The effect of infusion of hypertonic saline on glomerular filtration rate and arginine vasotocin, prolactin and aldosterone in the domestic chicken

Domestic fowl were infused for 60 min with isotonic saline followed by 90 min with hypertonic saline. Plasma electrolyte concentrations, osmolality and haematocrit were measured. Urine electrolyte excretion rates, osmolar output and urine flow rates were also monitored. From these results fractional excretions of electrolytes were calculated. The renal function markers inulin and ρ-amino hippuric acid were infused to enable the measurement of glomerular filtration rate and plasma clearance of ρ-amino hippuric acid, respectively. Plasma samples were also taken to assay for the hormones prolactin, aldosterone and arginine vasotocin. Plasma electrolytes and osmolality, fractional excretion of electrolytes and osmolar output all increased, while haematocrit decreased, throughout the experiment. However, no significant change was found in urine flow rate and little change was seen in glomerular filtration rate. The clearance of ρ-amino hippuric acid, which provides an indication of renal plasma flow, increased during hypertonic saline infusion. Plasma concentrations of aldosterone and prolactin decreased during the experiment and plasma concentrations of arginine vasotocin increased. Infusion of hypertonic saline had no consistent effect on glomerular filtration rate, which may be due to conflicting influences of expansion of the extracellular fluid volume and increased plasma osmolality. Accepted: 19 January 1998     

Renal Excretion of Digoxin in Swine and Goats

In experiments on swine and goats the renal excretion of digoxin was examined, and it was found that the renal clearance of non-protein-bound digoxin in swine was lower than creatinine clearance which expresses filtration clearance. Correlation analysis showed that the renal clearance of digoxin in swine was not significantly influenced by the concentration of non-protein-bound digoxin in plasma and the pH of the urine, while there was a significant positive correlation between the clearance and the urine flow rate (Table 4). On the other hand, the renal clearance of digoxin in goats was significantly influenced by the concentration of non-proteinbound digoxin in plasma and by urine pH (Table 4). From these results it is concluded that glomerular filtration and back-diffusion are involved in the renal handling of digoxin in both swine and goats. In addition active tubular secretion is also involved in the renal excretion of digoxin in goats.     

Effect of prostaglandin inhibition on glomerular filtration rate in normal and uremic rabbits

Studies were performed to assess the effect of alterations in prostaglandin biosynthesis on glomerular filtration rate in rabbits with normal renal function and after surgical reduction of renal mass. In normal animals, the administration of either of two cyclo-oxygenase inhibitors resulted in a 53% reduction in urine prostaglandin E excretion, but no change in creatinine clearance. Creatinine clearance rates were almost 71% lower in the uremic animals when compared to the animals with normal renal function. Despite the reduction in renal mass, urine prostaglandin E excretion rates in the uremic animals were over twice that seen in normal rabbits. When factored by either glomerular filtration rate or remaining renal mass, urine prostaglandin E excretion rates in uremic rabbits when compared to normal animals were increased more than 9-times and 4-times respectively. Administration of cyclo-oxygenase inhibitors in the uremic animals resulted in a 71% decrease in urine prostaglandin E excretion and, unlike the non-uremic animals, a 53% fall in creatinine clearance. These findings suggest that intact renal prostaglandin biosynthesis is a necessary factor in the homeostatic adaptive mechanisms which maintain the glomerular filtration rate in animals with decreased renal mass.     

Analysis of elimination mechanisms of some 99mTc-complexes

The biological behaviour of complexes of ^99mTc with aminopolycarboxylic and aminocarbohydroxamic ligands EDTA (ethylenediaminetetraacetic acid), DTPA (diethylenetriaminepentaacetic acid), EDTAH (ethylenediaminetetraacetohydroxamic acid) and HIDAmH (N-2-hydroxyethyl-N-carboxymethyl-aminoacetohydroxamic acid) was studied in rabbits. The pharmacokinetic parameters determined in intact rabbits were compared with the results obtained in the study of renal and hepatic clearance of the complexes under study. Hepatobiliary excretion, which in [^99mTc]EDTA forms 20–30% of the total excreted amount, is of negligible magnitude in the other ^99mTc-complexes studied (<2%). Their renal clearance is not influenced by the inhibition of tubular secretion with probenecid. Binding to plasma proteins increases in the order [^99mTc]DTPA < [^99mTc]EDTA <[^99mTc]HIDAmH <[^99mTc]EDTAH and the elimination half-life increases in the same order. The value of renal clearance of the complexes studied related to inulin clearance correlates well with the fraction of the free drug in the plasma. In rabbits the complexes under study are excreted mainly by the mechanism of glomerular filtration in the kidney.     

Renal effects of atrial natriuretic factor in domestic fowl

The renal hemodynamic and tubular effects of ANF were investigated using the Sperber technique in chickens. This technique takes advantage of the unique portal circulation of the avian kidney and permits direct access to the renal peritubular space independent of renal arterial blood flow and glomerular filtration. Infusion of ANF into the avian renal portal system increased urine flow rate and sodium excretion by as much as 300% and 100%, respectively. These changes occurred in the absence of significant alterations in glomerular filtration rate or renal plasma flow. There was no significant difference in urine flow, sodium excretion or glomerular filtration rate between the ANF-infused kidney and the contralateral, non-infused kidney. We conclude that the diuretic and natriuretic effects of ANF do not depend on changes in glomerular filtration rate and that the site of action of ANF is the renal medulla.     

The effects of two analogues of arginine-vasopressin (ornithine-vasopressin and desamino-D-arginine-vasopressin) on kidney function in sheep.

The effects of intravenous infusion of ornithine-vasopressin (OVP) and desamino-D-arginine-vasopressin (dDAVP) were studied in normal and hydrated Merino sheep. In normal sheep, OVP resulted in a diuresis, increased urinary sodium and potassium excretion, and a fall in the plasma potassium concentration. Renal plasma flow remained constant but glomerular filtration rate and filtration fraction rose markedly. dDAVP in normal sheep was antidiuretic, but its only significant effect was a small decrease in plasma osmolality. In the hydrated sheep OVP was antidiuretic and resulted in increased urinary excretion of sodium and potassium, and a fall in the plasma potassium level. Renal plasma flow fell, but glomerular filtration and filtration fraction tended to rise. dDAVP in the hydrated sheep was also antidiuretic but urinary sodium and potassium excretion was reduced. Renal plasma flow and glomerular filtration fell, with a small decrease in filtration fraction. These results suggest that the diuretic effect in normal sheep and the electrolyte-excreting effects in both normal and hydrated sheep of OVP are related to the increase in glomerular filtration, which in turn is dependent on the vasopressor activity of the hormone. The increase in glomerular filtration caused by OVP is due to an increase in the filtration fraction of an unchanged renal plasma flow, which could be brought about by an increase in renal efferent arteriolar tone. The effects of hydration of the sheep were the conventional increased urine flow, decreased urine osmolality and decreased solute-free water reabsorption. Sodium and potassium excretion rose slightly and plasma osmolality fell. Renal plasma flow and glomerular filtration both increased with little change in filtration fraction. These effects could be brought about by suppression of endogenous vasopressin and a decrease in both afferent and efferent renal arteriolar tone.     

Albuminuria associated with CD2AP knockout mice is primarily due to dysfunction of the renal degradation pathway processing of filtered albumin

Here we address the assumption that the massive intact albuminuria accompanying mutations of structural components of the slit diaphragm is due to changes in glomerular permeability. The increase in intact albumin excretion rate in Cd2ap knockout mice by >100-fold was not accompanied by equivalent changes in urine flow rate, glomerular filtration rate or increases in dextran plasma clearance rate, which demonstrates that changes in glomerular permeability alone could not account for the increase in intact albumin excretion. The albuminuria could be accounted for by inhibition of the tubule degradation pathway associated with degrading filtered albumin. There are remarkable similarities between these results and all types of podocytopathies in acquired and toxin-induced renal disease, and nephrotic states seen in mice with podocyte mutations.     

Comparaison de l’estimation du débit de filtration glomérulaire par le 99mTc-DTPA au radiotraceur de référence le 51Cr-EDTA comparativement aux méthodes basées sur la mesure de la créatininémie

Since the end of 2018, the distribution of the reference tracer for the measurement of glomerular filtration rate (GFR), the 51Cr-EDTA, is no longer provided by radiopharmaceutical companies around the world. In this study, we propose to compare the measurement of glomerular filtration rate by 99mTc-DTPA to that by 51Cr-EDTA. A double estimation of GFR by plasma clearance was performed in 12 patients, 10 of which were referred for GFR calculation prior to possible kidney donation. Linear regression coefficients and intraclass correlation coefficient (ICC) were calculated for the GFR measurement by 99mTc-DTPA, and by MDRD, CKD-EPI and Cockcroft and Gault formulas, relative to the 51Cr-EDTA measurement. The clearance measurement with 99mTc-DTPA is on average 7.25 [2.00; 14.96] mL/min/1.73m² higher than that of 51Cr-EDTA. The GFR measurement with 99mTc-DTPA showed a trend towards better agreement with the 51Cr-EDTA measurement in terms of linear regression parameters, but also in terms of ICC compared to the MDRD, CKD-EPI and Cockcroft and Gault methods. In conclusion, our study supports the use of the 99mTc-DTPA tracer in place of 51Cr-EDTA and shows a higher reliability compared to methods based on blood creatinine measurement.     

Renal handling of zinc in insulin-dependent diabetes mellitus patients

Hyperzincuria is a common feature in diabetic patients, which is still not understood. Based on the above consideration, the aim of the present study was to investigate the renal handling of zinc in insulin-dependent diabetes mellitus (IDDM) patients. The glomerular filtration rate, urinary zinc excretion, zinc clearance, zinc clearance/creatinine clearance ratio, zinc tubular reabsorption, glycosuria, plasma glucose, C-peptide, glucagon, and cortisol were investigated in 10 normal individuals (Group C1 and Group C2, respectively) and 10 IDDM patients (Group E1: hyperglycemic and glycosuric and Group E2: normoglycemic and aglycosuric) during placebo or venous zinc tolerance test. The results showed that urinary zinc excretion and renal zinc clearance were increased after zinc injection in normal individuals (Group C2) and IDDM patients (Groups E1 and E2) when compared with normal individuals-placebo (Group C1). However, these renal parameters were statistically more significant in the hyperglycemic and glycosuric diabetics (Group E1). Because patients in Group E1 had the lowest plasma C-peptide levels and showed a strong negative correlation between CZn⁺⁺/Ccr ratio and this hormone, we suggest that in this setting insulin inhibits urinary zinc excretion.     

Cross sectional longitudinal study of spot morning urine protein:creatinine ratio, 24 hour urine protein excretion rate,glomerular filtration rate,and end stage renal failure in chronic renal disease in patients without diabetes.

OBJECTIVE: To evaluate whether the protein:creatinine ratio in spot morning urine samples is a reliable indicator of 24 hour urinary protein excretion and predicts the rate of decline of glomerular filtration rate and progression to end stage renal failure in non-diabetic patients with chronic nephropathy. DESIGN: Cross sectional correlation between the ratio and urinary protein excretion rate. Univariate and multivariate analysis of baseline predictors, including the ratio and 24 hour urinary protein, of decline in glomerular filtration rate and end stage renal failure in the long term. SETTING: Research centre in Italy. SUBJECTS: 177 non-diabetic outpatients with chronic renal disease screened for participation in the ramipril efficacy in nephropathy study. MAIN OUTCOME MEASURES: Rate of decline in filtration rate evaluated by repeated measurements of unlabelled iohexol plasma clearance and rate of progression to renal failure. RESULTS: Protein:creatinine ratio was significantly correlated with absolute and log transformed 24 hour urinary protein values (P = 0.0001 and P < 0.0001, respectively.) Ratios also had high predictive value for rate of decline of the glomerular filtration rate (univariate P = 0.0003, multivariate P = 0.004) and end stage renal failure (P = 0.002 and P = 0.04). Baseline protein:creatinine ratios and rate of decline of the glomerular filtration rate were also significantly correlated (P < 0.0005). In the lowest third of the protein:creatinine ratio (< 1.7) there was 3% renal failure compared with 21.2% in the highest third (> 2.7) (P < 0.05). CONCLUSIONS: Protein:creatinine ratio in spot morning urine samples is a precise indicator of proteinuria and a reliable predictor of progression of disease in non-diabetic patients with chronic nephropathies and represents a simple and inexpensive procedure in establishing severity of renal disease and prognosis.     

Long-Term Responses to Loss of Renal Mass: Glomerular Changes: Compensatory Renal Hypertrophy in Dogs: Single Nephron Glomerular Filtration Rate

Kidney weight, length of superficial and juxtamedullary proximal tubules, glomerular diameter, kidney filtration rate and PAH clearance, sodium excretion and intrarenal distribution of filtration (with ¹⁴C-ferrocyanide) were measured in the remaining hypertrophic kidneys of dogs 10 days after unilateral nephrectomy. Whereas kidney weight increased to 75 percent of the original total renal mass, proximal tubule length and mean glomerular diameter remained unchanged. PAH and creatinine clearance, and absolute, but not fractional, sodium excretion, rose significantly. The ratio superficial/juxtamedullary filtration rate remained unchanged, indicating parallel increases of filtration in both cortical regions of hypertrophied kidneys.     

Effect of salmon calcitonin on renal excretion of adenosine 3', 5' monophosphate in man.

Intravenous infusion of salmon calcitonin in six healthy subjects produced an increase in the plasma levels and urinary excretion of cyclic AMP. Cyclic AMP clearance diminished but remained higher than inulin clearance. Salmon calcitonin was also infused in six hypertensive patients with normal glomerular filtration rate. Arterial and renal venous plasma concentration of cyclic AMP were clearly raised. The difference between both these concentrations was not significant in the control periods but became marked during the treatment and post treatment periods demonstrating a net extraction of cyclic AMP from plasma by the kidneys. Renal extraction of cyclic AMP was lower than its urinary excretion in the control periods whereas it was clearly higher after salmon calcitonin was given. This shows that salmon calcitonin stimulates the production of cyclic AMP in extra-renal tissues and that the excess of cyclic AMP formed is catabolized by the kidneys.     

Exogenous fluorescent tracer agents based on pegylated pyrazine dyes for real-time point-of-care measurement of glomerular filtration rate

Novel pyrazine carboxamides bearing hydrophilic poly(ethylene glycol) (PEG) moieties were designed, synthesized, and evaluated for use as fluorescent glomerular filtration rate (GFR) tracer agents. Among these, compounds 4d and 5c that contain about 48 ethylene oxide units in the PEG chain exhibited the most favorable physicochemical and renal clearance properties. In vitro studies show that these two compounds have low plasma protein binding, a necessary condition for renal excretion. In vivo animal model results show that 4d and 5c have a higher urine recovery of the injected dose than iothalamate (a commonly considered gold standard GFR agent). Pharmacokinetic studies show that these two compounds exhibit a plasma clearance equivalent to iothalamate, but with a faster (i.e. lower) terminal half-life than iothalamate (possibly from restricted distribution into the extracellular space due to large molecular size and hydrodynamic volume). Furthermore, the plasma clearance of 4d and 5c remained unchanged upon blockage of the tubular secretion pathway with probenecid, a necessary condition for establishment of clearance via glomerular filtration exclusively. Finally, noninvasive real-time monitoring of this class of compounds was demonstrated by pharmacokinetic clearance of 5c by optical measurements in rat model, which correlates strongly with plasma concentration of the tracer. Hence, 4d and 5c are promising candidates for translation to the clinic as exogenous fluorescent tracer agents in real-time point-of-care monitoring of GFR.     

Evidence for a secretory component in the handling of unconjugated bilirubin by the isolated perfused rat kidney

Previous studies in rats have suggested that the urinary excretion of unconjugated bilirubin (UB) comprises only a small fraction of the pigment that reaches the tubular lumen by glomerular filtration and escapes from tubular cell reabsorption. However, additional data also indicated that UB interacts with renal peritubular cell membranes impairing the secretion of p-aminohippurate (PAH). In this study we examined the possibility of a secretory step which could also be involved in the renal excretory mechanism for UB. An isolated rat kidney preparation was used, and the uptake of UB by renal tissue, the UB appearance in the urine, and the secretion of PAH were analyzed throughout the perfusion. The results indicated that the UB urinary excretion rate changed independently of UB filtered load. The latter remained almost unchanged during the perfusion, whereas the excretion rate of UB and the UB-to-creatinine (Cr) clearance ratio increased significantly. Furthermore, a relationship between the uptake of UB by the kidney, the UB-to-Cr clearance ratio, and the decrease in PAH secretion rate, was proved. In addition, when probenecid was added to the perfusate solution the cumulative uptake of UB by the kidney and the rate of excretion of UB in the urine were diminished. We conclude that the mechanism of UB excretion by the kidney may be considered as the result of a process involving glomerular filtration plus tubular secretion followed by a back diffusion step from the lumen in a similar way to other endogenous compounds, thus explaining the virtual absence of UB from the normal urine.     

垂体在刺激脑内渗透压感受器引起的肾脏反应中的作用

实验在α氯醛糖和氨基甲酸乙酯混合麻醉的大鼠中进行。脑室内注射高张盐水(icv.HS)后,肾血浆流量、肾小球滤过率、尿量、尿钠排出量、尿钾排出量和渗透物质清除率均增加,游离水清除率下降。去除垂体后,icv.HS不再能引起上述肾脏反应。另外给大鼠静脉注射血管升压素(VP)拮抗剂(V_1和V_2受体拮抗剂),并不能削弱上述icv.HS引起的肾脏反应。脑室内注射高张盐水后,尿中多巴胺(DA)排出量无显著增多;给予多巴脱羧酶抑制剂苄丝肼也不能削弱icv.HS引起的肾脏反应。上述实验结果表明,在本实验条件下刺激脑内渗透压感受器引起的肾脏反应依赖于垂体的完整性,但看来并不依赖于外周的VP和DA,故垂体通过何种机制介导icv.HS引起上述肾脏反应,有待于进一步的研究。     

Abnormal Glomerular Filtration Rate,Renal Plasma Flow,and Renal Protein Excretion in Recent and Short-term Diabetics

Glomerular filtration rate and renal plasma flow were simultaneously determined in comparable groups of 43 diabetics less than 40 years of age and with a duration of diabetes less than 10 years and 32 control subjects. The average glomerular filtration rate in the diabetic group was significantly higher than that in the control group (P <0·01). The average renal plasma flow in the diabetic group was found to be significantly lower than that in the control group (P <0·05). The filtration fraction in both male and female diabetics was significantly higher than in the male and female control groups (P <0·001). These changes were found to be present even in recent juvenile diabetics with disease of a duration of less than one year. No correlation was apparent between the average levels of serum growth hormone and glomerular filtration rate.The urinary protein excretion was determined in 36 diabetic and 38 healthy subjects comparable with regard to glomerular filtration rate. In the diabetic group there was a greater frequency of cases with higher protein excretion rates (P <0·02). The average protein excretion rate was increased even in diabetics with less than one year''s duration of the disease.The results of the changes in renal haemodynamics in subjects with recent and short-term diabetes are compatible with the presence of a constrictive state of the vas efferens leading to an increase in the filtration pressure. The increase in protein excretion rate may similarly be a consequence of this process or of an increase in the glomerular permeability with augmented molecular sieving of proteins or both.     

The effect of vasopressin upon the excretion of calcium by the sheep.

Vasopressin (140 muU/min) was infused intravenously into 12 conscious merino ewes for 2 hr. Urine flow rate and free water clearance were consistently reduced. There was no effect upon renal plasma flow, glomerular filtration rate or the rate of excretion of sodium, potassium, magnesium, chloride or phosphate. Although all animals received 75 mmol calcium chloride into the rumen on the previous day, five commenced the experiment with calcium excretion rates of less than 1 mumol/min. In these, vasopressin further decreased calcium excretion. In seven animals with calcium excretion rates between 2 and 20 mumol/min vasopressin had no effect upon either total calcium or free ionized calcium excretion rate.     

Hemoglobin radiolabeling: In vitro and in vivo comparison of iodine labeling with iodogen and a new method for technetium labeling

Radiolabeled hemoglobin may be a useful tool in the study of the body distribution of hemoglobin solutions developed as plasma expanders with oxygen-transporting capacity. The present investigation compares the suitability of two radiolabeling techniques for hemoglobin. ¹²⁵I labeling of hemoglobin with Iodogen® as iodinating agent caused major changes in the chromatographic behaviour and an accelerated plasma clearance of the labeled hemoglobin in rats. A recently developed two-step procedure for ^99mTc labeling gave better results. The label had only minimal influence on the chromatographic behaviour of hemoglobin. In vivo, no free label occurred in the circulation and no transfer of the label to other plasma proteins took place. The plasma clearance of ^99mTc-labeled hemoglobin in rats was slowed. However, this could be explained entirely by diminishing glomerular filtration, probably by inhibition of the dissociation of the hemoglobin molecule into dimers. The plasma clearance of hemoglobin modified by intramolecular cross-linking, which prevents dissociation of the molecule into dimers and thus excretion by the kidney, was not influenced by the label.We conclude that the ^99mTc labeling procedure is suitable for in vivo distribution studies of hemoglobin when it is taken into account that the urinary excretion is underestimated. For cross-linked hemoglobin, which is more promising as plasma expander, no such restriction exists.     

Renal function of rats in response to 37 days of head-down tilt

Spaceflight induces changes in human renal function, suggesting similar changes may occur in rats. Since rats continue to be the prime mammalian model for study in space, the effects of chronic microgravity on rat renal function should be clarified. Acute studies in rats using the ground-based microgravity simulation model, head-down tilt (HDT), have shown increases in glomerular filtration rate (GFR), electrolyte excretion, and a diuresis. However, long term effects of HDT have not been studied extensively. This study was performed to elucidate rat renal function following long-term simulated microgravity. Chronic exposure to HDT will cause an increase in GFR and electrolyte excretion in rats, similar to acute exposures, and lead to a decrease in the fractional excretion of filtered electrolytes. Experimental animals (HDT, n=10) were tail-suspended for 37 days and renal function compared to ambulatory controls (AMB, n=10). On day 37 of HDT, GFR, osmolal clearance, and electrolyte excretion were decreased, while plasma osmolality and free water clearance were increased. Urine output remained similar between groups. The fractional excretion of the filtered electrolytes was unchanged except for a decrease in the percentage of filtered calcium excreted. Chronic exposure to HDT results in decreased GFR and electrolyte excretion, but the fractional excretion of filtered electrolytes remained primarily unaffected.     

Early changes in renal function following chemically induced nephropathy

The functional changes in the rat kidney 24 h after administration of 2-bromoethanamine hydrobromide (BEA) have been extensively described. There is, however, little information regarding earlier alterations. The present study was designed to measure early changes in renal function in order to clarify further pathomechanisms of the BEA-induced lesion. Experiments were performed in two groups of Wistar rats with different infusion rates during the first 3 h following injection of 100 mg/kg BW BEA compared to sham-injected rats. Analysis included measuring urine flow, osmolality, urea, sodium and potassium as well as inulin and para-aminohippuric acid clearance. Our studies show a tubular as well as a glomerular involvement in BEA-induced nephropathy. A significantly higher urine flow occurred already in the first 30 min following injection of BEA. Urine osmolality began to decrease after 90 min, Na excretion was elevated at 3 h, K excretion was not significantly different from the control group, urea excretion was increased after 30 min. Contrary to other studies we found a continuously decreasing glomerular filtration rate and PAH clearance during the first 3 h. Our results suggest an early effect of BEA on tubular function (increasing sodium excretion), papillary concentration capacity (increasing urine flow combined with decreasing osmolality) and glomerular function (decreasing glomerular filtration rate).