MEFV mutation analysis of familial Mediterranean fever in Japan.

BACKGROUND: Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent attacks of fever with serosal inflammation. FMF gene (MEFV) mutations have been identified primarily in patients from Mediterranean populations. Although several clinical cases have been reported in Japan, there have been few reports to date on mutation analysis. We studied FMF patients and their relatives to examine the clinical and genetic features of this disease in the Japanese population. METHODS: Twelve Japanese FMF patients who met the Tel Hashomer criteria and a total of 17 relatives from 5 of 10 families underwent molecular genetic studies to detect MEFV mutations. The characteristics of these Japanese FMF patients and geno-phenotypical correlations were examined. RESULTS: Almost all of our patients had been suffering for a long time from fever of unknown origin and one patient also had systemic amyloidosis. In our 12 FMF patients, we detected the substitutions E84K, L110P, E148Q, R761H and M694I. We also newly diagnosed 2 relatives as having FMF based on clinical symptoms and the existence of FMF mutations. One patient was homozygous for E148Q, the patient with systemic amyloidosis was a homozygote for M694I and 4 patients from 3 families were compound heterozygotes for E148Q and M694I. Three patients in one family were compound heterozygotes for E148Q, L110P and M694I. There were 3 patients who were heterozygous for E84K, L110P-E148Q or M694I and had no other nucleotide changes in the exons of MEFV. On the other hand, 2 relatives who had never experienced symptoms of FMF were homozygous for L110P-E148Q as well as compound heterozygous for E148Q/E148Q-R761H. E148Q and M694I were the most frequently detected substitutions in our study. CONCLUSIONS: MEFV mutations occur in Japanese FMF patients though FMF is rare in Japan. The identification of MEFV mutations could be a reliable diagnostic test for FMF. The results of genetic analyses on 14 Japanese FMF patients in this study revealed that E148Q and M694I are frequent alleles.

Successful management of critical limb ischemia with intravenous sodium thiosulfate in a chronic hemodialysis patient.

Vascular calcification is common among hemodialysis (HD) patients and contributes to the development of peripheral arterial disease. A 57-year-old Japanese man who had been on HD for 30 years was referred to us for severe pain with multiple ulcers on his toes and fingers. He was an ex-smoker and had no diabetes mellitus. On admission, he had ulcers on his big toes bilaterally and right 2nd - 4th fingers. Peripheral pulses were strong and his ankle-brachial pressure index was above 1.3. Laboratory data were as follows: calcium 9.9 mg/dl, albumin 3.3 g/dl, phosphate 3.0 mg/dl, Ca x P product 30, and parathyroid hormone 98 pg/ml. He had a parathyroidectomy in 1998 and 1999. X-rays of his hands and legs showed diffuse subcutaneous arteriolar calcification. Angiography revealed no local stenotic lesions. Despite intensive therapies including hyperbaric oxygen therapy, painful gangrene developed on his right big toe and the pain was so intense that he could not go to sleep in a supine position. We infused intravenous sodium thiosulfate (20 g) 3 times weekly, based on previous reports. Within 4 - 5 days, he experienced rapid and dramatic symptom relief. The score of the visual analogue pain scale improved from 10/10 - 2/10. The signs of ischemia, measured by transcutaneous partial oxygen pressure and thermography, improved significantly. During the infusion of sodium thiosulfate, the patient complained of nausea, vomiting and hyperosmia. These adverse symptoms were resolved after discontinuation of the infusion. Pain relief was sustained and he could walk after 2 weeks of infusion. Our case supports the use of sodium thiosulfate as a novel therapeutic choice for critical limb ischemia with severe vascular calcification in chronic HD patients.

Two unusual cases of Anderson-Fabry disease in a Japanese family.

A 16-year-old Japanese girl was admitted to our hospital on February 27, 2001, for acute renal failure. She had not shown proteinuria or hematuria in any school examination through 2000. The first renal biopsy specimen showed focal segmental glomerulosclerosis and tubulointerstitial change. Electron microscopy showed numerous myeloid bodies in the glomerular epithelium suggesting the diagnosis of Anderson-Fabry disease. After electron microscopy, we measured WBC alpha-galactosidase A, which was slightly decreased to 36.1 nmol/mg P/h (normal: 49.8 - 116.4). WBC alpha-galactosidase A levels for other family members were 74.3 for the mother, 4.8 for the father, 45.6 for the elder sister, and 16.3 for the younger sister. During the follow-up, she had two episodes of nephrotic syndrome, which responded well to steroid therapy. Both second and third renal biopsy showed numerous myeloid bodies by electron microscopy. A 52-year-old man, the father of the case one patient, was admitted for renal biopsy because of proteinuria and low levels of WBC alpha-galactosidase. Biopsy specimen showed typical changes under light microscopy and typical myeloid bodies by electron microscopy. Our cases underscore the importance of electron microscopy when examining the biopsy specimen and suggest that undiagnosed Anderson-Fabry disease may be present, in particular on chronic dialysis.

Left ventricular diastolic dysfunction in patients with chronic renal failure: impact of diabetes mellitus.

AIMS: Left ventricular (LV) hypertrophy and LV diastolic dysfunction are cardiac changes commonly observed in patients with chronic renal failure (CRF) as well as hypertension. Although the impairment of LV diastolic function in patients with diabetes mellitus has been shown, little is known about the specific effect of diabetes on LV diastolic function in patients with CRF. The present study was designed to investigate the impact of diabetic nephropathy on LV diastolic dysfunction, independent of LV hypertrophy, in CRF patients. METHODS: In 67 patients with non-dialysis CRF as a result of chronic glomerulonephritis (n = 33) or diabetic nephropathy (n = 34), and 134 hypertensive patients with normal renal function, two-dimensional and Doppler echocardiographic examinations were performed, and LV dimension, mass, systolic function, and diastolic function were evaluated. RESULTS: LV mass was increased and LV diastolic dysfunction was advanced in subjects with CRF compared with hypertensive controls. In the comparison of echocardiographic parameters between the two groups of CRF patients, i.e. chronic glomerulonephritis and diabetic nephropathy groups, all indices of LV diastolic function were more deteriorated in the diabetic nephropathy group than in the chronic glomerulonephritis group, although LV structure including hypertrophy and systolic function did not differ between the groups. In a multiple regression analysis, the presence of diabetes (i.e. diabetic nephropathy group) was a significant predictor of LV diastolic dysfunction in CRF subjects, independent of other influencing factors such as age, blood pressure, renal function, anaemia and LV hypertrophy. CONCLUSION: The present findings suggest that LV diastolic dysfunction, independent of LV hypertrophy, is specifically and markedly progressed in patients with CRF as a result of diabetic nephropathy.

Angiotensin-converting enzyme (ACE) insertion/deletion polymorphism and survival in a cohort of chronic hemodialysis patients.

BACKGROUND: There are conflicting reports regarding the relationship between the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and the initiation and progression of cardiovascular disease. Moreover, there is no report regarding the relationship between the ACE I/D polymorphism and the prognosis of chronic dialysis patients. METHODS: We examined the frequency of the ACE I/D polymorphism in 727 chronic hemodialysis patients in Okinawa, Japan, and observed the prognosis over 2 years in 407 men and 320 women with mean age (SD) of 55.5 (13.9) years with a mean duration of dialysis of 84.3 (66.6) months. RESULTS: Genotype frequencies were 42.1% for II, 43.2% for ID, and 14.7% for DD. The relative risks of death were examined by Cox-proportional hazards analysis after adjusting for age, sex, age at the start of dialysis, presence of diabetes mellitus and hypertension and total cholesterol and serum albumin levels. The adjusted hazard ratio (95% confidence interval) was 1.03 (0.38 - 2.85) for DD genotype and 1.50 (0.83 - 2.70) for DD+ID genotype when compared to II genotype. CONCLUSION: ACE I/D polymorphism appears to have no relation to the short-term prognosis in chronic hemodialysis patients.

High heart rate relates to clustering of cardiovascular risk factors in a screened cohort.

Increased heart rate (HR) is a predictor of cardiovascular mortality, so the present study used a screened cohort to investigate whether the clustering of cardiovascular risk factors is associated with increased HR. Individuals who were receiving medication for hypertension or heart disease and those who did not have an ECG record or who had a record of arrhythmia were excluded. In total, 8,508 subjects (5,299 men, 3,209 women; age range, 18-89 years) were studied. Subjects were divided into 2 HR classes using the value of mean HR+ 1 SD as the cut-off point: low HR (HR < 77 beats/min, n=7,320) and high HR (HR > or = 77 beats/min, n=1,188). For logistic regression analysis, the dependent variable was HR class and the independent variables were the number of risk factors (ie, hypertension, diabetes mellitus, and hypertriglyceridemia each of which was associated positively with HR class by multivariate analysis). The odds ratios and 95% confidence intervals for the number of risk factors were 1.412 (1.216-1.640) for 1 risk factor, 2.800 (2.269-3.455) for 2, and 4.582 (2.815-7.459) for 3. Multivariate regression analyses showed that the number of risk factors from 0 to 3 correlated positively with high HR. HR increased significantly with clustering of risk factors even with low HR (regression coefficient was 1.147, p<0.0001). Modifying the risk factors may lower HR and reduce cardiovascular mortality.

Pregnancy outcome in nephrotic syndrome with mixed connective tissue disease.

We describe two pregnancies of a young woman with mixed connective tissue disease. In June 1983, she was diagnosed as having Raynaud's phenomenon, arthralgia, and proteinuria. She then developed nephrotic syndrome. Methylprednisolone was initially prescribed at a large dose of 1 g/day which was slowly tapered to 5 mg/day. The proteinuria disappeared. During both pregnancies (the first beginning in December 1988 and the second in May 1992), the patient was placed on a prednisolone maintenance dose (5 mg/day). Both neonates were born healthy at term with no complications. Continuing prednisolone may be useful in pregnant women, and aggressive treatment to prevent mixed connective tissue disease exacerbation may be appropriate during pregnancy.

Treatment of severe hypothyroidism reduced serum creatinine levels in two chronic renal failure patients.

Short-term hypothyroidism has been associated with a reversible rise in serum creatinine levels in patients with normal renal function. A remarkable decline in serum creatinine levels associated with a treatment of severe and prolonged hypothyroidism has rarely been reported so far. We present here 2 patients with chronic renal failure in whom treatment for hypothyroidism resulted in a significant and sustained reduction of their serum creatinine levels. These cases indicate that because hypothyroidism may aggravate the serum creatinine levels, TSH should be considered in screening procedures of patients with chronic renal failure presenting with recent accelerated aggravation of renal function. Hypothyroidism per se, one of its complications or one of its associated autoimmune diseases might play a role in modifying the underlying renal problem.

[Antihypertensive drug therapy: adverse effects and drug interactions].

The number of classes of antihypertensive drugs has been growing. The options of choice of the drugs now are so great that it seems not to be difficult to reduce blood pressure effectively. Newly developed classes have been shown to provide beneficial effects in variety of hypertension-related processes. However, each drug shows significant differences in adverse effects, incidental properties and interactions with non-antihypertensive drugs. To improve quality of life, compliance with medication, and beneficial effects on pathophysiological and cardiovascular risk conditions of patients, we should be well acquainted with adverse effects and possible disadvantages produced by antihypertensive drugs in particular situations.

Molecular forms of plasma and urinary adrenomedullin in normal, essential hypertension and chronic renal failure.

OBJECTIVES: Human adrenomedullin precursor is converted to glycine-extended adrenomedullin (AM-Gly), an intermediate inactive form of adrenomedullin. Subsequently, AM-Gly is converted to active form of mature adrenomedullin (AM-m). The aim of the present study was to investigate (i) whether sex or age influences plasma and urinary AM-m and AM-Gly levels in normal subjects; (ii) the daytime variability of plasma AM-m and AM-Gly levels in normal subjects; (iii) AM-m and AM-Gly levels and its ratio in plasma and urine in normal subjects, individuals with essential hypertension (HT), and chronic renal failure (CRF); and (iv) the ratio of AM-m and AM-total (T) in plasma of various veins and aorta. METHODS: We measured plasma levels and urinary excretions of AM-m, AM-Gly and AM-T (AM-m + AM-Gly) by recently developed immunoradiometric assay in normal subjects (n = 81), HT (n = 28) and CRF (n = 30). We also determined the molecular forms of plasma adrenomedullin taken from various sites during angiography in patients with suspected renovascular hypertension (n = 9). RESULTS: There were no differences in plasma and urinary excretions of two molecular forms of adrenomedullin among sexes or ages in normal subjects. There was no daytime variation of plasma two molecular forms of adrenomedullin in normal subjects. Plasma AM-m, AM-Gly and AM-T levels were increased in patients with HT and CRF compared with normal subjects, whereas urinary AM-m, AM-Gly and AM-T excretions were decreased in patients with HT and CRF compared with normal subjects. Urinary AM-m: AM-T ratios were significantly higher than plasma AM-m: AM-T ratios. Plasma AM-m and AM-T levels taken from various veins were similar, and they were significantly higher than those of aorta, although there were no differences in plasma AM-Gly levels between aorta and veins. CONCLUSIONS: These results suggest that in normal subjects, and individuals with HT and CRF: (i) plasma and urinary excretions of AM-m and AM-Gly are not affected by age or sex; (ii) AM-m in parallel with AM-Gly is increased; (iii) urine contains a higher percentage of active adrenomedullin than plasma; and (iv) plasma AM-m may be partly metabolized in the lung.

Cause of residual hypertension after adrenalectomy in patients with primary aldosteronism.

The cause of residual hypertension after adrenalectomy for primary aldosteronism (PA) is unknown. The purpose of this study is to investigate the characteristic pathological kidney features associated with PA. Between 1977 and 1999 at our hospital, 26 patients with PA caused by a unilateral adrenal cortical adenoma (Conn's syndrome) underwent unilateral adrenalectomy with concurrent open-wedge renal biopsy. Patients were categorized into two groups: (1) those with normotension with diastolic blood pressure less than 90 mm Hg who were not administered antihypertensive drugs, and (2) those with residual hypertension with diastolic blood pressure of 90 mm Hg or greater who were administered medication for 6 months after surgery. Thirteen patients were cured of hypertension postoperatively, and 12 patients were administered antihypertensive medications. Glomerulosclerosis, renal arteriolosclerosis, and preoperative left ventricular mass (LVM) index were worse in the group with residual hypertension than in that with normotension (17.8% +/- 7.8% versus 9.6% +/- 3.8%; P = 0.01; 2.5 +/- 0.5 versus 1.6 +/- 0.4, Bader's grade; P = 0.005; and 165 +/- 31 versus 139 +/- 24 g/m(2); P = 0.02, respectively). Severity of tubulointerstitial injury, preoperative duration of hypertension, preoperative severity of proteinuria, plasma aldosterone level, and serum potassium concentration were not significantly different between the two groups. In conclusion, severity of glomerulosclerosis and arteriolosclerosis and LVM are related to blood pressure after adrenalectomy in patients with PA.

Alterations of intrarenal adrenomedullin and its receptor system in heart failure rats.

Calcitonin receptor-like receptor/receptor activity-modifying protein 2 (CRLR/RAMP2) and CRLR/RAMP3 complexes have been reported to be specific adrenomedullin (AM) receptors. In the present study, we evaluated the pathophysiological significance of renal AM and its receptor system in aortocaval shunt (ACS) rats. Renal AM levels were measured serially during 5 weeks after the operation. Renal gene expressions of AM, CRLR, RAMP2, and RAMP3 were measured at 2 weeks (decompensated phase) and 5 weeks (compensated phase) after the operation. Immunohistochemical localizations of renal AM were also evaluated. Furthermore, the relations between urinary sodium excretion (UNaV) and renal AM levels were evaluated. Renal AM levels were higher in ACS than in control animals only at 1, 2, and 3 weeks after the operation. At 2 weeks after the operation, renal AM mRNA expression was also higher in ACS than in control animals. CRLR, RAMP2, and RAMP3 mRNAs were expressed in the kidney, but there were no differences between the 2 groups. Immunohistochemistry revealed the positive AM immunostaining within the renal tubular cells, and it was more intense in ACS than in control animals. There were significant correlations between UNaV and renal AM levels. At 5 weeks after the operation, there were no differences in mRNA levels of AM, CRLR, RAMP2, and RAMP3 between the 2 groups. There was a significant correlation between UNaV and medullary AM levels. The present findings suggest that increased renal AM levels in decompensated heart failure, presumably due to increased AM production in renal tubules, in part, are involved in the regulation of sodium excretion.

Significance of hyperuricemia on the early detection of renal failure in a cohort of screened subjects.

A high level of serum creatinine (S-Cr) is a predictor of end-stage renal disease (ESRD), but only a few studies have investigated the prevalence of high S-Cr and its correlates in a large population. We analyzed the data collected from 6,403 subjects (4,222 men and 2,181 women) who participated in the Okinawa General Health Maintenance Association (OGHMA) screening both at 1997 and 1999. The computer-saved data included sex, age, blood chemistries, blood pressure, medical histories, and lifestyles. Multivariate Cox proportional hazard analyses were performed to identify the correlates of developing high S-Cr levels: > or = 1.4 mg/dl in men and > or = 1.2 mg/dl in women. The prevalence of high S-Cr was 3.0% (N=193), which was 4.1% in men (N=175) and 0.8% in women (N=18), and increased with age in both sexes at the 1997 screening. Among those who showed normal levels of S-Cr in 1997 (N=6,210), 241 subjects (223 men and 18 women) developed high S-Cr. The 2-year cumulative incidence of high S-Cr was 5.5% in men and 0.8% in women. Other than sex, serum uric acid was the most significant correlate for developing high S-Cr. The adjusted relative risk (95% confidence interval) of those with serum uric acid 8.0 mg/dl and over was 2.91 (1.79-4.75) in men and 10.39 (1.91-56.62) in women when compared to those with serum uric acid less than 5.0 mg/dl. Prevalence of high levels of S-Cr was relatively high in men. Other than gender, serum uric acid was a significant positive correlate of developing high S-Cr in this sample of the Japanese population.

Effects of a low-energy diet and an insulin-sensitizing agent on ambulatory blood pressure in overweight hypertensive patients.

OBJECTIVE: To clarify the role of insulin resistance and hyperinsulinaemia in the pathogenesis of obesity-related hypertension. DESIGN: An open study comparing the effects of weight reduction by low-energy diet and treatment with troglitazone, an insulin-sensitizing agent. SETTING: A tertiary teaching hospital. PATIENTS: Thirty overweight hypertensive patients (15 men and 15 women, mean age 61 years, mean body mass index 29.1 kg/m2). INTERVENTIONS: Fifteen patients were assigned to a weight-reduction programme by low-energy diet (3360 kJ/day) for 3 weeks; the remaining 15 patients were treated with troglitazone (400 mg/day) for 8 weeks. MAIN OUTCOME MEASURES: Casual and ambulatory blood pressures, glucose and lipid metabolism, and insulin sensitivity. RESULTS: The baseline values of body mass index, fasting and post-glucose plasma insulin, and casual and ambulatory blood pressures were comparable between the two groups. Weight reduction (4.1 +/- 0.3 kg, mean +/- SEM) was associated with significant decreases in plasma insulin, blood glucose, homeostasis model assessment (HOMA) insulin resistance index, serum triglyceride, casual blood pressure (7.7 +/- 2.3/ 3.9 +/- 1.4 mmHg) and 24 h blood pressure (8.3 +/- 1.9/ 4.3 +/- 1.1 mmHg). Treatment with troglitazone caused comparable decreases in the metabolic parameters and HOMA index, but did not change casual or 24 h blood pressure (0.8 +/- 3.4/0.8 +/- 2.1 and 1.5 +/- 2.4/ 1.0 +/- 1.9 mmHg, respectively). CONCLUSIONS: Insulin resistance/hyperinsulinaemia may not have an important role in the pathogenesis of obesity-related hypertension. The antihypertensive effect of weight reduction seems to be mediated mainly by other mechanisms.

Urocortin, a member of the corticotropin-releasing factor family, in normal and diseased heart.

In the present study we investigated the form of expression, action, second messenger, and the cellular location of urocortin, a member of the corticotropin-releasing factor (CRF) family, in the heart. Urocortin mRNA, as shown by quantitative RT-PCR analysis, is expressed in the cultured rat cardiac nonmyocytes (NMC) as well as myocytes (MC) in the heart, whereas CRF receptor type 2beta (CRF-R2beta), presumed urocortin receptor mRNA, is predominantly expressed in MC compared with NMC. Urocortin mRNA expression is higher in left ventricular (LV) hypertrophy than in normal LV, whereas CRF-R2beta mRNA expression is markedly depressed in LV hypertrophy compared with normal LV. Urocortin more potently increased the cAMP levels in both MC and NMC than did CRF, and its effect was more potent in MC than in NMC. Urocortin significantly increased protein synthesis by [(14)C]Phe incorporations and atrial natriuretic peptide secretion in MC and collagen and increased DNA synthesis by [(3)H]prolin and [(3)H]Thy incorporations in NMC. An immunohistochemical study revealed that urocortin immunoreactivity was observed in MC in the normal human heart and that it was more intense in the MC of the human failing heart than in MC of the normal heart. These results, together with the recent evidence of urocortin for positive inotropic action, suggest that increased urocortin in the diseased heart may modulate the pathophysiology of cardiac hypertrophy or failing heart, at least in part, via cAMP signaling pathway.