Antihypertensive effects of cicletanine and renal protection in Dahl salt-sensitive rats.

We designed experiments to reveal the antihypertensive properties of cicletanine, a novel antihypertensive drug, in Dahl salt-sensitive (Dahl-S) rats. Cicletanine (39 mg/kg body weight per day for 6 weeks) ameliorated the development of hypertension in Dahl-S rats fed a high-salt (4% NaCl) diet. This blood pressure reduction was associated with a decrease in heart weight and vascular wall thickness. Moreover, urinary prostacyclin (PGl2) excretion was increased with cicletanine treatment, being inversely related to systolic blood pressure. Proteinuria and urinary excretion of n-acetyl-beta-D-glucosaminidase were decreased and glomerular filtration rate was increased with this treatment. Morphological investigation revealed an improvement in glomerulosclerosis, renal tubular damage and intrarenal arterial injury in the salt-induced hypertensive rats. In contrast, trichloromethiazide, which decreased blood pressure to the same extent as cicletanine, lowered urinary PGl2 excretion and generally did not ameliorate the deteriorated renal functions and morphological abnormalities. Thus, these data indicate that cicletanine ameliorates the development of hypertension in Dahl-S rats and protects the cardiovascular and renal systems against the injuries seen in the hypertension. The enhanced vasodepressor PGl2 synthesis probably participates, to some extent, in these beneficial properties of long-term cicletanine treatment.     

Changes of systemic prostacyclin and thromboxane A2 in sodium taurocholate-and cerulein-induced acute pancreatitis in rats

Systemic prostacyclin and thromboxane A₂ production in rat experimental acute pancreatitis has been evaluated by measuring the urinary excretion of the 2,3-dinor 6-keto prostaglandin F₁ and 2,3-dinor thromboxane B₂, respectively. Acute pancreatitis was induced by intraductal administration of 4.5% sodium taurocholate (0.1 ml/100 mg body weight) and intravenous cerulein perfusion (5 g/kg/hr) for 6 hr, respectively. Urinary excretion of 2,3-dinor 6-keto prostaglandin F₁ and 2,3-dinor thromboxane B₂ were much more important in sodium taurocholate- than in cerulein-induced acute pancreatitis. These data confirm an altered prostacyclin and thromboxane metabolism occurring in experimental acute pancreatitis. Phospholipase A₂ activity and the effect of gabexate mesilate on the arachidonate metabolism were also evaluated.This work was supported by the Fondo de Investigación Sanitaria (89/386).     

Plasma levels and urinary excretion of prostaglandins in patients with rheumatoid arthritis

Summary No significant differences were found in plasma concentrations and urinary excretion of prostaglandin E₂ (PGE₂), 6-keto-prostaglandin-F₁ (6-keto-F PGF₁) and thromboxane B₂ (T–xB₂), between rheumatoid arthritis patients and controls. However, urinary excretion of PGE_e and 6-keto-PGF₁ tended to be greater and plasma levels of TxB₂ lower in rheumatoid arthritis. Plasma concentrations and urinary excretion showed no marked circadian variation, although night or morning values were slightly lower. Plasma and urine prostaglandins do not correlate with clinical symptomatology in rheumatoid arthritis.     

Renal excretion of kallikrein and eicosanoids in patients with Type 1 (insulin-dependent) diabetes mellitus. Relationship to glomerular and tubular function

Summary Glomerular filtration rate, renal plasma flow, renal tubular sodium reabsorption (derived from lithium clearance) and renal excretion rates of kallikrein, prostaglandin E₂ and systemic and renally-derived metabolites of prostacyclin and thromboxane A₂ were measured in patients with Type 1 (insulin-dependent) diabetes mellitus and in normal subjects. Diabetic patients with glomerular hyperfiltration had greater active kallikrein and prostaglandin E₂ excretion than patients with normal glomerular filtration rate or than normal control subjects. Both active kallikrein and prostaglandin E₂ excretion correlated directly with glomerular filtration rate. Active kallikrein excretion correlated directly with the reabsorption of sodium in the distal tubule. The excretion rates of 6-keto prostaglandin F₁, 2,3 dinor 6-keto prostaglandin F₁, thromboxane B₂, 2,3 dinor thromboxane B₂ and 11-dehydro thromboxane B₂ excretion were not different between the groups. This study confirms in man our previous finding of increased renal kallikrein production in the hyperfiltering streptozotocin-diabetic rat model. Given that kinins generated by kallikrein are extremely potent vasodilators and stimulate the renal production of eicosanoids that also regulate glomerular function, our findings suggest that increased kallikrein activity and prostaglandin E₂ production may contribute to renal vasodilatation and hyperfiltration in human diabetes. The localization of kallikrein in the distal connecting tubule makes it plausible that altered sodium transport in the distal tubule may be a signal to increase generation of kallikrein.     

Nitric oxide in ischaemic acute renal failure of streptozotocin diabetic rats

Summary Changes in nitric oxide (NO) levels were determined in ischaemic acute renal failure in streptozotocin-induced diabetes mellitus rats. Two weeks after streptozotocin administration and immediately after right nephrectomy, the left renal artery was occluded for 60 min. Similar procedures were carried out in non-diabetic rats. The nitrite (NO₂) + nitrate (NO₃) levels were measured in plasma and urine. The effects of chronic oral supplementation with l-arginine and an NO synthase inhibitor (N-omega-nitro-l-arginine) were also studied in both diabetic and non-diabetic rats before and after renal artery clamping. The rats with diabetic acute renal failure had a much lower creatinine clearance (90±22 l · min^–1 · 100 g body weight^–1, p<0.005), and higher fractional excretion of sodium (FENa)% (10.90±4.2, p<0.001) and protein excretion (2078±69 g/ml creatinine clearance, p<0.001) compared with the respective values in the non-diabetic groups (163±30; 1.46±86; 453.3±31). The plasma and urine NO₂ + NO₃ levels were significantly higher in the untreated diabetic rats compared with the untreated normal rats before ischaemia (p<0.001). The ischaemic acute renal failure in non-diabetic rats increased the plasma and urinary NO₂ + NO₃ excretion after ischaemia. The urinary excretion of these metabolites decreased significantly and their plasma levels remained unchanged in the ischaemic diabetic rats. The l-arginine administration resulted in a small but significantly higher creatinine clearance after clamping in the non-diabetic rats. The NO synthase inhibitor caused deterioration in renal function in all ischaemic and non-ischaemic groups. In summary, the greater vulnerability to ischaemia of the diabetic kidney seems to be associated with both impaired response to and impaired production of NO.Abbreviations IARF Ischaemic acute renal failure - STZ streptozotocin - NOSi nitric oxide synthase inhibitor - ARF acute renal failure - Ccr creatinine clearance - FENa% fractional excretion of sodium     

Cicletanine avoids the proliferation of vascular smooth muscle in the spontaneously hypertensive rat

The vasodilator and antiproliferative effects of the antihypertensive agent, cicletanine, were studied on mesenteric arteries (MA) and cultured mesenteric artery myocytes derived from spontaneously hypertensive (SHR) and normotensive Wistar Kyoto (WKY) rats. Cicletanine induces relaxation of precontracted MA with an 1050 value of approximately 30-50 microM. Cicletanine inhibits the proliferation of cultured myocytes (passage 5) with an 1050 of 440 +/- 24 microM for SHR and 517 +/- 12 microM for WKY, p less than 0.05, indicating that a log-unit shift in sensitivity exists between its vasodilator and antiproliferative actions. Preliminary experiments suggest that the antiproliferative action of cicletanine is accompanied by an inhibition of DNA synthesis [( 3H] - thymidine uptake) in myocytes of SHR and a stimulation of DNA synthesis in myocytes of the WKY. Cicletanine also lowers free intracellular Ca2+ (determined using fura-2) in myocytes of SHR but not the WKY. In other cell systems, cicletanine has been shown to stimulate prostacyclin production. However, in the present experiments, inhibition of the cyclooxygenase pathway (5 microM indomethacin) attenuated the antiproliferative action of cicletanine by only 30% in cells of the SHR and was without affect in the WKY. In summary, we have shown that cicletanine has distinct antiproliferative effects cultured vascular myocytes. In SHR myocytes, the antiproliferative action is accompanied by a fall in intracellular Ca2+, stimulation of the cyclooxygenase pathway and an inhibition of DNA synthesis. Different mechanisms may be operant in cells of the WKY. It is proposed that the antiproliferative effects of cicletanine may play a role its antihypertensive actions.     

The effect of short-term glucagon infusion on kidney function in normal man

Summary Kidney function was studied in six normal males before and during a 2 h glucagon (10 ng/kg/min) infusion. The following variables were determined during each 20 min clearance period; glomerular filtration rate (GFR), renal plasma-flow (RPF), filtration fraction (FF), urinary albumin and ₂-microglobulin-excretion rates. Glucagon infusion resulted in a fourfold increase in plasma glucagon concentration. The infusion induced a significant increase in GFR (+9%), FF (+ 9%) and urinary ₂-microglobulin excretion rate (+ 32%), (p<0.01). RPF and urinary albumin excretion rates were not significantly changed. We suggest that glucagon may contribute to the reversible kidney function alterations typically found in poorly regulated juvenile diabetes, a state with relative or absolute hyperglucagonaemia.     

Effect of Amiloride and Spironolactone on Renal Tubular Function and Central Blood Pressure in Patients with Arterial Hypertension during Baseline Conditions and after Furosemide: A Double-Blinded,Randomized, Placebo-Controlled Crossover Trial

This study demonstrates that the increased potassium content in the body seems to change both the blood pressure and renal tubular function. We wanted to test the hypotheses that amiloride and spironolactone induced potassium retention reduces ambulatory blood pressure (ABP) and central blood pressure (CBP) during baseline conditions and after furosemide and that the tubular transport via the epithelial sodium channels (ENaCs) and aquaporin-2 (AQP2) water channels was increased by furosemide in arterial hypertension. Each of three 28-day treatment periods (placebo, amiloride, and spironolactone) was completed by a 4-day period with standardized diet regarding calories and sodium and water intake. At the end of each period, we measured pulse wave velocity (PWV), central systolic blood pressure (CSBP), central diastolic blood pressure (CDBP), glomerular filtration rate (GFR), free water clearance (C_H2O), fractional excretion of sodium (FE_Na) and potassium (FE_K), urinary excretion of AQP2 (u-AQP2), urinary excretion of γ-fraction of the ENaC (u-ENaCγ), and plasma concentrations of renin (PRC), angiotensin II (p-Ang II), and aldosterone (p-Aldo) at baseline conditions and after furosemide bolus. Ambulatory blood pressure and CBP were significantly lowered by amiloride and spironolactone. During 24-hour urine collection and at baseline, GFR, C_H2O, FE_Na, FE_K, u-AQP2 and u-ENaCγ were the same. After furosemide, C_H2O, FE_Na, FE_K, u-AQP2, u-ENaCγ, PRC, p-Ang II, p-Aldo, PWV and CDBP increased after all treatments. However, during amiloride treatment, FE_K increased to a larger extent than after spironolactone and during placebo after furosemide, and CSBP was not significantly reduced. The increases in water and sodium absorption via AQP2 and ENaC after furosemide most likely are compensatory phenomena to antagonize water and sodium depletion. Amiloride is less effective than spironolactone to reduce renal potassium excretion.

Trial registration: ClinicalTrials.gov identifier: NCT0138088.     

Technique for 24 Hour Recording of Continuous High Fidelity Arterial Pressure and Electrocardiogram in Ambulatory Patients

Angiotensin converting enzyme inhibition by MK 421, SA 446 or captopril (6 mg/kg/day ip) for up to 6 days induced significant fall in systolic blood pressure and plasma angiotensin II concentration. The hypotensive effect was greater in sodium depleted rats than in sodium repleted rats. The hypotensive effect was also accompanied by increased excretion of urinary prostaglandin E₂, however the levels of urinary prostaglandin E₂ in sodium repleted rats were not different from those in sodium depleted rats. Urinary kinin excretion was increased during infusion of MK 421, SA 446 or captopril in sodium depleted rats, whereas no significant change was found in sodium repleted rats. Thus the present results suggest that renal prostaglandin E system may not be essential for the hypotensive effect of these inhibitors. In addition, the greater hypotensive effect of these inhibitors in sodium depleted rats may be in part due to stimulated renal kinin system.     

Role of Renal Kallikrein in the Derangement of Sodium and Water Excretion in Cirrhotic Patients

The renal kallikrein-kinin system is involved in the regulation of intrarenal blood flow and natriuresis. To study whether deranged sodium and water excretion in terminal cirrhosis is associated with an altered renal kallikrein-kinin system, urinary kallikrein excretion (U_kalV) was measured. Low U_kalV excretion was found in cirrhosis. In particular, nine cirrhotics with ascites showed a significantly lowered ratio of U_kalV to urinary aldosterone excretion when compared with eight cirrhotics without ascites. Continuous infusion in cirrhosis and ascites of prostaglandin E₁ (0.1 ng/kg/min) for 3 days resulted in marked increases in both daily urine volume and urinary sodium excretion; this was associated with a significant elevation of U_kalV. These results suggest that in cirrhosis the impairment in renal sodium and water excretion may be attributed, at least in part, to deficient activation of the renal kallikrein-kinin system.     

Increased renal sodium absorption by inhibition of prostaglandin synthesis during fasting in healthy man. A possible role of the epithelial sodium channels

Background

Treatment with prostaglandin inhibitors can reduce renal function and impair renal water and sodium excretion. We tested the hypotheses that a reduction in prostaglandin synthesis by ibuprofen treatment during fasting decreased renal water and sodium excretion by increased absorption of water and sodium via the aquaporin2 water channels and the epithelial sodium channels.

Methods

The effect of ibuprofen, 600 mg thrice daily, was measured during fasting in a randomized, placebo-controlled, double-blinded crossover study of 17 healthy humans. The subjects received a standardized diet on day 1, fasted at day 2, and received an IV infusion of 3% NaCl on day 3. The effect variables were urinary excretions of aquaporin2 (u-AQP2), the beta-fraction of the epithelial sodium channel (u-ENaCbeta), cyclic-AMP (u-cAMP), prostaglandin E2 (u-PGE2). Free water clearance (CH2O), fractional excretion of sodium (FENa), and plasma concentrations of vasopressin, angiotensin II, aldosterone, atrial-, and brain natriuretic peptide.

Results

Ibuprofen decreased u-AQP2, u-PGE2, and FENa at all parts of the study. During the same time, ibuprofen significantly increased u-ENaCbeta. Ibuprofen did not change the response in p-AVP, u-c-AMP, urinary output, and free water clearance during any of these periods. Atrial-and brain natriuretic peptide were higher.

Conclusion

During inhibition of prostaglandin synthesis, urinary sodium excretion decreased in parallel with an increase in sodium absorption and increase in u-ENaCbeta. U-AQP2 decreased indicating that water transport via AQP2 fell. The vasopressin-c-AMP-axis did not mediate this effect, but it may be a consequence of the changes in the natriuretic peptide system and/or the angiotensin-aldosterone system

Trial Registration

Clinical Trials Identifier: NCT00281762     

The influence of glucose-induced hyperinsulinaemia on renal glomerular function and circulating catecholamines in normal man

Summary The circulatory, renal, and hormonal responses to physiological elevation of plasma insulin induced with oral glucose have been studied in seven healthy subjects. Glomerular filtration rate, urinary excretion rates of albumin and ₂-microglobulin, haematocrit, pulse rate, blood pressure and plasma catecholamine concentrations have been measured. Physiological hyperinsulinaemia following glucose ingestion was associated with an increase in nor-adrenaline levels and brief tachycardia. No effect was noted on haematocrit, creatinine clearance, urinary albumin excretion, plasma adrenaline concentrations and arterial blood pressure. Urinary ₂-microglobulin excretion rates fell shortly after the elevation of plasma insulin, probably indicating enhanced tubular reabsorption. Thus, glucose-induced physiological hyperinsulinaemia does not reduce glomerular filtration rate nor does it increase transglomerular passage of albumin, effects seen after the intravenous bolus injection of 6–8 U of insulin in diabetics.     

Plasma Vitamin D Level and Change in Albuminuria and eGFR According to Sodium Intake

Background and objectives

Low circulating 25-hydroxyvitamin D [25(OH)D] and high sodium intake are both associated with progressive albuminuria and renal function loss in CKD. Both vitamin D and sodium intake interact with the renin-angiotensin-aldosterone system. We investigated whether plasma 25(OH)D or 1,25-dihydroxyvitamin D [1,25(OH)₂D] is associated with developing increased albuminuria or reduced renal function and whether these associations depend on sodium intake.

Design, setting, participants, & measurements

Baseline plasma 25(OH)D and 1,25(OH)₂D were measured by liquid chromatography tandem mass spectrometry, and sodium intake was assessed by 24-hour urine collections in the general population–based Prevention of Renal and Vascular End-Stage Disease cohort (n=5051). Two primary outcomes were development of urinary albumin excretion >30 mg/24 h and eGFR (creatinine/cystatin C–based CKD Epidemiology Collaboration) <60 ml/min per 1.73 m². Participants with CKD at baseline were excluded. In Cox regression analyses, we assessed associations of vitamin D with developing increased albuminuria or reduced eGFR and potential interaction with sodium intake.

Results

During a median follow-up of 10.4 (6.2–11.4) years, 641 (13%) participants developed increased albuminuria, and 268 (5%) participants developed reduced eGFR. Plasma 25(OH)D was inversely associated with increased albuminuria (fully adjusted hazard ratio [HR] per SD higher, 0.86; 95% confidence interval [95% CI], 0.78 to 0.95; P=0.003) but not reduced eGFR (HR, 0.99; 95% CI, 0.87 to 1.12; P=0.85). There was interaction between 25(OH)D and sodium intake for risk of developing increased albuminuria (P interaction =0.03). In participants with high sodium intake, risk of developing increased albuminuria was inversely associated with 25(OH)D (lowest versus highest quartile: adjusted HR, 1.81; 95% CI, 1.20 to 2.73, P<0.01), whereas this association was nonsignificant in participants with low sodium intake (HR, 1.29; 95% CI, 0.94 to 1.77; P=0.12). Plasma 1,25(OH)₂D was not significantly associated with increased albuminuria or reduced eGFR.

Conclusions

Low plasma 25(OH)D is associated with higher risk of developing increased albuminuria, particularly in individuals with high sodium intake, but not of developing reduced eGFR. Plasma 1,25(OH)2D is not associated with risk of developing increased albuminuria or reduced eGFR.     

Estimation of 24‐Hour Sodium Excretion from Spot Urine Samples

J Clin Hypertens (Greenwich). 2010;12:174–180. ^©2010 Wiley Periodicals, Inc. Despite the effects of sodium intake on blood pressure and on response to antihypertensive medication, sodium intake is rarely monitored in clinical practice. The current method, the 24‐hour urine collection for sodium excretion, is cumbersome, often incorrectly performed, and not commonly ordered. Further, its results have limited meaning because of the substantial day‐to‐day variation in sodium intake. A spot urine test to enable convenient, inexpensive, and serial monitoring of sodium excretion would be desirable. In this study, the accuracy of predicting 24‐hour sodium excretion from a spot urine sample was assessed. The urine sodium/creatinine ratio was determined from the following urine samples: an “AM sample,” submitted at the beginning of the 24‐hour urine collection; a “PM sample” collected in the later afternoon/early evening before dinner, at roughly the midpoint of the collection; and a “random sample,” collected after its completion. The ratio was then corrected for 24‐hour creatinine excretion. The strongest correlation between predicted and actual 24‐hour sodium excretion was observed with the PM sample collected near the midpoint (r=0.86, P<.001). This sample also identified persons with sodium excretion <100 mEq/d with a sensitivity of 100% and specificity of 82%. The sodium/creatinine ratio from a spot urine sample collected in the late afternoon/early evening at roughly the midpoint of the 24‐hour collection, and adjusted for 24‐hour creatinine excretion, strongly correlated with 24‐hour sodium excretion. Additional studies are merited to further evaluate the role of the spot urine sample in assessing sodium intake.

The important effects of sodium intake on blood pressure (BP) and on response to antihypertensive drug therapy have been widely recognized. Despite this, few physicians objectively measure or monitor the sodium intake of their hypertensive patients.The main methods in current use for assessing sodium intake are dietary recall and measurement of 24‐hour urine sodium excretion. Dietary recall is often inaccurate, and many patients are truly unaware of the amount of sodium they consume. ^{1 , 2 , 3} Measurement of 24‐hour urine sodium excretion has major drawbacks. It is cumbersome and inconvenient. Many patients will not do it, and among those who do, many perform the collection incorrectly. As many as 30% submit undercollections, understating actual sodium intake. ⁴ Further, results reflect the intake of only the preceding day or two, which, because of the considerable day‐to‐day variability in sodium intake, often is not representative of that individual’s usual sodium intake.Currently, hypertension is usually managed without knowledge of patients’ sodium intake. This can affect both control of hypertension and risk of adverse effects. For example, when diuretics are prescribed, the risk of adverse effects is magnified if a high dose is given to patients who consume little sodium, and the risk of inadequate BP control is magnified if a low dose is given to patients with a high sodium intake. Level of sodium intake can play an important role in resistant hypertension and the need for, and efficacy of, high‐dose diuretics in its treatment. ^{5 , 6} A preferable method, from a perspective of ease and convenience, to serially monitor sodium excretion, would be assessment of sodium excretion from spot urine samples. This would require measurement of the spot urine sodium concentration along with a measure of the state of concentration or dilution of the urine, such as the urine creatinine concentration, as is currently used to estimate 24‐hour excretion of other analytes such as albumin and catecholamines.Unfortunately, the spot urine sodium/creatinine ratio has inherent limitations in estimating 24‐hour sodium excretion. First, sodium excretion varies considerably from day to day and hour to hour, and, therefore, spot urine results can differ substantially from results of 24‐hour collections. Second, the accuracy of the sodium/creatinine ratio is reduced by the considerable interindividual differences in 24‐hour creatinine excretion. Thus, for example, if one individual excreted 800 mg/d of creatinine daily while another excreted 2400 mg, and both had the same sodium/creatinine ratio, the ratio would be misleading in that it would indicate the same 24‐hour sodium excretion for both, even though sodium excretion would actually be 3‐fold higher in the individual who excretes 2400 mg. The use of a spot urine method, or a brief timed collection, for assessing sodium excretion has previously been examined. ^{7 , 8 , 9} Nevertheless, the spot urine method has not been adopted for clinical use. We have undertaken studies to reassess its accuracy and usefulness in estimating 24‐hour sodium excretion.     

Relationship of urinary kallikrein excretion to renal water and sodium excretion

The circadian rhythms of urine volume and urinary excretion of sodium, potassium, kallikrein, and aldosterone were analyzed by a multivariate method (cosinor method) in 20 healthy Japanese women on an ordinary diet. The relationship of urinary kallikrein and aldosterone excretion to urine volume and urinary sodium and potassium excretion was studied by assessing the correlation of the circadian rhythms. The acrophases in the circadian rhythms of urine volume (16:51) and urinary sodium excretion (16:55) appeared after the acrophase of urinary kallikrein excretion (15:28). There was a highly significant correlation between the circadian rhythm of urinary kallikrein excretion and the circadian rhythms of urine volume (r = 0.948) and urinary sodium excretion (r = 0.921). These results suggest that the renal kallikrein-kinin system participates in the regulation of renal water and sodium excretion in persons on an ordinary diet. A highly significant relationship between the acrophases in the circadian rhythms of urine volume and sodium excretion (r = 0.935) also suggests that water and sodium excretion may have a mutual influence on the kidneys. There were positive correlations between the circadian rhythms of potassium excretion and kallikrein excretion and potassium excretion and sodium excretion; and the latter relationship was relatively closer than the former. The acrophase in the circadian rhythm of aldosterone excretion did not correlate well with the acrophases of the other urine variables including sodium excretion.     

Higher dietary salt intake is associated with microalbuminuria,but not with retinopathy in individuals with type 1 diabetes: the EURODIAB Prospective Complications Study

Aims/hypothesis

High dietary salt intake has been associated with elevated BP and may also have a deleterious effect on microvascular complications. We studied the cross-sectional associations between dietary salt intake (estimated from 24 h urinary sodium excretion) and urinary potassium excretion on the one hand, and the prevalence of microvascular complications on the other, in individuals with type 1 diabetes.

Methods

We measured sodium and potassium concentrations in two 24 h urine samples in 1,212 individuals with type 1 diabetes (40?±?10 years old, 51% men) who participated in the EURODIAB Prospective Complications Study. We used multiple logistic regression analyses to investigate associations between dietary salt intake and microvascular complications adjusted for age and sex, and additionally for BMI, smoking, urinary potassium excretion, antihypertensive medication and physical activity, and total energy, protein, alcohol, saturated fat and fibre intake.

Results

After full adjustment, 1 g/day higher dietary salt intake was positively associated with the presence of microalbuminuria (OR 1.06 [95% CI 1.01, 1.10]), but not macroalbuminuria (OR 0.99 [95% CI 0.94, 1.05]), non-proliferative retinopathy (OR 1.00 (95% CI 0.96, 1.04]) or proliferative retinopathy (OR 1.02 (95% CI 0.95, 1.08]). After excluding individuals with cardiovascular disease and/or antihypertensive medication (n?=?418), we found a non-significant association with microalbuminuria (OR 1.04 [95% CI 0.99, 1.10]) and macroalbuminuria (OR 1.05 [95% CI 0.96, 1.16]). The association between dietary salt intake and microalbuminuria was stronger in individuals with a BMI above 25 kg/m² (OR 1.11 [95% CI 1.04, 1.18]) than in those with BMI below 25 kg/m² (OR 1.03 [95% CI 0.97, 1.09]). No significant associations were found between urinary potassium excretion and microvascular complications.

Conclusions/interpretation

In individuals with type 1 diabetes, higher dietary salt intake, as determined by 24 h urinary sodium excretion, may be positively associated with microalbuminuria, particularly in overweight individuals.     

Urinary Potassium Excretion and Renal and Cardiovascular Complications in Patients with Type 2 Diabetes and Normal Renal Function

Background and objectives

We investigated the association of urinary potassium and sodium excretion with the incidence of renal failure and cardiovascular disease in patients with type 2 diabetes.

Design, setting, participants, & measurements

A total of 623 Japanese type 2 diabetic patients with eGFR≥60 ml/min per 1.73 m² were enrolled in this observational follow-up study between 1996 and 2003 and followed-up until 2013. At baseline, a 24-hour urine sample was collected to estimate urinary potassium and sodium excretion. The primary end point was renal and cardiovascular events (RRT, myocardial infarction, angina pectoris, stroke, and peripheral vascular disease). The secondary renal end points were the incidence of a 50% decline in eGFR, progression to CKD stage 4 (eGFR<30 ml/min per 1.73 m²), and the annual decline rate in eGFR.

Results

During the 11-year median follow-up period, 134 primary end points occurred. Higher urinary potassium excretion was associated with lower risk of the primary end point, whereas urinary sodium excretion was not. The adjusted hazard ratios for the primary end point in Cox proportional hazards analysis were 0.56 (95% confidence interval [95% CI], 0.33 to 0.95) in the third quartile of urinary potassium excretion (2.33–2.90 g/d) and 0.33 (95% CI, 0.18 to 0.62) in the fourth quartile (>2.90 g/d) compared with the lowest quartile (<1.72 g/d). Similar associations were observed for the secondary renal end points. The annual decline rate in eGFR in the fourth quartile of urinary potassium excretion (–1.3 ml/min per 1.73 m²/y; 95% CI, –1.5 to –1.0) was significantly slower than those in the first quartile (–2.2; 95% CI, –2.4 to –1.8).

Conclusions

Higher urinary potassium excretion was associated with the slower decline of renal function and the lower incidence of cardiovascular complications in type 2 diabetic patients with normal renal function. Interventional trials are necessary to determine whether increasing dietary potassium is beneficial.     

Renal hemodynamics and the renin-angiotensin system in cirrhosis

Renal hemodynamics and the renin-angiotensin-aldosterone system were investigated in 15 cirrhotic patients without renal failure on controlled sodium intake of 140–160 mEq/day and related to the degree of sodium retention as measured by urinary sodium excretion. Fourteen patients were free of clinical ascites when studied. The distribution of renal blood flow was measured by the noninvasive technique of computerized radioisotope renography. In 11 patients, outer cortical renal plasma flow, expressed as a percentage of total effective renal plasma flow, was directly proportional to sodium excretion (P0.01). Three patients with severe sodium retention (UNa V10 mEq) had estimated outer cortical renal plasma flows of 274 ml/min/1.73 M² as compared to eight cirrhotics with better (UNa V50 mEq) sodium tolerance (mean=438 ml/min/1.73 M²). A significant inverse correlation (P0.01) existed between outer renal cortical blood flow and plasma renin activity. No significant relationship was observed between glomerular filtration rate, total effective renal plasma flow, plasma aldosterone concentration and sodium excretion. These results provide further evidence that a renal vascular abnormality exists in cirrhosis, and that diminished outer cortical renal perfusion is related to the elevated renin levels and sodium intolerance observed in cirrhotic patients.Dr. Rosoff's work was supported by a research fellowship from the Bank of America-Giannini Foundation, San Francisco, California.This paper was presented in abstract form at the AGAAASLD meeting, Miami, Florida, May 27, 1976.     

Urinary excretion of 1,5-anhydro-D-glucitol accompanying glucose excretion in diabetic patients

Summary The urinary excretion of 1,5-anhydro-D-glucitol, a pyranoid polyol, in humans was studied. The plasma of nondiabetic human subjects contained high concentrations of this polyol (>110 mol/l), and there was a tendency for the 24-h excretion of it to become more variable in direct proportion to its plasma concentration. In contrast, diabetic patients showed lower plasma concentrations of this polyol, and the variation in the 24-h excretion of 1,5-anhydro-D-glucitol was especially notable among the patients with an extremely low plasma concentration of the polyol. This diabetic group showed a statistically significant correlation (p<0.01), between the urinary 1,5-anhydro-D-glucitol and urinary glucose. This correlation was more markedly demonstrated during a 100-g oral glucose tolerance test: parallel changes were observed in the concentrations of 1,5-anhydro-D-glucitol and glucose in the urine collected every hour after the glucose load. These observations led to the proposal that low plasma concentration of this polyol, which is observed in diabetes mellitus, may be the result of a frequent and/or prolonged high blood glucose concentration beyond the renal threshold for glucose excretion.     

Pharmacokinetic and pharmacodynamic study of ipragliflozin in Japanese patients with type 2 diabetes mellitus: A randomized,double-blind,placebo-controlled study

Aims

Ipragliflozin is a novel and highly selective sodium–glucose transporter 2 (SGLT2) inhibitor that reduces plasma glucose levels by enhancing urinary glucose excretion in patients with type 2 diabetes mellitus (T2DM). We examined the pharmacokinetic and pharmacodynamic characteristics of two oral doses of ipragliflozin in Japanese patients with T2DM.

Methods

In this randomized, placebo-controlled, double-blind study, patients were treated with placebo, 50 mg or 100 mg ipragliflozin once daily for 14 days. Plasma and urine pharmacodynamic parameters were measured on Days −1 and 14, and pharmacokinetic parameters on Day 14. Pharmacodynamic characteristics included area under the curve (AUC) for plasma glucose and insulin for 0–3 h (AUC_0–3h) and 0–24 h (AUC_0–24h). Pharmacokinetic characteristics included AUC_0–24h, maximum ipragliflozin concentration (C_max), and time to maximum plasma ipragliflozin concentration (t_max).

Results

Thirty patients were enrolled; 28 were included in pharmacokinetic/pharmacodynamic analyses and 30 in safety analyses. Administration of 50 and 100 mg ipragliflozin significantly reduced fasting plasma glucose, as well as the AUC_0–3h and AUC_0–24h for plasma glucose relative to placebo. Both doses of ipragliflozin also reduced AUC_0–24h for insulin, body weight, and glycoalbumin, while urinary glucose excretion increased remarkably. C_max and AUC_0–24h were 1.7- and 1.9-fold higher, respectively, in the 100-mg group than in the 50-mg group.

Conclusions

Ipragliflozin increased urinary glucose excretion and improved fasting and postprandial glucose, confirming its pharmacokinetic/pharmacodynamic properties in Japanese patients with T2DM.