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Increased protein intake versus maltodextrin intake for 4 weeks lowers blood pressure. Concerns exist that high-protein diets reduce renal function. Effects of acute and 4-week protein intake versus maltodextrin intake on renal acid load, glomerular filtration rate and related parameters were compared in this study. Seventy-nine overweight individuals with untreated elevated blood pressure and normal kidney function were randomized to consume a mix of protein isolates (60 g/day) or maltodextrin (60 g/day) for 4 weeks in energy balance. Twenty-four-hour urinary potential renal acid load (uPRAL) was compared between groups. A subgroup (maltodextrin N = 27, protein mix N = 25) participated in extra test days investigating fasting levels and postprandial effects of meals supplemented with a moderate protein- or maltodextrin-load on glomerular filtration rate, effective renal plasma flow, plasma renin, aldosterone, pH, and bicarbonate. uPRAL was significantly higher in the protein group after 4 weeks (P ≤ 0.001). Postprandial filtration fraction decreased further after the protein-supplemented breakfast than after the maltodextrin-supplemented breakfast after 4 weeks of supplementation (P ≤ 0.001). Fasting and postprandial levels of glomerular filtration rate, effective renal plasma flow, renin, aldosterone, angiotensin-converting enzyme, pH and bicarbonate did not differ between groups. In conclusion, 4 weeks on an increased protein diet (25% of energy intake) increased renal acid load, but did not affect renal function. Postprandial changes, except for filtration fraction, also did not differ between groups. These data suggest that a moderate increase in protein intake by consumption of a protein mix for 4 weeks causes no (undesirable) effects on kidney function in overweight and obese individuals with normal kidney function.

Aims To determine the acute effect of glucagon-like peptide-1 (GLP-1) receptor agonist exenatide and the involvement of nitric oxide (NO) on renal haemodynamics and tubular function, in healthy overweight men. Methods Renal haemodynamics and tubular electrolyte handling were measured in 10 healthy overweight men (aged 20–27 years; BMI 26–31 kg/m2) during intravenous administration of placebo (saline 0.9%), exenatide, and exenatide combined with the NO-synthase inhibitor L-NG-monomethyl arginine (L-NMMA). Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippurate clearance techniques, respectively, based on timed urine sampling. Glomerular hydrostatic pressure and vascular resistance of afferent and efferent renal arterioles were calculated using the Gomez formulae. Urinary electrolytes, osmolality and pH were also measured. Results GFR increased by a mean of 18 ± 20 (+20%; p = 0.021) and ERPF increased by a median (interquartile range) of 68 (26; 197) ml/min/1.73 m2 (+14%; p = 0.015) during exenatide infusion versus placebo. During L-NMMA infusion, exenatide increased GFR by mean 8 ± 12 ml/min/1.73 m2 (+9%; p = 0.049). Exenatide increased estimated glomerular pressure by +6% (p = 0.015) and reduced afferent renal vascular resistance by −33% (p = 0.038), whereas these effects were blunted during L-NMMA infusion. Exenatide increased absolute and fractional sodium excretion, urinary osmolality and urinary pH. The tubular effects of exenatide were not altered by concomitant L-NMMA infusion. Conclusions Exenatide infusion in healthy overweight men acutely increases GFR, ERPF and glomerular pressure, probably by reducing afferent renal vascular resistance, and at least partially in an NO-dependent manner. As baseline renal haemodynamics in patients with type 2 diabetes differ from those in healthy individuals, clinical studies on the renal effects of GLP-1 receptor agonists are warranted.

The measurement of glomerular filtration rate by the clearance of inulin or creatinine has evolved over the past 50 years into an estimated value based solely on plasma creatinine concentration. We have examined some of the misconceptions and misunderstandings of the classification of renal disease and its course, which have followed this evolution. Furthermore, renal plasma flow and tubular function, which in the past were estimated by the clearance of the exogenous aryl amine, para-aminohippurate, are no longer measured. Over the past decade, studies in experimental animals with reduced nephron mass and in patients with reduced renal function have identified small gut-derived, protein-bound uremic retention solutes (“uremic toxins”) that are poorly filtered but are secreted into the lumen by organic anion transporters (OATs) in the proximal renal tubule. These are not effectively removed by conventional hemodialysis or peritoneal dialysis. Residual renal function, urine produced in patients with advanced renal failure or undergoing dialysis treatment, may represent, at least in part, secretion of fluid and uremic toxins, such as indoxyl sulfate, mediated by proximal tubule OATs and might serve as a useful survival function. In light of this new evidence of the physiological role of proximal tubule OATs, we suggest that measurement of renal tubular function and renal plasma flow may be of considerable value in understanding and managing chronic kidney disease. Data obtained in normal subjects indicate that renal plasma flow and renal tubular function might be measured by the clearance of the endogenous aryl amine, hippurate.

Background The role of kidney hypoxia is considered pivotal in the progression of chronic kidney disease. A widely used method to assess kidney oxygenation is blood oxygen level dependent ( BOLD )–magnetic resonance imaging ( MRI ), but its interpretation remains problematic. The BOLD ‐ MRI signal is the result of kidney oxygen consumption (a proxy of glomerular filtration) and supply (ie, glomerular perfusion). Therefore, we hypothesized that with pharmacological modulation of kidney blood flow, renal oxygenation, as assessed by BOLD ‐ MRI , correlates to filtration fraction (ie, glomerular filtration rate/effective renal plasma flow) in healthy humans. Methods and Results Eight healthy volunteers were subjected to continuous angiotensin‐ II infusion at 0.3, 0.9, and 3.0 ng/kg per minute. At each dose, renal oxygenation and blood flow were assessed using BOLD and phase‐contrast MRI . Subsequently, “gold standard” glomerular filtration rate/effective renal plasma flow measurements were performed under the same conditions. Renal plasma flow decreased dose dependently from 660±146 to 467±103 mL/min per 1.73 m 2 (F[3, 21]=33.3, P 2 (F[1.8, 2.4]=6.4, P =0.013). Cortical transverse relaxation rate (R2*; increases in R2* represent decreases in oxygenation) increased by 7.2±3.8% (F[3, 21]=7.37, P =0.001); medullar R2* did not change. Cortical R2* related to filtration fraction ( R 2 0.46, P Conclusions By direct comparison between “gold standard” kidney function measurements and BOLD MRI , we showed that cortical oxygenation measured by BOLD MRI relates poorly to glomerular filtration rate but is associated with filtration fraction. For future studies, there may be a need to include renal plasma flow measurements when employing renal BOLD ‐ MRI .

Antenatal corticosteroid exposure reduces renal function and alters the intrarenal renin-angiotensin system to favor angiotensin activation of angiotensin type 1 receptor (AT1R) mediated responses in ovine offspring. This study aimed to assess whether antenatal steroid exposure would affect renal responses to the direct intrarenal infusion of angiotensin-(1-7) in rams and the angiotensin receptors involved in mediating responses to the peptide. Adult, uninephrectomized rams exposed to either betamethasone or vehicle before birth received intrarenal angiotensin-(1-7) infusions (1 ng/kg/min) alone or in combination with antagonists to angiotensin receptors for 3 h. Basal sodium excretion (UNa) was significantly lower and mean arterial pressure was significantly higher in betamethasone- compared to the vehicle-treated sheep. Angiotensin-(1-7) decreased UNa more in betamethasone- than in vehicle-treated sheep. Candesartan reversed the response to angiotensin-(1-7) but D-Ala(7)-angiotensin-(1-7) did not. Angiotensin-(1-7) infusion decreased effective renal plasma flow in both groups to a similar extent and the response was reversed by candesartan, but was not blocked by D-Ala(7)-angiotensin-(1-7). Glomerular filtration rate increased significantly in both groups after 3 h infusion of angiotensin-(1-7) plus candesartan. These results suggest that antenatal exposure to a clinically relevant dose of betamethasone impairs renal function in rams. Moreover, angiotensin-(1-7) appears capable of activating the AT1R in uninephrectomized rams.

To evaluate the technical feasibility, safety and functional outcomes of zero ischaemia laparoscopic and robotic partial nephrectomy with controlled hypotension for renal tumours larger than 4 cm. We evaluated 121 consecutive patients with American Society of Anaesthesiologists (ASA) scores 1–2 who underwent laparoscopic (n = 70) or robotic (n = 51) partial nephrectomy with controlled hypotension with either tumour size ≤4 cm (group 1, n = 78) or tumour size >4 cm (group 2, n = 43) performed by a single surgeon from December 2010 to December 2011. Operative data, complications, serum creatinine, estimated glomerular filtration rates and effective renal plasma flow calculated from 99mTc-mercaptoacetyltriglycine renal scintigraphy were compared. Differences between groups were evaluated by the Chi-square test and the Student’s t test. A significant difference in mean intraoperative blood loss and postoperative complications was found between the two groups: 168 ml (range: 10–600 ml in group 1) and 205 ml (range: 90–700 ml in group 2); p = 0.005, and 6.4 % versus 18.6 %; p = 0.004, respectively. The mean percentage decrease of ERPF of the operated kidney was 1.8 % in group 1 and 4.1 % in group 2. Laparoscopic and robotic partial nephrectomy with controlled hypotension for tumours >4 cm in ASA 1–2 patients was feasible with significant higher intraoperative blood loss and postoperative complications compared to smaller renal masses. The benefits of avoiding hilar clamping to preserve kidney function seem excellent.

Homeostatic and excretory functions of the kidney depend on blood flow (∼25% cardiac output) and glomerular ultrafiltration (∼20% renal plasma flow). Blood flow distribution is not uniform, with only 10% reaching the medulla. Selectivity of ultrafiltration is related to molecular size, shape and electrostatic charge of molecules, and structure of the glomerular capillary barrier with its negatively charged glycoproteins. Ultrafiltration, determined by the balance between hydrostatic and colloid osmotic pressures (Starling forces) in the glomerular capillary and Bowman's space, occurs along the length of the capillary: hydrostatic pressure is relatively unchanged and always exceeds plasma colloid osmotic pressure plus pressure in Bowman's space. Ultrafiltration is influenced by changes in renal plasma flow, altered surface area (mesangial cell activity) and changes in vascular resistance afforded by afferent and efferent arterioles (mediated by sympathetic nerve activity, vasoconstrictors and vasodilators). Autoregulation of renal plasma flow minimizes changes in ultrafiltration (hence, filtered load). Myogenic and tubuloglomerular feedback mechanisms are responsible for autoregulation, but their relative contribution is yet to be resolved. Clearance measurements are used to assess renal plasma flow (RPF), glomerular filtration rate (GFR) (creatinine, inulin), filtration fraction (GFR/RPF), net reabsorption or secretion, and proximal and distal nephron function (lithium, free-water) but all have their limitations.

Objectives To evaluate and compare the relative contribution of different therapeutic agents for renoprotection against complete unilateral ureteric obstruction (UUO), using a rabbit model sampled at different times. Materials and methods Eighty-four male New Zealand White rabbits were divided into seven groups of 12 rabbits; a sham group, a control (left UUO + no medication) or left UUO and treated with either enalapril, losartan, verapamil, l -arginine or antioxidant (vitamin E and selenium mixture). Rabbits in the control and treated groups were subjected to 3, 10 and 21 days of complete ureteric ligation and then killed humanely. The control and treated groups were evaluated at baseline and at the end of the experiment, by measuring split effective renal plasma flow (ERPF) using diuretic renography, and the split glomerular filtration rate (GFR) using selective creatinine clearance. Renal histopathology was evaluated using a tubulo-interstitial damage score. Results In the sham group there was no significant effect on any of the evaluated variables. For split ERPF, losartan showed the highest renoprotective effect, saving 44% and 77% of ERPF at 3 and 21 days after UUO, respectively. Losartan was also the best renoprotective agent for GFR. For renal histopathology, enalapril showed the earliest and greatest improvement as assessed by the damage score, reaching 60% at 21 days after UUO. l -Arginine was the next best effect to blockade the renin-angiotensin system for renoprotection. Conclusion We suggest that blockade of the renin-angiotensin system provides the best renoprotection against the effects of complete UUO.

OBJECTIVE To test the idea that a pause (~3-min) in the delivery of shock waves (SW) soon after the initiation of treatment is unnecessary for achieving a reduction in renal injury, if treatment is begun at a low power setting that generates low-amplitude SWs. MATERIALS AND METHODS Anesthetized female pigs were assigned to one of three SWL treatment protocols that did not involve a pause in SW delivery of more than 10 seconds (2000 SWs at 24 kV; 100 SWs at 12 kV + ~10-sec pause + 2000 SWs at 24 kV; 500 SWs at 12 kV + ~10-sec pause + 2000 SWs at 24 kV; all SWs delivered at 120 SWs/min using an unmodified Dornier HM3 lithotripter). Renal function was measured before and after SWL. The kidneys were then processed for quantification of the SWL-induced hemorrhagic lesion. Values for lesion size were compared to previous data collected from pigs in which treatment included a 3-min pause in SW delivery. RESULTS All SWL treatment protocols produced a similar degree of vasoconstriction (23–41% reduction in GFR and ERPF) in the SW-treated kidney. The mean renal lesion in pigs treated with 100 low-amplitude SWs delivered before the main dose of 2000 high-amplitude SWs (2.27% FRV) was statistically similar to that measured for pigs treated with 2000 SWs all at high-amplitude (3.29% FRV). However, pigs treated with 500 low-amplitude SWs before the main SW dose had a significantly smaller lesion (0.44% FRV) that was comparable to the lesion in pigs from a previous study in which there was a 3-min pause in treatment separating a smaller initial dose of 100 low-amplitude SWs from the main dose of 2000 high-amplitude SWs (0.46% FRV). Time between the initiation of the low- and high-amplitude SWs was ~4-min for these latter two groups compared to ~1-min when there was negligible pause after the initial 100 low-amplitude SWs in the protocol. CONCLUSIONS Pig kidneys treated by SWL using a 2-step low-to-high power ramping protocol were protected from injury with negligible pause between steps, provided the time between the initiation of low-amplitude SWs and switching to high-amplitude SWs was ~4-min. Comparison with results from previous studies shows that protection can be achieved using various step-wise treatment scenarios in which either the initial dose of SWs is delivered at low-amplitude for ~4-min, or there is a definitive pause before resuming SW treatment at higher amplitude. Thus, we conclude that renal protection can be achieved without instituting a pause in SWL treatment. It remains prudent to consider that renal protection depends on the acoustic and temporal properties of SWs administered at the beginning stages of a SWL ramping protocol, and that this may differ according to the lithotripter at hand. Keywords: kidney, lithotripsy, swine, tissue injury INTRODUCTION An undesirable side effect of SWL treatment is that SWs can injure renal and surrounding tissue [1]. The primary acute lesion is vascular trauma with breakage of blood vessels and pooling of blood within the parenchyma, which if extending to the kidney surface will result in subcapsular or perirenal hematomas [1]. Along with the vascular insult, there is damage to tubules and the production and release of proinflammatory cytokines and injurious agents (e.g. iron/reactive oxygen metabolites; vasoconstrictor peptides/ischemia; metabolic toxins) that can result in fibrosis and the loss of functional tissue [1,2]. Such SW-induced injury has been linked to adverse outcomes such as hypertension, diabetes and exacerbation of kidney stone disease [3–5]. This raises concern about the long-term safety of SWL, and developing SWL treatment strategies that reduce or prevent tissue injury would certainly help mitigate such concerns. One approach to reduce SWL-induced tissue injury has been to alter the manner in which SWs are delivered to the kidney [2,6], and in this regard we have reported that treatment of the pig kidney with low-amplitude SWs followed by a 3-min pause in treatment prior to applying high-amplitude SWs will reduce SWL-induced hemorrhagic lesion sizes by as much as 20-fold [7]. In fact, similar protocols in which low-amplitude SWs were substituted with a relatively small number of higher-amplitude SWs were also shown to reduce SW-induced tissue damage, implicating the 3-min pause in treatment to be a critical factor in the development of the renal protective response [8]. On the other hand, some clinical centers begin SWL treatment at a low power setting to condition the patient to treatment-related discomfort and then gradually ramp up to higher levels with continuous delivery of SWs. That is, there is typically no pause in treatment during the lithotripsy session [9–12]. It is unclear even with power ramping if continuous delivery of SWs can be used to protect the kidney from injury. Therefore, we sought to determine in our pig model, using a 2-step ramping protocol, whether a definitive pause in SW delivery is needed in order to protect the kidney from SWL-related tissue damage.

We evaluated urinary endothelin (ET)-1-like Immunoreactivity (uET-1 L) excretion in Wilms tumor (WT) survivors and investigated its relationships with glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). Glomerular hemodynamics were also assessed by Gomez formulae.Seventeen WT survivors underwent renal sequential scintigraphy for residual kidney function determination including ERPF and GFR. Forty-five healthy individuals were selected as the control group. uET-1 L was measured by radioimmunoassay from the 24-h urine collection.In WT survivors, uET-1 L excretion was significantly higher than in controls. Significant correlations were found between uET-1 L and ERPF and GFR. Cluster analysis, applied on uET-1 L, identified two different patient groups. Between them, GFR and ERPF were significantly different. No significant difference existed between the two clusters for age and sex, elapsed time from nephrectomy, treatment, or nephrectomy side. Applying Gomez formulae, significant difference was found for afferent and total renal resistance.According to our results, uET-1 L seems to be a marker of glomerular injury in patients with renal mass loss revealing renal overload condition. The uET-1 L role in renal damage progression and hemodynamic glomerular worsening in nephrectomized patients should be proven by prospective long-term follow-up studies, even for potential ET-1 receptor antagonist therapeutic use.

Objective A decrease in renal function after partial nephrectomy caused by ischemic damage or nephron loss cannot be distinguished by conventional methods. We quantified renal function using a new 99m Tc-mercaptoacetyltriglycine ( 99m Tc-MAG3) renal scintigraphy parameter. Material and Methods We included 32 patients with a normally functioning contralateral kidney who received open partial nephrectomy with average warm ischemic time of 26.0 (range 14–46) min in this study. Effective renal plasma flow (ERPF) was calculated from 99m Tc-MAG3 renal scintigraphy before and at 1 week and 6 months after surgery. We also analyzed regional 99m Tc-MAG3 uptake in the surgically nonaffected parts. Results One week after surgery, average ERPF in the operated kidney decreased to 66.4% from baseline (from 177.8 to 116.9 mL/min/1.73 m 2 ) and regional 99m Tc-MAG3 uptake decreased to 83.4%. A stronger correlation was found between ischemic time and the decrease in regional 99m Tc-MAG3 uptake ( P P = .029). The decrease in regional 99m Tc-MAG3 uptake remained at 6 months in the group with ischemic time ≥25 minutes, whereas it recovered when ischemic time was Conclusion This new parameter quantified ischemic renal damage better than the conventional split functional evaluation. When warm ischemic time was ≥25 minutes, irreversible diffuse damage was seen in surgically preserved nephrons.

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.

Background: Women with a history of preeclampsia are at increased risk to develop end-stage renal disease. In this longitudinal study, we evaluated renal function in women with a history of severe preeclampsia and parous controls over a period of 14 years. Methods: Renal function was measured 1 and then 14 years postpartum by para-aminohippurate and inulin clearances in 20 women with a history of severe preeclampsia and 8 parous controls. Results: The difference in glomerular filtration rate 1 year postpartum between women with a history of preeclampsia and parous controls (112 ± 10 and 125 ± 8 ml/min/1.73 m2, p < 0.01) had disappeared 14 years postpartum (104 ± 10 and 109 ± 13 ml/min/1.73 m2, p = 0.37). There was a consistent trend for a lower effective renal plasma flow both 1 and 14 years postpartum (477 ± 90 and 543 ± 92, p = 0.09 and 473 ± 85 and 543 ± 98 ml/min/1.73 m2, p = 0.07). Conclusions: This explorative study suggests no accelerated renal function loss in the first decade after preeclampsia.

Aims Increased plasma uric acid (PUA) levels are associated with impaired renal function in patients with Type 1 diabetes, but the mechanisms are not well understood. Our aim was to evaluate whether higher PUA levels are associated with increased afferent arteriolar resistance in patients with Type 1 diabetes vs. healthy controls, thereby influencing renal function. Methods PUA, GFR (inulin) and effective renal plasma flow (ERPF; para-aminohippurate) were measured in 70 otherwise healthy patients with Type 1 diabetes and 60 healthy controls. Gomez's equations were used to estimate afferent (RA ) and efferent (RE ) arteriolar resistances, glomerular hydrostatic pressure (PGLO ) and filtration pressure (ΔPF ). The relationships between PUA and glomerular haemodynamic parameters were evaluated by univariable linear regression correlation coefficients. Results In patients with Type 1 diabetes, higher PUA correlated with lower PGLO (P = 0.002) and ΔPF (P = 0.0007), with higher RA (P = 0.001), but not with RE (P = 0.55). These associations were accompanied by correlations between higher PUA with lower GFR (P = 0.0007), ERPF (P = 0.008), RBF (P = 0.047) and higher RVR (P = 0.021). There were no significant correlations between PUA and renal haemodynamic parameters in the healthy controls. Conclusions The association between higher PUA with lower GFR and lower ERPF in patients with Type 1 diabetes is driven by alterations in the estimated RA . PUA-mediated RA may be caused by increased tone or thickening of the afferent renal arteriole, which might potentiate renal injury by causing ischaemia to the renal microcirculation.

Background The renin-angiotensin-aldosterone system (RAAS) plays a key role in the progression of heart failure (HF) and concomitant kidney dysfunction. Despite the use of RAAS blockade, sustained activation of RAAS has been suggested to link with adverse outcome. We aimed to investigate the prognostic value of active plasma renin concentration (APRC) and prorenin in patients with HF treated with RAAS-blocking agents and its relationship with kidney function parameters.Methods One hundred clinically stable patients with HF, treated with RAAS-blocking agents, were studied. Renal function parameters including effective renal plasma flow and glomerular filtration rate were measured invasively. The combined end point consisted of all-cause mortality, heart transplantation, and admission to hospital for HF.Results Mean age was 58 +/- 12 years, and 76% were men. Mean left ventricular ejection fraction was 28 +/- 9, and median APRC levels were 24.3 ng/mL per hour. Active plasma renin concentration was most strongly associated with mean arterial pressure (r = 0.60, P Conclusions Our data indicate that APRC is a strong prognostic factor in patients with HF in the presence of RAAS inhibition, especially in patients with kidney dysfunction. (Am Heart J 2011;162:487-93.)

Objective: To evaluate the clinical usefulness of effective renal plasma flow (ERPF) measured using preoperative mercaptoacetyltriglycine-3 (MAG3) renogram for the prediction of chronic renal insufficiency after nephrectomy. Methods: A total of 47 patients underwent preoperative MAG3 renal scintigraphy and subsequent unilateral nephrectomy. Correlations between the 5-year postoperative estimated glomerular filtration rate (eGFR) and the preoperative ERPF of the contralateral kidney (cERPF), ERPF of the diseased kidney (dERPF), total ERPF (tERPF), cERPF to dERPF ratio, serum creatinine (sCr) level, eGFR, as well as the influence of preoperative comorbidities (diabetes, hypertension) on the postoperative eGFR, were evaluated with both univariate and multivariate analyses. Results: Multiple linear regression analysis showed that preoperative cERPF significantly correlated with postoperative eGFR. However, a much stronger correlation was observed between the preoperative and postoperative eGFR. Multiple logistic regression analysis showed that only preoperative eGFR was a significant predicator of the development of advanced-stage chronic kidney disease (CKD). Conclusions: Preoperative MAG3 renogram is not superior to eGFR measurement as a prognostic indicator of long-term renal function after unilateral nephrectomy.

The purpose of this study was to evaluate the effects of antihypertensive drugs on renal hemodynamics in hypertensive patients during an adrenergic activation by mental stress (MS), which induces renal vasoconstriction in healthy subjects. Renal hemodynamics was assessed twice in 30 middle-aged essential hypertensive patients (57±6 years)-after 15 days of pharmacological wash-out and after 15 days of treatment with Trandolapril (T, 4 mg, n=10), Verapamil (V, 240 mg, n=10), or both (T 2 mg+V 180 mg, n=10). Each experiment consisted of 4 30-min periods (baseline, MS, recovery I and II). Renal hemodynamics was evaluated with effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) from plasminogen activator inhibitor and inulin clearance, respectively. MS increased blood pressure (BP) to a similar extent before and after each treatment. Before treatment, the increasing BP was not associated with any modification of ERPF in the 3 groups. Renal vascular resistances (RVR) markedly increased during MS (+23% in the T group, +21.6% in the V group, and +32.9% in the T+V group); GFR remained constant during the whole experiment. After treatment, ERPF decreased significantly during MS in the T group (-15%, P0.05) and in the V group (-11.7%, p0.01); in the T+V group, ERPF modifications were not statistically significant (P=0.07). In the T group, ERPF reverted to baseline values at the end of the stimulus, whereas in the V group, renal vasoconstriction was more prolonged. Only in hypertensive patients treated with 4 mg of T, RVR reverted to baseline during the recovery I, whereas in the V group, RVR remained elevated for the whole experiment. No modifications of GFR were observed in all groups. The kidney of hypertensive patients cannot react to a sympathetic stimulus with the physiological vasoconstriction. A short-term antihypertensive treatment with 4 mg of T restores the physiological renal response to adrenergic activation.

BACKGROUND Calcineurin inhibitor nephrotoxicity remains an issue for recipients of solid organ transplants. After cyclosporine A (CsA) microemulsion administration, effective renal plasma flow (ERPF) and glomerular filtration rate(GFR) are decreased coincident with the maximal concentration (Cmax) of CsA. The pharmacokinetic (PK) profile of the once-daily formulation of tacrolimus extended release (Tac ER) includes an equivalent AUCPK 0-24 hr and a lower Cmax versus twice-daily Tac immediate release. METHODS Eighteen healthy subjects were allocated once-daily Tac ER and twice-daily CsA in a prospective, randomized,open-label, two-period, two-sequence single crossover study. CsA was targeted to C2 of 700 to 1400 ng/mL, and Tac ER was targeted to C0 of 5 to 10 ng/mL. Pharmacodynamic (PD) assessments were conducted preexposure, and PD and PK were assessed during a 6-hr postdose period after 10-day exposure. RESULTS The achieved mean C(o) Tac and CsA were 6.4 +/- 1.16 and 201 +/- 57 ng/mL, respectively. At Cmax, the change in ERPF was +30 +/- 127 vs. -70 +/- 96 mL/min/1.73 m2 relative to baseline for Tac ER and CsA (P=0.0085). The ERPF and GFR AUC (PD 0-6) hr were 3645 +/- 887 vs. 3210 +/- 582 mL/1.73 m2 (P=0.027) and 604 +/- 98 vs. 543+/- 79 mL/1.73 m2(P=0.023) for Tac ER versus CsA, respectively. Both systolic and diastolic blood pressures were significantly greater with exposure to CsA compared with Tac ER. CONCLUSIONS Acute reductions in ERPF and GFR are attenuated with Tac ER compared with CsA and may correlate with the differing PK profiles of these calcineurin inhibitors.

The molecular structure of p-18F-fluorohippurate (18F-PFH) is similar to that of p-aminohippurate, a gold standard for the measurement of effective renal plasma flow. The objective of this study was to investigate 18F-PFH as a new PET renal agent. Methods:18F-PFH was synthesized by reacting N-succinimidyl-4-18F-fluorobenzoate (18F-SFB) with glycine at 90°C (pH 8) for 20 min. In vitro stability was determined by incubating 18F-PFH in fresh human plasma at 37°C for 60 min. In vivo stability was determined by high-performance liquid chromatography analysis of urine collected from a normal rat at 40 min after injection of 18F-PFH. The plasma protein binding and erythrocyte uptake were determined using plasma collected from a normal rat at 5 min after injection of 18F-PFH. The plasma clearance of 18F-PFH was determined using a single-injection clearance method in normal and probenecid-treated rats. Biodistribution studies were conducted in normal rats at 10 min and 1 h after injection of 18F-PFH. Dynamic PET/CT studies were conducted in normal rats injected with 18F-PFH. Results: In normal rats, the plasma clearance of 18F-PFH was 4.11 ± 1.09 mL/min/100 g, which reduced by approximately 50% (P = 0.03) to 2.01 ± 0.08 mL/min/100 g in probenecid-treated rats. About 45.3% of 18F-PFH was found to associate with plasma proteins in vivo in normal rats. Biodistribution studies of 18F-PFH in normal rats showed 72.1 ± 6.4 percentage injected dose and 88.6 ± 6.2 percentage injected dose, respectively, in urine at 10 min and 1 h after injection. The uptake in other organs was negligible. High-performance liquid chromatography analysis of urine collected from a rat at 40 min after injection of 18F-PFH indicated that it was excreted intact, with no metabolic products. Dynamic PET revealed a rapid clearance of 18F-PFH through the renal–urinary pathway. The PET-derived renograms revealed a time to peak activity of 3.0 ± 1.0 min. Conclusion: These combined results warrant further investigation of 18F-PFH as a radiopharmaceutical for the assessment of renal function by PET.

BACKGROUND AND PURPOSE The RhoA/Rho associated kinases (ROCK) pathway has been implicated in the pathophysiology of diabetic nephropathy (DN). Early stages of diabetes are associated with renal haemodynamic changes, contributing to later development of DN. However, the role of RhoA/ROCK, known regulators of vascular tone, in this process has not been studied. EXPERIMENTAL APPROACH Blood pressure (BP), glomerular filtration (GFR), effective renal plasma flow and filtration fraction (FF) in response to the ROCK inhibitors Y27632 (0.1 and 0.5 mg·kg−1) and fasudil (0.3 and 1.5 mg·kg−1) were examined in streptozotocin-diabetic rats and non-diabetic controls. KEY RESULTS Diabetic rats demonstrated baseline increases in GFR and FF. In contrast to similar decreases in BP in diabetic and control rats, renal vasodilator effects and a decrease in FF, following ROCK inhibition were observed only in diabetic rats. The vasodilator effects of Y27632 and a further decrease in FF, were also detected in diabetic rats pretreated with the angiotensin antagonist losartan. The effects of ROCK inhibitors in diabetic rats were modulated by prior protein kinase C (PKC)β inhibition with ruboxistaurin, which abolished their effects on FF. Consistent with the renal vasodilator effects, the ROCK inhibitors reduced phosphorylation of myosin light chain in diabetic kidneys. CONCLUSIONS AND IMPLICATIONS The results indicate greater dependence of renal haemodynamics on RhoA/ROCK and beneficial haemodynamic effects of ROCK inhibitors in diabetes, which were additive to the effects of losartan. In this process, the RhoA/ROCK pathway operated downstream of or interacted with, PKCβ in some segments of the renal vascular tree.

Die Belastungsrenografie mit 99mTc-Mercapto-acetyltriglycin (99mTc-MAG3) ermoglicht es, eine krankheitsspezifische renale Funktionsstorung der essenziellen Hypertonie nachzuweisen. Szintigrafisch wird die Storung bei Belastung erkennbar als deutliche, bilaterale parenchymale Tracerretention. Clearancebestimmungen bei Belastung zeigten, dass diese Tracerretention Ausdruck einer ausgepragten Minderung der glomerularen Filtrationsrate (GFR) ist, wahrend der effektive renale Plasmafluss (ERPF) vergleichsweise unverandert blieb. Die bislang mit der Belastungsrenografie und mit Clearancebestimmungen erhobenen Ergebnisse weisen darauf hin, dass die physiologisch stabile Filtrationsfraktion (FF) (FF=0,2) bei etwa 60% der Patienten mit essenzieller Hypertonie hochgradig pathologisch wird (FF

Background: Many studies have reported the occurrence of lethal acute renal failure after snakebites. Bungarus candidus (Malayan krait) is a medically important venomous snake distributed widely throughout Southeast Asia. The best known features of systemic envenoming by B. candidus are neurotoxic. Objective: Obtain more information on effects of B. candidus venom on changes in systemic and renal hemodynamics in experimental animals. Methods: Twelve adult male New Zealand white rabbits were used to study the effect of B. candidus venom on general circulation and renal hemodynamics. An anesthetized animal was intravenously injected with B. candidus venom at a dosage of 50μg/kg bodyweight. All changes of parameters were observed after initial post venom injection and recorded at 30 min intervals until 150 minutes after envenomation. Results: After envenomation, cardiovascular responses showed a marked decrease in mean arterial pressure within two minutes, afterwards gradually returning closely to baseline values. There were stepwise decreases in heart rate and cardiac output, while total peripheral resistance was slightly increased. The renal hemodynamics significantly decreased by glomerular filtration rate, effective renal plasma flow and effective renal blood flow, while the filtration fraction significantly increased. Envenomed animals showed a reduction in renal fraction, while renal vascular resistance stepwise increased. The plasma potassium level tended to increase. Animals showed stepwise decreases in urinary excretion of Na+, K+ and Cl-. A marked decrease in plasma calcium level was apparent at 120 minutes, while plasma creatine phosphokinase and lactate dehydrogenase levels increased at 30-120 minutes. Conclusion: A significant drop in blood pressure was attributed to a sustained fall in cardiac output, which would be associated with a reduction in heart rate. Sustained hypotension would contribute to reduction of renal blood flow, which results in decreased GFR.

OBJECTIVES To examine the effects of atorvastatin on renal hemodynamics and urinary microalbumin levels in rats with acute unilateral ureteral obstruction (UUO). Previous studies have demonstrated that treatment with statins attenuated renal structural damages in rodents with chronic UUO. However, it is not known whether statins afford protection of renal function. METHODS UUO was created by ligation of the left ureter in rats maintained on a regular diet or the same diet but supplemented with atorvastatin (50 mg/kg/d) for 2 weeks. Renal clearance experiments were performed after release of UUO at 1 hour, 6 hours, or 12 hours. RESULTS Atorvastatin treatment lowered plasma triglyceride but not cholesterol levels. Both glomerular filtration rate and effective renal plasma flow were significantly greater in atorvastatintreated rats after release of UUO at 1 hour, 6 hours, and 12 hours. Significant reduction of urinary microalbumin to creatinine ratios occurred in the atorvastatin-treated group at 12 hours but not earlier. CONCLUSIONS Atorvastatin treatment affords protection of renal function in acute UUO and reduces urinary microalbumin levels without lowering cholesterol levels. This pleiotropic action of atorvastatin on preservation of renal hemodynamics may be important in attenuating subsequent renal structural injury in chronic UUO.

During acute kidney injury (AKI), lowered glomerular filtration rate (GFR) is believed to be consequent to reduced renal plasma flow (RPF). We aimed to systematically evaluate the evidence for such an association. Using specific search terms, we systematically interrogated the Pub Med electronic reference database for studies of human AKI where renal plasma or blood flow and GFR were measured; older articles were then identified by screening bibliographies of retrieved reports. We identified 22 articles describing 250 patients (203 native kidney, 47 in renal allograft). Of these studies, 8 articles (110 patients) estimated effective renal plasma flow (ERPF) by clearance techniques and 14 articles (140 patients) estimated true renal plasma flow (TRPF). Mean RPF was 272 mL/min (95% CI 213-331) and GFR 13.9 mL/min (9.9-17.9). Mean TRPF was significantly greater than mean ERPF (344 vs. 180, p=0.004) despite lower mean GFR (8.8 vs. 20.4, p=0.002). There was no significant association between RPF and GFR between studies. Eleven studies presented individual patient data (76 patients: 49 TRPF, 27 ERPF); here, individual patient ERPF was associated with GFR (r2=0.52), but TRPF was not. During AKI in man, there is only a limited association between ERPF and GFR, and no detectable association between TRPF and GFR.

OBJECTIVE To present our findings of simultaneous bilateral percutaneous nephrolithotomy (sbPCNL) on bilateral renal haemodynamic and excretory function in an in vivo pig model, as despite sbPCNL being a treatment strategy for patients with bilateral renal stones, the functional response of both kidneys to such a procedure is unknown. MATERIALS AND METHODS Nine anaesthetized female pigs (≈70 kg) had a single-tract PCNL procedure in the left kidney and then the right kidney in one session (sbPCNL). Percutaneous access was achieved by a 30 F balloon dilator system. Bilateral renal function was measured before, 1.5 and 4.5 h after sbPCNL and included glomerular filtration rate (GFR), effective renal plasma flow (RPF), renal extraction of para-aminohippurate (EPAH, a measure of the efficiency of tubular organic anion transport), urine flow (UV), absolute sodium excretion (UNaV) and fractional sodium excretion (FENa). RESULTS Both kidneys had similar baseline haemodynamic and excretory function, and showed comparable changes after sbPCNL. Bilateral GFR and RPF decreased by ≈35% at 1.5 and 4.5 h after sbPCNL; EPAH was reduced to a similar degree in both kidneys at 1.5 h after sbPCNL and remained depressed throughout the observation period; bilateral UV and UNaV progressively decreased by ≈30% and ≈60% at 1.5 and 4.5 h after sbPCNL, respectively; bilateral FENa did not significantly change at 1.5 h after sbPCNL but decreased significantly by ≈50% at 4.5 h. CONCLUSIONS Both kidneys responded in a similar fashion after sbPCNL, with declines in haemodynamic and excretory function. These bilateral functional responses were comparable to those previously reported after unilateral PCNL, and help to reduce concerns that PCNL of both kidneys in one session could lead to greater functional complications, at least acutely.

Bovine aprotinin, a reversible inhibitor of plasmin and kallikrein, has been clinically approved for over two decades to prevent perioperative blood loss during cardiac surgery. However, because of postoperative renal dysfunction in thousands of these patients, aprotinin was voluntarily withdrawn from the market. Our earlier studies indicated that a R24K mutant of the first Kunitz-type domain of human tissue factor pathway inhibitor-2 (R24K KD1) exhibited plasmin inhibitory activity equivalent to aprotinin in vitro. In this study, we compared the effects on renal function after infusion of aprotinin and recombinant R24K KD1 in chronically instrumented, conscious rats. Aprotinin-infused rats exhibited statistically significant decreases in glomerular filtration rate and effective renal plasma flow relative to rats infused with phosphate-buffered saline (PBS) or R24K KD1 dissolved in PBS. In addition, aprotinin-treated rats exhibited marked increases in serum creatinine, blood urea nitrogen, urinary protein, and effective renal vascular resistance, whereas these renal parameters remained essentially unchanged in vehicle and R24K KD1-treated rats for a one-week period. Moreover, with use of a highly sensitive apoptosis detection assay, a significant increase in the rate of early and late apoptotic events in renal tubule cells occurred in aprotinin-treated rats relative to R24K KD1-treated rats. In addition, histological examination of the rat kidney revealed markedly higher levels of protein reabsorption droplets in the aprotinin-infused rats. Our data collectively provide suggestive evidence that R24K KD1 does not induce the renal dysfunction associated with aprotinin, and may be an effective clinical alternative to aprotinin as an antifibrinolytic agent in cardiac surgery.

Background: The beneficial effects of vasopressin on diuresis and creatinine clearance have been demonstrated when used as an additional/alternative therapy in catecholamine-dependent vasodilatory shock. A detailed analysis of the effects of vasopressin on renal perfusion, glomerular filtration, excretory function and oxygenation in man is, however, lacking. The objective of this pharmacodynamic study was to evaluate the effects of low to moderate doses of vasopressin on renal blood flow (RBF), glomerular filtration rate (GFR), renal oxygen consumption (RVO 2 ) and renal oxygen extraction (RO 2 Ex) in post-cardiac surgery patients. Methods: Twelve patients were studied during sedation and mechanical ventilation after cardiac surgery. Vasopressin was sequentially infused at 1.2, 2.4 and 4.8U/h. At each infusion rate, systemic haemodynamics were evaluated by a pulmonary artery catheter, and RBF and GFR were measured by the renal vein thermodilution technique and by renal extraction of 51 chromium-ethylenediaminetetraacetic acid, respectively. RVO 2 and RO 2 Ex were calculated by arterial and renal vein blood samples. Results: The mean arterial pressure was not affected by vasopressin while cardiac output and heart rate decreased. RBF decreased and GFR, filtration fraction, sodium reabsorption, RVO 2 , RO 2 Ex and renal vascular resistance increased dose-dependently with vasopressin. Vasopressin exerted direct antidiuretic and antinatriuretic effects. Conclusions: Short-term infusion of low to moderate, non-hypertensive doses of vasopressin induced a post-glomerular renal vasoconstriction with a decrease in RBF and an increase in GFR in post-cardiac surgery patients. This was accompanied by an increase in RVO 2 , as a consequence of the increases in the filtered tubular load of sodium. Finally, vasopressin impaired the renal oxygen demand/supply relationship.

Cilnidipine, a dual calcium channel antagonist, is assumed to regulate hypertension via N- and L-type calcium channel. The N-type calcium channel is associated with sympathetic nerve activation. This effect may improve the glome- rular hemodynamics in the injured nephron, and may mitigate the progression of renal injury. To clarify the effect of cil- nidipine in instances of already existing decreased renal blood flow, we examined the alteration of renal hemodynamics before and after cilnidipine therapy in patients with advanced chronic kidney disease (CKD). Cilnidipine was adminis- trated daily to 17 CKD patients with hypertension for 12 months. Another 16 patients were similarly administered am- lodipine during this study, a long-acting L-type calcium channel antagonist has also been shown to be renoprotective. Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and protein excretion in 24-hour accumulated urine were measured at the start and end of the study. The parameters of renal hemodynamics were calculated by Gomez's es- timation equation. Systolic blood pressure decreased to 80 % of the level at the beginning of the study, and ERPF in- creased to 127 % of the level at baseline. Glomerular capillary pressure on single nephron was reduced to 90 %, although total GFR decreased within the non-statistical change. Especially, renal vascular resistance ratio (RA/RE) on single neph- ron improved to 120 %. Cilnidipine improves ERPF and glomerular hypertension without worsening total renal function. N- and L-type calcium channel antagonist is effective and safe for patients with advanced CKD as a result of improve- ment of glomerular capillary resistance.

Background/Aims: Tubulo-glomerular feedback (TGF) is a key mechanism for controlling glomerular filtration. Nephrectomy for kidney donation provides a good opportunity for studying TGF status before and after a defined loss of renal function. Methods: A total of 22 kidney donors were studied before and one year after nephrectomy. Effective renal plasma flow and glomerular filtration rate were measured by means of para-amino-hippurate and inulin plasma clearances before and after intravenous acetazolamide. Results: TGF activation was not dependent on sex, age or familiality for hypertension either before or after nephrectomy, however, it increased the filtration fraction before, but not after nephrectomy. Nephrectomy did not affect TGF response, but elicited a correlation between TGF response and renal plasma flow, not present in the intact state. Donors with a more activated TGF before nephrectomy had a lower filtration fraction that increased after nephrectomy, while subjects with a less activated TGF before nephrectomy had a higher basal filtration fraction that showed a blunted increase after nephrectomy. Conclusion: TGF is a stable mechanism quantitatively unaltered by nephrectomy, age, sex, menopausal status or family history of hypertension. However, its degree of activation before nephrectomy determines different responses to the loss of a kidney.

To evaluate the significance of collagen levels, nonenzymatic glycation, and effective renal plasma flow in diabetes, we studied 52 Streptozocin induced-diabetic rats. After 10 weeks of diabetes, rats were injected i.v. 0.5 microCi/g 99mTechnetium Mercaptoacetyl triglycine and effective renal plasma flow was calculated from the renograms obtained. The collagen content and hydroxymethyl furfural levels of kidney and tail tissue as well as renal plasma flow increased significantly in diabetic rats (p < 0.05). The increase in renal plasma flow indicates that hyperperfusion may play a role in diabetic nephropathy mechanism. The correlation between renal plasma flow and glycation was not as high as the correlations between blood glucose concentrations and hydroxymethyl furfural and collagen levels, suggesting that factors other than glycation are important in increasing the renal plasma flow.

Background— Urinary excretion is currently regarded as the main mechanism of elimination of N-terminal prohormone brain natriuretic peptide (NT-proBNP). The clinical implications and the value of measurement of urinary NT-proBNP in patients with heart failure are largely unknown. Methods and Results— We studied 94 patients (age, 58±11 years; 79% men) with chronic heart failure (CHF) and 20 age- and sex-matched healthy control subjects. Glomerular filtration rate and effective renal plasma flow were measured as clearance of 125 I-iothalamate and 131 I-hippuran, respectively. NT-proBNP levels were determined in both plasma and 24-hour urine collections. Mean left ventricular ejection fraction of CHF patients was 0.28±0.09. Plasma NT-proBNP levels were higher in CHF patients compared with control subjects (median, 547 versus 41 pg/mL; P P r =−0.72 and r =−0.65 respectively; both P P =0.026). Conclusions— Urinary NT-proBNP excretion is lower in patients with CHF compared with control subjects and is inversely related to plasma NT-proBNP. Urinary NT-proBNP is associated with renal plasma flow but not with estimated glomerular filtration rate. Elevated levels of plasma NT-proBNP in patients with CHF might be explained not only by myocardial stress but also by a marked decrease in urinary excretion.

Radioisotope renography with 13I-hippuran has been undertaken in 14 kidney donors with normal renal function 26–53 months after unilateral nephrectomy. Immediately after renography simultaneous creatinine, 125iothalamate and 131I-hippuran clearances were determined. Ratios calculated within the first 2.5 min of the renogram could not be correlated to clearance values or to the size of the remaining kidney. There was a statistically significant correlation between clearance values and renal size. The range of the ratios calculated was 5–10%, whereas the range of clearance values was 15–30%. 131I-hippuran reached the bladder after a minimum of 2.0 min. There was a correlation between transit time and time to the renogram's maximum.

Glomerular filtration rate (GFR) by clearance of inulin and creatinine and effective renal plasma flow (ERPF) by para-aminohippurate clearance was investigated in 8 normal volunteers on low protein (LP) and high protein (HP) diet for 6 days in the basal state and after a mixed protein-rich test meal. Plasma immunoreactive insulin (IRI), glucagon (IRG) and growth hormone (IRHGH) were followed before and after the test meal. GFR was higher on HP than on LP diet and increased within one hour after the test meal. ERPF also increased significantly after the meal on LP diet. IRI increased maximally at 60 min after the test meal and then declined gradulally. IRG increased after a latency period of 90 min and IRHGH consistently did not change. Since the increase in GFR was significant already one hour after the test meal, i.e. before IRG was changed, we conclude that glucagon is not a mediator of the protein-induced increased in GFR. Neither insulin nor growth hormone appeared to be involved.

The glomerular filtration rate (GFR), the effective renal plasma flow (ERPF), and the filtration fraction (FF) have been studied in 38 patients with different renal diseases and varying degrees of renal insufficiency. All diagnoses were verified by percutaneous renal biopsy. Eighteen living kidney donors comprised a control material. In 10 patients in terminal uremia no characteristic functional pattern was found. Twelve patients with interstitial nephritis had a significantly increased FF, 9 with the nephrotic syndrome had a significantly decreased FF, whereas 7 with glomerulonephritis without the nephrotic syndrome did not demonstrate FF values different from those found in normals. A good correlation was found between the size of the FF and the concentration of serum albumin. Creatinine clearance overestimated the true GFR in patients with renal disease. The FF was not significantly increased in hypertensive patients.

The hemodynamic adaptation and the change in the renin-aldosterone system during treatment with a new vasodilating drug, prazosin (Peripress®), were studied in 14 patients with essential hypertension before and after 2 and 4 months of treatment. The mean daily dose was 2 mg/day for the first 2 months and was increased individually up to 7.0 mg/day during the last 2 months in those patients whose mean arterial blood pressure (MAP) remained elevated. The reduction of MAP was mainly due to a decline in peripheral resistance, but also to a decrease in cardiac output in 4 of the patients. Effective renal plasma flow increased from 220 to 254 ml/min m2, probably as a result of a fall in vascular resistance in the kidneys. The plasma volume showed a small, transient increase after 2 months, from 19.0 to 20.0 ml/cm body height, whereas pulmonary plasma volume was unchanged, indicating a slight redistribution of plasma between the pulmonary and the systemic circulation. Body weight increased from 75.1 to 77.1 kg which, although a crude parameter, might indicate volume expansion. Plasma renin activity showed a small, transient increase after 2 months, from 0.46 to 0.65 nmol A1/I h, whereas plasma aldosterone concentration was unchanged, indicating that a volume expansion was not a result of a stimulated renin-aldosterone system. The serum sodium and chloride concentrations fell from 142.7 to 140.2 mmol/l and from 105.9 to 103.1 mmol/***l, respectively.

CP-690,550 is a Janus kinase inhibitor being developed to prevent allograft rejection and treat several autoimmune diseases. This study examines the effect of multiple doses of CP-690,550 on renal function in healthy volunteers. Thirty-four volunteers are randomized in a 2:1 ratio in a double-blinded manner to receive CP-690,550 15 mg twice daily or placebo twice daily for 14 days. Volunteers are confined in-house to receive a controlled regimen of water intake and sodium intake of 4 to 5 g/d. The effect of CP-690,550 on glomerular filtration rate (GFR) is measured by iohexol serum clearance, effective renal plasma flow (ERPF) by para-aminohippuric acid (PAH) urinary clearance, and creatinine clearance by 24-hour urine collection on day 1 (predose) and day 15. Steady-state pharmacokinetics and tolerability are assessed. Comparing the day 15 and day 1 (predose) values shows that geometric mean ratios for iohexol serum clearance, PAH urinary clearance, and creatinine clearance are 0.995, 0.925, and 0.948, respectively. When adjusted for the corresponding placebo day ratios, the geometric mean ratios are 1.09, 0.978, and 1.05, respectively. CP-690,550 is well tolerated. These findings indicate that CP-690,550 does not affect GFR, ERPF, or creatinine clearance in healthy volunteers.

Objective Renal vasoconstriction has been blamed as a cause of perioperative renal dysfunction after cardiac surgery. Endothelial function is a critical determinant of vascular tonus, including vasoconstriction. The objective of this study was to establish whether the release of the endothelial vasodilator nitric oxide (NO) or NO products is altered in patients undergoing surgery with cardiopulmonary bypass in 3 different clinical conditions. Design Observational and randomized prospective study. Setting University hospital. Participants Adults and pediatric patients undergoing elective cardiac surgery with cardiopulmonary bypass. Interventions Three groups of patients were studied: group 1, 10 patients undergoing elective coronary artery surgery; group 2, 20 patients undergoing elective coronary artery surgery randomized to 2 hematocrit values during cardiopulmonary bypass, high (27%) and low (23%); and group 3, 10 pediatric patients undergoing surgical repair of noncyanotic cardiac defects. Measurements and Main Results NO products (NO2 + NO3) and cyclic guanosine monophosphate (cGMP) in urine were measured before, during hypo- and normothermic cardiopulmonary bypass, and 1 hour postoperatively. Filtration fraction was calculated. The glomerular filtration rate and effective renal plasma flow were measured with inulin and 131I-hippuran clearances, respectively. Urinary alpha glutathione s-transferase was measured pre- and postoperatively in groups 1 and 3. NO products, as well as cGMP, decreased significantly during hypo- and normothermic cardiopulmonary bypass in all groups. This was not because of urine dilution or the degree of hemodilution. Age did not appear to alter this response. Filtration fraction decreased during cardiopulmonary bypass. Alpha glutathione s-transferase was normal pre-and postoperatively. Conclusions Cardiac surgery with cardiopulmonary bypass is associated with a significant decrease of NO products. In the absence of kidney damage, decreased NO products could represent a physiologic response to cardiopulmonary bypass; however, endothelial dysfunction cannot be excluded.

To develop a (99m)Tc renal tracer with a capacity to measure effective renal plasma flow comparable to that of the clinical gold standard (131)I-o-iodohippurate ((131)I-OIH) and superior to that of (99m)TcO-mercaptoacetyltriglycine, which has a clearance only 50%-60% that of (131)I-OIH, we investigated (99m)Tc-tricarbonyl nitrilotriacetic acid (Na(2)[(99m)Tc(CO)(3)(NTA)]). This radiopharmaceutical, which is based on an aminopolycarboxylate ligand, is formed as a single species and has a dangling carboxylate group favoring tubular transport.Na(2)[(99m)Tc(CO)(3)(NTA)] was prepared by using commercially available NTA and an IsoLink kit and isolated by high-performance liquid chromatography. The stability of Na(2)[(99m)Tc(CO)(3)(NTA)] in isotonic saline was assessed for 24 h and was further evaluated by incubation in 0.1 M cysteine and histidine for 4 h at 37 degrees C. The biodistribution of Na(2)[(99m)Tc(CO)(3)(NTA)], coinjected with (131)I-OIH as an internal control, was evaluated in 5 normal Sprague-Dawley rats at 10 min, 5 normal Sprague-Dawley rats at 60 min (group A), and 6 rats with renal pedicle ligation at 60 min (group B) after injection. Clearance and extraction fraction studies were conducted in 2 normal Sprague-Dawley rats, and urine and plasma from 2 additional normal rats each were analyzed for metabolites by high-performance liquid chromatography.The radiochemical purity of Na(2)[(99m)Tc(CO)(3)(NTA)] was greater than 99%, the complex was stable for 24 h at physiologic pH, and the challenge experiments showed no degradation. In normal rats, the percentage dose in the urine at 10 and 60 min was 108% +/- 9% and 101% +/- 5%, respectively, that of (131)I-OIH; minimal hepatic or gastrointestinal activity was demonstrated. In group B rats, Na(2)[(99m)Tc(CO)(3)(NTA)] was better retained in the blood and had less excretion into the bowel than did (131)I-OIH (P0.01). The plasma clearances of Na(2)[(99m)Tc(CO)(3)(NTA)] and (131)I-OIH were comparable, but the extraction fraction of Na(2)[(99m)Tc(CO)(3)(NTA)] was 93.5% +/- 3.8%, compared with 67.9% +/- 6.1% for (131)I-OIH. Plasma protein binding of Na(2)[(99m)Tc(CO)(3)(NTA)] averaged 67% +/- 7%, and red cell uptake was 7% +/- 2%.Na(2)[(99m)Tc(CO)(3)(NTA)] is stable, exists as a single species, and has pharmacodynamic properties in rats comparable to those of (131)I-OIH.

Nitric oxide is generated from L-arginine by nitric oxide synthase (NOS), an enzyme that exists in several isoforms. Some studies found that a polymorphism (G894T) in the endothelial NOS gene was associated with decreased nitric oxide bioactivity and vascular complications. However, it is not known whether the enzyme had a reduced activity. Here we measured the effect of an infusion of L-arginine on renal hemodynamic function in subjects segregated by the presence or absence of the T allele. If this polymorphism represented a functional variant, subjects with the GT/TT form should exhibit a blunted renal hemodynamic response to L-arginine compared to those with a GG allele. All subjects were given a diet controlled for sodium and protein intake. GG subjects had lower mean arterial pressure and an augmented glomerular filtration rate at baseline. In response to a graded L-arginine infusion, this group had significant changes in effective renal plasma flow, glomerular filtration rate, filtration fraction, renal vascular resistance, and renal blood flow. The renal response to L-arginine in GT/TT subjects was blunted. Circulating cGMP levels and endothelial NOS mRNA expression, measured in skin biopsies by real-time PCR, did not differ between the groups. Our study shows that the G894T allele of endothelial NOS is associated with a blunted response to L-arginine, suggesting this polymorphism may be a functional variant in humans.

SUMMARY Experimental studies of renal blood flow have been made with radio-Hippuran I125using isolated perfused canine kidneys. These studies were made in two groups. First, the renogram curve was analysed by applying theoretical equations and it was shown that quantitative values could be obtained for the effective renal blood flow. In the second group of experiments the analysis of the rate of disappearance of the isotope from the blood showed a definite relationship with directly measured renal blood flow, but this could not be resolved into a quantitative value. The authors' thanks are due to Professor Ralph Shackman for his encouragement and guidance in this work, to Mr E. Gains and his technical staff for their help, to the Department of Photography and Medical Illustration of the Post-graduate School for their assistance in drawing of the charts, and to Mr Ole Kalnaes, Radiofysisk laboratorium, Arhus Kommunehospital, for his help with mathematical equations. The expenses incurred in these experiments were defrayed by a grant to one of us (A. E. K.) from the Medical Research Council.

Study Objective. To determine whether coadministration of misoprostol with the nonsteroidal antiinflammatory drug diclofenac lessens the increase in blood pressure and improves the alterations in renal hemodynamics induced by diclofenac. Design. Prospective, randomized, double-blind, placebo-controlled, crossover study. Setting. Two university research centers. Patients. Nineteen senior (mean age 62 yrs [range 55–73 yrs]), salt-sensitive patients with stage 1 or 2 hypertension. Intervention. After a 3-week antihypertensive withdrawal lead-in phase, patients received either diclofenac 75 mg alone or diclofenac 75 mg plus misoprostol 200 μg twice/day for 14 days. After a 10-day washout period, patients received the alternate treatment. Measurements and Main Results. Blood pressure was measured by 24-hour ambulatory blood pressure monitoring, effective renal plasma flow (ERPF) rate was determined by para-aminohippurate clearance, and glomerular filtration rate (GFR) was measured by iothalamate clearance. Mean arterial pressure (MAP = diastolic blood pressure + 0.33[systolic - diastolic blood pressure]) and rate-pressure product (RPP = systolic blood pressure x heart rate x 10−2) were also used to compare treatment groups. Diclofenac alone increased MAP by a mean ± SEM of 5.0 ± 1.0 mm Hg and RPP by 337 ± 181 units compared with baseline. The ERPF rate and GFR decreased by 40.5 ± 26.9 ml/minute and 14.1 ± 6.5 ml/minute, respectively. Diclofenac plus misoprostol decreased the diclofenac-induced increase in MAP by 3.3 ± 1.0 mm Hg (95% confidence interval [CI] 1.1–5.3 mm Hg, p=0.004) and decreased the RPP by 724 ± 238 units (95% CI 225–1223 units, p=0.007). The ERPF rate increased by 56.1 ± 35.0 ml/minute (95% CI −24.7–137.0 ml/min, p=0.15) and GFR by 18.1 ± 7.1 ml/minute (95% CI 1.9–34.5 ml/min, p=0.03). Diclofenac alone was relatively well tolerated; no adverse effects were reported with diclofenac plus misoprostol. Conclusion. In senior salt-sensitive patients with hypertension, coadministration of misoprostol with diclofenac attenuated the blood pressure elevation and renal vasoconstrictive effects of diclofenac and was well tolerated.

Background Age, gender, menopausal status, a family history of hypertension, and renal vascular response to angiotensin II are involved in the progression of renal failure from its very beginning. Methods In order to investigate their importance on this progression, we measured effective renal plasma flow (ERPF) and glomerular filtration rate (GFR), and calculated glomerular pressure (Pglo) and afferent and efferent arteriole resistances (by means of Gomez formulae) in 26 normotensive kidney donors before and after nephrectomy. Results Renal reactivity to angiotensin was the only variable that affected changes in renal and glomerular hemodynamics after the loss of renal tissue: in subjects with greater angiotensin reactivity, higher afferent resistances (Ra) and lower glomerular filtration and pressure before nephrectomy change to higher efferent resistances (Re) and higher Pglo and filtration after nephrectomy. Conclusions In normotensive donors with a normal compensatory response to nephrectomy, baseline renal reactivity to angiotensin II can influence renal and glomerular hemodynamics 1 year after nephrectomy.

BACKGROUND AND OBJECTIVE In patients with chronic glomerular nephropathy associated arterial hypertension and proteinuria are considered to be cardinal risk factors in the progressive deterioration of renal function. Treatment regimens which reduce proteinuria and hypertension improve prognosis. The effect of the new beta-receptor blockers compared to common ACE-Inhibitors is of special interest. PATIENTS AND METHODS The studied cohort consisted of 11 patients with CGN, hypertension and proteinuria > 400 mg/24 h. Four drugs were given for 4 weeks, doubly blinded and randomized according to a "Latin-square design": Celiprolol (beta-1-antagonist, beta-2-agonist, 200 mg/d), Atenolol (selective beta-1-antagonist, 50 mg/d), Ramipril (ACE-inhibitor, 2.5 mg/d) and placebo. There was a two-week wash-out phase between each of the four treatment phases. At the end of each treatment phase glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by inulin and para-amino-hippuric acid (PAH) clearance. Proteinuria was determined in the course of a three-day collection period at the end of each treatment phase. During this period blood pressures were measured with a continuous 24-hour blood pressure monitor. RESULTS Mean arterial blood pressure (MAP) was significantly reduced, compared with placebo, by all three antihypertensives (108 +/- 9 mm Hg with placebo, 98 +/- 12 mg Hg with atenolol, 101 +/- 11 mm Hg with celiprolol and 98 +/- 8 mm Hg with ramipril; P < 0.01). Celiprolol produced a significant rise In ERPF (322 +/- 109 ml/min with placebo, 391 +/- 110 ml/min with celiprolol: P < 0.05). GFR was slightly, but not significantly, reduced by celiprolol and atenolol. Filtration fraction remained unchanged with atenolol and celiprolol, while it was slightly, but not significantly, reduced with ramipril. Compared with the placebo, all three drugs significantly reduced proteinuria (P < 0.05): 1.8 +/- 1.3 g/24 h with placebo, 1.2 +/- 1.2 g/24 h with atenolol, 1.2 +/- 1.1 g/24 h with celiprolol and 1.4 +/- 1.4 g/24 h with ramipril. CONCLUSION These data indicate that, in addition to ACE inhibitors, the new generation of beta-receptor blockers in particular, because of their vasodilator action, favourably influence proteinuria and renal blood flow in patients with CGN and arterial hypertension.

Little is known about the role of the renin-angiotensin-aldosterone system and the renal prostaglandins in modulating the renal vasoconstrictive and natriuretic effects of synthetic urodilatin (URO) in healthy humans.Twelve volunteers were pretreated in a randomized, single-blind, crossover study with losartan 50 mg a day or placebo for 5 days. Another 12 healthy subjects received indomethacin 25 mg three times a day or placebo for 4 days and a single dose on day 5. All subjects received a URO infusion (15 ng kg(-1) min(-1)) on day 5. Radioactive tracers and the lithium clearance technique were used.The effective renal plasma flow (ERPF) decreased significantly during URO infusion: losartan pretreatment 573+/-63 to 461+/-76 mL/min versus placebo 540+/-89 to 432+/-90 mL/min. The urinary sodium excretion rate (UNa) increased significantly during URO infusion: losartan 335+/-115 to 502+/-134 umol/min (micromol/min) (UNa) versus placebo 386+/-142 to 476+/-137 umol/min (micromol/min) (UNa). In the indomethacin pretreated subjects, ERPF decreased significantly from 530+/-109 to 446+/-55 mL/min versus 533+/-89 to 449+/-69 mL/min in the placebo group. UNa increased significantly from 395+/-142 to 768+/-254 umol/min (micromol/min) (UNa) in the indomethacin group versus 282+/-117 to 552+/-242 umol/min (micromol/min) (UNa) in placebo.The renal vasoconstrictive and natriuretic effects of synthetic URO are not modified by sustained inhibition of the angiotensin II receptor or the cyclooxygenase in man in a sodium replete state.

Vascular calcifications are common among patients with hypertension. The vitamin K-dependent protein matrix Gla-protein plays an important role in preventing arterial calcification. Since a decrease in renal clearance is a prevalent clinical problem in patients with hypertension, we aimed to study the renal clearance of matrix Gla-protein from the circulation in these patients having a wide range of creatinine clearances. Ninety moderate to severe hypertensive patients who were scheduled for renal angiography were enrolled in the study. In these patients, renal arterial and renal venous blood was sampled prior to the administration of contrast material in order to determine the total renal and single kidney clearance of matrix Gla-protein. The average renal fractional extraction of matrix Gla-protein was 12.8%. There was no significant correlation between creatinine clearance (range 26-154) and renal fractional extraction of matrix Gla-protein in this population. The extraction of matrix Gla-protein was not influenced by the presence of a renal artery stenosis. In conclusion, we demonstrate that the kidney is able to extract matrix Gla-protein from the plasma at a constant level of 12.8%, independent of renal function in hypertensive subjects.

BACKGROUNDIn hypertension, sodium sensitivity (SS) of blood pressure is associated with renal hemodynamic abnormalities related to increased activity of the renal renin-angiotensin aldosterone system (RAAS). The renal mechanisms of SS in normotensives are unknown. Therefore, we studied whether SS is related to renal hemodynamics and renal responsiveness to angiotensin II (Angll) in young healthy adults.METHODSBlood pressure (mean arterial pressure (MAP)) and renal function were measured in 34 healthy men after 1-week low-sodium diet (LS; 50 mmol Na+/24 h), 1-week high-sodium diet (HS; 200 mmol Na+/24h), and 1-week HS-ACEi (enalapril 20 mg/day).The responses of effective renal plasma flow (ERPF; I-131-Hippuran clearance) to graded infusion of Angll were assessed during each condition.RESULTSThe sodium-induced change in MAP ranged from -7to+14mmHg. SS (a sodium-induced increase in MAP > 3 mm Hg) was present in 13 subjects. ERPF was lower in SS subjects during LS and during HS-ACEi. The Angll-induced decrease in ERPF was blunted in SS on LS (-25 +/- 6 vs. -29 +/- 7% in sodium-resistant (SR) subjects, P CONCLUSIONSS normotensive subjects have a blunted renal response to exogenous Angll. This is ameliorated by ACE, supporting a role for inappropriately high intrarenal RAAS activity. As these findings cannot be attributed to subclinical renal hypertensive damage, high intrarenal RAAS activity and altered renal hemodynamics may be primary phenomena underlying SS.