalin and interleukin-18 predict renal dysfunction in patients with familial Mediterranean fever and amyloidosis?

BACKGROUND: The aim of this study was to evaluate whether neutrophil gelatinase-associated lipocalin (NGAL) and interleukin-18 (IL-18) predict renal disfunction in patients with familial Mediterranean fever (FMF). METHODS: This prospective study consisted of 102 patients with FMF in attack-free period, and 40 matched healthy controls. Of the patients, nine were diagnosed as amyloidosis. The patients were divided into two groups according to eGFR as below 120 mL per minute and above 120 mL per minute. Also, patients were divided into three groups according to the degree of urinary albumin excretion as normoalbuminuric, microalbuminuric, and macroalbuminuric. The serum levels of IL-18 (sIL-18) and NGAL (sNGAL), and urinary levels of IL-18 (uIL-18) and NGAL (uNGAL) were measured by using ELISA kits. RESULTS: The levels of sIL-18, sNGAL, uIL-18, and uNGAL were detected significantly higher in FMF patients, particularly in patients with amyloidosis, when compared to controls. sNGAL, uIL-18, and uNGAL were significantly higher in patients with eGFR < 120 mL per minute than in patients with eGFR ≥ 120 mL per minute. sNGAL, uIL-18, and uNGAL were correlated significantly with urinary albumin excretion, additionally, were inverse correlated with eGFR. The most remarkable findings of this study are of the higher values of sIL-18, sNGAL, uIL-18, and uNGAL in both normoalbuminuric FMF patients and patients with eGFR ≥ 120 mL per minute. CONCLUSIONS: The results of this study suggest that sIL-18, uIL-18, sNGAL, and uNGAL are reliable markers of early renal disfunction in FMF patients, and may let us take measures from the early stage of renal involvement.

The relation between urinary angiotensinogen and proteinuria in renal AA amyloidosis patients.

OBJECTIVE: The aim of this study was to evaluate the relationship of local intrarenal renin angiotensin system (RAS) with proteinuria in patients with renal AA amyloidosis. METHODS: Thirty-two patients with renal AA amyloidosis (19 male, mean age: 45 ± 13 years) and sixteen healthy controls (5 male, mean age: 32 ± 5 years) were included in this study. Spot urine samples were obtained to measure urinary angiotensinogen (AGT) using human AGT-ELISA, urinary creatinine and protein levels. Logarithmic transformations of urinary AGT-creatinine ratio log(UAGT/Ucre) and urinary protein-to-creatinine ratio (UPCR) were done to obtain the normal distributions of these parameters. RESULTS: Log(UAGT/UCre) was significantly higher in patients compared with the controls (1.88 ± 0.92 µg/g vs. 1.25 ± 0.70 µg/g; p = 0.023). Importantly a significantly positive correlation was found between log(UAGT/Ucre) and logUPCR in patients (r = 0.595, p = 0.006). CONCLUSIONS: Urinary AGT levels are higher in renal AA amyloidosis patients than in controls. Also, there is a significant positive correlation between urinary AGT and proteinuria in renal AA amyloidosis.

Urinary glycosaminoglycan levels as a marker of renal amyloidosis in patients with familial Mediterranean fever.

INTRODUCTION AND AIM: Familial Mediterranean Fever (FMF) is an autosomal recessive disease with a defect in the pyrine gene and is manifested with short attacks of inflammatory serositis, fever, and erysipelas-like skin lesions. Secondary amyloidosis is the most serious complication of the disease, in which extracellular deposits of amyloid (an amorphous and eosinophilic protein) are seen in tissues. Glycosaminoglycans are mucopolysaccharide molecules that take place in amyloid deposits with fibrillar links to amyloid. They form glycoproteins by linking to proteins, and their free forms are excreted in the urine in the form of polysaccharides. The aims of this study were to evaluate if the urinary levels of glycosaminoglycans have a predictive value in the diagnosis of amyloidosis secondary to FMF and if these levels are affected by treatment with colchicine. MATERIALS AND METHODS: The study included 55 volunteer patients (age range: 18-36 years) with FMF (15 with amyloidosis) of the same socio-economic circumstances without other concomitant inflammatory, malignant, or chronic diseases, along with 20 healthy subjects as control. Urinary glycosaminoglycan levels were determined twice, once when the patients were on medication and once after they have stopped treatment for two weeks. RESULTS: Initial mean urinary GAG levels were significantly lower in amyloidosis patients. Mean urinary GAG levels determined two weeks after the cessation of colchicine was also significantly lower than controls in both amyloidosis and non-amyloidosis FMF patients. Likewise, in patients with a disease duration longer than ten years, urinary GAG levels were also lower than those with a disease duration of less than three years. CONCLUSION: Urinary GAG level can have a predictive value for amyloidosis in patients with FMF, and it can also be used as a non-invasive marker for screening the effects of colchicine on fibrillogenesis as well as for the follow-up of the patients.

Urine leukotriene B4 in familial Mediterranean fever and other forms of right lower abdominal pain.

BACKGROUND: Acute right lower abdominal pain may present a diagnostic dilemma. Leukotrienes have been found to be elevated in familial Mediterranean fever (FMF), a disease manifesting with recurrent episodes of "acute abdomen." OBJECTIVES: To determine whether urine leukotriene B4 (LTB4) may differentiate between an FMF attack and some other forms of acute right lower abdominal pain. METHODS: The LTB4 level was determined, using a commercial enzyme-linked immunosorbent assay (ELISA), in urine samples obtained from 36 patients with acute (< 24 hours) right lower abdominal pain presenting to the emergency department, and from 18 healthy volunteers. RESULTS: Compared with the healthy control subjects, LTB4 was significantly higher in those who had FMF (12 patients, p < 0.03). In other forms of acute right lower abdominal pain, including appendicitis (eight patients), urologic disorders (eight patients), and nonspecific abdominal pain (eight patients), intermediate levels of LTB4 were observed, not significantly different from those of either FMF patients or healthy control subjects. CONCLUSIONS: In the samples tested, urine LTB4 levels were not instrumental in differentiating FMF from other acute right lower abdominal pain.

Oxidative stress status in familial Mediterranean fever with or without proteinuria.

Although several studies have indicated oxidative system abnormalities in patients with familial Mediterranean fever, it is still obscure whether proteinuria seen in this disease has an effect on the oxidative system. In the present study, oxidative system changes were investigated in familial Mediterranean fever with or without proteinuria. Plasma malondialdehyde levels in proteinuric and nonproteinuric patients were higher than those of the controls and they were also significantly higher in the patients with proteinuria compared to patients without proteinuria. The patients had significantly lower plasma glutathione peroxidase activities than the controls. Glutathione peroxidase activities did not show statistically significant differences between the patients with and those without proteinuria. A significant difference was not established for erythrocyte superoxide dismutase activities. These data suggest that there is an increase in lipid peroxidation in familial Mediterranean fever. Decreased plasma glutathione peroxidase activities seem to be responsible for increased plasma malondialdehyde levels in both patient groups. However, the fact that higher plasma malondialdehyde levels in proteinuric patients were observed compared to nonproteinuric patients in the presence of the unchanged plasma glutathione peroxidase activities in these groups suggests that the nephrotic state may have a contribution to this situation.

Urine leukotriene B4 in familial Mediterranean fever.

OBJECTIVE: To determine urinary leukotriene B4 (LTB4) levels and their role in FMF: METHODS: Urinary LTB4 levels were studied using a commercial ELISA kit in 12 FMF patients during abdominal attacks, and 20 FMF patients during remission. RESULTS: Urinary LTB4 levels in FMF patients during attacks were comparable to those during remission, but higher than normal levels (p = 0.03). CONCLUSIONS: These findings suggest a persistent activation of the leukotriene pathway in FMF. Whether elevated LTB4 levels are the cause or the effect of inflammation is yet to be determined.

Urinary glycosaminoglycans in the course of familial Mediterranean fever.

UNLABELLED: Familial Mediterranean fever (FMF) is characterised by recurrent fever and serositis. The most important complication of the disease is amyloidosis. Cheap and non-invasive methods would be important in predicting or establishing the early diagnosis of amyloidosis. For this purpose, we studied the role of urinary glycosaminoglycans (GAG). The study group included 123 FMF patients without an attack and 11 patients with FMF associated amyloidosis. Ten healthy children and ten patients with primary nephrotic syndrome served as controls. In patients with amyloidosis, urinary GAG were lower than in patients with FMF, patients with nephrotic syndrome and controls (median and range: 8.54 mg hexuronic acid/g creatinine (1.87-25.5), 5.8 (1.7-17.26), 23.12 (8.74-28.06) and 19.25 (14.2-26.9) respectively, P<0.01). There was a significant negative correlation between the duration of the disease and urinary GAG ( r= -043, P=0.002). In 49 FMF patients with a low GAG, urinary GAG increased significantly after an increase in the colchicine dose (median and range: 6.64 mg hexuronic acid/g creatinine (1.77-19.39) and 9.45 mg hexuronic acid/g creatinine (2.36-28.9), P<0.01). CONCLUSION: These results suggest that urinary glycosaminoglycan levels may be a predictor of amyloidosis in patients with familial Mediterranean fever. We also suggest that effective colchicine doses may be monitored by following urinary glycosaminoglycan excretion.

Tubular functions in familial Mediterranean fever.

In this study, we aimed to evaluate renal tubular function in familial Mediterranean fever (FMF). Urinary N-acetyl-beta-D glucosaminidase (U-NAG, beta2-microglobulin (U-beta2M) and microalbumin (Ua) levels were measured in children with different clinical stages of FMF (58 patients with FMF, 9 patients with amyloidosis secondary to (FMF). Control groups were healthy children (n=21), children with upper respiratory tract infection (URTI) (n=21) and with steroid sensitive nephrotic syndrome (SSNS) (n=18). U-NAG was significantly increased in patients with a recent diagnosis of FMF compared to patients with FMF on colchicine and to healthy controls. In patients with recently diagnosed FMF, a marked decrease in U-NAG, U-beta2M and Ua were determined after three months on colchicine therapy. On the other hand, U-NAG and Ubeta2M levels were increased in patients with FMF during attacks and then decreased in the post-attack period. U-beta2M in patients with FMF during attacks was significantly different from patients with URTI. Finally, U-NAG and U-beta2M were increased significantly in patients with FMF-amyloidosis and SSNS when compared with other FMF groups and healthy controls, respectively. In conclusion, the high U-NAG value in newly diagnosed patients compared to that of patients taking colchicine and the decline of U-NAG and U-beta2M levels after attack to the levels observed in colchicine users (without a significant change in Ua value) suggest that the renal injury early in the course of FMF might be dominantly at the level of the tubuli.

Increased urinary leukotriene E(4) during febrile attacks in the hyperimmunoglobulinaemia D and periodic fever syndrome.

BACKGROUND: The hyperimmunoglobulinaemia D and periodic fever syndrome is a hereditary periodic fever, caused by deficiency of the enzyme mevalonate kinase. It is unclear how this defect leads to recurrent fever episodes. AIM: To assess the involvement of cysteinyl leukotrienes in the pathogenesis of fever attacks as reflected by urinary leukotriene E(4) (LTE(4)) excretion. METHODS: Urinary LTE(4) was measured in seven patients while febrile and afebrile. RESULTS: LTE(4) was raised during fever in all subjects (46-199 nmol/mol creatinine, mean 92; normal <40). Urinary LTE(4) was normal between attacks, as well as in normal children with fever as a result of miscellaneous causes. CONCLUSION: Our results suggest that cysteinyl leukotrienes play a role in the pathophysiology of this disorder. As no effective treatment is yet available, leukotriene receptor antagonists might offer a new therapeutic approach for patients with the hyperimmunoglobulinaemia D and periodic fever syndrome.

[Identification of the gene for hyper-IgD syndrome: a model of modern genetics]. / Identificatie van het gen voor het hyper-IgD-syndroom: een schoolvoorbeeld van moderne genetica.

Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) is a rare autosomal recessive disorder. Patients suffer from recurrent attacks (3-6 days) with fever, abdominal distress, lymphadenopathy, skin lesions and arthralgias. Patients display a constantly elevated serum IgD which serves as a biological marker of the disease. Recently, the gene for HIDS was discovered by two independent groups using positional and functional cloning methods. One group used linkage analysis (positional cloning) and was able to locate the gene for HIDS on the long arm of chromosome 12 (12q24). Mevalonate kinase was an interesting candidate gene because patients with a near complete absence of this enzyme (mevalonic aciduria) do exhibit attacks of fever. Indeed subsequent data showed that there was a decreased enzyme activity due to missense mutations in the mevalonate kinase gene. The other group detected slightly elevated urinary excretion of mevalonic acid during attacks in a HIDS patient (functional cloning). The enzyme activity of mevalonate kinase was lower in cultured cells and sequence analysis identified several missense mutations in cDNA encoding for mevalonate kinase. Mevalonate kinase is a key enzyme in the cholesterol synthesis pathway and it is rather surprising that a defect in the cholesterol metabolism can cause a periodic inflammatory disease such as HIDS.

Serum concentration and urinary excretion of beta 2-microglobulin and microalbuminuria in familial Mediterranean fever.

Familial Mediterranean fever is characterised by recurrent and self limited attacks of fever and polyserositis and its devastating complication is the development of renal amyloidosis. In order to detect the presence of early glomerular and tubular damage in patients with familial Mediterranean fever and to assess the possible role of beta 2-microglobulin in the inflammatory attacks of this disease, serum and urine beta 2-microglobulin concentrations and microalbuminuria were evaluated in these patients. A total of 20 patients with familial Mediterranean fever were studied on and off colchicine treatment; seven of these patients developed a familial Mediterranean fever attack when they were off treatment. During the familial Mediterranean fever attacks serum beta 2-microglobulin concentrations decreased, whereas fractional excretion of beta 2-microglobulin, urine beta 2-microglobulin creatinine, and urine albumin/creatinine ratios increased. We conclude that glomerular and tubular functions deteriorate during the attacks. Further studies are needed to discover the effector(s) causing these transient glomerular and tubular disorders.

Urinary albumin excretion in patients with familial Mediterranean fever: a pilot study.

Amyloidosis of the kidney is the most threatening complication in familial Mediterranean fever (FMF), and colchicine has been shown to reduce its occurrence. In the preclinical stage of kidney amyloidosis, no proteinuria is observed by the standard Albustix method. However, whether these patients have normal or increased urinary albumin excretion is not known. The purpose of this study was to evaluate albumin excretion in FMF patients treated with colchicine and to compare these values to those of a normal control group. Twenty-two subjects with FMF were compared with 16 normal subjects matched with regard to age and body surface area. The two groups did not differ with regard to female/male ratio and arterial pressure. Urine samples were collected overnight while patients were recumbent and in the daytime while they were ambulant. After measuring albumin concentration (Ua) by radio-immunoassay and creatinine concentration through the standard method, the urinary albumin excretion rate (UaV) and urinary albumin creatinine ratio (Ua/c) were calculated. In the FMF group, three patients had microalbuminuria--defined as an albumin excretion rate higher than 20 micrograms/min. Two of them had this condition only in the early morning collection. These three patients were characterized by a longer duration of symptoms (18 vs. 9 years). No patient in the control group had microalbuminuria. The mean UaV in the FMF group did not differ significantly from that of the control group.(ABSTRACT TRUNCATED AT 250 WORDS)