Urinary lipocalin-type prostaglandin D synthase: a potential marker for early gentamicin-induced renal damage?

Urinary excretion of lipocalin-type prostaglandin D synthase (L-PGDS) has been suggested to be a useful biomarker of early diabetic nephropathy. We studied whether L-PGDS is also a marker of gentamicin (GM)-induced renal damage in the "creatinine-blind" range. A prospective study was conducted in 6 patients who were given long-term intravenous administration of GM (18-42 days in combination with a beta-lactam/carbapenem antibiotic or vancomycin) for the treatment of infective endocarditis. Urinary excretions of L-PGDS, beta2-microglobulin, and N-acetyl-beta-D-glucosaminidase were measured in the early (within 10 days from commencement) and late (thereafter) phases of GM therapy. Systemic clearance of GM (CLGM) and creatinine clearance (CLcr) was also measured concomitantly. CLGM was reduced significantly (P < 0.05) by 10% from the early to late treatment phase, whereas urinary L-PGDS excretion showed a significant (P < 0.05) increase (from 7.3 +/- 4.6 to 8.7 +/- 5.0 mg/g creatinine, mean +/- SD) concomitantly. In contrast, no significant changes were observed for urinary beta2-microglobulin and N-acetyl-beta-D-glucosaminidase concentrations. In conclusion, urinary L-PGDS may be a promising biomarker for the early phase of GM-induced renal impairment.

[Improvement of dose monitor system in rotational gantry for proton therapy at national cancer center hospital East].

Quality assurance and quality control of delivered dose are important in proton therapy. The delivered proton dose is controlled using a dose monitor system which consists of two ionization chambers filled with free air. Response of the monitor for the delivered dose changes under the influence of temperature and pressure of surrounding air. In the dose monitor system at the National Cancer Center Hospital East, the monitor is near an X-tray tube which operates at a high temperature and is frequently used in every patient setup. Therefore the response of the dose monitor changes a lot with the temperature of the X-ray tube. In this report, temperature and pressure influence on the dose monitor was investigated in detail. Furthermore, a new method was presented to correct the monitor response using the real-time data of temperature and pressure at any time for each patient. This method improved the accuracy of delivered dose from 1% to 0.5%.

Morning rise of blood pressure assessed by home blood pressure monitoring is associated with left ventricular hypertrophy in hypertensive patients receiving long-term antihypertensive medication.

To assess the influence of morning rise of systolic blood pressure (SBP) as assessed by home blood pressure monitoring on the left ventricular mass index (LVMI) in relation to the blood pressure control status, we evaluated M-mode cardiac echocardiography in 626 hypertensive subjects (412 men and 214 women; mean age, 61.3+/-10.1 years) who were receiving antihypertensive medication. The subjects were requested to measure their blood pressure at home in the morning and evening over a 3-month period. They were distributed into the following four groups by the average (ME Ave) and the difference (ME Dif) of the morning and evening SBP. The well-controlled hypertensives with a morning rise of SBP (ME Ave<135 mmHg and ME Dif>or=10 mmHg; n=45; 7.2%) had a greater LVMI (122.9+/-22.7 vs. 92.7+/-15.6 g/m2, p<0.001) than the well-controlled hypertensives without a morning rise of SBP (ME Ave<135 mmHg and ME Dif<10 mmHg; n=367; 58.6%). The uncontrolled hypertensives with a morning rise of SBP (ME Ave>or=135 mmHg and ME Dif>or=10 mmHg; n=91; 14.5%) also had a greater LVMI (136.8+/-21.9 vs. 100.2+/-17.5 g/m2, p<0.001) than the uncontrolled hypertensives without a morning rise of SBP (ME Ave>or=135 mmHg and ME Dif<10 mmHg; n=123; 19.6%). A stepwise multivariate regression analysis revealed that the ME Dif was the most important factor related to the LVMI (r2=35.1% for all subjects, p<0001; r2=39.7% for men, p<0.001; and r2=18.7% for women, p<0.001). These results suggest that morning rise of blood pressure is an important factor influencing the development of left ventricular hypertrophy in hypertensive patients on antihypertensive medication.

Add-on effect of bedtime dosing of the alpha(1)-adrenergic receptor antagonist doxazosin on morning hypertension and left ventricular hypertrophy in patients undergoing long-term amlodipine monotherapy.

High morning blood pressure is related to target organ damage and future cardiovascular events. Chronobiologic therapies focusing on the early morning period may be an important strategy for antihypertensive therapy. The aim of this study was to clarify the add-on effects of bedtime dosing of the alpha(1)-adrenergic receptor antagonist doxazosin on morning blood pressure in patients with essential hypertension who were under long-acting calcium channel blocker amlodipine monotherapy. The add-on effects of doxazosin at the maximum dose of 6 mg at bedtime on home blood pressure and left ventricular geometry for 1 year were investigated in 49 subjects (37 men and 12 women, aged 57.5+/-9.1 years) with morning hypertension who had been treated with amlodipine alone for more than 1 year. Doxazosin induced a significant decrease in morning blood pressure (145.6+/-5.6/91.5+/-5.4 to 132.4+/-3.7/83.6+/-5.6 mmHg, p

[Two cases of heterozygous Fabry disease].

We report two cases of heterozygous Fabry disease with severe organ damage. Case 1 was a 47-year-old woman. In April 1977, at the age of 27 years, she had proteinuria and edema around the 26th week of her second pregnancy and was diagnosed as toxicosis of pregnancy. She had proteinuria after the delivery. In 1990, a renal biopsy showed zebra bodies under electron microscopic findings, and the patient was diagnosed as Fabry disease. In 1998, a myocardial biopsy showed identical findings. The patient developed severe hypertension and decreased renal function, and alpha-galactosidase enzyme replacement therapy was initiated. However, despite treatment, she was started on dialysis in 2004. Case 2 was a 40-year-old woman. In March 2003, the patient presented with severe hypertension. The patient had cerebral infarction, cardiac hypertrophy, old myocardial infarction and renal failure without diabetes mellitus, hyperlipidemia and collagen disease. The patient was diagnosed as Fabry disease from persistent numbness and pain in the four extremities, a family history of mortality due to heart disease, and skin biopsy findings. She is currently undergoing enzyme replacement therapy. It is generally known that female Fabry disease patients are asymptomatic or mildly symptomatic, as were the present two patients, but some can have marked organ disorders. Hence, even in female patients, it is necessary to consider Fabry disease as a causative disease of chronic renal failure.

Pravastatin has an additional depressor effect in patients undergoing long-term treatment with antihypertensive drugs.

BACKGROUND: Statins have been reported to have direct vascular effects independent of cholesterol reduction. To assess the antihypertensive effect of statins, a crossover study was designed to compare the depressor effect of pravastatin and probucol in hypertensive patients undergoing long-term treatment with antihypertensive drugs. METHODS: The subjects enrolled in this study were 52 hypertensive patients (22 men and 30 women, mean age 62.8 +/- 9.3 years) who were treated with the same antihypertensive drugs for more than 1 year and had serum cholesterol levels of more than 5.69 mmol/L. In 26 subjects, pravastatin at a dose of 10 mg/d was given first for 6 months followed by treatment with probucol at a dose of 500 mg/d, and vice versa in the remaining 26 subjects. Serum lipids, apolipoproteins, glucose, and insulin were measured on the final day of the control period, and pravastatin and probucol treatments. The homeostatic model assessment insulin resistance index (HOMA-IR) was used to assess insulin resistance. RESULTS: The blood pressure decreased after pravastatin treatment (141.2 +/- 4.7/81.3 +/- 4.9 to 136.5 +/- 5.3/80.6 +/- 5.1 mm Hg, P <.001/.499), but did not decrease after probucol treatment (141.2 +/- 4.7/81.3 +/- 4.9 to 141.4 +/- 4.9/80.8 +/- 4.9 mm Hg, P =.832/.634). Total cholesterol decreased significantly after pravastatin (6.69 +/- 0.69 to 5.23 +/- 0.77 mmol/L, P <.001) and probucol treatment (6.69 +/- 0.69 to 5.53 +/- 0.64 mmol/L, P <.001). The HOMA-IR was decreased by probucol (1.92 +/- 0.78 to 1.57 +/- 0.59, P =.029), whereas pravastatin had no effect on HOMA-IR. CONCLUSIONS: It can be concluded that the depressor effect of pravastatin may have an additional benefit in the treatment of hypertensive patients with hyperlipidemia without any adverse effect on insulin sensitivity.

Morning rise in blood pressure is a predictor of left ventricular hypertrophy in treated hypertensive patients.

To assess the relationship between home blood pressure and left ventricular mass, we evaluated cardiac echocardiography in 297 hypertensive subjects (188 men and 109 women; mean age, 62.8+/-10.3 years) who were treated with amlodipine monotherapy over 1 year (mean dose, 5.5+/-2.3 mg/day). The morning hypertension group (n=57; 19.2%), who had a morning home systolic blood pressure (HSBP) > or =135 mmHg and an evening HSBP <135 mmHg, had a significantly greater left ventricular mass index (LVMI) concomitant with an increase in the homeostasis model assessment insulin resistance index (HOMA-IR) compared to the good control group (n=174; 58.6%), whose morning and evening HSBP were both <135 mmHg, and had a LVMI roughly equivalent to that of the poor control group (n=63; 21.2%), whose morning and evening HSBP were both > or =135 mmHg. By grouping of subjects according to the difference between morning and evening HSBP (delta HSBP), subjects with a delta HSBP> or =10 mmHg had a significantly greater LVMI than subjects with a delta HSBP <10 mmHg. Increases in LVMI in these patients were still significant after adjustment for age, gender, dose of amlodipine, alcohol consumption, body mass index, office systolic blood pressure, and morning and evening HSBP. In a stepwise multivariate regression analysis, delta HSBP (r2=36.2%, p <0.001), morning HSBP (r2=5.5%, p <0.001), HOMA-IR (r2=1.4%, p=0.016) and age (r2=1.0%, p=0.026) were determined to be significant contributing factors for LVMI. This regression model could explain 44.1% of LVMI variability. These results suggest that morning rise in blood pressure is a dominant predictor of left ventricular hypertrophy.

[Adult onset Still's disease associated esophageal cancer: a case report].

We report a case of adult onset Still's disease in a 77 year old man, who was diagnosed as a esophageal cancer 9 months after the onset of this disease. At first malignant lesions in any organs were not found and steroid (prednisolone) therapy was begun and the patient was recovered from manifestations. But while tapering prednisolone to 15 mg, fever, arthritis and rash were observed again. Repeated examination revealed that he had suffered from esophageal cancer. This case is considered as a paraneoplastic syndrome of the esophageal cancer. Patients with adult onset Still's disease should be followed as a paraneoplastic syndrome.

Blood sugar control reverses the increase in urinary excretion of prostaglandin D synthase in diabetic patients.

BACKGROUND/AIMS: We investigated basal levels of serum and urinary lipocalin-type prostaglandin D synthase/beta-trace (L-PGDS) in type-2 diabetic patients and explored whether glycemic control affects L-PGDS status in another 55 diabetic inpatients with normoalbuminuria. METHODS: Fifty-five type-2 diabetic outpatients (HbA1c, 9.14 +/- 0.20%; creatinine (Cr), 85.1 +/- 2.4 micromol/l), and 55 age-matched healthy control subjects were recruited. Serum and urinary levels of L-PGDS were determined with respect to the stage of diabetic nephropathy. The L-PGDS was localized by immunohistochemistry. RESULTS: The urinary L-PGDS index increased in diabetic patients, compared with the controls (234.8 +/- 27.4 vs. 73.8 +/- 7.8 microg/mmol Cr, p < 0.001). Even in normoalbuminuric patients as well as in microalbuminuric patients, urinary L-PGDS indexes were higher than the controls (166.0 +/- 21.1, p < 0.0001 and 338.6 +/- 62.5 microg/mmol Cr, p < 0.0001, respectively), although the serum L-PGDS level was equal to that in the control subjects. Multiple regression analysis revealed that the urinary L-PGDS index was predicted solely by glucose levels and type-IV collagen index, whereas the serum L-PGDS was determined mainly by age and serum Cr. Glycemic control reduced the urinary L-PGDS index towards the normal range in diabetic patients with normoalbuminuria (172.3 +/- 6.6 vs. 118.1 +/- 2.6 (SE) microg/mmol Cr, p < 0.0001). Immunohistochemistry showed that L-PGDS was uniquely present in the renal tubules in diabetes while in nondiabetics, L-PGDS occurred solely in the peritubular interstitium, not in the tubular cells. CONCLUSION: Inadequate glycemic control is responsible for urinary L-PGDS excretion in the diabetic patients. Urinary L-PGDS is useful to predict subclinical renal injury associated with type-2 diabetes.

Clinical estimation of vancomycin measurement method on hemodialysis patient.

The fluorescence polarization immunoassay (FPIA) method is used to perform measurement of vancomycin hydrochloride (VCM) at many institutions. However, the values measured by the FPIA method are more vulnerable to overestimation than the high performance liquid chromatography (HPLC) method. In particular, it was not reported to perform exact therapeutic drug monitoring (TDM) measurement. Since overestimation is likely in patients with renal dysfunction, the HPLC method is preferable for TDM measurement. This study investigates the clinical conditions that lead to overestimation in the FPIA method, paying attention to the relation of clinical laboratory data inspection values and the existence of hemodialysis (HD). Overestimation in the evaluation of TDM using the FPIA method was clinically examined with 116 serum samples obtained from 18 cases medicated with VCM. The relevance between overestimation of patients who had not had HD performed was 72.7 +/- 61.7% (means +/- SD). In short, the overestimation was greatest in HD patients. Since overestimation did not affect the evaluation of clinical TDM, such as an effect and a side-effect, the TDM of VCM was shown to be satisfactorily evaluated by the simple FPIA method.

Lipocalin-type prostaglandin d synthase in essential hypertension.

Lipocalin-type prostaglandin D synthase (L-PGDS) reportedly well predicts cardiovascular injuries in humans. However, little is known about the implications of L-PGDS in hypertension. In the present study, we investigated the alterations of serum and urinary L-PGDS in hypertensive patients with or without renal dysfunction. A total of 111 patients with hypertension (EHT; 65 with normoalbuminuria, 23 with microalbuminuria, 12 with macroalbuminuria, 11 with renal failure) and 102 normotensive, nomoalbuminuric subjects (NT) were studied. L-PGDS was measured by enzyme-linked immunosorbent assay, and L-PGDS in the kidney was localized using immunohistochemical methods. Blood pressure was higher in EHT groups than in the NT group (P<0.0001). There were no differences in age, gender, BMI, TC, TG, and HbA1c levels among the groups. Serum creatinine and urinary albumin levels were higher in the group with renal failure. Serum levels of L-PGDS were increased in EHT with normoalbuminuria, as compared with NT (0.88 +/- 0.05 versus 0.65 +/- 0.02 microg/mL; P<0.001). Serum levels of L-PGDS increased with the renal function worsened and positively correlated with serum creatinine, particularly in patients with renal impairments (r=0.76, P<0.0001). Similarly, the urinary L-PGDS excretions in EHT with normoalbuminuria were higher than that in NT (2.31 +/- 0.29 versus 1.16 +/- 0.14 mg/gCr, P<0.001), whereas there were no differences in urinary albumin excretion between the 2 groups. Moreover, urinary L-PGDS excretion increased dramatically with an increase in albuminuria or proteinuria. L-PGDS was stained in the tubules and the interstitium of the kidney in nephrosclerosis. In conclusion, patients with hypertension exhibited a higher level of L-PGDS in serum and urine, and this became increasingly obvious along with advance in renal dysfunction. These data suggest that L-PGDS metabolism is related to blood pressure and kidney injuries associated with hypertension.