Beneficial effects of olmesartan and temocapril on urinary liver-type fatty acid-binding protein levels in normotensive patients with immunoglobin A nephropathy

BACKGROUND: Liver-type fatty acid-binding protein (L-FABP) is a clinical biomarker of tubulointerstitial damage, which plays an essential role in the progression of chronic kidney disease (CKD), including immunoglobin A (IgA) nephropathy. The effect of combination therapy with the angiotensin receptor blocker (ARB) and the angiotensin-converting enzyme inhibitor (ACEI) on CKD has not been elucidated. METHODS: Twenty-four normotensive patients with IgA nephropathy were randomly assigned to receive olmesartan 10 mg/day, temocapril 2 mg/day, or combination therapy with both drugs. Urinary levels of L-FABP as well as 8-hydroxydeoxyguanosine (8-OHdG) and protein excretion were measured before and after 3 months of treatment. The chronicity index and activity index were also assessed by histopathologic findings. RESULTS: Urinary levels of L-FABP and 8-OHdG were higher in patients with IgA nephropathy than in age-matched and sex-matched healthy controls (122.5 +/- 25.5 v 6.4 +/- 3.8 mug/g.creatinine, P < .001; and 22.6 +/- 4.4 v 4.8 +/- 1.4 ng/mg.creatinine, P < .01, respectively). Urinary levels of L-FABP were correlated with those of 8-OHdG (baseline, P = .0001; after 3 months, P = .008) and the severity of proteinuria (baseline, P = .0015; after 3 months, P = .0001). The percent reductions in urinary levels of L-FABP and 8-OHdG, protein excretion, and activity index after 3 months were greater in the combination therapy group, compared with each monotherapy group of olmesartan (P < .05) and temocapril (P < .05). CONCLUSIONS: The data suggest that a combination therapy of ARB plus ACEI has a greater beneficial effect on renal injury compared with monotherapy using ARB or ACEI in normotensive patients with IgA nephropathy.     

Low-dose candesartan cilexetil prevents early kidney damage in type 2 diabetic patients with mildly elevated blood pressure.

To determine the effect of a low-dose angiotensin receptor blocker, candesartan, on early kidney damage associated with diabetes. Fifty-two patients with type 2 diabetes with normo- and microalbuminuria participated in this study. Nineteen patients with high-normal and mildly high blood pressure received low-dose candesartan cilexetil at 4 mg daily (candesartan group), and 33 patients did not receive candesartan (control group). Blood pressure, urinary excretion of albumin, transferrin, and type IV collagen (expressed as urinary creatinine index) and plasma parameters were determined at baseline and at 2, 6, 12 and 18 months after the start of candesartan therapy. Baseline urinary albumin, transferrin, and type IV collagen excretions was similar in the control and candesartan groups. The higher baseline systolic blood pressure was decreased by candesartan treatment to a level similar to that in the control group, such that blood pressure was comparable between the control and candesartan groups during the run-in period. In the control group, urinary albumin excretion was significantly increased at 18 months when compared with baseline, while urinary albumin excretion did not increase in the candesartan group throughout the study. Urinary transferrin excretion was significantly increased at 6, 12, and 18 months when compared with baseline in the control group, while it did not increase in the candesartan group during the study. In both groups, urinary type IV collagen excretion did not change significantly during the study. Hemoglobin A1c, serum urea nitrogen, creatinine, albumin, and lipids were comparable between the two groups throughout the study. In conclusion, low-dose candesartan can prevent early kidney damage in type 2 diabetic patients with mildly higher blood pressure independently of its hypotensive action.     

Comparative effects of pioglitazone, glibenclamide, and voglibose on urinary endothelin-1 and albumin excretion in diabetes patients

Urinary endothelin (ET)-1 excretion is present in non-insulin dependent diabetes (NIDDM) patients with microalbuminuria, and an increase in circulating ET-1 precedes the microalbuminuric phase of renal injury related to diabetes. The aim of the present study was to determine whether various drugs alter urinary ET-1 levels and urinary albumin excretion (UAE) in NIDDM patients with microalbuminuria. Forty-five NIDDM patients with microalbuminuria were randomly assigned to three groups: those treated with pioglitazone at 30 mg/day (n=15), those treated with glibenclamide at 5 mg/day (n=15), and those treated with voglibose at 0.6 mg/day (n=15). Patients received these drugs for 3 months. UAE, urinary ET-1, and plasma ET-1 levels were measured in these patients before and after treatment. Before treatment, UAE, urinary ET-1, and plasma ET-1 levels differed little among the three groups. UAE in the 45 NIDDM patients (156.2+/-42.8 microg/min) was greater than that in 30 healthy controls (8.2+/-2.6 microg/min) (P<.001). Urinary ET-1 levels in the NIDDM patients (8.7+/-1.3 ng/g urinary creatinine (UC)) were significantly higher than that in the controls (2.4+/-0.2 ng/g UC) (P<.01). Plasma ET-1 levels, however, in the NIDDM patients (1.3+/-0.4 pg/ml) did not differ significantly from the levels in healthy controls (1.0+/-0.6 pg/ml). Pioglitazone but no glibenclamide or voglibose reduced UAE from 142.8+/-42.2 to 48. 4+/-18.2 microg/min (P<.01) and urinary ET-1 levels from 8.6+/-1.3 to 3.4+/-0.5 ng/g UC (P<.01). These data suggest pioglitazone to be effective in reducing UAE and urinary ET-1 concentrations in NIDDM patients with microalbuminuria.     

Valuable markers for contrast-induced nephropathy in patients undergoing cardiac catheterization

Background Contrast-induced nephropathy (CIN) frequently complicates cardiac catheterization, so the objectives of present study were to investigate the usefulness of cystatin C before catheterization and establish a cut-off level for CIN, and to examine the changes in cystatin C and several other markers in patients with and without CIN. Methods and Results Prospective study of consecutive 87 patients who underwent elective catheterization: moderate renal disease defined as glomerular filtration rate 30-59 ml . min(-1) .1.73 mm(-2); cystatin C and creatinine (Cr), urinary liver-type fatty acid-binding protein (L-FABP), alpha(1), beta(2) microglobulins, N-acetyl-beta-D-glucosaminidase, and microalbumin were measured immediately before, and 1, 2, and 3 days after catheterization. CIN occurred in 18 patients and receiver-operating characteristic analysis showed a higher area-under-the-curve for cystatin C compared with serum Cr (0.933 vs 0.832 p=0.012). At a cut-off level of >1.2 mg/L, cystatin C before catheterization exhibited 94.7% (95% confidence interval: 0.851-1.015) sensitivity and 84.8% specificity for detecting CIN. Cystatin C levels were higher in CIN patients than in those without CIN, even before catheterization (cystatin C: 1.08+/-0.22 vs 1.36+/-0.28 mg/L, p=0.007). Urinary L-FABP was increased on days 1 and 2 in patients with moderate renal disease. Conclusion Cystatin C was useful for predicting the occurrence of CIN. Urinary L-FABP was the only marker of transient renotubular damage. (Circ J 2008; 72: 1499 - 1505).     

Azelnidipine reduces urinary protein excretion and urinary liver-type fatty acid binding protein in patients with hypertensive chronic kidney disease

BACKGROUND: Hypoxia plays a significant role in the pathogenesis and progression of chronic renal disease. Urinary liver-type fatty acid binding protein (L-FABP) levels reflect the clinical prognosis of chronic renal disease. The calcium channel blocker azelnidipine has anti-oxidative properties and these may contribute to the beneficial effects of this drug. The aim of the present study was to determine whether azelnidipine and/or amlodipine affected urinary protein excretion or the urinary levels of 8-OHdG and L-FABP in hypertensive patients with mild chronic kidney disease (CKD). METHODS: Thirty moderately hypertensive chronic kidney disease patients were randomly assigned to 2 treatment groups: azelnidipine 16 mg once daily or amlodipine 5 mg once daily. Treatment was continued for 6 months. Urinary protein excretion and urinary levels of 8-OHdG and urinary L-FABP were measured before 3 and 6 months after the treatment period. RESULTS: Both drugs exhibited comparable and significant effects on the systolic and diastolic blood pressure. Azelnidipine decreased heart rate significantly after 3 and 6 months whereas amlodipine increased it significantly after 3 and 6 months. Urinary protein excretion, urinary 8-OHdG and urinary L-FABP levels decreased significantly after 3 months (p < 0.05) and 6 months (p < 0.05) in the azelnidipine group. In contrast, amlodipine showed little effect on urinary protein excretion or the urinary levels of 8-OHdG and L-FABP throughout the experimental period. CONCLUSIONS: Azelnidipine is renoprotective in hypertensive patients with mild CKD and this action is, at least in part, due to the anti-oxidative effect.     

Anti-proteinuric effect of an N-type calcium channel blocker, cilnidipine

The objective of the present study was to determine anti-proteinuric effect of an N-type calcium channel blocker-cilnidipine. Subjects were 43 essential or renal hypertensive subjects who had been taking calcium channel blockers other than cilnidipine for at least 6 months. All patients had proteinuria greater than 0.2 g/day in spite of fair blood pressure control (<150/90 mmHg). Calcium channel blockers in 25 patients (62+/-3 years) were switched to cilnidipine (cilnidipine group), whereas other 18 patients (58+/-3 years) continued to take originally prescribed calcium channel blockers (control group). The 24-hr urine collections were done at baseline and after 6 months of the follow-up period. Baseline characteristics including age, blood pressure levels, body mass index and creatinine clearance were similar between cilnidipine and control groups. Urinary protein excretion also was comparable between cilnidipine (0.61+/-0.10 g/day) and control (0.86+/-0.17 g/day) groups. Urinary protein significantly decreased after 6 months in cilnidipine group (- 0.21+/- 0.11 g/day, - 36%, p< 0.01), whereas it did not change in control group (+ 0.01+/- 0.15 g/day, 0.4%, ns). There were no significant changes in blood pressure, serum creatinine, creatinine clearance, estimated protein intake, and urinary salt excretion during the follow-up period in either group. The reduction of urinary protein by cilnidipine was evident in essential hypertensives (- 54+/-9%, n=18, p<0.01) but not in renal hypertensives (+10+/-35%, n=7, ns). Results suggest that cilnidipine has an anti-proteinuric effect especially in patients with essential hypertension.     

Effect of menopause and hormone replacement therapy on urinary excretion of pyridinium cross-links: a longitudinal and cross-sectional study

OBJECTIVE: To study longitudinally the effect of the menopause and hormone replacement therapy on the new markers of bone resorption: urinary excretion of pyridinoline and deoxypyridinoline. DESIGN AND PATIENTS: Urinary pyridinoline and deoxypyridinoline were measured every 3 months for 2-3 years in 15 healthy women aged 45-54 years. Nine remained premenopausal and six became post-menopausal during the study. Urinary pyridinoline and deoxypyridinoline were also measured before and after 3 months of either placebo or hormone replacement therapy in 65 post-menopausal women, aged 45-54 years, who were participating in a double-blind study. MEASUREMENTS: Urinary pyridinoline and deoxypyridinoline were measured in fasting urine samples by spectrofluorometry after high performance liquid chromatography and corrected for creatinine excretion. RESULTS: Urinary pyridinoline and deoxypyridinoline remained almost constant during the premenopausal period. Both started to increase 6 months after the last menstrual bleeding and the mean post-menopausal values were 30-50% higher than the premenopausal values in the same subjects (values in nmol/mmol creatinine given as mean +/- SEM: urinary pyridinoline (premenopausal) = 29 +/- 2 vs urinary pyridinoline (post-menopausal) = 38 +/- 6, P < 0.05; urinary deoxypyridinoline (premenopausal) = 8 +/- 1 vs urinary deoxypyridinoline (post-menopausal) = 12 +/- 1, P < 0.05). Three months of post-menopausal hormone replacement therapy decreased (P < 0.001) both to premenopausal levels. CONCLUSION: Urinary pyridinoline and deoxypyridinoline, new markers of bone resorption, remain fairly constant in the years before the menopause and start to increase about 6 months after the last menstrual bleeding. This increase is reversed by hormone replacement therapy.     

Effect of pioglitazone on urinary liver-type fatty acid-binding protein concentrations in diabetes patients with microalbuminuria

BACKGROUND: Urinary liver-type fatty acid-binding protein (L-FABP) is a useful marker for renal tubulointerstitial injury. Pioglitazone is reported to be effective in early diabetic nephropathy. The aim of the present study was to determine whether pioglitazone affects urinary L-FABP levels in diabetic nephropathy patients with microalbuminuria. METHODS: Sixty-eight patients with type 2 diabetes and microalbuminuria were randomized to a 12-month treatment with pioglitazone (30 mg/d, n = 17), glibenclamide (5 mg/d, n = 18), voglibose (0.6 mg/d, n = 17), or nateglinide (270 mg/d, n = 16). Pre- and posttreatment urinary albumin excretion (UAE) and urinary L-FABP concentrations were compared between the four treatment groups and 40 age-matched healthy subjects. RESULTS: Pretreatment UAE and urinary L-FABP levels differed little between the four groups. UAE and urinary L-FABP levels were significantly greater in the diabetes patients than in the healthy subjects (UAE: p < 0.001; L-FABP: p < 0.01). After 6 and 12 months, UAE and urinary L-FABP were significantly lower in the pioglitazone treatment group than in the other treatment groups (UAE: 6 months, p < 0.01 and 12 months, p < 0.001; L-FABP: 6 months, p < 0.05 and 12 months, p < 0.01). CONCLUSIONS: Pioglitazone, but not glibenclamide, voglibose, or nateglinide, appears to be effective in reducing UAE and the urinary L-FABP level, suggesting that pioglitazone has a specific role in ameliorating both glomerular and tubulointerstitial lesions associated with early diabetic nephropathy.     

Pharmacokinetic-pharmacodynamic interactions of candesartan cilexetil and losartan.

BACKGROUND: The variability of the blood pressure response to blockade of the angiotensin II type 1 receptor is influenced by renin status and pharmacokinetics and pharmacokinetic-pharmacodynamic interactions. OBJECTIVE: To compare the pharmacokinetic-pharmacodynamic interactions of two doses of an ester prodrug of a noncompetitive angiotensin II type 1 receptor antagonist, candesartan cilexetil, at 8 and 16 mg, with those of the reference angiotenisn II type 1 receptor blocker, losartan, at the standard dose (50 mg), in a human model that controls renin status. DESIGN AND METHODS: In a double-blind placebo-controlled crossover study, we compared the effects on renin and mean blood pressure over 24 h of single oral doses of candesartan cilexetil at 8 and 16 mg and losartan at 50 mg in 16 sodium-depleted normotensive subjects. RESULTS: The area under the curve (0-24 h) for plasma active renin did not differ significantly between 8 mg candesartan cilexetil and 50 mg losartan, but was significantly higher for 16 than for 8 mg candesartan cilexetil or for 50 mg losartan. The area under the curve (0-24 h) for the fall in mean blood pressure with 16 mg candesartan cilexetil (-197 +/- 96 mmHg/h) was significantly greater than that for placebo (-112 +/- 81 mmHg/h; P< 0.05) but the difference was not statistically significant compared with either 8 mg candesartan cilexetil (-158 +/- 95 mmHg/h) or 50 mg losartan (-144 +/- 66 mmHg/h). The area under the curve (0-24 h) for the fall in mean blood pressure did not significantly differ between 8 mg candesartan cilexetil, 50 mg losartan and placebo. The area under the curve (0-24 h) for plasma active renin was significantly correlated to that for plasma levels of the active metabolite of losartan, EXP 3174 (r = 0.65, n = 16, P< 0.01). No such correlation was detected for each single dose of candesartan cilexetil but a dose-response relationship was present when both doses were combined. CONCLUSIONS: The pharmacodynamic effects of a single oral dose of 16 mg candesartan cilexetil are greater than those of 50 mg losartan and 8 mg candesartan cilexetil. The variability in the pharmacokinetic-pharmacodynamic interaction is less pronounced for candesartan than for EXP 3174, which could result in reduced variability of the blood pressure effects in patients.     

Effects of candesartan cilexetil on oxidative state and renal function in 5/6 nephrectomized rats

We have investigated the influence of a novel angiotensin II type 1 receptor antagonist, candesartan cilexetil, on the oxidative state of renal tissue and renal function in 5/6 nephrectomized rats, and compared its effects with those of an angiotensin-converting enzyme inhibitor, enalapril. Candesartan cilexetil (1 and 5 mg/kg per day), enalapril (5 mg/kg per day) and vehicle were orally administered once daily for 16 weeks after 5/6 nephrectomy. There was a marked degree of proteinuria evident prior to treatment, an average of 5.69 mg/mg creatinine in the nephrectomized rats, vs 1 to 2 mg/mg creatinine in the control group matched for species and body weight. Inhibition of development of proteinuria by candesartan cilexetil was dose dependent. Enalapril also significantly blunted the rise in urinary protein. Malondi-aldehyde content in the homogenate from the renal cortex increased significantly in the nephrectomized rats compared to control animals. This elevation of malondi-aldehyde content was unaffected by administration of either candesartan cilexetil or enalapril. Antioxidative enzyme (glutathione peroxidase, superoxide dismutase, and catalase) activities in the renal tissue were not affected by any active treatment. Elevation of lipid peroxide in remnant renal tissue suggests that oxidative stress may contribute to the progression of renal injury in the nephrectomized rats. Neither candesartan cilexetil nor enalapril affected antioxidant defenses in renal tissue in nephrectomized rats, indicating that mechanisms other than alteration in oxidative stress are involved in the renoprotective effects of candesartan cilexetil and enalapril.     

Renoprotective effect of telmisartan in patients with chronic kidney disease

Although the activation of the renin-angiotensin system has a major role in the development of chronic renal failure, little is known about the effect of angiotensin receptor blockers on tubulointerstitial injury. To evaluate the renoprotective effect of telmisartan, we measured urinary protein excretion, urinary liver-type fatty acid binding protein (L-FABP) excretion, and urinary collagen IV in 30 hypertensive patients with chronic kidney disease (CKD). These patients were randomly assigned to receive 40 mg/day (n = 15) or 80 mg/day (n = 15) of telmisartan before the initiation of treatment and 6 and 12 months after treatment. Both doses of telmisartan reduced systolic and diastolic blood pressure after 6 (p < 0.001) and 12 (p < 0.001) months compared with baseline levels. Blood pressure reduction rate were similar between both doses. Urinary protein, urinary L-FABP excretion, and urinary collagen IV levels declined significantly 6 (p < 0.001) and 12 (p < 0.001) months after telmisartan treatment in both doses. The reduction rate in parameters was more pronounced in patients receiving 80 mg/day compared with those taking 40 mg/day telmisartan at 12 months (p < 0.001). Telmisartan reduces proteinuria, urinary L-FABP excretion, and urinary collagen IV levels in hypertensive CKD patients.     

Effect of a short-term treatment with alendronate on bone density and bone markers in patients with central diabetes insipidus.

The aim of this open prospective randomized study was to evaluate the effect of a 6-month treatment with alendronate on the bone mineral density (BMD) at lumbar spine in patients with central diabetes insipidus. Eighteen patients with central diabetes insipidus and 18 sex- and age-matched healthy subjects entered this study. At study entry, all subjects underwent BMD assessment at the lumbar spine and measurement of serum osteocalcin (OC) and cross-linked N-telopeptides of type I collagen (Ntx). Thereafter, 9 of the 18 patients were randomized to receive treatment with alendronate at a dose of 10 mg, orally, once daily for 6 months (group 1), whereas the remaining 9 patients did not receive any treatment affecting bone status during this period (group 2). After 6 months, bone metabolism and bone density study were repeated in all patients. At baseline, lumbar BMD values (0.86+/-0.03 vs. 1.01+/-0.02 g/cm2; P<0.001) and serum OC levels (4.7+/-0.3 vs. 7.9+/-0.2 microg/L; P<0.001) were significantly lower, whereas urinary Ntx levels were significantly higher [72.0+/-1.9 vs. 64.6+/-1.7 nmol bone collagen equivalents (BCE)/nmol creatinine (Cr); P<0.01] in patients than in controls. After randomization, no difference in lumbar BMD, serum OC, or urinary Ntx was found between patients of group 1 and group 2. At the 6 month follow-up, no difference in serum OC levels was found compared to baseline evaluation in patients of both group 1 and group 2. By contrast, a significant decrease in urinary Ntx levels was found in patients of group 1 (70.3+/-3.0 vs. 75.4+/-2.1 nmol BCE/nmol Cr; P<0.05), but not in patients of group 2 (68.8+/-3.3 vs. 68.5+/-3.0 nmol BCE/nmol Cr; P = NS). A significant increase in lumbar BMD values was found in patients of group 1 (0.88+/-0.04 vs. 0.83+/-0.04 g/cm2; P<0.05), whereas a significant decrease in lumbar BMD values was found in patients of group 2 (0.86+/-0.05 vs. 0.89+/-0.05 g/cm2; P<0.05). Lumbar BMD increased 7.0+/-1.5% in patients of group 1 and decreased 4.2+/-1.8% in patients of group 2 (P<0.001). In conclusion, this study demonstrated that a 6-month treatment with alendronate in patients with central diabetes insipidus was effective in significantly improving BMD at the lumbar spine, which was significantly worsened in untreated patients. Therefore, alendronate treatment could be used in patients with central diabetes insipidus with documented osteopenia or osteoporosis.     

In vivo inhibition of angiotensin receptors in the rat kidney by candesartan cilexetil: a comparison with losartan

The present study examined the in vivo effects of candesartan cilexetil compared with losartan on angiotensin II (Ang II) receptor binding in the rat kidney after oral administration. Male Sprague-Dawley rats (250 to 300 g) were gavaged with candesartan cilexetil or losartan in doses of 0.1, 0.3, 1, 3, 10, or 30 mg/kg, or corresponding vehicle. Rats were killed at 0, 1, 2, 8, or 24 h after drug administration, trunk blood collected, and kidneys removed. The effects of candesartan cilexetil and losartan on Ang II receptor binding were determined by quantitative in vitro autoradiography using the radioligand [125I]-[Sar1,Ile8] Ang II. Ang II receptor binding in the kidney was mainly due to AT1 receptors with high levels of binding localized to the inner stripe of the outer medulla and glomeruli in cortical regions. Candesartan cilexetil (0.1 to 30 mg/kg) inhibited Ang II receptor binding to all anatomical sites of the kidney, in a dose-dependent manner. Losartan (0.1 to 30 mg/kg) also produced dose-dependent inhibition of Ang II receptor binding but was approximately 10- to 30-fold less potent than candesartan cilexetil. Inhibition of Ang II receptor binding was near maximal about 1 h after administration of candesartan cilexetil (10 mg/kg) or losartan (10 mg/kg), with both drugs producing persistent blockade at 24 h despite plasma renin activity and plasma drug concentrations returning to near normal levels. In vitro, candesartan, losartan, and EXP3174 (1 x 10(-10) to 1 x 10(-5) mol/L) displaced [125I]-[Sar1,Ile8] Ang II binding from AT1 receptors in the kidney in a concentration-dependent manner with a rank order of potency of candesartan > EXP3174 > losartan. The concentration required to displace 50% of radioligand binding (IC50) by candesartan, EXP3174, and losartan was 0.9+/-0.1 nmol/L, 3.4+/-0.4 nmol/L, and 8.9+/-1.1 nmol/L, respectively. In conclusion, the findings of the present study suggest that candesartan cilexetil is more potent than losartan in antagonizing AT1 receptors in the kidney in vivo. Nonetheless, both candesartan cilexetil and losartan produce rapid, complete, and sustained blockade of AT1 receptors in the rat kidney. Tissue blockade of Ang II receptors in target organs, such as the kidney, may contribute to the beneficial effects of Ang II receptor antagonists as antihypertensive agents.     

Differentiation of pseudo- and idiopathic hypoparathyroidism by measuring urinary calcitonin

Calcitonin (CT) levels were determined in urine specimens from normal subjects and patients with pseudohypoparathyroidism type I (PHP), idiopathic hypoparathyroidism (IHP), pseudopseudohypoparathyroidism (PPHP), and surgical hypoparathyroidism (SHP). Urinary CT was measured by RIA after extraction of urine by gel chromatography on a 0.8 X 20-cm column of Bio-Gel P-2. The urinary CT level ranged from 420-1000 pg/mg creatinine (Cr; mean +/- SD, 631 +/- 229) in PHP (n = 6), from 50-270 (131 +/- 92) in IHP (n = 6), and from 35-93 (66 +/- 27) in SHP (n = 6), and was 185 pg/mg Cr in one patient with PPHP. The mean value in PHP was significantly (P less than 0.001) higher, and that in SHP was significantly (P less than 0.05) lower, than those in the age-matched normal subjects. In each patient with PHP and IHP before and after treatment with 1 alpha-hydroxycholecalciferol, urinary CT levels fluctuated between 700-1370 pg/mg Cr in PHP and from 43-195 pg/mg Cr in IHP. Increased urinary excretion of CT in patients with PHP suggests that CT secretion may be enhanced in this disease. The biological role of CT in PHP remains to be clarified.     

Renal protective effect in hypertensive patients: the high doses of angiotensin II receptor blocker (HARB) study.

Angiotensin receptor blockers (ARBs) are the recommended first-line antihypertensive treatment for managing chronic kidney disease, and strict blood pressure (BP) regulation is crucial for the reduction of proteinuria. Valsartan and candesartan are commonly used ARBs in Japan, with maximum permissible doses of 160 mg/day and 12 mg/day, respectively. We evaluated BP and proteinuria after changeover from the maximum dose of candesartan to the maximum dose of valsartan, in 55 poorly controlled hypertensive patients undergoing candesartan treatment who were unable to achieve optimal BP according to the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2004). We measured BP and pulse rate and assessed urinary protein excretion (UPE) before and after changeover. Changeover was associated with decreases in systolic BP and diastolic BP from 158/89 mmHg to 150/86 mmHg (p<0.01). Changeover was also associated with a reduction in UPE adjusted to urinary creatinine from 0.35+/-0.19 g/g creatinine to 0.19+/-0.37 g/g creatinine (p=0.0271) in patients who had high urinary protein levels prior to changeover without significant decreases in BP (p=0.0184). According to multiple regression analysis, higher UPE (p<0.0001) and a lower glomerular filtration rate (GFR) (p=0.0011) prior to changeover were independently correlated with reduction in UPE. Our results suggest that the maximum dose of valsartan is more effective than the maximum dose of candesartan for reducing BP and proteinuria.     

Urinary 11-dehydro-thromboxane B2: a quantitative index of platelet activation in cerebral infarction.

Thromboxane A2 (TXA2) biosynthesis was studied in healthy subjects, patients with chronic cerebral infarction, patients under chronic aspirin treatment and patients with atrial fibrillation. Urinary 11-dehydro-TXB2, as a major metabolite of TXA2, was measured by radioimmunoassay. The extent of carotid atherosclerosis was determined by B-mode ultrasonography. The mean +/- SD urinary excretion in patients with cerebral infarction and distinct carotid-atherosclerotic lesions (1,725 +/- 239 ng/g creatinine, n = 6) was significantly higher (p less than 0.01) than in healthy subjects (911 +/- 239 ng/g creatinine, n = 44) and patients with cerebral infarction who had no distinct carotid lesion (1,050 +/- 191 ng/g creatinine, n = 6). The urinary excretion of healthy subjects was higher (p less than 0.01) in smokers (1,063 +/- 244 ng/g creatinine, n = 17) than in non-smokers (815 +/- 183 ng/g creatinine, n = 27). Aspirin largely suppressed 11-dehydro-TXB2 excretion (266 +/- 114 ng/g creatinine, n = 7). Three of 5 patients with atrial fibrillation showed very high values. Our results indicated that platelet activation occurs in the atherosclerotic lesions, and that urinary 11-dehydro-TXB2 is the appropriate analytic target for detecting platelet activation.     

Urinary growth hormone (GH) measurements are useful for evaluating endogenous GH secretion

Daily (24-h) urinary GH excretion was measured using a highly sensitive sandwich enzyme immunoassay in 10 normal adults, 6 patients with hypopituitarism, 25 normal but short children who had normal plasma GH responses (peak plasma GH level, greater than 10 micrograms/L) to provocative tests, and 8 patients with acromegaly. The mean urinary GH values in the normal adults, patients with acromegaly, and patients with hypopituitarism were 13.8 +/- 4.0 (+/- SE) and 431.1 +/- 149.1 ng/g creatinine (Cr) (1.56 +/- 0.45 and 48.77 +/- 16.87 ng/mmol Cr) and undetectable, respectively; these mean values were significantly different from each other. In the normal but short children the urinary values ranged from undetectable to 55.8 ng/g Cr (6.31 ng/mmol Cr). All of the normal but short children and 4 patients with hypopituitarism participated in a 24-h endogenous GH secretion study. The urinary GH values correlated significantly with the mean 24-h plasma GH concentrations as an index of endogenous GH secretion (r = 0.81; P less than 0.001) and plasma somatomedin-C levels (r = 0.67; P less than 0.001), respectively. In 6 patients with acromegaly whose plasma GH levels were constant throughout a 4-h period, the urinary GH values also significantly correlated with the mean plasma GH levels (r = 0.95; P less than 0.01). These data indicate that urinary GH measurements reflect endogenous GH secretion and that measurement of urinary GH excretion is a useful, simple, and practical method for evaluating endogenous GH secretion.     

Increased Urinary Liver-Type Fatty Acid–Binding Protein Level Predicts Worsening Renal Function in Patients With Acute Heart Failure

Background

Urinary liver-type fatty acid–binding protein (L-FABP) is a potential biomarker for acute kidney injury, and it in turn increases cardiovascular mortality. We tested whether the urinary L-FABP level predicted short- and mid-term outcomes in patients with acute heart failure.

Renoprotective Effect of Telmisartan in Patients with Chronic Kidney Disease

Although the activation of the renin-angiotensin system has a major role in the development of chronic renal failure, little is known about the effect of angiotensin receptor blockers on tubulointerstitial injury. To evaluate the renoprotective effect of telmisartan, we measured urinary protein excretion, urinary liver-type fatty acid binding protein (L-FABP) excretion, and urinary collagen IV in 30 hypertensive patients with chronic kidney disease (CKD). These patients were randomly assigned to receive 40 mg/day (n = 15) or 80 mg/day (n = 15) of telmisartan before the initiation of treatment and 6 and 12 months after treatment. Both doses of telmisartan reduced systolic and diastolic blood pressure after 6 (p < 0.001) and 12 (p < 0.001) months compared with baseline levels. Blood pressure reduction rate were similar between both doses. Urinary protein, urinary L-FABP excretion, and urinary collagen IV levels declined significantly 6 (p < 0.001) and 12 (p < 0.001) months after telmisartan treatment in both doses. The reduction rate in parameters was more pronounced in patients receiving 80 mg/day compared with those taking 40 mg/day telmisartan at 12 months (p < 0.001). Telmisartan reduces proteinuria, urinary L-FABP excretion, and urinary collagen IV levels in hypertensive CKD patients.     

Oral adsorbent AST-120 ameliorates tubular injury in chronic renal failure patients by reducing proteinuria and oxidative stress generation

AST-120 is an oral adsorbent that attenuates the progression of chronic renal failure (CRF) and improves the prognosis of the patients under dialysis. Although tubulointerstitial injury is more important than glomerulopathy in terms of renal prognosis in patients with CRF, effect of AST-120 on tubular injury in CRF patients remains unknown. In this study, we examined whether and how AST-120 treatment could improve tubular damage in nondiabetic CRF patients. Fifty nondiabetic CRF patients were enrolled in the present study and divided into 2 groups: one was the AST-120-treated group (15 men and 10 women) and the other was the age-, sex-, and clinical variables-matched non-AST-120-treated control group. Patients were followed up for 12 months. We investigated the effects of AST-120 on serum levels of interleukin-6 (IL-6), proteinuria, and urinary excretion levels of 8-hydroxydeoxyguanosine (8-OHdG) and L-fatty acid binding protein (L-FABP), markers of oxidative stress and tubular injury, respectively. AST-120 treatment (6 g/d), but not control treatment, for 12 months significantly reduced IL-6, proteinuria, and urinary excretion levels of L-FABP and 8-OHdG, and inhibited the increase in serum creatinine in CRF patients. In univariate analyses, L-FABP levels were correlated with age, proteinuria, 8-OHdG, and IL-6. In multiple stepwise regression analysis, proteinuria and urinary 8-OHdG levels were independently related to L-FABP levels (R² = 0.605). Our present study demonstrated for the first time that AST-120 improved tubular injury in nondiabetic CRF patients. AST-120 may exert beneficial effects in CRF patients by protecting tubular damage partly via reduction of proteinuria and oxidative stress generation.