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Background Long-term survival of renal transplant recipients (RTR) has not improved over the past 20yr. The question rises to what extent lifestyle factors play a role in post-transplant weight gain and its associated risks after transplantation.Methods Twenty-six RTR were measured for body weight, body composition, blood lipids, renal function, dietary intake, and physical activity at six wk, and three, six, and 12months after transplantation.Results Weight gain ranged between -2.4kg and 19.5kg and was largely due to increase in body fat. RTR who remained body fat stable, showed more daily physical activity (p=0.014), tended to consume less energy from drinks and dairy (p=0.054), consumed less mono- and disaccharides (sugars) (p=0.021) and ate more vegetables (p=0.043) compared with those who gained body fat. Gain in body fat was strongly related to total cholesterol (r=0.46, p=0.017) and triglyceride (r=0.511, p=0.011) at one yr after transplantation.Conclusions Gain in adiposity after renal transplantation is related to lifestyle factors such as high consumption of energy-rich drinks, high intake of mono- and disaccharides and low daily physical activity. RCTs are needed to investigate potential benefits of lifestyle intervention on long-term morbidity and mortality.

Background and aims: We aimed to determine the effect of short-term dietary sodium restriction on plasma total cholesterol, LDL-C, HDL-C, triglycerides, apolipoprotein (apo) A-I, apo B and high molecular weight (HMW) adiponectin in non-obese, normotensive young men. Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), plasma renin activity (PRA) and aldosterone were also measured.Methods and results: Sixty-five men, aged 23 +/- 7 years, were randomly studied on a high sodium intake (HS, 228 +/- 77 mmol Na+/24 h) and a low sodium intake (LS, 36 +/- 27 mmol Na+/24 h), each period lasting 1 week. LS decreased GFR and ERPF and increased PRA and aldosterone (p Conclusion: Short term sodium restriction modestly decreases HDL-C, apo A-I and HMW-adiponectin in healthy men. Changes in GFR and ERPF and in the renin-angiotensin-aldosterone system as induced by LS may be involved in these responses. (C) 2010 Elsevier B. V. All rights reserved.

Both renal and cardiovascular morbidity and mortality is increased markedly in patients with type 2 diabetes. Besides the classic risk factors and markers such as glucose, blood pressure, blood lipid profile, and lifestyle (smoking, overweight), novel risk markers are identified, among them urine albumin excretion. Levels of urinary albumin excretion greater than normal are observed frequently in patients with type 2 diabetes. Moderately increased levels of albuminuria, so-called microalbuminuria, are predictive both for progressive renal function loss to diabetic nephropathy, and for cardiovascular morbidity and mortality: the higher the albuminuria level, the more chance of renal and cardiovascular complications. More advanced levels of albuminuria (overt albuminuria) are observed in patients in the diabetic nephropathy state. in this condition, renal and cardiovascular risk are extremely high, and again one may observe that the level of albumin excretion is predictive of renal and cardiovascular outcome. Several drug strategies decrease the level of urinary albumin excretion in type 2 diabetic patients. Data on using drugs that intervene in the renin-angiotensin-aldosterone-system (RAAS) are the most extensive and conclusive. RAAS intervention is a very effective strategy to decrease the amount of albumin in the urine, independent from the blood pressure decreasing characteristics of the treatment. RAAS intervention is associated with long-term renal and cardiovascular protection. Importantly, the degree of short-term albuminuria decrease is associated with the degree of renal and cardiovascular protection: the more albuminuria reduction, the more protection. The protective predictive power of the albuminuria effect of RAAS intervention is not related to (or dissociated from) the blood pressure decreasing effect of these drugs. The protective effect of RAAS intervention is present at normoalbuminuric, microalbuminuric, and overt albuminuria levels. This makes albuminuria a target for therapy in type 2 diabetes. New drug strategies that decrease or prevent albuminuria without affecting other risk factors currently are being tested, and not only will add to underscoring the need to treat albuminuria as a separate target, but also will assist in reducing the enormous residual risk burden of individual diabetic patients. Semin Nephrol 27:172-181 (C) 2007 Elsevier Inc. All rights reserved.

Urinary albumin excretion is a predictor for cardiovascular mortality and morbidity. We investigated which parameters determine baseline urinary albumin excretion in nondiabetic subjects, without renal disease. In addition, we evaluated the parameters that predict the albuminuria-lowering efficacy of an angiotensin-converting enzyme inhibitor. In this substudy of the Prevention of Renal and Vascular Endstage Disease Intervention Trial, 384 microalbuminuric patients were included. Patient and biochemical characteristics were obtained at baseline and after 3 months of double-blinded, randomized treatment (fosinopril 20 mg or placebo). Mean age was 51.1±11.5 years, and 65.6% were male. Median urinary albumin excretion was 22.2 mg per 24 hours. At baseline, mean arterial pressure (β standardized =0.161; P =0.006), urinary sodium excretion (β standardized =0.154; P =0.011), and estimated renal function were independently associated with albumin excretion. In these predominantly normotensive to prehypertensive subjects, fosinopril reduced albumin excretion by 18.5% versus a 6.1% increase on placebo after 3 months ( P standardized =−0.303; P

Verhave JC, Balje-Volkers CP, Hillege HL, de Zeeuw D, de Jong PE (University Medical Center Groningen, Groningen University, Institute of Drug Exploration, Groningen, the Netherlands). The reliability of different formulae to predict creatinine clearance. J Intern Med 2003; 253: 563–573. Objectives. Creatinine clearance (CCR) is a commonly used tool to measure glomerular filtration rate (GFR) in clinical practice. This tool requires collection of 24-h urine, which is quite bothersome. Several different formulae have been used to estimate GFR using plasma creatinine and other easy formulae to obtain biometrical data. We examined 10 formulae and compared them with actually measured CCR in a large sample of the general population. Design. Cross-sectional cohort study. Setting. University hospital outpatient clinic, a population based study. Subjects. A total of 8592 inhabitants of the city of Groningen, 28–75 years of age. The cohort is enriched for microalbuminuria. Results. In general, the formulae did not give an accurate estimation of CCR, particularly not in male and in obese subjects. Six formulae, including the Cockcroft–Gault gave a fairly good estimation of CCR in the overall population and in subgroups of specific gender, body mass index and age. All formulae however, gave an underestimation of the measured CCR in higher ranges of CCR and an overestimation in the lower ranges. Moreover, the age-related decline of CCR is hard to approximate with a formula. Conclusions. We conclude that formulae to estimate CCR in the general population, although giving a fairly good estimate of mean CCR, do not offer reliable data on CCR in the upper and lower ranges and do not adequately estimate the age–related decline in CCR.

1 In previous studies on the renal targeting of the ACE inhibitor captopril, we demonstrated that a 6 fold increased concentration of this drug could be obtained in the kidney after conjugation to the low-molecular-weight protein lysozyme. In this study, we investigated in unrestrained rats whether systemic administration of captopril-lysozyme also 'results in an enhanced effect on renal parameters, relative to the systemic effects.2 Renal effects: intravenous infusion of captopril-lysozyme for 6 h resulted in a more pronounced increment of renal blood flow (31 +/- 2% vs 17 +/- 4% at 0.5 mg kg(-1) 6h(-1), P 3 Systemic effects: conjugated captopril did not affect blood pressure in dosages up to 5 mg kg(-1) 6 h(-1). This effect coincided with a less pronounced inhibition of the pressor response to intravenously administered angiotensin 1 (-12 +/- 3% vs -66 +/- 5% at 1 mg kg(-1) 6 h(-1), P 4 An experiment of continued intravenous administration of captopril-lysozyme for 7 days in nephrotic syndrome demonstrated that the conjugate is also active in renal disease: the antiproteinuric response was substantially augmented (-67 +/- 5% vs - 15 +/- 7% at 4 mg kg(-1) 24 h(-1), P 5 These data demonstrate that intravenous administration of a captopril-lysozyme conjugate leads to more selective renal ACE inhibition and enhanced renal effects as well as less systemic effects compared to captopril itself.

Aims/hypothesis. Type I (insulin-dependent) diabetes mellitus is associated with an increased extracellular volume. Sodium restriction might seem a logical form of treatment but data on its renal effects is conflicting. We therefore studied the effects of sodium restriction on renal haemodynamics in uncomplicated Type I diabetes mellitus. Methods. Uncomplicated Type I diabetic patients (n = 24) and matched control subjects (n = 24) were studied twice in random order: after a week of 50 mmol or after 200 mmol sodium intake, respectively. The diabetic patients were studied under normoglycaemic clamp conditions. Glomerular filtration rate and effective renal plasma flow were measured as the clearances of iothalamate and hippuran, respectively. Results. During liberal sodium intake, glomerular filtration, effective renal plasma flow and filtration fraction were similar between the diabetic patients and the control subjects. Sodium restriction decreased the effective renal plasma flow in both groups, whereas glomerular filtration rate only decreased in the control subjects. Consequently, in the diabetic patients, the filtration fraction was increased on low sodium (4.1 +/- 8.4 %, p

The presence of an altered renal function in essential hypertension, advanced heart failure (HF) and after a myocardial infarction (MI) is associated with higher cardiovascular morbidity, and mortality. Indices of altered renal function (e.g., microalbuminuria, increased serum creatinine concentrations, decrease in estimated creatinine clearance or overt proteinuria) are independent predictors of cardiovascular morbidity, and mortality in any, of the three clinical situations. These parameters should then be routinely evaluated in clinical practice. These facts have several therapeutic implications. First, although there is no evidence-based information on the level of blood pressure that confers optimal renal protection, levels substantially, lower than past recommendations are advisable, Second, hypertensive kidney, damage should be prevented by, early treatment of hypertensive patients, particularly those with microalbuminuria. Finally, to avoid further aggravation of high cardiovascular risk, antihypertensive agents devoid of unwanted metabolic side effects should be used for the treatment of hypertensive vascular damage, In HF, the combination of an angiotensin-converting enzyme (ACE) inhibitor and a beta-blocker seem to be the most renoprotective. Renal outcome is also improved by, ACE inhibition after an MI. Finally,, renal and cardiovascular outcome seem to run in parallel in all these situations. (J Am Coll Cardiol 2001;38:1782-7) (C) 2001 by the American College of Cardiology.

Objective It is well-known that insulin induces renal sodium retention. It is not yet known whether insulin's renal effects are involved in the development of salt-sensitive hypertension. We assessed the effects of insulin on renal sodium handling and haemodynamics in 10 salt-sensitive (SS) and 10 salt-resistant (SR) essential hypertensives. Design After a baseline period of 90 min, all subjects underwent a euglycaemic clamp with sequential infusion of a physiological and supraphysiological dose of insulin (50 and 150 mU/kg per h) during 90 min periods each. Time-control studies were performed in the same subjects. Clearances of I-131-hippuran, I-125-iothalamate, sodium and lithium were used to evaluate renal plasma flow (RPF), C-Na/glomerular filtration rate (GFR) and fractional proximal and distal sodium reabsorption. Results Plasma insulin levels and insulin-mediated glucose uptake did not differ between both groups. RPF and GFR showed similar increases during both insulin infusions in both groups. During physiological hyperinsulinaemia, fractional sodium excretion decreased 38% (P = 0.009) in the SS group and 36% (P = 0.002) in the SR group. During supraphysiological hyperinsulinaemia, fractional sodium excretion decreased 49% (P = 0.01) in the SS group and 19% (P = 0.2) in the SR group, not statistically different between both groups. Fractional proximal sodium reabsorption was unaffected and fractional distal sodium reabsorption increased to a similar magnitude in both groups. Conclusion The comparable renal effects of acute exogenous hyperinsulinaemia in SS and SR hypertensives do not support a role for insulin in the development of salt-sensitive hypertension. However, the results do not yet exclude a role for chronic hyperinsulinaemia. (C) 2001 Lippincott Williams & Wilkins.

Background. Interference in the renin-angiotensin system with angiotensin-converting enzyme (ACE) inhibitors has proven to be effective in lowering albuminuria in patients with insulin-dependent diabetes mellitus (IDDM). We studied whether angiotensin II receptor antagonism reduces urinary albumin excretion (UAE) in IDDM patients, and the relationship between the antiproteinuric effect and changes in systemic and renal haemodynamics. Methods. Nine IDDM patients with microalbuminuria (30-300 mg/24 h) were studied. patients were studied after a 4 week placebo period, on days 3, 7 and 28 of treatment with losartan 50 mg once daily, and after a 4 week placebo-controlled recovery period. Results. Mean arterial pressure (MAP) was only slightly lowered during losartan treatment. Effective renal plasma flow (ERPF) was significantly increased on the third day of treatment and remained stable throughout the treatment period. Glomerular filtration rate (GFR) did not change throughout the study. Filtration fraction (FF) was maximally lowered on the third day of treatment and remained stable during treatment. UAE was already significantly lowered after 2 days of treatment, during both the day and night, and remained stable throughout the treatment period. The time course of the changes in UAE paralleled that of the changes in MAP, ERPF and FF. Conclusions. The angiotensin receptor antagonist losartan effectively lowers UAE in microalbuminuric IDDM patients. The changes observed in renal haemodynamics and UAE are concordant in time and maximal within only a few days of treatment. These results support the importance of the specific effects of interference in the renin angiotensin system (RAS) in microalbuminuric IDDM on blood pressure and renal haemodynamics in reducing urinary protein leakage, rather than non-haemodynamic, structural changes of the glomerular basement membrane.

Background Impaired vasodilatation in skeletal muscle is a possible mechanism linking insulin resistance to blood pressure regulation. Increased renal vascular resistance has been demonstrated in the offspring of essential hypertensives. We assessed whether insulin-mediated renal vasodilatation is impaired in insulin-resistant normal subjects.Design In two groups of 10 insulin-resistant and 10 insulin-sensitive normal subjects, we compared the effects of sequential physiological and supraphysiological insulin dosages (50 and 150 mU kg(-1) h(-1)) on renal plasma flow (RPF) and leg blood flow using the euglycaemic clamp technique, I-131-labelled Hippuran clearances and venous occlusion plethysmography. Time-control experiments were performed in the same subjects.Results Whole-body glucose uptake amounted to 4.9 +/- 2.1 and 11.0 +/- 2.4 mg kg (-1)min(-1) in the insulin-resistant and to 12.7 +/- 2.3 and 17.4 +/- 2.6 mg kg (-1)min(-1) in the insulin-sensitive subjects during physiological and supraphysiological hyperinsulinaemia, respectively. RPF increased more in insulin-sensitive compared to insulin-resistant subjects during physiological hyperinsulinaemia (13.7 vs. 6.8%, P Conclusions Our results suggest that the sensitivities of the skeletal muscle and renal vascular bed differ for insulin's vasodilatory action. Insulin-mediated increases in RPF are impaired in insulin-resistant but otherwise normal subjects during physiological hyperinsulinaemia.

Microalbuminuria (MA) is an important early sign of diabetic nephropathy. Hyperfiltration and impaired filtration in relation to albuminuria has been well investigated in diabetic subjects. This study tested the hypothesis that an increased urinary albumin excretion (UAE) is associated with renal functional abnormalities also in nondiabetic subjects. The relation between UAE and creatinine clearances (Ccr) in 7728 nondiabetic subjects was studied. Subjects were divided in four groups according to UAE (mg/24 h): 0 to 15 (control), 15 to 30 (high-normal albuminuria [HNA]), 30 to 300 (MA), >300 (macroalbuminuria). An elevated filtration and a diminished filtration were defined as a Ccr exceeding or below 2X the SD of the control group corrected for age and gender. Ccr followed a parabolic trend, with a higher Ccr in the HNA as compared with control and a lower Ccr in the MA and macroalbuminuria group as compared with HNA. With each increasing UAE level, male sex, age, body mass index, minimal waist circumference, systolic and diastolic BP, plasma glucose, and a positive family history for diabetes all followed a significant linear increasing trend (P

Background. Remikiren is an orally active renin inhibitor with established antihypertensive efficacy. As a single dose it induces renal vasodilatation, suggesting specific renal actions. Data on the renal effects of continued treatment by renin inhibition are not available, either in subjects with normal, or in subjects with impaired renal function. Methods. The effect of 8 days of treatment with remikiren 600 mg o.i.d. on blood pressure, renal haemodynamics, and proteinuria was studied in 14 hypertensive patients with normal or impaired renal function. The study was conducted on an ambulatory in-hospital basis and was designed in a single-blind, longitudinal order. Results. Remikiren induced a significant peak fall in mean arterial pressure of 11.2 +/- 0.8%, with corresponding trough values of -6 +/- 0.8%. This fall was somewhat more pronounced in the patients with renal function impairment (-13.3 vs -9.6%; P

We assessed the effect of insulin and atrial natriuretic peptide (ANP) on renal sodium handling in eight patients with sickle cell disease (SCD), who are characterized by loss of vasa recta and long loops of Henle, and matched control subjects. During insulin infusion (50 mU.kg(-1).h(-1)), fractional sodium excretion decreased by 0.44 +/- 0.72% (P = 0.13) in patients with SCD and by 0.57 +/- 0.34% (P = 0.002) in control;subjects, whereas fractional distal sodium reabsorption increased by 4.1 +/- 1.5% (P

We assessed the effect of insulin and atrial natriuretic peptide (ANP) on renal sodium handling in eight patients with sickle cell disease (SCD), who are characterized by loss of vasa recta and long loops of Henle, and matched control subjects. During insulin infusion (50 mU.kg(-1).h(-1)), fractional sodium excretion decreased by 0.44 +/- 0.72% (P = 0.13) in patients with SCD and by 0.57 +/- 0.34% (P = 0.002) in control;subjects, whereas fractional distal sodium reabsorption increased by 4.1 +/- 1.5% (P

The natriuretic response to a dopamine 1-like receptor agonist is blunted in spontaneously hypertensive rats (SHRs). Whether the renal vasodilator response to D-1-like receptor stimulation in SHRs is defective also is unclear. To determine whether the renal hemodynamic response to a D-1-like receptor is impaired in SHR, we examined the effect of a continuous infusion of the D-1-like receptor agonist fenoldopam (2 mu g/kg/min) on systemic and renal hemodynamics in conscious SHRs and Wistar-Kyoto (WKY) rats. As an active control, we used an equivalent antihypertensive dosage of captopril (10 mg/kg). Fenoldopam significantly increased effective renal plasma flow (ERPF) in WKY rats (+22 +/- 5%; p

The natriuretic response to a dopamine 1-like receptor agonist is blunted in spontaneously hypertensive rats (SHRs). Whether the renal vasodilator response to D-1-like receptor stimulation in SHRs is defective also is unclear. To determine whether the renal hemodynamic response to a D-1-like receptor is impaired in SHR, we examined the effect of a continuous infusion of the D-1-like receptor agonist fenoldopam (2 mu g/kg/min) on systemic and renal hemodynamics in conscious SHRs and Wistar-Kyoto (WKY) rats. As an active control, we used an equivalent antihypertensive dosage of captopril (10 mg/kg). Fenoldopam significantly increased effective renal plasma flow (ERPF) in WKY rats (+22 +/- 5%; p

We questioned the superiority of angiotensin converting enzyme (ACE) inhibitors to beta blocking drugs with regard to renal function outcome in patients with mild to moderate renal insufficiency and normal to moderately elevated blood pressure (BP). We therefore studied 89 patients in a prospective double-blind randomized trial comparing the effect of enalapril and atenolol on the slope of glomerular filtration rate (GFR). Mean baseline GFR was 53 +/- 20 ml/min, untreated BP 152 +/- 20 mm Hg systolic and 90 +/- 11 mm Hg diastolic and median proteinuria 0.6 g/24 hr (interquartile range 0.0 to 2.5). After a run-in period without antihypertensives, the test drug was titrated to lower diastolic BP to a predefined goal of 10 mm Hg below baseline and/or below 95 mm Hg. The median follow up was 3.9 years. Antihypertensive therapy resulted in a comparable decrease of BP in both study groups. Filtration fraction and proteinuria decreased in both groups. The slept of GFR over time was not different between both groups (-1.39 +/- 2.82 and -1.97 +/- 3.38 ml/min/year on atenolol and enalapril, respectively). In multiple regression analysis a higher baseline GFR, a greater decrease in GFR and in proteinuria during titration and a lower proteinuria during follow up were independently related to a better GFR slope. We conclude that the use of ACE inhibitors is not imperative in all patients with non-diabetic nephropathy.

We questioned the superiority of angiotensin converting enzyme (ACE) inhibitors to beta blocking drugs with regard to renal function outcome in patients with mild to moderate renal insufficiency and normal to moderately elevated blood pressure (BP). We therefore studied 89 patients in a prospective double-blind randomized trial comparing the effect of enalapril and atenolol on the slope of glomerular filtration rate (GFR). Mean baseline GFR was 53 +/- 20 ml/min, untreated BP 152 +/- 20 mm Hg systolic and 90 +/- 11 mm Hg diastolic and median proteinuria 0.6 g/24 hr (interquartile range 0.0 to 2.5). After a run-in period without antihypertensives, the test drug was titrated to lower diastolic BP to a predefined goal of 10 mm Hg below baseline and/or below 95 mm Hg. The median follow up was 3.9 years. Antihypertensive therapy resulted in a comparable decrease of BP in both study groups. Filtration fraction and proteinuria decreased in both groups. The slept of GFR over time was not different between both groups (-1.39 +/- 2.82 and -1.97 +/- 3.38 ml/min/year on atenolol and enalapril, respectively). In multiple regression analysis a higher baseline GFR, a greater decrease in GFR and in proteinuria during titration and a lower proteinuria during follow up were independently related to a better GFR slope. We conclude that the use of ACE inhibitors is not imperative in all patients with non-diabetic nephropathy.

Renal function measurement by clearance methods relies on accurately timed urine collection. In small experimental animals, renal function measurement is usually performed under anesthesia and/or with the application of bladder catheters to ensure accurate urine collection. To avoid both anesthesia and the need for bladder catheters we developed a method to measure glomerular filtration rate (GFR) in spontaneously voiding conscious rats. GFR was measured as the urinary clearance of constantly infused I-125-iothalamate. To correct for incomplete bladder emptying, urinary clearance of I-125-iothalamate was multiplied by the ratio of plasma and urinary clearance of simultaneously infused I-131-hippuran, a correction method that has been previously validated in humans. Reproducibility of the technique was evaluated by analysis of the results of four consecutive clearance periods during the day (intra-assay variation) in a group of 17 rats and of two consecutive clearance periods on two or three separate days in a group of 20 rats (inter-assay variation), all with normal renal function. Application of the correction method reduced the intra-assay coefficient of variation (mean +/- SD) from 37.4 +/- 14.3 to 5.4 +/- 2.3% (P

The effect of therapy on renal function after unilateral nephrectomy for Wilms' tumour was studied. In the second year following unilateral nephrectomy, glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were estimated simultaneously by measuring I-125-iothalamate clearance and I-131-hippurate clearance. Of 41 evaluable patients, 29 received chemotherapy as sole treatment modality following nephrectomy (group 1); 12 patients additionally received radiation therapy to a field that included the remaining kidney (group 2). Results were expressed as standard deviation scores (z-scores). In group 1, mean z-score for GFR was -0.27 (94.6% of normal) and in group 2 mean z-score was -1.51 (72.7% of normal for two kidneys) (P = 0.022, Mann-Whitney U-test). Mean z-score for ERPF was -0.09 (97.0%) in group 1 and -1.53 (73.8%) in group 2 (P = 0.039). It was concluded that the combination of chemotherapy and radiation therapy, in contrast to chemotherapy alone, negatively affects the ability of the remaining kidney to adjust its function after the loss of its counterpart.

11 beta-Hydrdxysteroid dehydrogenase (11 beta HSD) catalyzes the interconversion of cortisol and its inactive metabolite, cortisone, and protects the mineralocorticoid receptor from activation by cortisol. Sodium and fluid retention isa well documented phenomenon in insulin-dependent diabetes mellitus (IDDM), but it is not known whether diabetes-associated alterations in cortisol metabolism contribute td its pathogenesis. Therefore, we evaluated some aspects of cortisol metabolism by measuring urinary metabolites of cortisol and cortisone in eight microalbuminuric and eight normoalbuminmuric IDDM patients and eight matched control subjects. In both IDDM groups, the overnight excretion of tetrahydrocortisol (THF), allo-tetrahydrocortisol (allo-THF), and tetrahydrocortisone (THE) was lower than that in the control group (P

To study the hemodynamic and renal effects of the orally (p.o.) active dopamine (DA) agonist ibopamine, we examined 10 patients with mild to moderate congestive heart failure (CHF), who were stable while treated with digoxin and diuretics. All patients were in New York Heart Association (NYHA) functional class II-III; their mean age was 63 years (range 51-79 years), and mean left ventricular ejection fraction (LVEF) was 28% (range 18-36%). The protocol consisted of a control study-day with measurements of renal characteristics including glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and filtration fraction (FF). One week Later, systemic and renal hemodynamics were measured simultaneously before and after patients received one 100-mg tablet of ibopamine. Ibopamine caused a slight but significant increase in both ERPF (from 288 +/- 32 ml/min/1.73 m(2) at baseline to 316 +/- 32 ml/min/1.73 m(2) after ibopamine) and GFR (from 77 +/- 8 to 85 +/- 8 ml/min/1.73 m(2); both p

Imbalances in renal vasodilatory and vasoconstrictive mechanisms are responsible for the renal haemodynamic changes observed in Type 1 diabetes mellitus. Animal experiments have shown that noradrenaline (NA) infusion increases the intraglomerular pressure by predominantly efferent arteriolar vasoconstriction. The relationships between ambient plasma NA levels and renal haemodynamics were studied in 18 healthy control subjects (group C); in 17 normoalbuminuric diabetic patients (group D1) (albumin excretion rate (Ualb V)

The influence of CsA withdrawal on the glomerular filtration rate (GFR) and the effective renal plasma flow (ERPF) was prospectively studied in nine stable liver transplant recipients. Before CsA withdrawal (test 1), and 6 months thereafter (test 2) the renal function was determined by measuring GFR and the ERPF with I-125-iothalamate and I-131-hippuran respectively. The renal function was also stimulated with dopamine, with an amino-acid infusion and a combination of both. After CsA withdrawal the GFR increased, median from 74 ml min(-1) to 90 ml min(-1), (P

In order to study why the diagnostic sensitivity of I-123-hippurate renography for a renal artery stenosis is improved by angiotensin converting enzyme (ACE-) inhibition we used the model of the conscious chronically instrumented two-kidney, one-clip Goldblatt hypertensive dog. Urine flow (UV), renal blood flow (RBF), glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured (with constant infusion of I-125-iothalamate and I-131-hippurate, respectively) for both kidneys separately before and after a bolus injection of a mild unilateral renal artery stenosis (approximately 30% reduction of RBF). During ACE-inhibition, there were remarkable falls in poststenotic GFR (from 37 +/- 5 to 4 +/- 2 ml/min, p

We conducted a 2-year prospective randomised study to investigate the effects of a linoleic-acid-enriched diet on albuminuria and lipid levels in Type 1 (insulin-dependent) diabetic patients with elevated urinary albumin excretion (overnight urinary albumin excretion rate between 10 and 200-mu-g/min). Thirty-eight patients were randomly assigned to increase dietary polyunsaturated:saturated fatty acids ratio to 1.0 by replacement of saturated fat with linoleic-acid-rich products (n = 18, two dropouts, analysis was performed in n = 16) or to continue their usual diet (n = 20). The total fat and protein content of the diet was unaltered. Clinical characteristics, albuminuria, blood pressure, glomerular filtration rate, metabolic control and dietary composition were similar in the two groups at baseline. In the high linoleic acid diet group, linoleic intake rose from 7 +/- 4 to 11 +/- 2 energy % and polyunsaturated:saturated fatty acids ratio rose from 0.60 +/- 0.28 to 0.96 +/- 0.16 (p

A high sodium (HS) intake is associated to increased cardiovascular and renal risk, especially in overweight subjects. We hypothesized that abnormal sodium and fluid handling is involved, independent of hypertension or insulin resistance. Therefore, we studied the relation between BMI and sodium-induced changes in extracellular fluid volume (ECFV; distribution volume of (125)I-iothalamate) in 78 healthy men, not selected for BMI. A total of 78 subjects with a median BMI of 22.5 (range: 19.2-33.9 kg/m(2)) were studied after 1 week on a low sodium (LS) diet (50 mmol Na(+)/d) and after 1 week on HS (200 mmol Na(+)/d). The change from LS to HS resulted in an increase in ECFV of 1.2 +/- 1.81. Individual changes in ECFV were correlated to BMI (r = 0.361, P

Angiotensin converting enzyme (ACE) inhibitors are known to lower urinary protein excretion in human renal disease. This proteinuria lowering effect of ACE inhibition has been hypothesized to be a result of renal hemodynamic changes due to the inhibition of angiotensin II (Ang II) production. To test this hypothesis we studied the short-term effects of different doses of exogenous Ang II (5%, 10% and 20% of the pressor dose) on renal hemodynamics and urinary protein excretion in comparison with placebo infusion in six non-diabetic normotensive proteinuric patients, both before and after three months treatment with the ACE inhibitor, lisinopril. Lisinopril lowered proteinuria from 7.5 +/- 1.9 to 2.7 +/- 0.6 g/24 hr and induced a fall in blood pressure, renal vascular resistance and filtration fraction, whereas plasma Ang II level were similar to the pre-treatment values. Ang II infusion induced typical effects which appeared to be similar before and during lisinopril treatment: a dose-related fall in renal plasma flow and rise in systemic blood pressure, renal vascular resistance and filtration fraction, while the glomerular filtration rate remained relatively stable. However, neither before nor during lisinopril therapy did any changes in urinary protein loss occur during the infusions of Ang II, despite the fact that Ang II reversed the long-term systemic and renal hemodynamic changes induced by the ACE inhibitor. We conclude that the long-term antiproteinuric effect of the ACE inhibitor, lisinopril, is neither mediated through changes in circulatory Ang II levels nor influenced by acute changes in systemic and renal hemodynamics, suggesting a non-hemodynamic mechanism of action.

Although the renal clearance of Tc-99m-MAG3 is about 60% of the I-131-hippurate clearance, Tc-99m-MAG3 clearance may be useful to estimate ERPF. In one study, however, proteinuria seemed to influence the MAG3/hippurate clearance ratio. In order to establish whether proteinuria or serum albumin level has influence on this ratio, a comparison was made between Tc-99m-MAG3 clearance and I-131-hippurate clearance in 14 patients. There was a good linear correlation between MAG3 and hippurate clearance, although the standard error of estimate of ERPF from MAG3 was relatively large, which remained unexplained. No correlation was found between proteinuria and MAG3/hippurate clearance ratio nor between serum albumin level, GFR, FF, ERPF and the MAG3/hippurate clearance ratio. We therefore conclude that there is no correlation between proteinuria and albumin level and the MAG3/hippurate ratio. A reasonable estimation of ERPF with MAG3 can be made in patients with proteinuria and lowered serum albumin levels although the estimation may be less accurate.

Reduced glomerular filtration rate (GFR) is strongly associated with reduced survival in patients with chronic heart failure (CHF). Our aim was to determine different pathophysiologic markers that are associated with reduced renal function in CHF.We studied 86 patients with CHF (58 +/- A 12 years, 78% male). GFR and renal blood flow (RBF) were determined by (125)I-Iothalamate and (131)I-Hippuran clearances. Filtration fraction (FF) was calculated. We determined haemoglobin levels, endothelial function, inflammatory status, plasma renin activity (PRA) and N-terminal pro brain natriuretic peptide (NT-proBNP). Urinay albumin excretion (UAE) was measured in 24 h urine. Mean GFR was 74 +/- A 28 ml/min/1.73 m(2). GFR was strongly related to RBF (r = 0.915, P Reduced GFR is mainly dependent of decreased RBF in patients with CHF. Endothelial function and neurohormonal activation showed only mild associations with GFR. NT-proBNP showed a strong relationship with RBF, and may be used as a marker of reduced renal perfusion.

There is large interindividual variability in the antiproteinuric response to blockade of the renin-angiotensin-aldosterone system (RAAS). A low-sodium diet or addition of diuretics enhances the effects of RAAS blockade on proteinuria and BP, but the efficacy of the combination of these interventions is unknown. Therefore, this randomized, double-blind, placebo-controlled trial to determine the separate and combined effects of a low-sodium diet and hydrochlorothiazide (HCT) on proteinuria and BP was performed. In 34 proteinuric patients without diabetes, mean baseline proteinuria was 3.8 g/d, and this was reduced by 22% by a low-sodium diet alone. Losartan monotherapy reduced proteinuria by 30%, and the addition of a low-sodium diet led to a total reduction by 55% and the addition of HCT to 56%. The combined addition of HCT and a low-sodium diet reduced proteinuria by 70% from baseline (all P

Both renal and cardiovascular morbidity and mortality is increased markedly in patients with type 2 diabetes. Besides the classic risk factors and markers such as glucose, blood pressure, blood lipid profile, and lifestyle (smoking, overweight), novel risk markers are identified, among them urine albumin excretion. Levels of urinary albumin excretion greater than normal are observed frequently in patients with type 2 diabetes. Moderately increased levels of albuminuria, so-called microalbuminuria, are predictive both for progressive renal function loss to diabetic nephropathy, and for cardiovascular morbidity and mortality: the higher the albuminuria level, the more chance of renal and cardiovascular complications. More advanced levels of albuminuria (overt albuminuria) are observed in patients in the diabetic nephropathy state. in this condition, renal and cardiovascular risk are extremely high, and again one may observe that the level of albumin excretion is predictive of renal and cardiovascular outcome. Several drug strategies decrease the level of urinary albumin excretion in type 2 diabetic patients. Data on using drugs that intervene in the renin-angiotensin-aldosterone-system (RAAS) are the most extensive and conclusive. RAAS intervention is a very effective strategy to decrease the amount of albumin in the urine, independent from the blood pressure decreasing characteristics of the treatment. RAAS intervention is associated with long-term renal and cardiovascular protection. Importantly, the degree of short-term albuminuria decrease is associated with the degree of renal and cardiovascular protection: the more albuminuria reduction, the more protection. The protective predictive power of the albuminuria effect of RAAS intervention is not related to (or dissociated from) the blood pressure decreasing effect of these drugs. The protective effect of RAAS intervention is present at normoalbuminuric, microalbuminuric, and overt albuminuria levels. This makes albuminuria a target for therapy in type 2 diabetes. New drug strategies that decrease or prevent albuminuria without affecting other risk factors currently are being tested, and not only will add to underscoring the need to treat albuminuria as a separate target, but also will assist in reducing the enormous residual risk burden of individual diabetic patients. Semin Nephrol 27:172-181 (C) 2007 Elsevier Inc. All rights reserved.

The renin-angiotensin-aldosterone system is important in diabetic nephropathy, with the angiotensin-converting-enzyme DD-genotype being a renal risk factor. The D-allele is associated with higher ACE concentrations, but functional consequences in diabetes mellitus are not known. To analyse these consequences, we assessed renal and systemic responsiveness to angiotensin I infusion, with the response to angiotensin II as reference.Uncomplicated Type 1 (insulin-dependent) diabetic patients with contrasting genotypes (11 II and 11 DD) were studied, during low (50 mmol/24 h) and liberal (200 mmol/24 h) sodium diet, during a euglycaemic clamp. Angiotensin I was infused at 4 and 8 ng.kg(-1).min(-1), 1 h each, followed by infusions of angiotensin II after a 2-h wash-out period.During low sodium, DD-homozygotes showed higher blood pressure sensitivity to angiotensin I ( DD 21+/-5% vs II 15+/-5%, p0.01). With liberal sodium, no differences in blood pressure were detected, whereas angiotensin I induced a higher response of ERPF ( DD 40+/-5% vs II 35+/-4%, p0.05) and RVR ( DD 105+/-20% and II 89+/-16% p0.05) in DD-homozygotes. Differences were not explained by altered angiotensin II sensitivity. Multiple-linear regression analysis showed that angiotensin I induced responses of blood pressure and renal haemodynamics are higher in subjects carrying the DD-genotype. The magnitude of the responses was modulated by sodium intake and long-term glycaemic control.This study showed that responses of blood pressure and renal haemodynamics to angiotensin I are increased in diabetic subjects carrying the DD-genotype. Genotype-associated differences in ACE concentrations could, under certain circumstances, have functional consequences in uncomplicated Type 1 diabetes mellitus.

In experimental animal models of renal disease the degree of renal damage varies between individuals. This could be caused by variation in the noxious event or by differences in individual susceptibility. Intact endothelial function is assumed to provide a defense mechanism against progressive renal damage. This study hypothesized that interindividual differences in renal endothelial function might be involved in individual susceptibility to renal damage, and it investigated whether endothelial function of small renal arteries before induction of 5/6 nephrectomy (5/6 Nx) in rats was related to development of renal damage after 5/6 Nx. Wistar rats underwent 5/6 Nx, and small renal arteries of the removed right kidney were investigated for endothelium-dependent relaxation to acetylcholine (ACh, 10(-8) to 10(-4) mol/L). The contribution of underlying endothelial dilative mediators, NO, prostaglandins (PG), and endothelium-derived hyperpolarizing factor (EDHF), was assessed using the inhibitors, L-NMMA, indomethacin, and charybdotoxin+apamin, respectively. After 5/6 Nx, proteinuria developed in each rat ranging from 22 to 278 (84 +/- 14) mg/24 h at week 5 (n = 23). Interestingly, a significant inverse correlation between individual ACh-relaxation (expressed as area under curve in arbitrary units) and proteinuria 5 wk after 5/6 Nx was found (r = -0.54; P = 0.008; n = 23). An inverse correlation was also found between individual NO contribution as well as PG contribution and proteinuria 5 wk after 5/6 Nx (r = -0.86, P = 0.001, n = 11; and r = -0.74, P = 0.01, n = 11, respectively). In addition, individual ACh-relaxation was positively correlated with GFR measured 6 wk after 5/6 Nx (r = 0.58; P = 0.016; n = 17). This study demonstrates for the first time that individual renal endothelial dilatory function of the healthy rat predicts susceptibility to renal damage after 5/6 Nx, which seems to depend on individual endothelial NO and PG activity.

1 In previous studies on the renal targeting of the ACE inhibitor captopril, we demonstrated that a 6 fold increased concentration of this drug could be obtained in the kidney after conjugation to the low-molecular-weight protein lysozyme. In this study, we investigated in unrestrained rats whether systemic administration of captopril-lysozyme also 'results in an enhanced effect on renal parameters, relative to the systemic effects. 2 Renal effects: intravenous infusion of captopril-lysozyme for 6 h resulted in a more pronounced increment of renal blood flow (31 +/- 2% vs 17 +/- 4% at 0.5 mg kg(-1) 6h(-1), P

Aims/hypothesis. Type I (insulin-dependent) diabetes mellitus is associated with an increased extracellular volume. Sodium restriction might seem a logical form of treatment but data on its renal effects is conflicting. We therefore studied the effects of sodium restriction on renal haemodynamics in uncomplicated Type I diabetes mellitus. Methods. Uncomplicated Type I diabetic patients (n = 24) and matched control subjects (n = 24) were studied twice in random order: after a week of 50 mmol or after 200 mmol sodium intake, respectively. The diabetic patients were studied under normoglycaemic clamp conditions. Glomerular filtration rate and effective renal plasma flow were measured as the clearances of iothalamate and hippuran, respectively. Results. During liberal sodium intake, glomerular filtration, effective renal plasma flow and filtration fraction were similar between the diabetic patients and the control subjects. Sodium restriction decreased the effective renal plasma flow in both groups, whereas glomerular filtration rate only decreased in the control subjects. Consequently, in the diabetic patients, the filtration fraction was increased on low sodium (4.1 +/- 8.4 %, p

Background. Interference in the renin-angiotensin system with angiotensin-converting enzyme (ACE) inhibitors has proven to be effective in lowering albuminuria in patients with insulin-dependent diabetes mellitus (IDDM). We studied whether angiotensin II receptor antagonism reduces urinary albumin excretion (UAE) in IDDM patients, and the relationship between the antiproteinuric effect and changes in systemic and renal haemodynamics. Methods. Nine IDDM patients with microalbuminuria (30-300 mg/24 h) were studied. patients were studied after a 4 week placebo period, on days 3, 7 and 28 of treatment with losartan 50 mg once daily, and after a 4 week placebo-controlled recovery period. Results. Mean arterial pressure (MAP) was only slightly lowered during losartan treatment. Effective renal plasma flow (ERPF) was significantly increased on the third day of treatment and remained stable throughout the treatment period. Glomerular filtration rate (GFR) did not change throughout the study. Filtration fraction (FF) was maximally lowered on the third day of treatment and remained stable during treatment. UAE was already significantly lowered after 2 days of treatment, during both the day and night, and remained stable throughout the treatment period. The time course of the changes in UAE paralleled that of the changes in MAP, ERPF and FF. Conclusions. The angiotensin receptor antagonist losartan effectively lowers UAE in microalbuminuric IDDM patients. The changes observed in renal haemodynamics and UAE are concordant in time and maximal within only a few days of treatment. These results support the importance of the specific effects of interference in the renin angiotensin system (RAS) in microalbuminuric IDDM on blood pressure and renal haemodynamics in reducing urinary protein leakage, rather than non-haemodynamic, structural changes of the glomerular basement membrane.

Background Impaired vasodilatation in skeletal muscle is a possible mechanism linking insulin resistance to blood pressure regulation. Increased renal vascular resistance has been demonstrated in the offspring of essential hypertensives. We assessed whether insulin-mediated renal vasodilatation is impaired in insulin-resistant normal subjects. Design In two groups of 10 insulin-resistant and 10 insulin-sensitive normal subjects, we compared the effects of sequential physiological and supraphysiological insulin dosages (50 and 150 mU kg(-1) h(-1)) on renal plasma flow (RPF) and leg blood flow using the euglycaemic clamp technique, I-131-labelled Hippuran clearances and venous occlusion plethysmography. Time-control experiments were performed in the same subjects. Results Whole-body glucose uptake amounted to 4.9 +/- 2.1 and 11.0 +/- 2.4 mg kg (-1)min(-1) in the insulin-resistant and to 12.7 +/- 2.3 and 17.4 +/- 2.6 mg kg (-1)min(-1) in the insulin-sensitive subjects during physiological and supraphysiological hyperinsulinaemia, respectively. RPF increased more in insulin-sensitive compared to insulin-resistant subjects during physiological hyperinsulinaemia (13.7 vs. 6.8%, P

Microalbuminuria (MA) is an important early sign of diabetic nephropathy. Hyperfiltration and impaired filtration in relation to albuminuria has been well investigated in diabetic subjects. This study tested the hypothesis that an increased urinary albumin excretion (UAE) is associated with renal functional abnormalities also in nondiabetic subjects. The relation between UAE and creatinine clearances (Ccr) in 7728 nondiabetic subjects was studied. Subjects were divided in four groups according to UAE (mg/24 h): 0 to 15 (control), 15 to 30 (high-normal albuminuria [HNA]), 30 to 300 (MA), >300 (macroalbuminuria). An elevated filtration and a diminished filtration were defined as a Ccr exceeding or below 2x the SD of the control group corrected for age and gender. Ccr followed a parabolic trend, with a higher Ccr in the HNA as compared with control and a lower Ccr in the MA and macroalbuminuria group as compared with HNA. With each increasing UAE level, male sex, age, body mass index, minimal waist circumference, systolic and diastolic BP, plasma glucose, and a positive family history for diabetes all followed a significant linear increasing trend (P < 0.001). After adjustment for age, gender, body mass index, plasma glucose, a positive family history for diabetes, systolic and diastolic BP, antihypertensive medication, and smoking in a multivariate analysis, HNA and MA were independently associated with an elevated filtration (RR 1.8 [95% confidence interval, 1.30 to 2.51] and 1.7 [1.17 to 2. 45]). Macroalbuminuria was independently associated with a diminished filtration (4.3 [range, 1.97 to 9.36]). In conclusion, an elevated UAE might be an important and early sign for progressive renal function loss in a nondiabetic population.

We assessed the effect of insulin and atrial natriuretic peptide (ANP) on renal sodium handling in eight patients with sickle cell disease (SCD), who are characterized by loss of vasa recta and long loops of Henle, and matched control subjects. During insulin infusion (50 mU.kg(-1).h(-1)), fractional sodium excretion decreased by 0.44 +/- 0.72% (P = 0.13) in patients with SCD and by 0.57 +/- 0.34% (P = 0.002) in control;subjects, whereas fractional distal sodium reabsorption increased by 4.1 +/- 1.5% (P

We previously described a method to measure GFR in conscious spontaneously voiding rats. This method circumvents the need for anesthesia and for bladder instrumentation. If's main principle is the correction of renal I-125-iothalamate clearance for incomplete urine collection by the ratio of plasma and venal clearance of co-infused I-131-Hippuran. A disadvantage of this technique is the requirement of an infra-arterial catheter for infusion of the renal function tracers. We therefore tested whether intraperitoneal infusion of I-125-iothalamate and I-131-Hippuran can be used far such a GFR measurement in conscious spontaneously voiding rats. We found that during intraperitoneal administration, stable plasma levels of I-131-Hippuran could be obtained. However, urinary recovery of I-131-Hippuran was incomplete (66 +/- 32%), leading to a significant overestimation of GFR by 140 +/- 13% in comparison with the GFR measured by the intra-arterial technique. Thus intraperitoneal infusion of renal function tracers cannot replace intra-arterial infusion.

We questioned the superiority of angiotensin converting enzyme (ACE) inhibitors to beta blocking drugs with regard to renal function outcome in patients with mild to moderate renal insufficiency and normal to moderately elevated blood pressure (BP). We therefore studied 89 patients in a prospective double-blind randomized trial comparing the effect of enalapril and atenolol on the slope of glomerular filtration rate (GFR). Mean baseline GFR was 53 +/- 20 ml/min, untreated BP 152 +/- 20 mm Hg systolic and 90 +/- 11 mm Hg diastolic and median proteinuria 0.6 g/24 hr (interquartile range 0.0 to 2.5). After a run-in period without antihypertensives, the test drug was titrated to lower diastolic BP to a predefined goal of 10 mm Hg below baseline and/or below 95 mm Hg. The median follow up was 3.9 years. Antihypertensive therapy resulted in a comparable decrease of BP in both study groups. Filtration fraction and proteinuria decreased in both groups. The slept of GFR over time was not different between both groups (-1.39 +/- 2.82 and -1.97 +/- 3.38 ml/min/year on atenolol and enalapril, respectively). In multiple regression analysis a higher baseline GFR, a greater decrease in GFR and in proteinuria during titration and a lower proteinuria during follow up were independently related to a better GFR slope. We conclude that the use of ACE inhibitors is not imperative in all patients with non-diabetic nephropathy.

11 beta-Hydrdxysteroid dehydrogenase (11 beta HSD) catalyzes the interconversion of cortisol and its inactive metabolite, cortisone, and protects the mineralocorticoid receptor from activation by cortisol. Sodium and fluid retention isa well documented phenomenon in insulin-dependent diabetes mellitus (IDDM), but it is not known whether diabetes-associated alterations in cortisol metabolism contribute td its pathogenesis. Therefore, we evaluated some aspects of cortisol metabolism by measuring urinary metabolites of cortisol and cortisone in eight microalbuminuric and eight normoalbuminmuric IDDM patients and eight matched control subjects. In both IDDM groups, the overnight excretion of tetrahydrocortisol (THF), allo-tetrahydrocortisol (allo-THF), and tetrahydrocortisone (THE) was lower than that in the control group (P