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Although disturbed phosphate metabolism frequently accompanies chronic kidney disease (CKD), its causal role in CKD progression remains unclear. It is also not fully understood how excess salt induces organ damage. We here show that urinary phosphate-containing nanoparticles promote kidney injury in salt-sensitive hypertension. In Dahl salt-sensitive rats, salt loading resulted in a significant increase in urinary phosphate excretion without altering serum phosphate levels. An intestinal phosphate binder sucroferric oxyhydroxide attenuated renal inflammation and proteinuria in this model, along with the suppression of phosphaturia. Using cultured proximal tubule cells, we confirmed direct pathogenic roles of phosphate-containing nanoparticles in renal tubules. Finally, transcriptome analysis revealed a potential role of complement C1q in renal inflammation associated with altered phosphate metabolism. These data demonstrate that increased phosphate excretion promotes renal inflammation in salt-sensitive hypertension and suggest a role of disturbed phosphate metabolism in the pathophysiology of hypertensive kidney disease and high salt-induced kidney injury.

Spironolactone, a steroidal mineralocorticoid receptor antagonist, is recommended as add-on therapy for treatment-resistant/uncontrolled hypertension. However, caution is advised in patients with advanced chronic kidney disease (CKD) due to an increased risk for hyperkalemia. KBP-5074 is a nonsteroidal mineralocorticoid receptor antagonist under investigation for the treatment of treatment-resistant and uncontrolled hypertension in patients with moderate-to-severe CKD. BLOCK-CKD is a phase 2, international, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of KBP-5074, on top of current therapy, in patients with stage 3B/4 CKD (estimated glomerular filtration rate ≥15 and ≤44 mL/[min·1.73 m 2 ]) and resistant hypertension (trough cuff seated systolic blood pressure ≥140 mm Hg, despite treatment with maximally tolerated doses of 2 or more antihypertensive medicines with complementary mechanisms). Patients (n=240) will be randomized 1:1:1 to once-daily treatment with KBP-5074 0.25 mg, KBP-5074 0.5 mg, or placebo, stratified by estimated glomerular filtration rate (≥30 versus <30 mL/[min·1.73 m 2 ]) and systolic blood pressure (≥160 versus <160 mm Hg). Approximately 30% of enrolled patients should have an estimated glomerular filtration rate of 15 to 29 mL/(min·1.73 m 2 ). The primary efficacy analysis is the change in trough cuff seated systolic blood pressure from baseline to day 84 for the KBP-5074 doses compared with placebo. Changes in urinary albumin-creatinine ratio will be assessed along with changes in serum potassium/incidence of hyperkalemia and changes in estimated glomerular filtration rate and serum creatinine. BLOCK-CKD will determine whether the addition of KBP-5074 will effectively lower blood pressure without an increased risk of hyperkalemia in patients who are not candidates for steroidal mineralocorticoid receptor antagonists due to advanced CKD. Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT03574363.

Whether the abnormal circadian rhythm of urinary sodium excretion is associated with hypertension in chronic kidney disease (CKD) is poorly understood. In this study, we assessed the relationship between the circadian rhythm of urinary sodium excretion and hypertension. Urinary samples were collected during both the day (07:00 to 22:00) and night (22:00 to 07:00) to estimate night/day urinary sodium excretion ratios. Blood pressure (BP) and clinical data were also measured. A total of 1,099 Chinese CKD patients were recruited, 308 patients were excluded, and 791 patients were final enrolled in this study. Among them, 291 patients were normotensive and 500 were hypertensive CKD patients. A 1:1 propensity score matching (PSM) analysis was performed with age and estimated glomerular filtration rate (eGFR) matched between 190 normotensive and hypertensive patients. In the full cohort and PSM cohort, multivariate regression analysis showed that the night/day urinary sodium excretion ratio was an independent risk factor for clinical hypertension, whereas 24 h urinary sodium excretion, diurnal and nocturnal urinary sodium excretion were not. When the night/day urinary sodium excretion ratios were further divided into tertiles (tertile 1 < 0.47, tertile 2, 0.47-0.84 and tertile 3 > 0.84), multivariate analysis showed that tertile 3 was independently associated with hypertension in the full and PSM cohorts. In addition, tertile 3 was also independently associated with eGFR ≤ 60 mL/min/1.73 m 2 and left ventricular hypertrophy. These data suggested that an abnormal circadian rhythm of urinary sodium excretion was independently associated with hypertension and target-organ damage. Individualized salt intake and therapeutic strategies should be used to normalize the natriuretic dipping profile in CKD patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Although angiotensin II (AngII) is known to cause renal injury and fibrosis, the underlying mechanisms remain poorly characterized. Here we show that hypertensive nephropathy (HN) patients and AngII-infused mice exhibit elevated levels of circulating miR103a-3p. We observe a positive correlation between miR-103a-3p levels and AngII-induced renal dysfunction. miR-103a-3p suppresses expression of the sucrose non-fermentable-related serine/threonine-protein kinase SNRK in glomerular endothelial cells, and glomeruli of HN patients and AngII-infused mice show reduced endothelial expression of SNRK. We find that SNRK exerts anti-inflammatory effects by interacting with activated nuclear factor-κB (NF-κB)/p65. Overall, we demonstrate that AngII increases circulating miR-103a-3p levels, which reduces SNRK levels in glomerular endothelial cells, resulting in the over-activation of NF-κB/p65 and, consequently, renal inflammation and fibrosis. Together, our work identifies miR-103a-3p/SNRK/NF-κB/p65 as a regulatory axis of AngII-induced renal inflammation and fibrosis.

Metabolic acidosis is associated with poor outcomes in CKD. Because impaired renal ammonium excretion is important in the pathogenesis of acidosis, urine ammonium excretion might be a better and perhaps earlier acid-base indicator of risk than serum bicarbonate, particularly in patients without acidosis. We evaluated the association between baseline ammonium excretion and clinical outcomes in African American Study of Kidney Disease and Hypertension participants ( n =1044). Median daily ammonium excretion was 19.5 (95% confidence interval [95% CI], 6.5 to 43.2) mEq. In Cox regression models (adjusted for demographics, measured GFR, proteinuria, body mass index, net endogenous acid production, and serum potassium and bicarbonate), hazard ratios of the composite outcome of death or dialysis were 1.46 (95% CI, 1.13 to 1.87) in the low tertile and 1.14 (95% CI, 0.89 to 1.46) in the middle tertile of daily ammonium excretion compared with the high tertile. Among participants without acidosis at baseline, the adjusted hazard ratio for those with ammonium excretion <20 mEq/d was 1.36 (95% CI, 1.09 to 1.71) compared with those with ammonium excretion ≥20 mEq/d. Additionally, compared with participants in the high ammonium tertile, those in the low ammonium tertile had higher adjusted odds of incident acidosis at 1 year (adjusted odds ratio, 2.56; 95% CI, 1.04 to 6.27). In conclusion, low ammonium excretion is associated with death and renal failure in hypertensive kidney disease, even among those without acidosis. Low ammonium excretion could identify patients with CKD and normal bicarbonate levels who might benefit from alkali before acidosis develops., (Copyright © 2017 by the American Society of Nephrology.)

Background: Uric acid (UA) levels correlate positively with the prevalence of chronic kidney disease (CKD) and/or hypertension. We tested the hypothesis that UA may also have a link to a new incidence of CKD and hypertension., Methods: Study design is a cohort study and the predictor is UA levels. Of the 15,470 screened cases, 8223 participants without CKD were eligible for the analysis of the incidence of CKD. Among these CKD candidates, 7569 participants were eligible for the analysis of the new development of hypertension. The observation period was 4 years., Results: Relationship of UA with new cases of CKD. Higher UA levels had a closer association with the new development of CKD; 1.1 % (UA < 5 mg/dL), 1.5 % (5.0-5.9 mg/dL), 1.7 % (6.0-6.9 mg/dL), and 3.4 % (≧7 mg/dL), respectively (p < 0.001 by the Chi-square test). Cox proportional hazard analysis showed that the estimates of the CKD development were eGFR [Hazard Ratio (HR) 0.816, 95 % confidence intervals (CI) 0.791-0.840] and male gender (HR 0.562, 95 % CI 0.322-0.982). UA levels and new development of hypertension. Higher UA levels had a closer association with the new development of hypertension; 5.0 % (UA < 5 mg/dL), 8.9 % (5.0-5.9 mg/dL), 10.6 % (6.0-6.9 mg/dL), and 11.8 % (≧7 mg/dL), respectively (p < 0.001 by the Chi-square test). Cox proportional hazard analysis showed that the estimates of the hypertension development were BMI (HR 1.190, 95 % CI 1.155-1.226), age (HR 1.021, 95 % CI 1.010-1.032), HDL-cholesterol (HR 1.013, 95 % CI 1.007-1.019), male gender (HR 1.791, 95 % CI 1.338-2.395), UA level (HR 1.112, 95 % CI 1.024-1.207), and eGFR (HR 1008, 95 % CI 1.002-1.013). Furthermore, the logistic analysis showed that the odds ratio (OR) to estimate hypertension in the high UA group (UA ≧ 7 mg/dL; OR 1.33, 95 % CI 1.01-1.80) was greater than that in the low UA group (UA < 5 mg/dL). Kaplan-Meier analysis also confirmed the finding that the higher the UA levels the greater the hypertension development (p < 0.001 by the Log-rank test and Cox proportional hazard analysis)., Conclusion: High UA levels are associated with the new development of hypertension, but not with the incidence of CKD.

Background/aims: Angiotensin converting enzyme 2 (ACE2) is highly expressed in the kidney and recognized to be renoprotective by degrading Angiotensin II to Angiotensin (1-7) in diabetic nephropathy. However, little is known about the role of urinary ACE2 (UACE2) in diabetes. The present study was performed to evaluate UACE2 levels in type 2 diabetic patients with various degrees of albuminuria and its associations with metabolic parameters. The effect of RAS inhibitors on UACE2 excretion was also assessed., Methods: A total of 132 type 2 diabetic patients with different degrees of albuminuria and 34 healthy volunteers were studied. UACE2 levels and activity were measured., Results: Compared to healthy controls, UACE2 to creatinine (UACE2/Cr) levels were significantly increased in both albuminuric and non-albuminuric diabetic patients. UACE2/Cr levels were much higher in hypertensive diabetic patients compared with their normotensive counterparts and treatment with RAS inhibitors markedly attenuated the augmentation. Furthermore, UACE2/Cr was positively correlated with fasting blood glucose, hemoglobin A1C (HbA1C), triglyceride, and total cholesterol. In multiple regression analysis, UACE2/Cr was independently predicted by HbA1C and RAS inhibitors treatment., Conclusions: UACE2 increased in type 2 diabetic patients with various degrees of albuminuria and RAS inhibitors suppresses UACE2 excretion. UACE2 might potentially function as a marker for monitoring the metabolic status and therapeutic response of RAS inhibitors in diabetes., (© 2015 S. Karger AG, Basel.)

Background and Objective: Nephrotic range proteinuria can occur in patients with biopsy proven hypertensive nephrosclerosis (HN). We analysed the differential clinical and evolution characteristics of these patients compared with other glomerular diseases., Material and Method: This is a case-control descriptive analysis obtained from the renal pathology registry of our hospital. Clinical features, treatment and evolution of these patients (cases) were compared with nephrotic patients with other glomerular diseases (controls)., Results: Five point one percent of biopsies with HN diagnosis. Case/control characteristics were: proteinuria 4.7 [3-11.4] versus 5.5 [3-28.1] g/24h/1.73m(2) (P=NS). Normal albumin compared with controls (39.5 [6.4] versus 29.4 [10] g/dL; P=.001), significant oedemas only in 10 versus 63% of controls. HN were older (58.8 [12.6] versus 45.5 [19.6] years), had longer hypertension duration before renal biopsy and more previous cardiovascular events (39 versus 16%). Mean blood pressure was higher (166/90 versus 133/75mmHg; P=.01) and had worse renal outcome., Conclusions: HN must be included in the differential diagnosis of nephrotic range proteinuria in hypertensive patients. The absence of oedema and normal serum albumin are distinctive clinical characteristics that can help in decision-making before performing a renal biopsy., (Copyright © 2013 Elsevier España, S.L.U. All rights reserved.)

Significance: The kidney helps to maintain low blood pressure in the human body, and impaired kidney function is a common attribute of aging that is often associated with high blood pressure (hypertension). Kidney-related pathologies are important contributors (either directly or indirectly) to overall human mortality. In comparison with other organs, kidney has an unusually wide range of oxidative status, ranging from the well-perfused cortex to near-anoxic medulla., Recent Advances: Oxidative stress has been implicated in many kidney pathologies, especially chronic kidney disease, and there is considerable research interest in oxidative stress biomarkers for earlier prediction of disease onset. Proteomics approaches have been taken to study of human kidney tissue, serum/plasma, urine, and animal models of hypertension., Critical Issues: Redox proteomics, in which oxidative post-translational modifications can be identified in protein targets of oxidative or nitrosative stress, has not been very extensively pursued in this set of pathologies., Future Directions: Proteomics studies of kidney and related tissues have relevance to chronic kidney disease, and redox proteomics, in particular, represents an under-exploited toolkit for identification of novel biomarkers in this commonly occurring pathology.

Aim: Spot urine measurement of albumin is now the most commonly accepted approach to screening for proteinuria. Exertion prior to the collection may potentially influence the result of spot urine albumin estimation. We aim to evaluate the effect of exercise on albuminuria in subjects at various stages of diabetic nephropathy in comparison with healthy control volunteers., Methods: Thirty-five people with diabetes (19 with normoalbuminuria (NA), nine with microalbuminuria (MA) and seven with overt proteinuria (OP)) and nine control subjects were assessed. A 1 km treadmill walk was performed. Four spot urine specimens were collected: first morning void, immediately prior to exercise, and 1 h and 2 h after exercise. A random effects linear regression mixed model was used to assess the effect of exercise on albumin/creatinine ratio (uACR). Results are presented separately for male and female subjects with diabetes due to a significant exercise/gender interaction (P < 0.05)., Results: No significant effect of exercise on uACR was seen in control subjects. In NA males with diabetes no effect of exercise was seen, while in females uACR 1 h after exercise was significantly higher than the early morning sample (3.55 mg/mmol (96% confidence interval 0.27-6.83). Both female and male diabetes subjects with MA have increase in uACR 1 h after exercise (87.8, -24.3-199.4 and 6.7, 2.1-11.3). For both males and females with OP, uACR was significantly increased 1 h post exercise (67.5, 22-113 and 21.6, 8.4-34.8, respectively). In all groups uACR at 2 h after exercise was not significantly different to the early morning sample., Conclusions: Exercise increased uACR estimation in normoalbuminuric subjects with diabetes with a larger effect in females. Whether exercise unmasks early diabetic nephropathy in NA subjects requires further study., (© 2011 The Authors. Nephrology © 2011 Asian Pacific Society of Nephrology.)

Objective: The intrarenal renin-angiotensin system (RAS) activation plays a pivotal role in immunoglobulin A nephropathy (IgAN) pathogenesis, which is still largely undefined. Recently, vasopressin (AVP) has been advocated to contribute to the genesis and progression of chronic kidney diseases (CKD) directly, and indirectly, via RAS activation. Our aim is to explore the intrarenal activity of AVP, its relationship with RAS activity, as well as its modulation by therapies in IgAN., Design: In this observational study, we measured plasma copeptin, a surrogate marker of AVP, the urine excretion of aquaporin 2 (AQP2), a protein reflecting renal AVP action, and angiotensinogen (AGT), a parameter of renal RAS activation, and their relationship with renal function in 44 IgAN patients at the time of renal biopsy, without any drug therapy, and after 6-month treatment with ACEi or steroid+ACEi. Twenty-one patients with other CKD and 40 healthy subjects were recruited as controls., Methods: ELISAs were used to measure all variables of interest., Results: At baseline, IgAN patients showed higher urinary levels of AQP2, compared with controls and patients with other CKD. Urinary AQP2 and AGT levels strongly correlated with the presence of arterial hypertension. Steroids+ACEi caused the decrease of all the variables examined. The fall of urinary AQP2 and AGT following drug treatments was associated with the decrease of daily proteinuria., Conclusion: Our findings would support the involvement of AVP-AQP2 axis, interacting with the RAS, in the progression of IgAN and candidate AQP2 as a possible novel marker of the disease.

Background: Few studies have examined the association between obesity and markers of kidney injury in a chronic kidney disease population. We hypothesized that obesity is independently associated with proteinuria, a marker of chronic kidney disease progression., Study Design: Observational cross-sectional analysis., Setting & Participants: Post hoc analysis of baseline data for 652 participants in the African American Study of Kidney Disease (AASK)., Predictors: Obesity, determined using body mass index (BMI)., Measurements & Outcomes: Urine total protein-creatinine ratio and albumin-creatinine ratio measured in 24-hour urine collections., Results: AASK participants had a mean age of 60.2 ± 10.2 years and serum creatinine level of 2.3 ± 1.5 mg/dL; 61.3% were men. Mean BMI was 31.4 ± 7.0 kg/m(2). Approximately 70% of participants had a daily urine total protein excretion rate <300 mg/d. In linear regression analyses adjusted for sex, each 2-kg/m(2) increase in BMI was associated with a 6.7% (95% CI, 3.2-10.4) and 9.4% (95% CI, 4.9-14.1) increase in urine total protein-creatinine and urine albumin-creatinine ratios, respectively. In multivariable models adjusting for age, sex, systolic blood pressure, serum glucose level, uric acid level, and creatinine level, each 2-kg/m(2) increase in BMI was associated with a 3.5% (95% CI, 0.4-6.7) and 5.6% (95% CI, 1.5-9.9) increase in proteinuria and albuminuria, respectively. The interaction between older age and BMI was statistically significant, indicating that this relationship was driven by younger AASK participants., Limitations: May not generalize to other populations; cross-sectional analysis precludes statements regarding causality., Conclusions: BMI is associated independently with urine total protein and albumin excretion in African Americans with hypertensive nephrosclerosis, particularly in younger patients., (Copyright © 2010 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Dietary sodium intake is associated with blood pressure and hypertension risk. However, most of the studies have been conducted in whites and it is not clear whether the effects exist in Asian populations., Objective: The purpose of the present study was to investigate the role of 24-h urinary sodium excretion and hypertension risk among ethnic Chinese., Design: A prospective cohort design on community., Setting and Participants: One thousand five hundred and twenty middle-aged and elderly participants who were free from hypertension at baseline and had available urine electrolyte data., Main Outcome Measures: Hypertension incidence., Results: During a median 7.93 years of follow-up (interquartile range = 4.07-9.04 years), we documented 669 cases of incident hypertension. The multivariate risk was 1.26 (95% confidence interval = 1.01-1.57; P = 0.043) for individuals in the highest quartile of urinary sodium excretion as compared with those in the second quartile. A significant J-shape relationship between urinary sodium excretion and the risk of hypertension was observed, with the test for linear relation being rejected (P = 0.046). Participants who were in the highest quartile of urinary sodium excretion and higher baseline blood pressure had a 2.43-fold increased risk of hypertension (95% confidence interval = 1.72-3.22) compared with those in the lowest quartiles of urinary sodium and lower blood pressure., Conclusion: Urinary sodium excretion was associated with the risk of hypertension among ethnic Chinese. Urinary sodium excretion, as a marker of dietary sodium intake, can be useful for a comprehensive evaluation of hypertension risk in Asian populations.

Blood pressure (BP) follows a circadian rhythm, with 10% to 15% lower values during nighttime than during daytime. The absence of a nocturnal BP decrease (dipping) is associated with target organ damage, but the determinants of dipping are poorly understood. We assessed whether the nighttime BP and the dipping are associated with the circadian pattern of sodium excretion. Ambulatory BP and daytime and nighttime urinary electrolyte excretion were measured simultaneously in 325 individuals of African descent from 73 families. When divided into sex-specific tertiles of day:night ratios of urinary sodium excretion rate, subjects in tertile 1 (with the lowest ratio) were 6.5 years older and had a 9.8-mm Hg higher nighttime systolic BP (SBP) and a 23% lower SBP dipping (expressed in percentage of day value) compared with subjects in tertile 3 (P for trend <0.01). After adjustment for age, the SBP difference across tertiles decreased to 5.4 mm Hg (P=0.002), and the SBP dipping difference decreased to 17% (P=0.05). A similar trend across tertiles was found with diastolic BP. In multivariate analyses, daytime urinary sodium and potassium concentrations were independently associated with nighttime SBP and SBP dipping (P<0.05 for each). These data, based on a large number of subjects, suggest that the capacity to excrete sodium during daytime is a significant determinant of nocturnal BP and dipping. This observation may help us to understand the pathophysiology and clinical consequences of nighttime BP and to develop therapeutic strategies to normalize the dipping profile in hypertensive patients.

Objective: Evaluate the value of random urinary protein-creatinine (PrCr) and calcium-creatinine (CaCr) ratios to predict 24-h proteinuria in hypertensive pregnancies., Study Design: Spot urine samples were collected before routine 24-h urine collections from consecutive pregnant women with hypertension (n=83). Reliability of spot urinary PrCr and CaCr to detect significant proteinuria (>or=300 mg/day) using 24-h urine protein as 'gold-standard' was assessed by receiver-operating characteristic (ROC) curve., Results: Fifty-one patients (61.4%) had significant proteinuria (45 pre-eclampsia, 5 superimposed pre-eclampsia, 1 renal hypertension). Area under ROC curve to predict proteinuria was 0.82 (95% confidence interval (CI) 0.73 to 0.92, P<0.001) for PrCr and 0.55 (95% CI 0.43 to 0.68, P=0.2) for CaCr. A cutoff value of >0.19 for PrCr best predicted significant proteinuria with sensitivity, specificity, positive and negative predictive values and likelihood ratios (positive and negative), respectively, of 80.4, 68.8, 80.4, 68.8%, 2.57 and 3.51., Conclusion: Spot urinary PrCr predicts total urinary protein excretion in hypertensive pregnancies.

Background: Systemic hypertension is an important problem in older cats associated with kidney disease and hypokalaemia, suggesting that excessive activity of the renin-angiotensin-aldosterone system might contribute to the hypertensive state. Fluctuations in plasma renin activity and plasma aldosterone concentrations complicate the interpretation of these assays., Objectives: The aim of this study was to determine whether measurement of urinary aldosterone excretion in cats aided the investigation of hypertension., Methods: Urine concentrations of free (ethyl acetate extract) and 18-glucuronidated aldosterone (acid hydrolysis before extraction) were measured by radioimmunoassay in normal, normotensive and hypertensive azotaemic cats (n=11 per group). Urine samples from 11 healthy human volunteers and eight normal dogs were also analysed for comparison. Urinary aldosterone concentration was corrected for the urinary creatinine concentration., Results: Cats excreted 7.3 times less free aldosterone than human beings, and no free aldosterone was detected in dog urine. Acid hydrolysis led to large increases in aldosterone recovery from both human beings and dog but not feline urine. No significant effect of hypertension or azotaemia on feline urinary aldosterone concentration was found., Clinical Significance: Measurement of aldosterone in feline urine using the available methodology has limited or no utility in investigating feline hypertension.

Background: The relationship between the progress of tubular damage and renal insufficiency in autosomal-dominant polycystic kidney disease (ADPKD) is a subject of doubtless interest, and is the object of this present work., Methods: A total of 92 adult ADPKD patients of both genders were studied, none of which presented end-stage renal disease (ESRD), and classified according to an ultrasound score based on kidney size and number of cysts. Urinary albumin and beta-N-acetylhexosaminidase (Hex) and its isoenzymes were determined, together with serum glutathione peroxidase, cystatin C, creatinine, and urea., Results: A frequent elevation of the urinary Hex was found and an alteration of its isoenzymatic profile, with 31% of the normotensive patients with normoalbuminuria already presenting an increased proportion of Hex B isoenzyme. Keeping age constant, a partial significant correlation was found between the ultrasound score and the proportion of Hex B (r = 0.352, P < 0.05), but not with albuminuria or cystatin C. In 42 patients the different biochemical variables were again determined after 1 year, finding that in the 13 normotensive patients with normoalbuminuria there had been a significant decrease in the concentration of cystatin C (P < 0.05), and a significant increase in the urinary excretion of albumin and Hex B isoenzyme (P < 0.05). By the other hand, in the other 29 patients with micro- or macroalbuminuria and hypertension, no significant differences were found., Conclusion: The results point toward an important participation of tubular damage in the pathogenesis of this disease. It may also be suggested that in normotensive and normoalbuminuric ADPKD patients, a gradual increase of glomerular filtration would be produced. After the start of hypertension and microalbuminuria, the glomerular filtration rate (GFR) would decrease progressively, although more slowly.

Background: Aldosterone has essential roles in regulating intravascular volume and blood pressure, and is suggested to influence cardiac structure. However, the association of polymorphisms in the aldosterone synthase gene (CYP11B2) with hypertension or cardiac hypertrophy remains controversial., Objective: To evaluate the distribution of polymorphisms in the CYP11B2 gene and the possible associations between genotypes and blood pressure, urinary excretion of aldosterone or electrolytes and echocardiographic measurements, in a Japanese population., Methods and Results: We examined the association of two common diallelic polymorphisms within CYP11B2, one in the promoter -344T/C and the other an intron 2 gene conversion, with blood pressure, 24-h urinary excretion of aldosterone and electrolytes, and echocardiographic measurements, in a Japanese population. We confirmed significant linkage disequilibrium between these polymorphic loci and ethnic differences in frequency of the alleles. The -344C and -344T haplotypes apparently diverged before the intron conversion polymorphism was generated on the latter haplotype. Allele frequencies did not differ between 535 normotensive and 360 hypertensive individuals or between hypertensive individuals with higher and lower concentrations of renin. The only significant correlation was a positive correlation of left ventricular mass with 24-h urinary excretion of sodium, which occurred only in individuals with the -344CC genotype or the intron 2 conversion (-/-) genotype., Conclusions: The -344CC or intron 2 conversion (-/-) genotype in CYP11B2 may be a risk factor for developing sodium-sensitive cardiac hypertrophy. Ethnic differences in the distribution of CYP11B2 genotypes combined with differences in salt intake might account for inconsistencies between previous reports.

Objective: This study was performed to test the significance of urinary angiotensinogen (UAGT) in essential hypertensive patients stratified as a function of plasma renin and aldosterone., Methods and Results: A sample of 248 essential hypertensives, investigated under their usual sodium diet and either off-medication or under a standardized treatment, was separated into two groups on the basis of upright plasma active renin and aldosterone medians. Patients with plasma active renin and aldosterone below medians are referred to as the low renin-aldosterone essential hypertensive group (LRA-EH). Others subjects are defined as other essential hypertensives (O-EH). Blood pressure (BP) was recorded by 24-h ambulatory monitoring. UAGT was measured by a specific enzyme-linked immunosorbent assay for total angiotensinogen. Because UAGT was markedly increased in the presence of overt proteinuria (>/= 300 mg/24 h), proteinuric patients (n = 29) were excluded from subsequent analyses. UAGT was a significant predictor of systolic and diastolic BP in LRA-EH females (P < 0.01 and P = 0.05, respectively) but not in males. By contrast, urinary sodium excretion (P < 0.001) and maintenance of treatment (P = 0.002) were significant predictors of systolic BP in males. These correlations were not observed in O-EH, whether males or females., Conclusions: In the present study, UAGT stands as a strong predictor of BP in women with low plasma renin/aldosterone, suggesting an involvement of the tubular renin-angiotensin system in these subjects. Higher sodium intake or the need to maintain treatment may account in part for the lack of a similar relationship in males.

To investigate the faster rate of renal disease progression in men compared with women, we addressed the following questions in the renal wrap (RW) model of hypertension: 1) Do sex differences exist in RW-induced renal injury, which are independent of sex differences in blood pressure? 2) Do sex differences in nitric oxide (NO) production exist in RW hypertension? Male (M) and female (F) rats underwent sham-operated (M-Sham, n = 7; F-Sham, n = 10) or RW (M-RW, n = 13; F-RW, n = 14) surgery for 9 wk. Markers of renal injury, including the glomerulosclerosis index (F-RW, 0.70 +/- 0.1 vs. M-RW, 2.2 +/- 0.6; P < 0.05), mean glomerular volume (F-RW, 1.05 +/- 0.050 x 10(6) vs. M-RW, 1.78 +/- 0.15 x 10(6) microm(3); P < 0.001), and proteinuria (F-RW, 68.7 +/- 15 vs. M-RW, 124 +/- 7.7 mg/day; P < 0.001) were greater in RW males compared with RW females. Endothelial NO synthase protein expression was elevated in the renal cortex (3.2-fold) and medulla (2.2-fold) 9 wk after RW in males, whereas no differences were observed in females. Neuronal NO synthase protein expression was unchanged in the renal cortex in males and in both the renal cortex and medulla in females, whereas in the male medulla, neuronal NOS was decreased by 57%. These data suggest the degree of renal injury is greater in male compared with female rats in RW hypertension despite similar degrees of hypertension and renal function and may involve sex differences in renal NO metabolism.

Background: Australian Aborigines in remote areas are experiencing an epidemic of renal disease, type 2 diabetes, hypertension, and cardiovascular disease. Adult deaths are increased 3- to 6-fold, and renal failure more than 20-fold. Renal disease is marked by albuminuria. We describe its distributions and correlations in two remote communities in the Northern Territory., Methods: Observations in Community 1 included a screen of 939 adult participants (18+ years, 90% recruitment), a treatment program, and 8 to 11 years of follow-up. In Community 2, a screen of 259 people, or 60% of adults, included HbA1c, homocysteine, C-reactive protein (CRP), CMV serology, and carotid intimal media thickness (CIMT). Albumin/creatinine ratio (ACR) was measured by immunoassay in g/mol on random urine, with microalbuminuria defined as 3.4 to 33, and overt albuminuria as ACR 34+., Results: Dipstick urine protein trace+ correctly classified 76% of people with ACR 3.4+, and dipstick protein 1+ correctly classified 82% of people with ACR 34+. ACR was stable to glucose loading and water diuresis in subsets of people in Community 1. ACR levels rose steeply with age. Rates of micro- and overt albuminuria in Community 1 were 28% and 21%, and in Community B were 31% and 13%. ACR correlated inversely with estimated glomerular filtration rate (GFR). ACR also correlated directly with weight, blood pressure, cholesterol, triglycerides, random glucose, HbA1c, homocysteine, and GGT levels, and inversely with HDL cholesterol. ACR correlated with skin sores, scabies, high titer antibodies to Helicobacter pylori, high-titer CMV antibodies, with CRP over a greatly elevated range and, inversely, with birth weight. Finally, ACR correlated with CIMT. Baseline ACR predicted loss of GFR over time. ACR 3.4+ predicted all-cause and cardiovascular hospitalization, while ACR 34+ predicted all renal failure developing over 11 years and all-cause natural deaths and cardiovascular disease deaths. ACEi treatment for people with ACR 34+ reduced renal failure and natural deaths, but the hierarchical effect of higher ACRs within that group for renal and nonrenal deaths was maintained., Conclusion: Random urine ACR is a stable and robust marker of renal disease, which is multideterminant. A broad base of shared risk factors probably explains the simultaneous emergence of the excessive renal and nonrenal chronic disease morbidities from which these populations suffer. Thus, albuminuria is a unifying marker for the harmful effects of the spectrum of chronic disease, and perhaps beyond. Dipstick urine protein is a useful surrogate for ACR when resources are constrained and disease burdens high.

Objective: To investigate whether endothelin and aldosterone participate in the increased prevalence and severity of nephrosclerosis in human low-renin hypertension, analogous to observations in experimental hypertension., Design: Comparison of endothelin, aldosterone and their relationships with proteinuria, in hypertensive patients with high aldosterone : renin ratios (HARR group, n = 14) or normal aldosterone : renin ratios (NARR group, n = 15)., Methods: Urine protein and radioimmunoassay measurements of plasma renin activity, endothelin and aldosterone were carried out in individuals taking their usual diet, and after salt loading and salt depletion., Results: Compared with the NARR group, patients in the HARR group had higher blood pressure, greater salt sensitivity of their blood pressure, significantly greater urine protein and lower serum potassium concentrations, lower renin activities [0.14 +/- 0.03 ng AngiotensinI (AI)/l per s compared with 0.76 +/- 0.16 ng AI/l per s; P < 0.005], blunted renin-aldosterone responses to salt loading and salt depletion, enhanced catecholamine responses to salt depletion, and increased plasma endothelin (5.1 +/- 0.5 fmol/ml compared with 3.7 +/- 0.3 fmol/ml; P < 0.03). In the HARR group, endothelin and aldosterone concentrations were highly correlated, and both correlated with blood pressure and urine protein. In contrast, in the NARR group, endothelin and aldosterone did not correlate between them or with blood pressure, and only endothelin, not aldosterone, correlated with urine protein. Multivariate regression confirmed that the interaction between aldosterone and endothelin was the major predictor of urine protein in the HARR group (r = 0.442), whereas endothelin, renin and their interaction were predictors in the NARR group (r = 0.467)., Conclusions: Our results concur with experimental evidence for participation of endothelin in renal damage of angiotensin-dependent hypertension and for that of an endothelin-aldosterone interaction in low-renin hypertension. We propose that combined pharmacological antagonism of endothelin and aldosterone may confer renal protection beyond blood pressure reduction in patients with low-renin hypertension, a population at high risk for hypertensive nephrosclerosis.

Objectives: Hypertensive disorders in pregnancy are one of the major mortality risk factors for mother and fetus. Although pathomechanisms of hypertension are extreme complex, the involvement of kidneys usually occurs. N-acetyl-beta-D-glucosaminidase (NAG) is a lysosomal enzyme which is located in renal tubular cells. Therefore an elevation of urinary NAG activity serves as a marker of tubular cell damage., Aim: Evaluation of renal tubular damage in pregnant women with different types of hypertension by determination of urinary NAG activity., Material and Methods: The study comprised 84 pregnant women in third trimester, divided according to type of hypertension into 3 subgroups: pregnancy induced hypertension (n = 58), preeclampsia (n = 13) and chronic hypertension (n = 13). The control group comprised 36 healthy pregnant women. Urinary NAG activity was measured in the second morning urine samples by colorimetric method and the results were expressed as NAG/creatinine ratios (NAG/Cr)., Results: The highest NAG/Cr ratios were found in women with preeclampsia (median-1.520 U/mmol) and in women with pregnancy induced hypertension (median-0.874 U/mmol) and both results differed significantly from those in controls (median-0.782 U/mmol). There was slight positive correlation between NAG/Cr ratios and systolic blood pressure (r = 0.225, p < 0.05)., Conclusions: Hypertension in pregnancy may lead to renal tubular damage, however clinical significance of this phenomenon requires further studies.

Objective: To observe the therapeutic effects of valsartan on hypertension secondary to chronic renal diseases., Methods: Sixty-four patients with renal hypertension were examined for plasma K(+), Na(+), Cl(-), 24-hour urine protein, blood urea nitrogen (BUN), serum creatinine (SCr), erythropoietin (EPO) before and 8 weeks after of valsartan therapy., Results: After valsartan therapy for 8 weeks, no significant changes took place in plasma K(+), Na(+), Cl(-), BUN, SCr, EPO, but 24-hour urine protein was significantly reduced., Conclusion: Valsartan significantly reduce 24-hour urine protein without significantly affecting plasma K(+), Na(+), Cl(-), BUN, SCr, and EPO in patients with hypertension secondary to chronic renal diseases.

To assess the roles of polyamines (putrescine, spermidine, and spermine) and ornithine decarboxylase (ODC), the rate-limiting enzyme of polyamine synthesis, in the development of salt-sensitive hypertension, we evaluated activity and expression of ODC, urinary polyamine excretion, and antizyme (endogenous ODC inhibitor protein) expression in Dahl salt-sensitive (SS) and salt-resistant (SR) rats after they were fed on a low (0.3%) or high (4%) salt diet for 4 weeks. We also examined the effects of spermidine and difluoromethylornithine (DFMO: a specific inhibitor of ODC) on the systolic blood pressure and ODC protein expression in SS rats fed a high salt diet. Renal ODC activity and urinary polyamine excretion in SS rats were lower than those in SR rats after 4 weeks treatment with a low or high salt diet. The renal ODC protein expression of SS rats was paradoxically increased as compared to the SR group. A high salt diet did not alter ODC activity but increased ODC protein only in SS rats. ODC mRNA and antizyme protein expressions were not significantly different among the four groups. Spermidine supplementation attenuated and DFMO exaggerated hypertension in SS rats fed a high salt diet. Spermidine down-regulated and DFMO up-regulated renal ODC protein in SS rats on a high salt diet. ODC activity was decreased but protein was paradoxically increased in kidneys of SS rats. ODC protein was suggested to increase in compensation for the inhibition of its activity. Impaired ODC activity and polyamine production in the kidney may exaggerate salt-sensitive hypertension in SS rats.

Information regarding daily intake of sodium (Na) is useful for both normotensive and hypertensive subjects. We measured urinary excretion of sodium (U-Na) and urinary excretion of potassium (U-K) to estimate daily salt intake in a cohort of health screening subjects in Okinawa, Japan. Urine samples were obtained from 2,411 subjects (1,554 men and 857 women) who were examined on a half-day dry-doc at the Okinawa General Health Maintenance Association (OGHMA). Four hundred and one subjects were examined twice, once between September and November in 1997, and once between September and November in 1998. The mean U-Na was 182 mEq/day for men and 176 mEq/day for women. The mean U-K was 54 mEq/day for men and 50 mEq/day for women. U-Na was higher in young men, and U-K was lower in young women. In both men and women, smokers had a significantly lower Na excretion compared to nonsmokers. Subjects treated for hypertension had a significantly lower Na excretion (173 mEq/day) compared to subjects not treated for hypertension (192 mEq/day). Our findings suggest that Na excretion in screened subjects in Okinawa is lower than the national average. Sodium excretion, however, was higher in young men than in elderly subjects, and K excretion was lower in young women than in elderly subjects. Both trends are disadvantageous for controlling hypertension.

Inhibition of the angiotensin-converting enzyme (ACE) exerts a renoprotective effect in adult patients with chronic kidney disease. We evaluated prospectively changes in blood pressure (BP), protein excretion and renal function after administration of the long-acting ACE inhibitor ramipril as monotherapy during 6 months in 14 moderately hypertensive children aged 5-18 years with various nephropathies. Four patients initially had a decreased glomerular filtration rate (GFR below 60 ml/min/1.73 m2). BP was evaluated by ambulatory 24-h monitoring. After 2 weeks of treatment by oral ramipril (1.5 mg/m2 once daily), mean values of systolic and diastolic 24-h ambulatory BP fell by more than 5 mmHg in nine patients. In eight patients the dose was doubled. At the end of the study systolic BP was below the 95th percentile in 9 and diastolic BP in 13 patients. The initially reduced nocturnal dip increased significantly. Of 11 patients with an increased albumin excretion (median 1.3 g/g creatinine), 6 responded to ramipril by a median reduction of 78% (range 24-83%), whilst in 5 albuminuria increased (median +19%). GFR was well preserved and no other adverse effects from the drug were noted. The study demonstrates that ramipril is an efficacious antihypertensive agent in children with renal hypertension. It is well tolerated, even in mild renal insufficiency. In addition, the drug has a persistent antiproteinuric action in about half of the patients contributing to conserve renal function.

Background: Microalbuminuria is a risk factor for cardiovascular disease, but the underlying pathomechanisms are still poorly understood. A relationship between C-reactive protein (CRP), a sensitive marker of inflammation, and atherosclerotic disease has been reported recently., Methods: We hypothesized that microalbuminuria might be associated with chronic inflammation and investigated the relationship of urinary albumin excretion, as assessed from the albumin-to-creatinine ratio (ACR), in an untimed morning urine specimen, and two inflammatory markers (CRP and fibrinogen) in the large, triethnic population of the Insulin Resistance Atherosclerosis Study (IRAS). After exclusion of subjects with macroalbuminuria, 1481 subjects were studied., Results: Both inflammatory markers were related to urinary ACR (r = 0.17 for CRP and r = 0.14 for fibrinogen, both P = 0.0001), an association that remained significant after adjustment for demographic variables, diabetic status, smoking, and use of angiotensin-converting enzyme inhibitors (P < 0.01). Mean levels of CRP and fibrinogen were elevated in microalbuminuric (N = 262) versus normoalbuminuric (N = 1219) subjects (5.37 +/- 0.47 vs. 3.80 +/- 0.15 mg/L and 295.7 +/- 4. 0 vs. 278.2 +/- 1.6 mg/dL, both P < 0.0001). The associations were consistent among nondiabetic and type 2 diabetic subjects and among the three ethnic groups of the IRAS (non-Hispanic whites, blacks, Hispanics). In a logistic regression model, fibrinogen was independently associated with microalbuminuria (P = 0.047), along with hypertension, female gender, waist circumference, and fasting blood glucose, while CRP was not independently related to microalbuminuria in this model (P = 0.26)., Conclusion: We have shown an association of CRP and fibrinogen with urinary albumin excretion in the microalbuminuric range in type 2 diabetic and nondiabetic individuals. Chronic inflammation therefore emerges as a potential mediator between microalbuminuria and macrovascular disease.

Background: In non-insulin-dependent diabetes mellitus (NIDDM), there is a clustering of an elevated urinary albumin excretion rate (U-AER) in nondiabetic relatives of albuminuric patients. Whether this is also the case in insulin-dependent diabetes mellitus (IDDM) is unknown., Methods: Overnight U-AER was measured in 186 nondiabetic first-degree relatives of 80 IDDM patients with diabetic nephropathy (U-AER > 200 microg/min or 300 mg/24 hours; DN+) and in 52 relatives of 25 IDDM patients without nephropathy (U-AER < 20 microg/min; DN-). The two groups of relatives were comparable regarding gender distribution, age, obesity, blood pressure, prevalence of antihypertensive therapy, and smoking habits., Results: No difference was found in overnight U-AER between relatives of patients with DN+ and DN- [median (range), 3.4 (0.1 to 372) vs. 4.0 (0.2 to 62) microg/min, respectively, P = NS]. The proportion of relatives with a U-AER = 10 microg/min was 12% in DN+ compared with 8% in DN- (P = NS). Among relatives of DN+, those with antihypertensive treatment (AHT+) had higher U-AER compared with those without [AHT+ vs. AHT-, 5.0 (0.5 to 372) vs. 3.4 (0.1 to 26.5) microg/min, P < 0.01], a phenomenon that was not seen among relatives of DN-[AHT + vs. AHT-, 3.6 (2.1 to 24.3) vs. 4.0 (0. 2 to 61.5) microg/min, P = NS]. However, this analysis was impaired by the small number of relatives of DN- with hypertension (N = 7)., Conclusions: In IDDM, we found no clustering of elevated U-AER in nondiabetic relatives of patients with nephropathy. This is different from what has been reported in NIDDM, and suggests heterogeneity in the genesis of albuminuria in diabetes.

Animal experiments have shown an increase in prepro-endothelin-1 (prepro-ET-1) mRNA expression in the clipped kidney but none in the aortic and mesenteric arteries in 2-kidney, 1-clip Goldblatt hypertensive rats. The present study was aimed at investigating whether plasma and renal endothelin-1 (ET-1) systems are differently activated in patients with renovascular hypertension (RH). The plasma concentration and urinary excretion of ET-1 were measured in 5 patients with RH (before and after successful renal angioplasty), in 7 patients with essential hypertension (EH), and in 8 normotensive control subjects. Immediately before renal angioplasty, plasma samples for ET-1 and plasma renin activity (PRA) measurements were withdrawn from the aorta and both renal veins. Unlike the PRA, the plasma ET-1 concentration did not significantly differ between the involved and the uninvolved sides. The urinary ET-1 excretion level (Fig 1) was markedly increased in patients with RH (30+/-4 ng/g urinary creatinine (UC) vs. 2.5+/-0.2 ng/g UC and 2.6+/-0.5 ng/g UC in control subjects and patients with EH, respectively; P<.001), whereas the plasma ET-1 concentration was normal (0.8+/-0.2 pg/mL vs. 0.65+/-0.3 pg/mL and 0.8+/-0.2 pg/mL in control subjects and EH, respectively, not significant). Renal angioplasty was followed in all patients by normalization of blood pressure and PRA. One week after angioplasty, urinary ET-1 decreased to one fourth of baseline (8.04+/-5.23 ng/g UC, P<.001 vs. values before angioplasty and P<.04 vs. control subjects) and normalized 1 month thereafter (3.13+/-1.62 ng/g UC, not significant vs. control subjects), whereas plasma ET-1 remained steady. The present findings clearly indicate that in patients with RH, urinary ET-1 excretion is increased, whereas plasma ET-1 concentration remains normal. Successful percutaneous transluminal renal angioplasty induced a notable reduction in ET-1 urinary excretion, whereas it did not affect ET-1 plasma concentration.

Aims/hypothesis: Results from animal models of glomerular hypertension have suggested that this disorder is one cause of albuminuria in diabetic nephropathy. We evaluated this hypothesis clinically., Methods: The subjects were 20 patients with Type II (non-insulin-dependent) diabetes mellitus but without uraemia or hypertension: 8 had normoalbuminuria and 12 had albuminuria (> or = 20 micrograms/min). In the 2-week study, patients were on a diet with ordinary amounts of sodium for 1 week and on a sodium-restricted diet for 1 week. Urinary excretion of sodium and albumin and the systemic blood pressure were measured daily. Intrarenal haemodynamics, in terms of the glomerular pressure and resistance of afferent and efferent arterioles, were calculated from renal clearance, the plasma total protein concentration, and the pressure-natriuresis relation. In 8 of the 12 patients with albuminuria, an angiotensin-converting enzyme inhibitor, cilazapril, was given orally (2 mg/day) and the 2-week study was repeated., Results: In patients with albuminuria, resistance of efferent arterioles and the glomerular pressure were higher than in patients with normoalbuminuria (glomerular pressure, 53 +/- 5 vs 43 +/- 5 mmHg, means +/- SD, p < 0.001). Urinary excretion of albumin correlated (n = 20, r = 0.675, p < 0.001) with the glomerular pressure but not with systemic pressure. The increased glomerular pressure and the albuminuria were decreased by cilazapril but systemic pressure was not., Conclusions/interpretation: These findings are consistent with the hypothesis that glomerular hypertension is present in Type II diabetic patients with early nephropathy and can cause albuminuria.

Linkage studies in the fawn-hooded hypertensive rat have suggested that genes influencing susceptibility to hypertension-associated renal failure may exist on rat chromosome 1q. To investigate this possibility in a widely used model of hypertension, the spontaneously hypertensive rat (SHR), we compared susceptibility to hypertension-induced renal damage between an SHR progenitor strain and an SHR congenic strain that is genetically identical except for a defined region of chromosome 1q. Backcross breeding with selection for the markers D1Mit3 and Igf2 on chromosome 1 was used to create the congenic strain (designated SHR.BN-D1Mit3/Igf2) that carries a 22 cM segment of chromosome 1 transferred from the normotensive Brown Norway rat onto the SHR background. Systolic blood pressure (by radiotelemetry) and urine protein excretion were measured in the SHR progenitor and congenic strains before and after the induction of accelerated hypertension by administration of DOCA-salt. At the same level of DOCA-salt hypertension, the SHR.BN-D1Mit3/Igf2 congenic strain showed significantly greater proteinuria and histologically assessed renal vascular and glomerular injury than the SHR progenitor strain. These findings demonstrate that a gene or genes that influence susceptibility to hypertension-induced renal damage have been trapped in the differential chromosome segment of the SHR.BN-D1Mit3/Igf2 congenic strain. This congenic strain represents an important new model for the fine mapping of gene(s) on chromosome 1 that affect susceptibility to hypertension-induced renal injury in the rat.

Recent studies with normal rats indicated that systemic administration of the angiotensin II (AngII) type 1 (AT1) receptor blocker candesartan elicited divergent renal hemodynamic and excretory responses depending on the magnitude of associated decreases in mean arterial pressure. To evaluate the responses to candesartan in hypertensive rats, experiments were performed 25 d after unilateral renal arterial constriction with a 0.25-mm clip. The rats were anesthetized and prepared for acute clearance experiments. Control arterial pressure responses to a bolus AngII dose (50 ng) averaged 35+/-7 mmHg; the control decreases in cortical renal blood flow (RBF), measured with laser Doppler flowmetry, were 58+/-9%. The vasoconstrictor responses to AngII were abolished by candesartan doses of 1 and 0.1 mg/kg. Treatment with 0.01 mg/kg candesartan attenuated the arterial pressure responses but did not prevent the cortical RBF decreases. The highest dose of candesartan (1 mg/kg) elicited rapid reductions in arterial pressure (from 154+/-5 to 122+/-9 mmHg), leading to associated decreases in RBF (from 5.5+/-0.2 to 4.6+/-0.4 ml/min x g) and sodium excretion (from 0.4+/-0.1 to 0.2+/-0.1 microEq/min x g). The 0.1 mg/kg dose of candesartan led to gradual reductions in arterial pressure (from 155+/-5 to 140+/-5 mmHg), and there were significant increases in RBF (from 5.4+/-0.2 to 6.8+/-0.4 ml/min x g) and decreases in renal vascular resistance. However, this dose still decreased urine flow and sodium excretion. In contrast, when candesartan was administered at 0.01 mg/kg, a dose that did not significantly decrease arterial pressure, there were significant increases in RBF (26+/-11%) and urine flow (43+/-19%) and proportionately greater increases in sodium excretion (284+/-89%) and fractional sodium excretion (351+/-99%). These data demonstrate the divergent renal hemodynamic and sodium excretory responses to AT1 receptor blockade in hypertensive rats, depending on the magnitude of decreases in arterial pressure. The lower candesartan dose, which did not cause hypotension, elicited substantial increases in RBF and proportionally much greater increases in sodium excretion, revealing the direct renal vasodilation and natriuretic effects of AT1 receptor blockade.

Aim: To investigate clinicomorphological relationships between elevated urinary excretion of fibronectin (FN) and development of fibrosis in the kidney in patients with lupus nephritis (LN) and chronic glomerulonephritis (CGN)., Materials and Methods: Urinary FN excretion was measured at radial immunodiffusion in 54 LN patients. Of them, 15 patients had inactive LN, 39 patients had active LN varying in clinical forms. Urinary FN was also measured by passive hemagglutination in 36 CGN patients (11 inactive CGN and 25 active CGN cases). Biopsy specimens were obtained from 49 patients with active nephritis (43 with CGN and 6 with LN). FN deposits were studied immunohistochemically and morphometrically with determination of relative fibrosis area., Results: Urinary FN excretion in patients with nephritis was higher than in healthy controls. In active CGN and LN the levels of FN were significantly higher than in inactive CGN and LN. The highest FN urinary concentrations were registered in patients with severe CGN and LN, especially in the presence of renal failure and arterial hypertension. Among them, the highest individual values were observed in patients with rapidly progressive nephritis. No positive correlations were found between the degree of the urinary FN excretion increment and degree of proteinuria. This suggests local-renal origin of most urinary FN. Morphologically, FN deposits were revealed in 73% of the biopsies. In most of the patients with severe nephritis both in CGN and LN there was a diffuse distribution of FN in the glomerules and interstitium. A correlation with a morphological nephritis type was absent, but existed between FN presence in the renal biopsies and relative area of interstitium (fibrosis)., Conclusion: FN excreted in high amounts with urine in nephritis originates from the kidneys and reflects severity of fibrogenesis in the kidney.

Microalbuminuria (MA) is present in hypertensive autosomal-dominant polycystic kidney disease (ADPKD) patients, but has not been reported in normotensive ADPKD patients. We examined the prevalence of MA and the effect of different determinants on urinary albumin excretion in a group of 42 normotensive ADPKD patients. Metabolic parameters, plasma renin activity and aldosterone and serum angiotensin-converting enzyme (ACE) activity were determined. A 24-h urine sample two or three times over a 6-month period was collected to evaluate MA. Each patient underwent an echocardiography to measure left ventricular mass. Eight patients (19%) showed MA (61.6 mg/day, range 37-164), whereas 34 patients (81%) were normoalbuminuric (8.8 mg/day, range 2-29). The groups were matched for all possible confounding variables, but microalbuminuric patients showed a tendency towards greater systolic blood pressure, plasma renin activity and left ventricular mass. There was no correlation between MA and age, sex, body mass index, systolic or diastolic blood pressure, plasma renin activity, serum ACE levels or left ventricular index. The present study demonstrates a high prevalence of MA in normotensive ADPKD patients. MA may be a predictor of early renal and vascular damage in these patients.

Background: Microalbuminuria (MA) is a strong predictor of cardiovascular disease, but its causes are incompletely understood. Hyperhomocysteinemia is a recently recognized risk factor for cardiovascular disease independent of established risk factors. It is not known whether hyperhomocysteinemia is associated with MA, and thus could be a possible cause of microalbuminuria., Methods: We studied an age-, sex- and glucose-tolerance-stratified random sample of a 50- to 75-year old general Caucasian population (N = 680). The urinary albumin-to-creatinine ratio (ACR) was measured in an early morning spot urine sample. MA was defined as an ACR > 3.0 mg/mmol., Results: The prevalence of MA was 4.3% (13 of 304) in subjects with normal glucose tolerance, 9.2% (17 of 185) in impaired glucose tolerance and 18.3% (30 of 164) in non-insulin-dependent diabetes mellitus (NIDDM); it was 3.7% (15 of 402) in subjects without hypertension and 17.9% (45 of 251) in those with hypertension. After adjusting for age, sex, glucose tolerance category, hypertension, dyslipidemia and smoking, the odds ratio [OR; 95% confidence interval (95%CI)] for MA per 5 mumol/liter total homocysteine increment was 1.33 (1.08 to 1.63). Additional adjustment for HbA1c, waist-hip ratio, protein intake and serum creatinine did not attenuate the association between MA and total homocysteine. A 0.1 g/kg.day increment of protein intake was also associated with an increased risk for MA after adjustment for age, sex, classical risk factors and serum total homocysteine [OR (95% CI); 1.20 (1.08 to 1.32)]., Conclusion: Both hyperhomocysteinemia and protein intake are related to microalbuminuria independent of NIDDM and hypertension. Hyperhomocysteinemia may partly explain the link between MA and increased risk of cardiovascular disease.

We report a hypertensive child with renal artery stenosis who exhibited increased urinary excretion of norepinephrine (NE) and normetanephrine (NMN), while vanillylmandelic acid (VMA) excretion was within the normal range. The NMN values prompted us to investigate the patient for pheochromocytoma; for this purpose, NE was determined by plasma catecholamine assays in venous samples obtained by catheterization. The moderately increased NE levels could not be localized to any particular sampling site. Arteriography demonstrated right renal artery abnormalities. Following right nephrectomy with preservation of the right adrenal gland, arterial blood pressure returned to normal. The cause of increased NMN excretion without a concomitant rise in VMA during hypertension is discussed.

Twentyseven patients admitted for surgery for primary hyperparathyroidism were studied preoperatively. Fifteen were normotensive and 12 were either hypertensive, diastolic blood pressure > 95 mmHg or had a raised serum creatinine measuring 109.7 (55-171) mumol/l. The beta 2 microglobulin (beta 2M) urinary excretion was measured on all patients. The beta 2M levels were raised in all patients preoperatively even in those patients who had normal values for conventional renal function tests. Following curative surgery the values are returned to the normal range. The patients were followed up for a mean of 4.2 (2.8-5.6) years. Six patients who were initially normotensive subsequently developed hypertension and the initial beta 2M ratio was significantly higher 386 (122-680) micrograms/l compared to those who remained normotensive 186 (95-340) micrograms/l (p < 0.05). Even higher preoperative beta 2M excretion was found in the initial hypertensive group 505 (87-1160) micrograms/l compared to those who later developed hypertension 386 (122-680) micrograms/l, p < 0.001. This preliminary study suggests that preoperative beta 2M urinary excretion may be of value in identifying those patients who will subsequently develop hypertension, an identified long term cause of death in patients operated on for primary hyperparathyroidism. Further studies are indicated.

The aim of this study was to determine the most appropriate urine collection for detecting differences in the excretion rates of albumin, gamma glutamyl transpeptidase (GGT) and N-acetyl-beta-D-glucosaminidase (NAGA) between normotensive subjects and hypertensive patients on treatment. Twenty treated hypertensive patients, mean (SEM, standard error of mean) age; 52.2 (6.2) years and 20 normotensive subjects, mean age 49.2 (4.2) years, were studied in a consecutive sampling design. Urinary excretion rates of albumin, GGT and NAGA were determined in consecutive timed urine samples collected overnight and during 3-5 h the next morning. Mean (SEM) overnight excretion rates for albumin, GGT and NAGA for normotensive subjects were 11.05 (1.18) micrograms/min, 17.00 (2.20) mU/min and 6.55 (0.39) mU/min, respectively, which were significantly lower than those of hypertensive subjects which were 20.77 (2.14) micrograms/min, 21.84 (1.65) mU/min and 10.92 (0.87) mU/min, respectively (P < 0.05). The mean (SEM) percentage increases in urinary albumin, GGT and NAGA in morning urine collections of normotensive subjects of 15.22 (3.88)%, 34.04 (6.45)% and 11.54 (3.63)%, respectively were significantly lower than 107.03 (15.04)%, 121.96 (16.71)% and 72.75 (7.50)% found in hypertensive patients (P < 0.05). These data suggest that were urinary albumin and tubular enzyme excretion to be used as correlates of hypertensive renal damage, ambulatory urine collections may be more sensitive than overnight collections.

Renal endothelin-1 (ET-1) production is diminished in spontaneously hypertensive rats. An increase has been reported of renal ET-1 production associated with progression of renal disease in rats with reduced renal mass. The purpose of the present study was to investigate the evolution over time of the urinary ET-1 excretion in an experimental model of renal mass reduction not caused by renal infarction. Rats were subjected to 2/3 nephrectomy (right nephrectomy and resection of the lower left renal pole) and thereafter randomly assigned to a no-treatment control group or to treatment with recombinant erythropoietin, recombinant erythropoietin plus verapamil, or recombinant erythropoietin plus enalapril. The urinary ET-1 excretion was decreased by week 16 after nephrectomy as compared with healthy animals and with the levels 6 weeks after nephrectomy. The temporal evolution of urinary ET-1 excretion in the various groups of rats showed a trend toward decrease in all groups except the one receiving enalapril. The urinary ET-1 excretion correlated directly with creatinine clearance and inversely with tubulointerstitial damage. We observed an inverse correlation between urinary ET-1 excretion and arterial blood pressure 16 weeks after nephrectomy. These results indicate that renal ET-1 production decreases with the progression of renal disease and in relation with the severity of tubulointerstitial damage. The decrease in renal ET-1 production might contribute to the development and perpetuation of renal disease-associated arterial hypertension; this situation may be favorably modified by the use of enalapril.

The pathophysiological role of renal natriuretic depressor systems and endogenous digitalis like factor (EDLF) on blood pressure (BP) elevation was studied in reduced renal mass rats (RRM) with saline loading for a model of volume dependent hypertension. Fifty-four male Sprague-Dawley rats were operated on to remove varying proportions of their kidney mass (5/6 RRM, n = 13; 4/6 RRM, n = 16; 3/6 RRM, n = 12) or sham operated (control, n = 13). They were given 1% saline to drink for 4 weeks. BP was elevated significantly at the 1st week in 5/6 RRM and continued to increase until the 4th week, but this was not seen in the other 3 groups. Urine volume (UV) and urinary sodium excretion (UNaV) increased after saline loading in all groups. Urinary kallikrein excretion was significantly lower in order of the 5/6, 4/6 and 3/6 RRM at the basal state and after saline loading. A significant negative correlation was observed between urinary kallikrein and BP. Urinary PGE2 was increased in each RRM in order of the 5/6, 4/6 and 3/6 RRM groups. A significant positive correlation was observed between urinary PGE2 and BP, UV or UNaV. The basal urinary DA excretion was significantly lower in 3 RRMs than in the control. After saline drinking, urinary DA increased in 3 RRMs, while differences disappeared in the control and RRMs. Urinary EDLF increased immediately after the initiation of saline loading in all groups, except the control group, and returned to the basal level 2 weeks later in 3/6 and 4/6 RRM. Only in 5/6 RRM, the urinary EDLF remained higher than the basal level.(ABSTRACT TRUNCATED AT 250 WORDS)

In this study, disturbance of immune response as a pathogenic mechanism for human volume hypertension was investigated and compared to nephritis in its correlation with the metals such as zinc, iron and aluminum as environmental factors. Urinary gamma-GTP excretions in patients with nephritis or hypertension were higher than in healthy people, whereas the plasma renin activity in these patients were lower on the average than in healthy individuals. Hypertensive patients participating in this study were diagnosed as the volume hypertension type from our clinical and other results. The serum IgM and IgA levels in renal patients showed a tendency to be lower than in the healthy people used as control. Urinary IgA excretion in hypertensive patients was increased in association with increasing excretions of aluminum and/or iron into urine. The values of regression coefficients in the urine samples for aluminum and iron vs. IgA, respectively, were very high at r = 0.900 (n = 9, p < 0.05) and 0.736 (n = 9, p < 0.05). These correlations were shown to be very useful indicators in diagnosing volume hypertension. Moreover, hypertensive patients in this study were demonstrated to have a high regression coefficient (r = -0.702, n = 7; p < 0.05) for calcium vs. renin in the serum. In the hypertension, augmentation of serum calcium significantly decreased plasma renin activity.

1. We investigated the effects of short- and long-term administration of efonidipine hydrochloride (NZ-105), 1,4-dihydropyridine derivative, in conscious spontaneously hypertensive rats (SHR). 2. Oral administration of NZ-105 for 12 weeks caused diuretic and natriuretic effects, which were not attenuated during the experimental period. 3. In the short-term experiment for investigating the mechanism of the diuretic effect, intravenous injection of NZ-105 (0.03 mg/kg of body weight) significantly increased the urine volume (UV), renal plasma flow (RPF) and glomerular filtration rate (GFR). The increment rate of UV and RPF was 105.4 +/- 17.8% and 111.7 +/- 72.8%, respectively, which were larger than the increment rate of GFR (38.5 +/- 14.0%). 4. The diuretic or natriuretic effect of NZ-105 was suggested to be due to both the inhibition of sodium reabsorption and, at least in part, the increase of GFR.

Because little is known about disordered metabolism of uric acid as a pathogenetic mechanism of renal damage in non-insulin-dependent diabetes mellitus (NIDDM) it was studied in 75 NIDDM and 48 IDDM patients. Clinical examination of the patients included evaluation of purin metabolism according to serum uric acid, diurnal urine excretion, uric acid clearance. Hyperuricemia occurred more frequently in NIDDM. Positive correlation was observed between hyperuricosuria and the severity of diabetic nephropathy which was more pronounced in IDDM.

In a subset of dialysis patients, erythropoietin (rHuEpo) treatment exacerbates hypertension. The mechanism of this pressor effect is unknown; however, it has been suggested that decreased endogenous nitric oxide (NO) activity may play a role. To explore this hypothesis, Sprague-Dawley rats were given rHuEpo (150 U/kg s.c. three times per week) or corresponding vehicle. Blood pressure, haematocrit, and urinary excretion of the stable NO metabolites, nitrite (NO2) and nitrate (NO3), were determined at baseline and 3 weeks. After 3 weeks of rHuEpo treatment there was a significant increase in blood pressure and haematocrit, while in vehicle-treated rats blood pressure and haematocrit remained at basal levels. Urinary excretion of NO2+NO3 increased compared to basal in rHuEpo, but not vehicle rats. Thus in normal rats rHuEpo does have a significant pressor effect, but this is not associated with decreased activity of the endogenous NO system. Thus decreased endogenous NO activity is not responsible for rHuEpo-associated hypertension. These data further suggest that endogenous NO activity is increased in rHuEpo-treated rats, perhaps as a counter-regulatory mechanism that limits the pressor effect. Whether this mechanism is active in the setting of rHuEpo-treated chronic renal failure in humans is unknown.