Total Renal Plasma Flow Research Articles

Comparison of the gamma-Pareto convolution with conventional methods of characterising metformin pharmacokinetics in dogs

A model was developed for long term metformin tissue retention based upon temporally inclusive models of serum/plasma concentration ( C ) having power function tails called the gamma-Pareto type I convolution (GPC) model and was contrasted with biexponential (E2) and noncompartmental (NC) metformin models. GPC models of C have a peripheral venous first arrival of drug-times parameter, early C peaks and very slow washouts of C . The GPC, E2 and NC models were applied to a total of 148 serum samples drawn from 20 min to 72 h following bolus intravenous metformin in seven healthy mongrel dogs. The GPC model was used to calculate area under the curve (AUC), clearance ( CL ), and functions of time, f(t), for drug mass remaining (M), apparent volume of distribution (V_{d}), as well as t_{1/2} f(t) for C , M and V_{d}. The GPC models of C yielded metformin CL -values that were 84.8% of total renal plasma flow (RPF) as estimated from meta-analysis. The GPC CL -values were significantly less than the corresponding NC and E2 CL -values of 104.7% and 123.7% of RPF, respectively. The GPC plasma/serum only model predicted 78.9% drug M average urinary recovery at 72 h; similar to prior human urine drug M collection results. The GPC model t_{1/2} of M , C and V_d, were asymptotically proportional to elapsed time, with a constant limiting t_{1/2} ratio of M/C averaging 7.0 times, a result in keeping with prior simultaneous C and urine M collection studies and exhibiting a rate of apparent volume growth of V_d that achieved limiting constant values. A simulated constant average drug mass multidosing protocol exhibited increased V_d and t_{1/2} with elapsing time, effects that have been observed experimentally during same-dose multidosing. The GPC heavy-tailed models explained multiple documented phenomena that were unexplained with lighter-tailed models.

Renovascular remodeling and renal injury after extended angiotensin II infusion.

Chronic angiotensin II (ANG II) infusion for 1 or 2 wk leads to progressive hypertension and induces inward hypertrophic remodeling in preglomerular vessels, which is associated with increased renal vascular resistance (RVR) and decreased glomerular perfusion. Considering the ability of preglomerular vessels to exhibit adaptive responses, the present study was performed to evaluate glomerular perfusion and renal function after 6 wk of ANG II infusion. To address this study, male Wistar rats were submitted to sham surgery (control) or osmotic minipump insertion (ANG II 200 ng·kg(-1)·min(-1), 42 days). A group of animals was treated or cotreated with losartan (10 mg·kg(-1)·day(-1)), an AT1 receptor antagonist, between days 28 and 42 Chronic ANG II infusion increased systolic blood pressure to 185 ± 4 compared with 108 ± 2 mmHg in control rats. Concomitantly, ANG II-induced hypertension increased intrarenal ANG II level and consequently, preglomerular and glomerular injury. Under this condition, ANG II enhanced the total renal plasma flow (RPF), glomerular filtration rate (GFR), urine flow and induced pressure natriuresis. These changes were accompanied by lower RVR and enlargement of the lumen of interlobular arteries and afferent arterioles, consistent with impairment of renal autoregulatory capability and outward preglomerular remodeling. The glomerular injury culminated with podocyte effacement, albuminuria, tubulointerstitial macrophage infiltration and intrarenal extracellular matrix accumulation. Losartan attenuated most of the effects of ANG II. Our findings provide new information regarding the contribution of ANG II infusion over 2 wk to renal hemodynamics and function via the AT1 receptor.

Blood flow to the avian kidney: The use of transit‐time ultrasonic flow probes

A simplified model was used to assess blood flow to the kidney of the anaesthetised domestic fowl. The left kidney was intact and the right kidney consisted of the caudal division with associated vasculature. Transonic perivascular flow probes were placed around the right proximal ischiadic artery and renal vein. Snares around the caudal renal portal vein, common iliac vein and proximal ischiadic artery of the right kidney allowed manipulation of arterial and portal blood flow. Reduction of the pressure in the right renal artery to 50 mm Hg decreased right kidney arterial plasma flow and glomerular filtration rate (GFR). The plasma flow in the right renal vein and the clearance of para-aminohippuric acid by the right kidney remained unchanged. The true filtration fraction of the right kidney, determined from the ratio of GFR to the arterial flow increased slightly. Portal plasma flow and arterial plasma flow contributed 57% and 43%, respectively, to total renal plasma flow during normal arterial and portal flow. J. Exp. Zool. 284:15–22, 1999. © 1999 Wiley-Liss, Inc.

Blood flow to the avian kidney: The use of transit-time ultrasonic flow probes

A simplified model was used to assess blood flow to the kidney of the anaesthetised domestic fowl. The left kidney was intact and the right kidney consisted of the caudal division with associated vasculature. Transonic perivascular flow probes were placed around the right proximal ischiadic artery and renal vein. Snares around the caudal renal portal vein, common iliac vein and proximal ischiadic artery of the right kidney allowed manipulation of arterial and portal blood flow. Reduction of the pressure in the right renal artery to 50 mm Hg decreased right kidney arterial plasma flow and glomerular filtration rate (GFR). The plasma flow in the right renal vein and the clearance of para-aminohippuric acid by the right kidney remained unchanged. The true filtration fraction of the right kidney, determined from the ratio of GFR to the arterial flow increased slightly. Portal plasma flow and arterial plasma flow contributed 57% and 43%, respectively, to total renal plasma flow during normal arterial and portal flow. J. Exp. Zool. 284:15–22, 1999. © 1999 Wiley-Liss, Inc.

Acute, Subacute, and Chronic X-ray Effects on Glomerular Hemodynamics in Rats

In order to evaluate the effects of x-rays on glomerular hemodynamics, surgically exposed left kidneys of Munich-Wistar rats were irradiated with 15 Gy in a single dose. The animals were studied 45 min (acute group, n = 8), 14 days (subacute group, n = 7), and 60 days (chronic group, n = 7) after irradiation and compared with their respective controls. A decrease in total glomerular filtration (55%) and renal plasma flow (40%) rates with marked elevation of total renal vascular resistance (180%), p < 0.05, occurred within 45 min. Significant changes also occurred in the microcirculation; i.e., single-nephron glomerular filtration (SNGFR), glomerular plasma flow (QA), and glomerular capillary hydraulic pressure (PGC) declined by 35%, 40%, and 12%, respectively, due to an increase in total arteriolar resistance (90%), p < 0.05. Within 14 days, SNGFR was similar to control in spite of a moderate elevation of afferent arteriolar resistance (26%) and reduction in PGC (11%), p < 0.05, and QA (20%). Kf was significantly elevated (46%), p < 0.05. The chronic group presented a response pattern similar to that of the acute group, although less severe. Histopathological changes were not relevant and were restricted to tubules. The present results suggest that: (a) Acutely, there was a marked reduction in filtration, flow, and PGC with significant elevation of resistances. (b) Within 14 days, the maintenance of SNGFR was probably the result of an offsetting effect between QA and PGC decreases and Kf elevation. (c) After 60 days, the homeostatic mechanism was not sufficient to maintain normal renal function. (d) A functional effect is probably the most important pathogenetic mechanism, at least during the initial phase, for the development of radiation nephropathy since no morphological alterations were observed.

Long-Term Follow-Up of a Human Subject With a Remnant Kidney

It has been proposed that once functioning renal mass has been reduced below a critical level, either as the result of disease, congenital absence of a kidney, or surgical ablation, that hyperfiltration and glomerular hypertension lead to progressive glomerular sclerosis and end-stage renal failure. We report the clinical course and renal function of a human subject followed for 10.8 years after extensive renal ablation. Functioning renal mass was estimated at one fourth to one fifth of normal. During the follow-up period, creatinine clearance increased from 0.27 mL/s (16 mL/min) to 0.88 mL/s (53 mL/min), the total renal plasma flow (all of which was to the left kidney) increased from 62 mL/min to 190 mL/min, and 24-hour urine protein excretion increased from 0.09 g to 0.4 g. Despite probable glomerular hyperfiltration, neither progressive glomerular dysfunction nor end-stage renal failure developed over a period of 10 years.

A direct modeling approach to the early renal vascular transit of 99mTc chelates.

Delay channel integral methods are developed and applied for analyzing human renal scintiangiographic data produced after peripheral venous injection of a 99mTc chelete. The results include information for two renal vascular compartments (C1, C2) and a residual compartment (Cr). Each vascular compartment is associated with a fraction of the total renal plasma flow (A1, A2) and a mean transit time (T1, T2). The residual compartment has the residual plasma flow fraction Ar. The results obtained in 40 normal kidneys are presented and compared theoretically to the results from other methods.

Renal effects of atrial natriuretic factor in primate.

Baboons (Papio hamadryas) were infused intravenously with a nonhypotensive dose (0.1 microgram X min-1 X kg-1) of synthetic human atriopeptin III (ANF) for 60 min. Throughout the infusion in intact animals, ANF significantly increased glomerular filtration rate (GFR) (clearance of inulin) (P less than 0.001), and, to a lesser extent, total renal plasma flow (RPF) [clearance of p-aminohippurate (PAH)] (P less than 0.02) and filtration fraction (P less than 0.02). Concomitant increases in urinary flow rate and in the excretion of osmoles, sodium, chloride, potassium, phosphorus, and calcium were highly significant (less than 0.001 for all). To minimize the hemodynamic impact of ANF on GFR, the same dose of ANF was infused into the same animals 8 wk after uninephrectomy. Base-line single-kidney GFR was then 50% increased. With ANF infusion RPF increased significantly (P less than 0.02), as in intact baboons, but ANF then had only marginally significant effects on GFR (P = 0.06) and insignificant effects on filtration fraction (P = 0.17). Nevertheless, the changes in urinary flow rate and solute excretion rates were highly significant (P less than 0.001 to less than 0.007). In both groups, all changes developed rapidly, were sustained during the infusion of ANF, and were readily reversible within 15 to 30 min of cessation of ANF infusion. The data dissociate in uninephrectomized primate the effects of ANF on water and solute excretion from those on GFR and filtration fraction. Both in intact and in uninephrectomized baboons, the changes in water and solute excretion were associated with small but significant changes in RPF.

Renal handling of norepinephrine and epinephrine in the pig.

To investigate the renal handling of catecholamines in the pig, intravenous infusions of 51Cr-EDTA and PAH were performed in 7 animals, and samples for simultaneous measurement of norepinephrine (NE), epinephrine (E), 51Cr-EDTA and PAH were obtained through catheters placed into the aorta, left renal vein and both urethers. For both kidneys together, 51Cr-EDTA clearance [GFR] averaged 48 +/- 14 (+/- SD) ml/min (2.23 +/- 0.66 ml/kg/min). In the left kidney, GFR averaged 22 +/- 9 ml/min, arteriovenous PAH extraction 0.87 +/- 0.09, and calculated total renal plasma flow 91 +/- 30 ml/min. Plasma NE and E were lower in renal venous than arterial blood (P less than 0.005), extraction ratios averaging 0.36 and 0.77, respectively. NE excretion rate in final urine (8.9 +/- 4.3 ng/min) exceeded transrenal NE extraction rate (5.2 +/- 3.9 ng/min) by 3.7 +/- 4.4 ng/min. In contrast, urinary E excretion rate (2.9 +/- 2.0 ng/min) was slightly lower than transrenal E extraction rate (3.6 +/- 3.8 ng/min). These observations suggest that in pig kidneys, plasma PAH extraction rate and GFR related to body weight are quite similar to values in man. Three quarters of circulating E are extracted for the most part by tubular secretion, and the slightly smaller amount appearing in urine is consistent with some intrarenal metabolism. NE, presumably originating from intrarenal neuronal release and/or de novo production, is secreted into the urine.

Renal interstitial volume of the rat kidney

The intravascular plasma volume and the interstitial volume of the rat kidney were determined by an indicator dilution method with a bolus injection of 125-I-labelled human serum albumin and 51-Cr-EDTA into the renal artery and subsequent recording of the indicator-dilution curves in the venous effluent, sampled at intervals of 0.33 s. The curves allowed determination of both the mean transit time of the two indicators and total renal plasma flow. The volumes of distribution were obtained by multiplying these two factors. Under control conditions the plasma volume was 93.0 +/- 11.2 microliters/100 g rat (mean +/- SE), which is 17.9% of the total kidney volume. The interstitial volume was 68.3 +/- 8.6 microliters/100 g, corresponding to 13.1% of the total kidney volume. During expansion with 0.15 M NaCl, 10% of body weight, the plasma and interstitial volumes were not significantly increased. The values for the two volumes were 101.6 +/- 9.7 and 72.8 +/- 6.8 microliters/100 g, respectively. The kidney weight showed, in contrast a clear increase from 539 to 670 mg/100 g, reflecting the expansion of the proximal and distal tubules due to the increased glomerular filtration rate. It is concluded that although the saline load produced a rise in the renal interstitial pressure, the expected expansion of the interstitium became small, due to the parallel expansion of both the vascular and tubular systems which compress the renal interstitium.

The effects of sar1ala8-angiotensin II in vasopressin-treated dehydrated sheep.

Mildly dehydrated conscious Merino ewes were infused with vasopressin (AVP) at 5 mu x min-1 alone and simultaneously with the angiotensin II receptor blocker sar1ala8-angiotensin II (saralasin) at 15 micrograms x min-1. AVP was slightly pressor and produced an increase in the calculated total peripheral resistance, and an increase in glomerular filtration rate, urine flow and electrolyte excretion, without a change in total renal plasma flow. These results indicate renal efferent arteriolar vasoconstriction as well as other non-renal vasoconstriction. Saralasin infusion checked the rise in total peripheral resistance (which continued to increase after saralasin withdrawal), but caused a marked increase in renal vascular resistance resulting in a decrease in renal plasma flow and to a lesser extent in glomerular filtration rate. These results suggest that saralasin was acting as an angiotensin II agonist in the kidney, but as an antagonist elsewhere. Deductions from previous experiments in the literature of the renal function of angiotensin II, based on its supposed inhibition by saralasin, may not be justified.

Glomerular ultrafiltration in the pseudopregnant rat

Whole kidney and single nephron indices of glomerular ultrafiltration were measured by clearance and micropuncture techniques in anesthetized virgin, 9-day pregnant, and 9-day pseudopregnant Munich-Wistar rats. Whole kidney glomerular filtration rate (GFR) and single nephron glomerular filtration rate (SNGFR) were elevated in pregnant and pseudopregnant rats compared with virgins (0.78 +/- 0.05, 0.75 +/- 0.06 vs. 0.57 +/- 0.03 ml/min, P less than 0.005 and P less than 0.001; 32.1 +/- 2.5, 30.0 +/- 2.8 vs. 22.1 +/- 2.0 nl/min, P less than 0.01 and P less than 0.05, respectively). Total renal plasma flow rate (RPF) and single glomerular plasma flow rate (QA) were also increased in pregnant and pseudopregnant rats compared to virgins (3.05 +/- 0.19, 2.90 +2- 0.24 vs. 2.28 +/- 0.21 ml/min, P less than 0.01 and P less than 0.05; 109.0 +/- 15.8, 100.4 +/- 12.8 vs. 68.0 +/- 6.9 nl/min, both P less thn 0.05). There was little difference in the other determinants of ultrafiltration among the three groups. Plasma volume was measured in separate experiments and was higher in pregnant and pseudopregnant rats compared with virgins (9.4 +/- 0.2, 9.8 +/- 0.4 vs. 8.4 +/- 0.3 ml, P less than 0.01 and P less than 0.05, respectively). The gestational increase in GFR in the rat occurs as the result of increased RPF, which is due to both plasma volume expansion and renal vasodilation. Since the changes in renal hemodynamics seen in pseudopregnancy were almost identical to those occurring in pregnant rats, the early stimulus to increased GFR must be maternal and not fetoplacental in origin.

Aspirin-induced depression of glomerular filtration rate in normal humans: role of sodium balance.

The renal clearance of endogenous creatinine, inulin and para-aminohippurate was measured in 10 healthy human volunteers taking aspirin during severe dietary sodium restriction (10 meq/d) to clarify the clinical significance and pathophysiology of aspirin-induced changes in renal function. Sodium restriction alone had no effect on renal clearances but did increase plasma renin activity and urinary prostaglandin E excretion. The addition of aspirin decreased the urinary clearance of prostaglandin E but not plasma renin activity, and caused a significant fall in both endogenous creatinine (from 92.3 +/- 4.1 SE ml/min . 1.73 m2 body surface area to 80.8 +/- 4.4 mL/min . 1.73 m2, p = 0.02) and inulin (from 95.3 +/- 7.0 mL/min . 1.73 m2 to 80.9 +/- 7.0 mL/min . 1.73 m2, p less than 0.001). The fall in inulin clearance was directly related to the salicylate level. The clearance of para-aminohippurate showed only a slight, statistically insignificant decline with aspirin. The results of this study suggest that aspirin-induced depression of glomerular filtration rate may be independent of total renal plasma flow. Aspirin should be used cautiously, with careful attention to dosage, in sodium-restricted patients whose glomerular filtration rate may, in part, be under the homeostatic control of renal prostaglandins.

Assessment of total and divided renal plasma flow by 123I-hippuran renography

We studied 23 patients with suspected renal hypertension, including 12 with renal artery stenosis, or occlusion. Total effective renal plasma flow (ERPF) was measured in all patients by conventional p-aminohippurate (PAH) clearance and by 123I-hippuran clearance performed on the same day. A close correlation between the two techniques was obtained (r = 0.87, P less than 0.001) with the latter technique underestimating the former by a mean ratio of 0.89:1.00. We describe a technique for deriving ERPF for individual kidneys by 123I-hippuran renography, and the data obtained by this method correlate well with data obtained from bilateral ureteric catheterization studies (r = 0.076, P less than 0.001 for both affected and unaffected sides) in 17 patients. The renographic technique is particularly accurate in quantitating ERPF in the 12 patients with renal artery stenosis, and is recommended as the investigation of choice in the assessment of ERPF in patients with this condition.

Effects of prostaglandin inhibition on intrarenal hemodynamics in acutely saline-loaded rats.

We studied the effect of inhibition of the prostaglandin (PG)-synthesizing enzyme system in female Sprague-Dawley rats following acute expansion of the extracellular fluid volume (ECV). In 57 conscious rats expansion of the ECV with isotonic saline corresponding to an increase in body weight of 10% was induced. Prior to ECV expansion 31 rats received indomethacin (10 mg/kg of body wt) by stomach tube. In six non-ECV-expanded rats indomethacin had no effect on glomerular filtration rate (GFR) and renal plasma flow (RPF). In ECV-expanded rats pretreated with indomethacin, GFR was unaltered but 125I-hippuran clearance decreased, and filtration fraction significantly increased. Intrarenal 86Rb distribution was similar in control and ECV-expanded rats. Indomethacin caused a slight increase in relative cortical 86 RB activity in non-ECV-expanded rats, but had no effect on intrarenal 86Rb distribution in ECV-expanded rats. No difference in intracortical glomerular perfusion was noted between control and ECV-expanded rats. In indomethacin-treated ECV-expanded rats an increase in relative inner cortical perfusion was observed. Absolute perfusion remained unaltered. Thus the decrease in total RPF was entirely due to decreased perfusion of outer cortical nephrons. Renal prostaglandins therefore may play a permissive role for physical factors to promote renal sodium excretion in acute ECV expansion via changes in intrarenal hemodynamics.

Individual Renal Plasma Flow Determination in 2 Minutes

A method is described for determining effective renal plasma flow, using the renal counts 1 to 2 minutes after injection and applying background subtraction as a ratio to the total amount of radioactivity injected intravenously with appropriate correction for kidney depth. It appears that this simple approach for determination of effective renal plasma flow within a matter of 2 minutes is accurate and reliable, and should be useful for a number of applications when it is important to determine total and individual renal plasma flow. The approach is recommended as a screening procedure in lieu of the determination of blood urea nitrogen and serum creatinine, with the additional advantages of gross morphology and determination of individual renal plasma flow in an absolute as well as relative manner.

Prostaglandins and renal function in acute extracellular volume expansion

Mechanisms determining the natriuresis in ECV-expansion are not yet completely understood. The present study was therefore undertaken to investigate if prostaglandins (PG) are involved in the natriuresis of acute ECV-expansion and by which mechanisms PG may affect renal Na-absorption. In non-expanded rats the PG synthetase inhibitor indomethacin (INDO) had no effect on renal function. In 37 Sprague-Dawley rats ECV-expansion with isotonic saline corresponding to an increase in b.wt. of 10 % was induced. Twenty-one animals received an oral dose of 10 mg/kg b.wt. of INDO prior to ECV-expansion. Sixteen animals served as ECV-expanded controls (C). GFR (INDO: 12.5±1.0; C: 10.5±0.9 ml/min/kg b.wt.) did not significantly differ in both groups. However, total renal plasma flow (RPF) (INDO: 22.9±1.8; C: 30.1±2.7 m1/min/kg b.wt.), urinary flow rate (INDO: 1.11±0.20; C: 1.93±0.21 m1/min/kg b.wt.) and urinary excretion of sodium (INDO: 141±26; C: 267±46 μ Eq/min/kg b.wt.) and potassium (INDO: 13.0±0.9; C: 19.8±1.7 μEq/min/kg b.wt.) markedly decreased in animals pretreated with INDO. The results indicate that PG are involved in the natriuresis of acute ECV-expansion and suggest, that PG may inhibit the intrinsic capacity for Na-absorption in more proximal parts of the nephron possibly via intrarenal physical factors.

Renovascular Hypertension and Renal Prostaglandins

To the Editor.— In their article on renal and renovascular hypertension, Hunt et al 1 postulated that prostaglandins (PGs) might be involved in the pathogenesis of hypertension that is a result of kidney disease. In a study on functional changes accompanying renal artery stenosis in man, we had indirect evidence indicative of a role of PGs in the physiopathologic alterations occurring in renovascular hypertension. Eleven patients with unilateral stenosis of the main renal artery were studied. All patients had undergone surgery subsequent to the study, and their conditions had proved to be cured or notably improved by surgical treatment. 2 The main results are shown in the Table. In all cases, a striking decrease of extraction of p -aminohippurate and a decrease of reabsorbed sodium were found. Extraction of p -aminohippurate is considered as an index of the fraction of total renal plasma flow to the medulla. Although medullary flow

The release of renal prostaglandins during saline infusion in normal and hypertensive subjects.

1. Renal venous prostaglandin concentrations (PGA, PGE and PGF) were determined, together with renal plasma flow, urinary output and blood pressure changes, before and after infusion of sodium chloride solution (saline) in four normotensive and three hypertensive subjects. 2. No changes in blood pressure and in glomerular filtration rate were observed. 3. Saline infusion induced a significant increase in renal venous PGA and PGE, and also in total and non-cortical renal plasma flow and urinary output. There was an insignificant increase in renal venous PGF. 4. These findings show that prostaglandin release after saline infusion is associated with changes in renal blood flow and suggest that the natriuretic and diuretic effect of saline could be the result of prostaglandin release.

Stimulation of Glucose Release of the Rat Kidney &lt;i&gt;in vivo &lt;/i&gt;by Epinephrine and Isoprenaline

In anesthetized rats the glucose release of the kidneys was estimated from the glucose concentrations in the arterial and renal venous plasma, urinary glucose excretion and the total renal plasma flow. Net renal glucose release was found in control experiments. The glucose release of the kidneys decreased with rising arterial plasma glucose values. Epinephrine (220 mug/kg s.c.) and isoprenaline (10 mu/kg s.c.) enhanced arterial plasma glucose levels and increased mean renal glucose production significantly. The enhanced arterial plasma glucose levels and increased mean renal glucose production significantly. The enhanced glucose release after isoprenaline could be abolished by propranolol (1 mg/kg s.c.). The glycogen content of the kidney was found to be too small to account for the observed renal glucose release by glycogenolysis. Therefore, these in vivo data indicate enhanced renal gluconeogenesis after adrenergic stimulation. This effect is thought to be mediated by the beta-adrenergic receptors.