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).     

Ultrastructural changes in the components of the filtration barrier in the glomerular capillaries of a remaining kidney following its temporary ischemia

The components of the filtration barrier of the glomerular capillaries of the rat remaining kidney were studied ultrastructurally 3, 7, 14, 30, 60, 180 and 360 days after exposure to 30 minutes and to 1-2 hours of ischemia. Submicroscopic changes found in the glomerular capillaries and in compensation -adaptive processes occurring in the remaining kidney were ascertained to be dependent on the duration of ischemia and the time elapsed since recirculation in the kidney. After 30-minute ischemia experienced by the remaining kidney the structural alterations in the glomerular capillaries were not remarkable, disappearing 14 days following recirculation, with the emergence by that time of the signs of hyperplasia and hypertrophy of intracellular structures. After raising the time of temporary ischemia of the remaining kidney up to 60 min followed by recirculation, appreciable ultrastructural postischemic disorders were recorded in the components of the filtration barrier of the glomerular capillaries. In addition, the compensation-adaptive processes in the kidney remained suppressed for a longer period of time. All these disorders were particularly demonstrable as a result of 2-hour ischemia. It was also discovered that destructive processes dominated over reparative ones thereby leading to the animals' death at early times of experiment.     

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.     

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.     

Chronopharmacological study of furosemide; (IV). Examination in aged rats

We have previously reported that a time-dependent variability is observed in the diuretic effects of furosemide in young Wistar rats. The present study was undertaken to examine the influence of ageing on chronopharmacological profiles of furosemide in rats. Furosemide (5 mg/kg) was injected intra-arterially in young (10-11 week old) and aged (21-22 month old) Wistar rats at 1000 hrs or at 2200 hrs. Urine was collected for 60 min after the drug and urinary excretion of sodium and furosemide were determined respectively. Urine volume and urinary excretion of sodium and furosemide following the drug injection were significantly greater at 1000 hrs than at 2200 hrs in the young rats as observed in the previous study. However these administration time-dependent changes in the effects of furosemide and its urinary amount disappeared in the aged rats. These findings indicate that the mode of the time-dependent changes in the effects of furosemide is altered in aged Wistar rats.     

Chronopharmacological study of furosemide; (VI). Influence of prolonged exposure to continuous light

We have previously reported that a time-dependent variability is observed in the diuretic effects of furosemide in rats. The present study was undertaken to examine the influence of prolonged exposure to continuous light on chronopharmacological profiles of furosemide in Wistar rats. In study I, rats were maintained for more than 2 weeks under conditions of light (0700-1900 hrs) and dark (1900-0700 hrs) (L-D). Furosemide (30 mg/kg) was orally given at 1200 hrs or at 2400 hrs. Urine was collected for 8 hours after the drug and urinary excretion of sodium and furosemide were determined respectively. Thereafter, these rats were exposed to continuous light (L-L) for the next 4 weeks, and were again maintained under the L-D cycle. The identical trial of study I was repeated at the end of the L-L (study II) and the second L-D (study III) conditions. Urine volume and urinary excretion of sodium and furosemide following the drug were significantly greater at 1200 hrs than at 2400 hrs under conditions of L-D (study I and III). However these administration time-dependent changes in the effects of furosemide and its urinary amount disappeared with L-L condition (study II). These findings indicate that the mode of the time-dependent changes in the effects of furosemide is altered by prolonged exposure to continuous light.     

Relationship Between Orcadian Changes in Renal Hemodynamics and Circadian Changes in Urinary Glycosaminoglycan Excretion in Normal Rats

Circadian changes in renal hemodynamics and urinary glycosaminogly-can (GAG) excretion were studied in normal Sprague-Dawley rats to further investigate rhythms in kidney function. Urinary water, protein, and GAG excretion, as well as glomerular filtration rate (GFR) and renal plasma flow (RPF), were determined every 4h over the 24h cycle in an attempt to characterize any temporal changes. Urinary flow rate and proteinuria peaked during the dark activity period of the animals, consistently at the same hour, whereas the lowest values were detected during the resting phase. GAG are mucopolysaccharides entering the constitution of the glomerular basement membrane (GBM), which is the key component in the process of glomerular filtration. Similarly, the urinary excretion rate of GAG showed a circadian rhythmicity in phase with urinary water and protein excretion, with markedly increased values observed during the nocturnal phase of the animals. Moreover, GFR and RPF were demonstrated to exhibit large circadian variations in phase with renal excretory rhythmicity, showing nighttime values significantly greater compared to daytime ones. Strong correlations were found between GFR and RPF rhythms, as well as between GAG and GFR, and GAG and RPF rhythms, although the latter were not statistically significant. This pattern suggests that the circadian rhythmicity in urinary excretion rate of GAG in physiological conditions could presumably be secondary to the temporal changes in renal hemodynamics. In this respect, knowledge of renal chronobiology helpfully contributes to increase our understanding of renal physiology.     

Modification of radiation damage in the canine kidney by hyperthermia: a histologic and functional study

The purpose of this study was to evaluate the effect of hyperthermia on the histologic and functional response of the canine kidney, a late-responding normal tissue, to irradiation. Both kidneys were irradiated. Radiation was delivered in single doses of 0, 10, or 15 Gy. Whole-body hyperthermia was used to produce renal kidney temperatures approximating 42.0 degrees C for 60 min. Thirty-six beagles were placed randomly in the following six treatment groups: control, whole-body hyperthermia alone, 10 Gy alone, 10 Gy + whole-body hyperthermia, 15 Gy alone, and 15 Gy + whole-body hyperthermia. Renal histologic and functional changes were assessed at 1 to 9 months after therapy. No changes were seen in glomerular filtration rate or renal tissue volumes in control or hyperthermia alone groups. Renal vascular and glomerular volumes were not affected significantly by any combination of hyperthermia and/or radiation. In all groups receiving radiation, glomerular filtration rate decreased, percentage renal tubular volume decreased, and interstitial volume increased significantly after therapy. The magnitude of these changes in the functional and histologic response of the kidney and the latent period before expression of this damage were dependent on radiation dose. However, hyperthermia did not modify expression of radiation damage in the kidney based on glomerular filtration rate and histologic quantification of renal tissue components.     

Renal actions of atrial natriuretic peptide on the postischemic kidney

The objective of this study was to evaluate the renal actions of atrial natriuretic peptide (ANP) in the unilateral postischemic kidney of anesthetized dogs with a severe reduction in glomerular filtration rate. The dose of atrial natriuretic peptide (50 ng.kg-1.min-1) we gave did not alter the mean systemic arterial pressure, renal blood flow, and glomerular filtration rate in the normal kidney, as determined in foregoing studies. ANP was infused into the intrarenal artery continuously for 60 min after the release from 45 min of complete renal artery occlusion. In the vehicle-infused group, the glomerular filtration rate fell dramatically (6% of control), the renal blood flow decreased (60% of control), and the mean systemic arterial pressure tended to increase (136% of control). The urine flow rate and urinary excretion of sodium decreased significantly (25 and 25%, respectively) at 30 min after reflow in the postischemic period. Continuous renal artery infusion of ANP resulted in a marked increase in urine flow rate (246% of control) and the urinary excretion of sodium (286% of control). The administration of ANP led to an improvement in renal blood flow (99% of control) and glomerular filtration rate (40% of control), and attenuated the rise in mean systemic arterial pressure (109% of control), compared with findings in the vehicle-infused group. Plasma renin activity and prostaglandin E2 concentration in the renal venous blood were elevated after the release from complete renal artery occlusion in both groups. These results indicate that the vascular effects of ANP on the postischemic kidney were enhanced and that the peptide maintained the natriuretic effect.     

Acute Kidney Injury Urinary Biomarker Time-Courses

Factors which modify the excretion profiles of acute kidney injury biomarkers are difficult to measure. To facilitate biomarker choice and interpretation we modelled key modifying factors: extent of hyperfiltration or reduced glomerular filtration rate, structural damage, and reduced nephron number. The time-courses of pre-formed, induced (upregulated), and filtered biomarker concentrations were modelled in single nephrons, then combined to construct three multiple-nephron models: a healthy kidney with normal nephron number, a non-diabetic hyperfiltering kidney with reduced nephron number but maintained total glomerular filtration rate, and a chronic kidney disease kidney with reduced nephron number and reduced glomerular filtration rate. Time-courses for each model were derived for acute kidney injury scenarios of structural damage and/or reduced nephron number. The model predicted that pre-formed biomarkers would respond quickest to injury with a brief period of elevation, which would be easily missed in clinical scenarios. Induced biomarker time-courses would be influenced by biomarker-specific physiology and the balance between insult severity (which increased single nephron excretion), the number of remaining nephrons (reduced total excretion), and the extent of glomerular filtration rate reduction (increased concentration). Filtered biomarkers have the longest time-course because plasma levels increased following glomerular filtration rate decrease. Peak concentration and profile depended on the extent of damage to the reabsorption mechanism and recovery rate. Rapid recovery may be detected through a rapid reduction in urinary concentration. For all biomarkers, impaired hyperfiltration substantially increased concentration, especially with chronic kidney disease. For clinical validation of these model-derived predictions the clinical biomarker of choice will depend on timing in relation to renal insult and interpretation will require the pre-insult nephron number (renal mass) and detection of hyperfiltration.     

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     

Effect of acute and chronic renal denervation on renal function after release of unilateral ureteral obstruction in the rat.

The role of the renal nerves in determining renal function after relief of 24-h unilateral ureteral obstruction (UUO) was studied using clearance techniques in anaesthetized rats. Acute renal denervation during the first 1--2 h after relief of UUO resulted in a significant increase in glomerular filtration rate (GFR), renal plasma flow (RPF), urine flow, and sodium and potassium excretion, changes which were not seen in the sham-denervated postobstructive kidney. Acute denervation of sham-operated normal kidneys caused a similar natriuresis and diuresis but with no change in GFR or RPF. Chronic renal denervation 4--5 days before UUO denervated postobstructive controls, while chronic denervation alone was associated with a significantly higher urine flow and sodium excretion rate from the denervated kidney. The effectiveness of renal denervation was confirmed by demonstrating marked depletion of tissue catecholamines in the denervated kidney. It was concluded that renal nerve activity plays a significant but not a major role in the functional changes present after relief of UUO. Chronic renal denervation did not protect against the functional effects of unilateral ureteral obstruction.     

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.     

Hormonal, electrolyte, and renal responses to exercise are intensity dependent

Previous work indicates that the magnitude and direction of renal responses to exercise depend on the exercise intensity. To examine mechanisms responsible for these findings, renal and hormonal responses were studied in eight healthy male subjects (29.6 +/- 1.9 yr) before and immediately after four 20-min bouts of submaximal exercise (cycle ergometry) at work loads representing 25, 40, 60, and 80% of maximal oxygen consumption. Urine flow, osmotic clearance, glomerular filtration rate, and sodium excretion (UNa+V) all tended to rise at the 25% work load but were markedly reduced at the higher work intensities. Changes in urine flow paralleled changes in glomerular filtration rate (r = 0.91). Plasma vasopressin (ADH), aldosterone, and plasma renin activity tended to increase progressively with increases in work load, with the increases for all hormones reaching statistical significance when the level of exercise reached greater than or equal to 60% of maximal oxygen consumption. However, atrial natriuretic peptide was elevated (P less than 0.05) at all work loads from greater than 1.6-fold of control levels at the 25% work load to greater than 7-fold at the 80% work load. The increase in urine flow (6 of 8 subjects) and UNa+V (7 of 8 subjects) may be due to the increase in atrial natriuretic peptide and/or a 10% suppression (P less than 0.05) of ADH at the 25% work load.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronopharmacological study of furosemide; (V). Influence of pretreatment with 6-hydroxydopamine

Our previous indirect evidences suggested that the adrenergic nervous system is involved in the mechanisms responsible for the time-dependent changes in the effects of furosemide in Wistar rats. In the present study, the role of this system was examined more directly by means of 6-hydroxydopamine-induced sympathectomy. Thirty mg/kg of 6-hydroxydopamine hydrobromide (6-OH-DA) (n = 9) or its vehicle alone (n = 9) was injected intra-arterially (i.a.) twice in Wistar rats. Furosemide (5 mg/kg) was administered i.a. at 1000 hrs (03HALO*) or at 2200 hrs (15HALO). Urine was collected for 60 min after the drug and urinary excretion of sodium and furosemide were determined respectively. Urine volume and urinary excretion of sodium and furosemide were significantly greater at 1000 hrs (03HALO) than at 2200 hrs (15HALO) in the vehicle-injected rats as observed in the previous study. However these administration-time-dependent changes in the effects of furosemide disappeared in the rats with 6-OH-DA. Thus, the present study provides more direct evidence and supports our original hypothesis concerning the mechanisms of this chronopharmacological phenomenon of the agent. Since 6-OH-DA does not penetrate the central nervous system from the blood stream, the present data also indicate that the peripheral adrenergic system is involved in this event.     

Gender difference in the Oatp1-mediated tubular reabsorption of estradiol 17beta-D-glucuronide in rats

The gender difference in the urinary excretion of estradiol-17beta-glucuronide (E(2)-17betaG) was examined in rats. The urinary clearance of E(2)-17betaG was >250 times lower in male than in female rats. No such major gender difference was observed in its biliary excretion or metabolism in kidney homogenate. Both plasma protein binding and inulin clearance were comparable in male and female rats, suggesting that this gender difference cannot be explained by glomerular filtration. The urinary clearance with respect to the plasma unbound E(2)-17betaG in male rats was <1% of the glomerular filtration rate, indicating its potential reabsorption by the kidney, and this increased to a level comparable with that found in female rats when dibromosulfophthalein was coinfused. A marked increase in E(2)-17betaG urinary excretion was also observed in male rats that had undergone orchidectomy. Testosterone injections given to female rats reduced the urinary excretion to a level comparable with that of control male rats. The concomitant change in the expression of the gene product for organic anion-transporting polypeptide Oatp1, of which E(2)-17betaG is a typical substrate, was found in the kidney membrane fractions after these treatments. These results suggest that urinary E(2)-17betaG excretion is subject to hormonal regulation and that the large gender difference can be explained by regulation in Oatp1-mediated reabsorption.     

Natriuresis following fourth ventricle perfusion with high-sodium artificial CSF.

Perfusion of the fourth cerebral ventricle with high-sodium artificial cerebrospinal fluid was found to result in an increase in urinary sodium excretion in anesthetized cats. The natriuresis was accompanied by an increase in blood pressure and glomerular filtration rate. However, in animals with the changes in blood pressure and glomerular filtration rate prevented by alpha adrenergic blockade (phenoxybenzamine), the increase in urinary sodium excretion persisted. the data suggest the presence of a neural mechanism in the vicinity of the fourth ventricle sensitive to cerebrospinal fluid sodium levels and capable of affecting urinary sodium excretion independent of changes in blood pressure or glomerular filtration rate. The possible role of the area postrema and adjacent medulla is considered.     

Glomerular function in spontaneously diabetic rats.

This study was undertaken to determine whether hyperfiltration exists at the single nephron level and whether albumin excretion is increased early in the course of diabetes in Biobreeding rats. Diabetic rats were studied at 8-12 weeks after the onset of diabetes. Control animals were age-matched, diabetes-resistant rats. Urinary and tubular fluid albumin concentrations were measured by polyacrylamide gel electrophoresis. Clearance and micropuncture techniques were used to determine whole kidney and single nephron glomerular filtration rate, renal blood flow, and glomerular capillary pressure. The urinary albumin excretion rate (1.3 +/- 0.1 mg/24 hr) and the tubular fluid albumin concentration (4.7 +/- 0.7 mg/dl) in the diabetic group were significantly elevated when compared with urinary albumin excretion (0.9 +/- 0.1 mg/24 hr) and tubular fluid albumin concentration (2.5 +/- 0.5 mg/dl) in the control group. There were no significant differences in glomerular hemodynamics (whole kidney or single nephron glomerular filtration rate or glomerular capillary pressure) between diabetic and control rats. The kidney weight and kidney weight to body weight ratio were significantly higher in diabetic rats when compared with control rats. Early diabetes in Biobreeding rats is characterized by mild albuminuria and increased kidney size, but not glomerular hyperfiltration.     

Studies on Compensatory Adaptation of Renal Functions

Changes in the excretion of water and electrolyte in one kidney after exclusion of its partner have been studied in anesthetized dogs and rabbits. Complete clamping of the contralateral kidney pedicle or ureter results in a rapid increase in the excretion of water, sodium, potassium, chloride, calcium, phosphate and bicarbonate. This response is also observed in denervated kidneys. Pretreatment with the loop inhibitor, furosemide, does not preclude adaptation which, however, is blunted by acetazolamide, an inhibitor of proximal sodium and bicarbonate reabsorption. Free-water reabsorption during hypertonic saline diuresis is normal in the remaining kidney. Compensatory adaptation, thus, appears to be located in the proximal tubule. The regulatory response to contralateral kidney exclusion is already fully developed in one-month-old rabbits. Compensatory adaptation of electrolyte excretion is not accounted for by changes in extracellular fluid volume, plasma composition, glomerular filtration rate, effective renal plasma flow, aldosterone or vasopressin.     

Impact of Weaning from Acute Dialytic Therapy on Outcomes of Chronic Kidney Disease following Urgent-Start Dialysis

Discontinuation of acute, unplanned dialysis is always an important therapeutic goal in dialysis-requiring patients with existing chronic kidney disease. Only a limited proportion of patients could be weaned off dialysis and remained dialysis-free. Here we performed a multicenter, observational study to investigate factors associated with successful weaning from acute dialysis, and to explore the potential impact of weaning itself on outcomes of patients with chronic kidney disease following urgent-start dialysis. We recruited 440 chronic kidney disease patients with a baseline estimated glomerular filtration rate <45 ml/min per 1/73 m2, and used propensity score-adjusted Cox regression analysis to measure the effect of weaning from acute dialysis on death during the index hospitalization and death or readmission after discharge. Over 2 years, 64 of 421 (15.2%) patients who survived >1 month died, and 36 (8.6%) were removed from dialysis, with 26 (6.2%) remaining alive and dialysis-free. Logistic regression analysis found that age ≧ 65 years, ischemic acute tubular necrosis, nephrotoxic exposure, urinary obstruction, and higher predialysis estimated glomerular filtration rate and serum hemoglobin were predictors of weaning off dialysis. After adjustment for propensity scores for dialysis weaning, Cox proportional hazards models showed successful weaning from dialysis (adjusted hazard ratio 0.06; 95% confidence interval 0.01 to 0.35), along with a history of hypertension and serum albumin, were independent protectors for early death. Conversely, a history of stroke, peripheral arterial disease and cancer predicted the occurrence of early mortality. In conclusion, this prospective cohort study shows that compared to patients with chronic kidney disease who became end-stage renal disease after acute dialysis, patients who could be weaned off acute dialytic therapy were associated with reduced risk of premature death over a 2-year observation period.