Kidney Hemodynamics Research Articles

EFFECTS OF INTRARENAL ADMINISTRATION OF THE COX-2 INHIBITOR PARECOXIB DURING PORCINE SUPRARENAL AORTIC CROSS-CLAMPING

The aim of this study was to investigate the effects of intrarenal administration of the cyclooxygenase-2 inhibitor parecoxib during suprarenal aortic cross-clamping. In a prospective, controlled, blinded, randomized manner, 16 anesthetized and mechanically ventilated pigs were instrumented to measure systemic and right kidney hemodynamics, oxygen exchange, and metabolism. During 45 min of suprarenal aortic cross-clamping, animals received 40 mg of parecoxib (n = 8) or vehicle (n = 8) infused continuously into the right renal artery. Hemodynamic and metabolic data, right kidney venous blood, as well as urine samples were obtained before clamping, as well as before and 75 and 195 min after declamping. Clamping transiently increased mean arterial pressure in both groups. Systemic and renal blood flow did not differ between the pre- and postclamping measurements or between groups. Parecoxib attenuated the otherwise significant fall in right kidney creatinine clearance (controls: from 45 [7;111] to 17 [9;22] mL/min; parecoxib: from 39 [3;59] to 27 [11;45] mL/min, P = 0.039 and P = 0.297, respectively versus before clamping, P = 0.021 versus controls at 195 min) and prevented the impairment of renal lactate balance observed in the control group (controls: from 0.5 [-0.8;3.5] to 0.2 [-0.2;0.6] mumol/kg/min; parecoxib: from 0.6 [-1.0;2.0] to 0.4 [-1.2;0.6] mumol/kg/min, P = 0.038 and P = 0.285, respectively, versus before clamping). In conclusion, intrarenal parecoxib infusion beneficially influenced kidney function in this clinically relevant model of suprarenal aortic cross-clamping.

Renal haemodynamic alterations in contrast medium-induced nephropathy and the benefit of hydration

Though several suggestions have been put forward, the underlying mechanism of contrast medium-induced nephropathy (CIN) is not clear. Most probably, however, the culprit is a combination of various mechanisms working together to cause the development of CIN. The generally accepted main factors in the pathophysiology of CIN are the reduction in renal perfusion by contrast media (CM) combined with the toxic effects on the tubular cells. With regard to the literature, misconceptions are widespread when explaining the development of CIN, e.g. that osmolar challenge induces renal vasoconstriction due to the tubuloglomerular feedback mechanism (TGF). Although popular, this assumption is most probably false, since osmotic pressure is not the signal for the TGF. Much attention has been paid to reducing the osmolarity of CM further. In an effort to obtain iso-osmolar CM, dimers were formed. These CM have osmolarities in the near physiological range, but at the cost of increased viscosity. This seems to have adverse effects with regard to kidney haemodynamics. In contrast to the multifarious interpretations of CIN, it is generally accepted that hydration is effective in preventing CIN from occuring. There is no universally accepted explanation for the effect of hydration, but it may rely on enhancing renal medullary blood flow and reducing the viscosity of the fluid in the collecting duct.

Expression of endothelial nitric oxide synthase in developing rat kidney

Endothelium-derived nitric oxide (NO) is synthesized within the developing kidney and may play a crucial role in the regulation of renal hemodynamics. The purpose of this study was to establish the expression and intrarenal localization of the NO-synthesizing enzyme endothelial NO synthase (eNOS) during kidney development. Rat kidneys from 14 (E14)-, 16 (E16)-, 18 (E18)-, and 20-day-old (E20) fetuses and 1 (P1)-, 3 (P3)-, 7 (P7)-, 14 (P14)-, and 21-day-old (P21) pups were processed for immunocytochemical and immunoblot analysis. In fetal kidneys, expression of eNOS was first observed in the endothelial cells of the undifferentiated intrarenal capillary network at E14. At E16, strong eNOS immunoreactivity was observed in the endothelial cells of renal vesicles, S-shaped bodies (stage II glomeruli), and stage III glomeruli at the corticomedullary junction. At E18-20, early-stage developing glomeruli located in the subcapsular region showed less strong eNOS immunoreactivity than those of E16. The eNOS-positive immature glomeruli were observed in the nephrogenic zone until 7 days after birth. In fetal kidneys, eNOS was also expressed in the medulla in the endothelial cells of the capillaries surrounding medullary collecting ducts. After birth, eNOS immunostaining gradually increased in the developing vascular bundles and peritubular capillaries in the medulla and was highest at P21. Surprisingly, eNOS was also expressed in proximal tubules, in the endocytic vacuolar apparatus, only at P1. The strong expression of eNOS in the early stages of developing glomeruli and vasculature suggests that eNOS may play a role in regulating renal hemodynamics of the immature kidney.

Effect of sodium intake on blood pressure and albuminuria in Type 2 diabetic patients: the role of insulin resistance

This study was done to measure the effect of Na+ intake on blood pressure and albuminuria, in relation with insulin sensitivity and kidney haemodynamics, in Type 2 diabetic patients with and without microalbuminuria. Type 2 diabetic patients, 20 with microalbuminuria, 21 without, spent two consecutive 7-day periods, one on a high (250 mmol), the other on a low-Na+ (20 mmol) diet. Body weight, 24-h blood pressure and albuminuria were measured at the end of each period. At the end of high-Na+ diet insulin sensitivity (euglycaemic insulin clamp; 2 mU.kg(-1).min(-1)) and kidney haemodynamics were measured in nine patients from each group. Switching from low to high-Na+ diet resulted in an increase in blood pressure (7.4+/-4.7 mmHg; p<0.001), body weight (1.9+/-0.4 kg; p<0.05) and albuminuria [from 80 (31-183) microg/min to 101 (27-965) microg/min; p<0.01) in patients with microalbuminuria. No changes occurred in patients without microalbuminuria. Patients with microalbuminuria also had greater intraglomerular pressure (44+/-1 mmHg vs 36+/-1; p<0.001), calculated from glomerular filtration rate, renal plasma flow, plasma protein concentration and the relationship between pressure and natriuresis. In these patients insulin sensitivity was lower (5.16+/-49 vs 7.36+/-0.63 mg.kg(-1).min(-1); p=0.007). Urinary albumin excretion (r=0.40; p=0.009) and insulin sensitivity (r=-0.59; p=0.01) were correlated with intraglomerular pressure. High salt intake increases blood pressure and albuminuria in Type 2 diabetic patients with microalbuminuria. These responses are associated with insulin resistance and increased glomerular pressure. Insulin resistance could contribute to greater salt sensitivity, increased glomerular pressure and albuminuria.

Effects of endothelin-A receptor antagonism on bilateral renal function in renovascular hypertensive rats.

Recent studies indicated an enhanced expression of Endothelin (ET) in the kidney contralateral to the vascular clip in two-kidney, one-clip (2K-1C) Goldblatt hypertension. We proposed that the enhanced intrarenal ET production might be responsible for altered haemodynamic and excretory capability of the unclipped kidney (UK) of 2K-1C renovascular hypertensive rats. Therefore, we examined the changes in arterial pressure and split renal function in the clipped (CK) and UK simultaneously, in response to chronic administration of the selective ETA receptor blocker (A-127722), given orally at a dose of 30 mg/kg/day for 3 weeks starting from the beginning of the 4th week of clipping. Systolic pressure averaged 177 +/- 7 mmHg in control rats (n=15) and 164 +/- 9 mmHg in treated rats (n=16) and the difference was not statistically different. Glomerular filtration rate (GFR), renal plasma flow (RPF) and renal vascular resistance (RVR) in the UK were not different between control and treated groups. Data were then analyzed by classifying rats as moderate hypertensives (MAP < 180 mmHg), and severe hypertensives (MAP > 180 mmHg). In the moderately hypertensive group, average MAP was 143 +/- 5 mmHg and 138 +/- 4 mmHg in control (n=9) and treated (n=10) groups, respectively. In the severely hypertensive group, average MAP was 192 +/- 5 mmHg and 188 +/- 5 mmHg in control (n=6) and treated (n=6) groups, respectively. GFR and RPF were significantly improved in the UK of only the severely hypertensives who received the antagonist. However, the ET(A) antagonist blunted the sodium loss in both CK and UK of severely hypertensive rats. We conclude that ET(A) receptors do not play a role in the progression of hypertension in 2K-1C renovascular hypertensive rats. Yet, ET(A) receptors play an important role in altering renal hemodynamics of the unclipped kidneys in severe degrees of renovascular hypertension.

Usefulness and limits of distal echo-Doppler velocimetric indices for assessing renal hemodynamics in stenotic and non-stenotic kidneys.

Distal echo-Doppler velocimetric indices are widely used for revealing the presence of a renal artery stenosis but there is scarce information as to whether they reflect the renal hemodynamics in stenotic and nonstenotic kidneys. We evaluated the pulsatility and resistive indices (PI and RI), acceleration (A) and acceleration time (At) and correlated their values with those of effective renal plasma flow (ERPF), glomerular filtration rate (GFR), renal vascular resistance (RVR) and filtration fraction (FF) estimated by single kidney scintigraphy in 24 kidneys with 70-95% renal artery stenosis (atherosclerotic n = 17, fibromuscular n = 7) and in 27 non-stenotic kidneys (11 contralateral to renal artery stenosis and 16 of patients with essential hypertension). In patients with stenotic kidneys, these measurements were repeated within 7 days after a successful percutaneous transluminal renal angioplasty (PTRA) (in 11 arteries performed in combination with stent implantation). Prior to dilation we found that the stenotic kidneys had significantly lower values of ERPF, GFR and higher RVR than the non-stenotic kidneys and that these hemodynamic alterations were associated with those, also statistically significant, of the four velocimetric indices. In non-stenotic kidneys, there were highly significant relationships between PI and ERPF, and RVR (r = -0.68 and 0.81 respectively P < 0.01); similar relationships were found for RI (r = -0.67 and 0.78 P < 0.01) whereas no such correlations were found between these two velocimetric indices and GFR and FF; also no correlations were found between A and Atand ERPF, GFR, RVR and FF. In stenotic kidneys no significant correlations were found between any of the velocimetric and the hemodynamic indices. Renal artery dilation induced clear cut increments in ERPF, GFR and reduction in RVR in post-stenotic kidneys, which were associated with normalization of all four velocimetric indices. No relationships were observed between the renal hemodynamic and the velocimetric changes induced by dilation; however in post-stenotic kidneys the relationships between PI and RI, ERPF and RVR were restored as in nonstenotic kidneys. These data indicate that PI and RI can be used to assess ERPF and RVR both in non-stenotic and post-stenotic kidneys; however, none of the velocimetric indices examined in this study can provide valid informations on the renal hemodynamics of stenotic kidneys and on their changes induced by PTRA.

EFFECT OF NITRIC OXIDE INHIBITION ON KIDNEY FUNCTION IN EXPERIMENTAL RENOVASCULAR HYPERTENSION

We examined the effect of acute systemic blockade of nitric oxide (N0) synthesis on blood pressure and renal function in rats with angiotensin II dependent two-kidney, one-clip Goldblatt hypertension. Hypertensive animals had significantly higher blood pressures, plasma NO metabolite concentrations and urinary NO metabolite excretion rates than control rats. Intravenous administration of NG-nitro-L-arginine methylester (L-NAME) (10 mg/kg) increased mean arterial pressure in both hypertensive and control animals with the magnitude of increase being greater in hypertensive than control rats (32±3 vs. 20±2 mmHg,p< 0.05). L-NAME did not affect glomerular filtration rates of normal and clipped kidneys but significantly decreased non-clipped kidney glomerular filtration rate (1.1±0.1 vs. 0.7±0.1 ml/min per g kidney wt, p< 0.05). Blood flow to normal and non-clipped kidneys fell in response to L-NAME. Percent reduction in renal blood flow produced by L-NAME was significantly greater in non-clipped than normal kidneys (38±3 vs. 24±2%,p< 0.05). In contrast, clipped kidney blood flow increased after L-NAME (3.3±0.2 vs. 4.0±0.2 ml/min per g kidney wt,p< 0.05). An identical improvement in clipped kidney blood flow occurred when arterial pressure was raised with aortic constriction indicating that the systemic pressor effect of L-NAME was responsible for this finding. These results indicate that NO plays an important role in systemic and non-clipped kidney hemodynamics in renovascular hypertension. Because NO has little influence on stenotic kidney function, the stimulus for increased NO system activity in this disease appears to be vascular shear stress rather than elevated circulating or intrarenal angiotensin II concentrations.

Effect of transcatheter arterial chemoembolization on kidney hemodynamics and function in patients with cirrhosis and hepatocellular carcinoma

Background/Aims: Transcatheter arterial chemoem-bolization (TACE) may have deleterious effect on the kidney in patients with cirrhosis and hepatocellular carcinoma. The aim of the study was to test this hypothesis. Methods: Twenty-four patients with cirrhosis and hepatocellular carcinomas were included. They consisted of 16 patients undergoing a single TACE and eight patients undergoing diagnostic angiography. Doppler ultrasonography was used to measure hepatic artery pulsatility index (HA-PI) and renal artery pulsatility index (RA-PI) before and 1 day and 10 days after the procedure. Similarly, kidney function was assessed by measuring creatinine clearance. In addition, plasma renin activity, noradrenaline, and endothelin-1 were also measured. Results: In patients receiving diagnostic angiography, no significant changes in HA-PI were observed after the procedure. In contrast, HA-PI increased significantly 1 day after the procedure (19%, p<01) in patients undergoing TACE, although it returned to baseline value 10 days after the procedure. In patients undergoing diagnostic angiography, no significant changes in RA-PI were observed after the procedure. Similarly, no detectable changes in RA-PI were noted in patients undergoing TACE. A transient small reduction in creatinine clearance was noted after the procedure in patients undergoing diagnostic angiography (−12%, p<05) and in those undergoing TACE (−11%, p<05). However, the effect was similar in the two groups (two-way ANOVA, p=0.72). No significant changes in plasma renin activity, noradrenaline, and endothelin-1 were observed after either diagnostic angiography or TACE. Conclusions: These results suggest that TACE per se has no deleterious effect on the kidney hemodynamics and function in patients with cirrhosis and hepatocellular carcinoma.

Bradykinin in the Hypoxemic Kidney of the Newborn Rabbit

BACKGROUND Hypoxemia causes renal hypoperfusion in newborns, partly mediated by the activation of local vasoactive factors. Recently, we demonstrated that bradykinin (BK) regulates renal hemodynamics of the neonatal kidney. We investigated if the activation of the renal kallikrein-kinin system(KKS) contributes to the neonatal renal effects of hypoxemia. EXPERIMENTAL MODEL The effect of systemic hypoxemia (PaO2=40 mmHg) on renal function was investigated in newborn rabbits with intact (n=9) or blocked BK B2 receptors (n=8, Hoe 140, 300 μg/kg s.c.) PAH and inulin clearances were used as indices of renal blood flow (RBF) and GFR, respectively .RESULTS Hypoxemia induced a decrease in RBF (-26±5%) and GFR(-13±6%). Renal vascular resistance (RVR) and filtration fraction (FF) increased (RVR: 30±12%, FF: 15±3%). Acute hypoxemia-induced glomerular hemodynamic changes were not different after the blokade of BK B2 receptors (ΔRBF=-25±4%, ΔRVR=21±6%,ΔGFR=-16±4%, ΔFF=12±4). CONCLUSION Endogenous bradykinin accumulation does not contribute to the renal hemodynamic effects of neonatal hypoxemia. It is suggested that, in contrast to the plasma KKS, renal (tissue) KKS is not activated in hypoxemic newborns.

A REVIEW OF EQUINE RENAL IMAGING TECHNIQUES

Radiography has a limited role in the evaluation of the kidneys in foals and adult horses. Ultrasonography is the current method of choice for structural evaluation of the kidneys in horses as it provides additional information to standard serum chemistry and urinalysis evaluation. A variety of structural abnormalities have been identified in diseased equine kidneys with the use of ultrasound. Ultrasound guided renal biopsy is the preferred method for performing renal biopsy in the horse. The use of Duplex Doppler ultrasound may allow for the characterization of regional hemodynamics of the equine kidneys, but is currently an untapped method for evaluation of equine renal hemodynamics.Radionuclide methods including scintigraphy and quantitative renal function measurement can be used to provide further information about equine renal function. Scintigraphy can provide structural and possibly functional information. Quantitative methods using radiopharmaceuticals can provide precise measurement of glomerular filtration rate and effective renal blood flow. This method is especially helpful in identifying acute renal failure and in guiding response to treatment.All equine renal imaging techniques should be a supplement to the physical examination and standard laboratory tests. Additional diagnostic aids such as urinary tract endoscopy should also be considered in horses with hematuria, hydroureter, and suspected calculi. Taken together, all these modalities provide a through evaluation of the equine renal system and provide a basis for the clinician to select treatment options and provide prognostic information to the owner.

Role of nitric oxide in the hypoxemia-induced renal dysfunction of the newborn rabbit.

The current study was performed in 30 anesthetized and mechanically ventilated newborn rabbits to investigate the role of the endothelium-derived relaxing factor nitric oxide (NO) in the renal vasoconstriction observed during hypoxemia. Renal blood flow (RBF) and GFR were determined by the clearance of p-aminohippuric acid and inulin, respectively. In nine newborn rabbits (group 1), acute hypoxemia induced a significant decrease in RBF (-17 +/- 7%) and GFR (-11 +/- 6%). A second group of nine animals was used to determine the role of NO in regulating renal hemodynamics of the immature kidney in physiologic conditions. N omega-Nitro-L-arginine methyl ester (L-NAME), a NO synthesis inhibitor, significantly increased the renal vascular resistance by 31 +/- 9% and decreased RBF and GFR (-20 +/- 6% and -13 +/- 5%, respectively). Acute hypoxemia was induced in 12 additional newborn rabbits during L-NAME infusion (group 3) to define the role of NO in the renal vasoconstriction observed during hypoxemia. The changes in renal hemodynamics were greater in this group than in those induced by hypoxemia alone. The present results suggest that: 1) endogenous NO has a crucial role in maintaining basal renal perfusion, 2) the activity of NO synthase is maintained during acute hypoxemia, and 3) NO could blunt the effects of acute hypoxemia in the immature newborn rabbit kidney.

Ascending myogenic autoregulation: Interactions between tubuloglomerular feedback and myogenic mechanisms

A mathematical model of the renal vascular and tubular systems was used to examine the possibility that synergistic interactions might occur between the tubuloglomerular feedback (TGF) and myogenic autoregulatory mechanisms in the kidney. To simulate the myogenic mechanism, the renal vasculature was modelled with a resistance network where the total preglomerular resistance varies with intravascular pressure. In addition, a steady-state model of glomerular filtration, proximal and Henle's loop reabsorption, and TGF-modulation of afferent arteriolar resistance was derived. The results show that, if TGF acts on the distal portion of the preglomerular vasculature, then any TGF-induced vasoconstriction should raise upstream intravascular pressure and, thereby, trigger a myogenic (AMYO) response. The model further predicts that the magnitude of the AMYO response can be similar in magnitude to the TGF-induced increment in afferent resistance. Hence, the effects of TGF excitation on whole kidney hemodynamics may be much greater than predicted from measurements in single nephrons. Moreover, a significant fraction of the intrinsic myogenic autoregulatory response to increased renal perfusion pressure may result from a synergistic interaction between the TGF and myogenic mechanisms.

Role of endothelium-derived nitric oxide in control of renal microvasculature in aging male rats

The objective of this study was to evaluate the role of nitric oxide (NO) in the regulation of whole kidney and glomerular hemodynamics during aging. After 2 wk of oral treatment with N-nitro-L-arginine methyl ester (L-NAME; 4.5 mg.kg body wt-1.day-1) to inhibit NO synthesis, male rats, aged 3-5, 13-15, and 21-24 mo, were studied by micropuncture. Blood pressure increased by 50% in old (21-24 mo) rats with L-NAME but only 20-30% in the two younger groups. With L-NAME, renal vascular resistance increased fivefold in old rats but only twofold in younger groups. Glomerular capillary pressure increased 20-30% in younger L-NAME rats and 60% in older rats. Afferent and efferent resistances increased dramatically, and the glomerular capillary ultrafiltration coefficient decreased in all L-NAME-treated rats but most strikingly in the 21- to 24-mo-old group. Acute infusion of L-arginine significantly attenuated the effects of NO synthase inhibition on arterial pressure and renal hemodynamics in both young and old rats. This study confirms that NO synthesis blockade has a greater effect on renal hemodynamics in aging rats and implies that NO may play a progressively more important role in controlling renal function with advancing age.

Urinary kallikrein excretion in Type 1 (insulin-dependent) diabetes mellitus

Kidney haemodynamics appear to change after the early phases of diabetic nephropathy: increases in glomerular filtration rate and in renal plasma flow have been widely reported, while kidney size is increased. As the renal kallikrein-kinin system has been demonstrated to regulate kidney blood circulation, we have evaluated the excretion of urinary kallikrein in 87 Type 1 (insulin-dependent) diabetic patients with and without hyperfiltration. Urinary kallikrein excretion was measured in 24-h urine collections. The esterolytic activity was determined by fluorimetric assay. The excretion of urinary kallikreins was significantly higher in hyperfiltering patients (472 +/- 125 esterase units/24 h) than in normofiltering (168 +/- 77 esterase units/24 h) and control subjects (151 +/- 39 esterase units/24 h), p < 0.001. Furthermore, we observed a positive correlation between urinary kallikrein excretion and glomerular filtration rate (r = 0.785). These data suggest that variations of kallikrein and kinin concentrations may play a role in the alteration of renal haemodynamics in Type 1 diabetes. It is possible that the kinin-kallikrein system, the renin-angiotensin system and the prostaglandins may interact to determine the haemodynamic alterations which are present in the diabetic disease.

Magnetic resonance imaging of the kidney in type 1 (insulin-dependent) diabetes mellitus.

Reductions in the physiological cortical to medullary signal intensity ratio are found in magnetic resonance scans of the kidney in non-diabetic glomerular disease. Whether this abnormality can also characterise patients with Type 1 (insulin-dependent) diabetes mellitus and nephropathy is not known. We measured the cortical to medullary signal intensity ratio in magnetic resonance images of the kidney in 34 patients with Type 1 diabetes (ten with either clinical proteinuria or raised serum creatinine or both, nine with microalbuminuria, seven with normal urinary albumin excretion and long duration of diabetes and eight with Type 1 diabetes of short duration). The cortical to medullary signal intensity ratio showed a trend to cluster at lower values in the normoalbuminuric patients with normal serum creatinine rather than in the nine healthy individuals, independent of Type 1 diabetes duration (1.47 +/- 0.06 and 1.41 +/- 0.13 vs 1.63 +/- 0.16; five groups Scheffé F-test p = 0.05-0.1). Among the Type 1 diabetic patients, significant reductions in the cortical to medullary signal intensity ratio characterised overt nephropathy (1.19 +/- 0.15, p less than 0.05 vs all groups), but not microalbuminuria (1.47 +/- 0.13, p = NS), concomitantly with low glomerular filtration rate and elevated fractional excretion of uric acid, but independent of glycaemic control. The determinants of the renal cortical to medullary signal intensity ratio in Type 1 diabetes are uncertain. Reductions in the cortical to medullary signal intensity ratio may be a late finding in diabetic nephropathy, and parallel the accompanying impairment in kidney haemodynamics.(ABSTRACT TRUNCATED AT 250 WORDS)

Clearance rate of immunoglobulins and diabetic nephropathy

The interaction between the electrostatic charge of macromolecules and the fixed charges of glomerular basement membrane pores is of importance in protein permselectivity in addition to a number of other factors. In normal conditions anionic proteins are filtered to a lesser extent than cationic proteins of similar size and shape. In the early stages of diabetic nephropathy there are biochemical changes in the glomerulus, i.e. a decrease in glomerular fixed anionic charges, which lead to an increased vascular permeability to macromolecules. Attention has been focused on methods for detecting the initial permselectivity defects, to monitor the early preclinical stages of diabetic nephropathy over time. A promising methodological approach is the parallel evaluation of the clearance of two proteins similar in all main characteristics but differing in their electrostatic charge, i.e. the different subclasses of immunoglobulins. A preferential excretion of anionic molecules would be expected when a diabetic loss of charge selectivity is present. Studies have been performed in normal subjects and in type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetic patients both in basal conditions and after pharmacological challenges. In normal subjects in basal state anionic and cationic immunoglobulins were found to be excreted in a ratio of about 1 : 10 and the anionic/cationic ratio could be only minimally influenced by orthostatism or physical exercise. In diabetic patients of both type 1 and 2 the clearance of anionic immunoglobulins and the anionic/cationic immunoglobulin ratio were clearly increased in several randomly selected patients; in particular several normoalbuminuric patients showed enhanced immunoglobulin G4 clearances. The acute intravenous administration of an angiotensin-converting enzyme inhibitor in diabetic patients induced marked modifications of kidney haemodynamics and quantitative alterations of protein permselectivity, together with a selective decrement of anionic immunoglobulins in comparison with the excretion of total immunoglobulins. In conclusion, disproportions in the anionic/cationic immunoglobulin G ratio which are present in microalbuminuric and in a number of normoalbuminuric patients appear to detect initial abnormalities in diabetic kidney disease.

Role of nitric oxide in mediating renal response to volume expansion.

The objective of the present study was to determine the role of endothelium-derived nitric oxide in mediating the renal response to extracellular volume expansion with isotonic saline (5% body weight). In anesthetized dogs (n = 7) and before volume expansion, nitric oxide synthesis was inhibited in the right kidney by continuous intrarenal infusion of NG-nitro-L-arginine-methyl ester (1 microgram/kg/min). Arterial pressure and renal hemodynamics of both kidneys did not change significantly either during nitric oxide synthesis inhibition or during 5% volume expansion. However, in response to extracellular volume expansion, increases in natriuresis, diuresis, and fractional excretion of lithium (an index of proximal sodium reabsorption) were inhibited in the right kidney by 27%, 28%, and 41%, respectively, when compared with the contralateral kidney. Increases of renal interstitial hydrostatic pressure during 5% volume expansion were not statistically different between both kidneys. In another group of dogs (n = 4), the administration of L-arginine (0.5 mg/kg/min) into the right renal artery prevented the renal effects induced by the nitric oxide synthesis inhibitor during volume expansion. The findings in this study suggest that nitric oxide production plays an important role in regulating the renal response to extracellular volume expansion. The proximal tubule seems to be involved in the reduced renal excretory response to volume expansion during nitric oxide synthesis inhibition.

Impaired response to angiotensin II in Type 1 (insulin-dependent) diabetes mellitus. Role of prostaglandins and sodium-lithium countertransport activity

The pathogenesis of diabetic nephropathy remains elusive. A role for renal prostaglandins in antagonizing the hormonal effects of renin-angiotensin II has been postulated as a putative factor leading to hyperfiltration in patients with Type 1 (insulin-dependent) diabetes mellitus. Our aim was to elucidate the effects of angiotensin II on kidney haemodynamics and on blood pressure in eight normal subjects, in nine normotensive, in nine hypertensive with normal sodium-lithium countertransport activity in erythrocytes, in seven hypertensive without and in eight hypertensive Type 1 diabetic patients with microalbuminuria and with high sodium-lithium countertransport activity in erythrocytes. Angiotensin II infusion (4 ng.kg-1.min-1 for 60 min) decreased the glomerular filtration rate to a greater extent in normal subjects (-20%), than in normotensive patients (-5% p less than 0.01), in hypertensive patients with normal sodium-lithium countertransport activity in erythrocytes (-8% p less than 0.01) in hypertensive patients with high sodium-lithium countertransport (-6% p less than 0.01) and in hypertensive microalbuminuric patients (-5% p less than 0.01) with Type 1 diabetes. The urinary excretion rate of vasodilatory prostaglandins was two-three fold higher in all patients than in normal subjects. Acute indomethacin treatment restored a normal response to angiotensin II infusion in normotensive patients, but did not change the renal haemodynamic response in normal subjects. With regard to hypertensive patients with and without microalbuminuria indomethacin treatment restored a normal response to angiotensin II in some but not all patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Single-nephron responses to systemic administration of amino acids in dogs

It has been suggested that the tubuloglomerular feedback (TGF) system is responsible for renal vasodilation during systemic infusion of amino acid solutions. We evaluated the effect of intravenous administration of amino acids (serine, alanine, proline, and glycine; total dose of 0.075 mmol of amino acids.kg body wt-1.min-1) on whole kidney and single-nephron hemodynamics in pentobarbital sodium-anesthetized dogs. At spontaneous renal arterial pressure (RAP; 125.4 +/- 4.7 mmHg), measurements of single-nephron function obtained during tubular blockade, stop-flow pressure (SFP; 48.2 +/- 2.0 vs. 58.9 +/- 2.3 mmHg, P less than 0.01), and proximally determined single-nephron glomerular filtration rate (SNGFR-TPC; 73.9 +/- 7.0 vs. 93.4 +/- 7.6 nl/min, P less than 0.01) increased in parallel to the increases of outer cortical blood flow (OCBF; 15.4 +/- 1.1 vs. 19.1 +/- 1.5 units, P less than 0.05), renal blood flow (RBF; 4.60 +/- 0.18 vs. 5.73 +/- 0.22 ml.min-1.g kidney wt-1, P less than 0.01), and glomerular filtration rate (GFR; 0.885 +/- 0.034 vs. 1.116 +/- 0.034 ml.min-1.g kidney wt-1, P less than 0.01). Free-flow tubular fluid-to-plasma inulin ratios, determined from late proximal recollections during saline (control) and amino acid infusions failed to provide evidence for altered proximal reabsorption rate (1.63 +/- 0.12 vs. 1.58 +/- 0.17 during amino acids, NS). At reduced RAP (92.6 +/- 1.9 mmHg), where it is presumed that TGF-mediated vasodilation is already near maximal, the vasodilatory response to amino acid infusion was intact and single-nephron parameters measured during tubular blockade increased to the same extent as OCBF, RBF, and GFR.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Perfusion Pressure and Renal Flow upon Albumin Excretion in Isolated Perfused Kidneys

To explore the effects of renal hemodynamics upon urinary albumin excretion, sequential changes in perfusion pressure and/or flow were performed in isolated perfused rat kidneys. Elevation of perfusion pressure from 90 to 130 mm Hg increased renal flow from 48.9 +/- 1.1 to 54.3 +/- 1.4 ml/min and glomerular filtration rate (GFR) from 0.37 +/- 0.03 to 0.81 +/- 0.06 ml/min (p less than 0.001). Despite more than a doubling in GFR, albumin excretion remained unchanged (from 252 +/- 53 to 167 +/- 36 micrograms/min, p not significant), resulting in a decreased fractional clearance of albumin (theta) from 0.009 +/- 0.002 to 0.004 +/- 0.005 ml/min (p less than 0.01). To dissociate the effects of flow from those of pressure, angiotensin II was infused to decrease renal flow from 49.9 +/- 0.6 to 38.7 +/- 0.6 ml/min (p less than 0.001), while keeping perfusion pressure constant at 96 +/- 1 mm Hg. Although GFR was essentially unchanged (from 0.59 +/- 0.02 to 0.65 +/- 0.05 ml/min, p not significant), albumin excretion increased from 68 +/- 8 to 151 +/- 21 micrograms/min (p less than 0.001) and theta rose from 0.002 +/- 0.000 to 0.005 +/- 0.001 (p less than 0.02). Whole kidney hemodynamics acutely affect renal excretion of albumin in isolated kidneys.