Increase In Glomerular Filtration Rate Research Articles

Does Treatment With Clean Intermittent Catheterization in Boys With Posterior Urethral Valves Affect Bladder and Renal Function?

In boys with resected posterior urethral valves (PUV) deterioration of renal function is seen during childhood and adolescence, which may partly be caused by bladder dysfunction. We present data on renal and bladder function initially and at followup of boys with PUV in whom the bladder dysfunction has been treated since infancy. The study included 35 boys with PUV. Bladder regimen, including early toilet training from the age of 1.5 years and detrusor relaxant drugs for the treatment of incontinence from ages 4 to 6 years, was introduced to all patients. A total of 19 boys were started on clean intermittent catheterization (CIC) at a median age of 8 months due to pronounced bladder dysfunction with poor emptying, unsafe pressure levels, high grade reflux and renal impairment. No serious complications of CIC have been seen during followup. Of the 19 boys 2 stopped performing CIC due to noncompliance of the parents at 1 and 3 years, respectively. Initial renal function, measured as median glomerular filtration rate (GFR) in percent of expected for age, was 60% in the CIC group and 90% in the nonCIC group. At followup at a median age of 8 years the CIC group (n = 14, 3 transplanted boys excluded) had an increase in median differential GFR (difference between followup and initial GFR) of 7% (p <0.01), which was similar increase to that of the nonCIC group. In the 2 boys who stopped performing CIC renal function deteriorated with a median differential GFR of -24%. In the CIC group detrusor instability decreased. Poor compliance was seen in 6 of the 19 boys initially and only one remained poorly compliant. In 1 of the boys who stopped performing catheterization a low compliant bladder developed. In all of the other cases bladder capacity increased more than expected for age. The results suggest that treatment of bladder dysfunction in boys with PUV can counteract the deterioration in renal function seen during childhood but the number of patients in our study is limited.

Computer-assisted quantification of fibrosis in chronic allograft nephropaty by picosirius red-staining: a new tool for predicting long-term graft function.

Chronic allograft nephropathy (CAN) has become the predominant limiting factor for long-term transplant survival. A cardinal histomorphologic correlate for CAN is interstitial fibrosis. Currently, no method has been established in routine use that reliably quantifies the extent of interstitial fibrosis in renal grafts. We have used staining with picrosirius red followed by computerized image analysis to study the correlation between graft fibrosis and future development of glomerular filtration rate (GFR) in a group of children with advanced CAN. Renal biopsies were performed in 56 children (mean age, 13.7+/-3.6 years) after a mean period of 4.6+/-3.1 years after transplantation because of significant increases in serum creatinine. All biopsy specimens were stained with picrosirius red. The magnitude of fibrotic tissue was calculated by computerized image analysis. Linear regression analysis was performed correlating the intensity of graft fibrosis and the changes in the GFR at the time points of renal biopsy and 2 years later. There was a significant positive correlation (r=0.62, P<0.001) between the picrosirius red-stained cortical fractional interstitial fibrosis volume (V(intFib)) and the decrease of GFR within 2 years postrenal biopsy. When V(intFib) was below 5%, 82% of the patients had an increase in GFR within 2 years. Ninety-three percent of the patients with greater than 10% of fibrosis experienced a worsening renal function after 2 years. When comparing patients with stable GFR with patients having a decrease in GFR, a highly significant difference in V(intFib) was found (P=0.008). The quantitative measurement of fibrosis by picrosirius red staining appears to be a useful prognostic indicator for estimating long-term graft function in CAN and may provide an easy, fast, and inexpensive tool helpful for treatment decisions in patients developing CAN.

Vitamin C augments the renal response to L-arginine in smokers.

In the coronary and the forearm circulations, endothelium-dependent vasomotion is impaired in smokers, but can be augmented by -arginine or vitamin C. We examined whether smoking similarly affects the renal circulation. In 20 smokers (age 26 +/- 4 years) and in 20 non-smokers (age 28 +/- 3 years) changes of renal plasma flow (RPF), glomerular filtration rate (GFR), blood pressure and heart rate in response to the subsequent intravenous infusions of N(G)-monomethyl--arginine (L-NMMA), -arginine and -arginine plus vitamin C were studied by use of a constant infusion input clearance technique. Systemic haemodynamic parameters did not differ between smokers and non-smokers during each experimental phase. At baseline, RPF and GFR were similar between the groups. The infusion of L-NMMA led to a similar decrease of RPF, while GFR did not change in either group. During the infusion of -arginine RPF increased similarly. Finally, the co-infusion of -arginine plus vitamin C led to a significantly greater increase of RPF (+277 +/- 395 vs +79 +/- 76 ml/min, P = 0.03) and GFR (+12.1 +/- 10.6 vs +3.4 +/- 11.2 ml/min, P = 0.02) in smokers as compared to non-smokers. L-NMMA-induced vasoconstriction of the renal vasculature was similar in smokers compared to non-smokers. -arginine alone induced a similar increase of RPF. The co-infusion of vitamin C and -arginine led to a greater increase of RPF and GFR in smokers. This might suggest that oxidative stress is increased in the renal vasculature of smokers.

Relationship between diurnal blood pressure, renal hemodynamic function, and the renin-angiotensin system in type 1 diabetes.

In patients with diabetes, altered diurnal blood pressure (BP) regulation (high night-to-day [N/D] ratio, or "nondipping") is associated with increases in albumin excretion and a decline in the glomerular filtration rate (GFR) by an unknown mechanism. Because it is known that renin angiotensin system (RAS) activation and defective glucose control contribute to adverse renal outcomes, we examined renal responses to high glucose and to manipulation of the RAS in adolescents (mean age 14 +/- 2 years) with uncomplicated type 1 diabetes, segregated into two groups on the basis of the presence or absence of normal N/D BP ratio. In the first experiment, renal hemodynamic comparisons were made during euglycemia (4-6 mmol/l) and hyperglycemia (9-11 mmol/l), maintained by modified clamp techniques. The induction of hyperglycemia resulted in a significant increase in GFR and filtration fraction (FF) in the high N/D ratio group. In the second experiment, we examined the renal response to graded angiotensin II (Ang II) infusion while subjects were euglycemic and salt replete. High N/D ratio was associated with an enhanced FF response to Ang II. In the third experiment, the N/D ratio and GFR were assessed after 3 weeks of ACE inhibition. This maneuver corrected the high N/D ratio, but it had no effect on glomerular hyperfiltration. These results suggest that RAS activation does not explain the hyperfiltration state, nor can it explain the poor outcomes, at least in this population. However, the observed deleterious hemodynamic responses to high glucose and Ang II and the insensitivity to ACE inhibition may, taken together, provide an explanation for the adverse renal outcomes in patients with type 1 diabetes and high N/D ratio.

Growth Arrest-specific Gene 6 Is Involved in Glomerular Hypertrophy in the Early Stage of Diabetic Nephropathy

Nephropathy is one of the most common complications of diabetes mellitus. Glomerular hypertrophy is a hallmark in the early phase of the nephropathy. The mechanism of glomerular hypertrophy, however, remains incompletely understood. We have reported that Gas6 (growth arrest-specific gene 6) and its receptor, Axl, play a key role in the development of glomerulonephritis. Here we show the important role of Gas6/Axl in the pathogenesis of diabetic glomerular hypertrophy. In streptozotocin (STZ)-induced diabetic rats, mesangial and glomerular hypertrophy and an increase in the glomerular filtration rate (GFR) and albuminuria were observed after 12 weeks of STZ injection. The glomerular expression of Gas6 and Axl was increased in those rats. Administration of warfarin inhibited mesangial and glomerular hypertrophy and the increase in GFR and albuminuria in STZ rats. Moreover, we found less mesangial hypertrophy in STZ-treated Gas6 knockout mice than control mice. In vitro we found that stimulation of mesangial cells with Gas6 resulted in mesangial cell hypertrophy. Thus we have found a novel mechanism of glomerular hypertrophy through the Gas6/Axl-mediated pathway in the development of diabetic nephropathy. Inhibition of the Gas6/Axl pathway in diabetic patients might be beneficial to slow down the progression of diabetic nephropathy.

Renal function in proteinuric glomerular diseases correlates to the changes in urine IgM excretion but not to the changes in the degree of albuminuria.

Renal function in proteinuric glomerular diseases correlates to the changes in urine IgM but not to the changes in the degree of albuminuria. Albuminuria is believed to correlate to the progression of renal failure in glomerular diseases. Nevertheless, many patients with glomerular disorders maintain their renal function despite persistent albuminuria. In previous studies, we found that the baseline urine excretion of IgM, rather than the degree of albuminuria, predicts the renal outcome in glomerulopathies. In the present study, we examine correlations between changes in the content and in the amount of urine proteins and renal survival during a follow-up time of 3.5 years. An observational study of a mean of 44 (+/- 3.6) months was conducted in 37 proteinuric patients (21 males and 16 females) with biopsy-verified primary glomerular disease. The patients were subdivided, according to the findings at the end of the study, into 3 groups, 1 group with decreasing albuminuria (by more than 50%), 1 group with persisting albuminuria and low (< 0.04 mg/mmol creatinine) urinary IgM excretion and 1 group with persisting albuminuria and with high (> or = 0.04 mg/mmol) urinary IgM excretion. All patients that showed remission of albuminuria had also low IgM excretion at the end of the study. All these patients, except 1, maintained their renal function. Patients with persistent albuminuria and high urinary IgM excretion showed a decrease in the glomerular filtration rate (GFR) of a mean of 9.6 ml/min/year compared to a mean GFR increase by 1.5 ml/min/year in patients with low IgM excretion and the same degree of albuminuria (p < 0.01). Seven out of the 9 patients in the former group fall in GFR by more than 5 ml/min/year compared to only 1 of the 10 patients in the latter group. Furthermore, the GFR alterations that occurred during follow-up time correlated in a higher degree to the changes in urinary IgM excretion (r = 0.6, p < 0.01) than to the changes in the degree of albuminuria, (r = 0.4, p < 0.05). A stepwise regression analysis indicated that increased urine IgM excretion is a strong predictor of the GFR decline (r = 0.73, p < 0.001). High urinary IgM excretion correlates to decreased GFR in primary glomerular diseases regardless of the degree of albuminuria. In parallel, low urinary IgM excretion indicates beneficial prognosis in these diseases. Since IgM passes the glomerular barrier entirely through large shunts or defects in the glomerular capillary wall, decreased urine content of IgM might be considered as a sign of recovery in the glomerular damage.

Renal action of acute chloroquine and paracetamol administration in the anesthetized, fluid-balanced rat.

Chloroquine induces diuresis, natriuresis, and an increase in glomerular filtration rate (GFR) in the rat. These responses are modified in rats with analgesic nephropathy induced by long-term paracetamol (acetaminophen) administration. Here, the effects of acute paracetamol treatment on renal function and the response to chloroquine are reported. Under intraval anesthesia (100 mg kg-1) male Sprague-Dawley rats (n = 6/group) were infused with 2.5% dextrose for 3 h. After a control hour, they received either vehicle, chloroquine (0.04 mg h-1), paracetamol (priming dose of 210 mg kg-1 followed by 110 mg kg-1h-1) or chloroquine and paracetamol over the next hour. Compared with vehicle, chloroquine infusion resulted in increases in GFR (2.4 +/- 0.3 versus 4.8 +/- 0.6 ml min-1), urine flow (4.2 +/- 0.3 versus 10.4 +/- 0.7 ml h-1), and sodium excretion (47.7 +/- 4.1 versus 171.2 +/- 18.6 micromol h-1) and a reduction in urine osmolality (223.2 +/- 5.9 versus 121.7 +/- 23.9 mOsM kg-1). Paracetamol reduced sodium excretion but had no effect on urine flow, GFR, or urine osmolality. When combined, paracetamol blocked the chloroquine-induced diuresis (3.9 +/- 0.7 ml h-1) and natriuresis (22.6 +/- 8.5 micromol h-1), attenuated the increase in glomerular filtration rate (3.5 +/- 0.2 ml min-1), and raised urine osmolality (280.0 +/- 22.8 mOsM kg-1). The differing effects of acute and long-term paracetamol treatment on basal and chloroquine-mediated renal function suggest that the length of prior exposure to paracetamol, and thus the presence of analgesic nephropathy, is an important determinant of the renal response to chloroquine.

Blood pressure response to conventional and low‐dose enalapril in chronic renal failure

In chronic renal failure, the clearance of most ACE inhibitors including enalapril is reduced. Hence, with conventional dosage, plasma enalaprilat may be markedly elevated. It is unclear whether this excess of drug exposure affords an improved control of blood pressure. The aim of the present study was to evaluate short-term blood pressure response to two different plasma levels of enalaprilat. As part of an open, randomized, controlled trial of the effect of high and low dosage of enalapril on the progression of renal failure, short-term blood pressure response was evaluated. Data were analysed in all patients completing 3 months of follow-up. The patients were allocated to two trough plasma concentrations of enalaprilat, either above 50 ng ml(-1) (high) (n = 17) or below 10 ng ml(-1) (low) (n = 18), and the daily dose of enalapril titrated accordingly. Median (range) glomerular filtration rate (GFR) at baseline was 18 (7.9) in the high enalaprilat concentration group and 17 (7.3) ml min(-1) 1.73 m(2) in the low concentration group (NS). Nine patients in each group were on treatment with enalapril at baseline with a median daily dose of 5 mg in both the high (5-10) and low (2.5-20) concentration group. At 3 months' follow-up, the dose was 10 (2.5-30) and 1.9 (1.25-5) mg (P < 0.0001), respectively. After 3 months median trough concentrations of enalaprilat were 82.5 (22-244) ng ml(-1) and 9.1 (2.5-74.8) ng ml(-1) (P < 0.002). At baseline the median systolic blood pressures in the two groups were 140 (110-200) and 133 (110-165), in the high and low enalaprilat concentration groups, respectively, and after 3 months they were 135 (105-170) and 130 (105-170) mmHg (NS). Median diastolic blood pressure was 80 mmHg in each group both at baseline (65-100) and at follow-up (60-95) (NS). There was no difference between the groups in concomitant antihypertensive treatment (number of patients treated, mean daily dose) during the observation period. Proteinuria remained stable during the study period in both groups; patients in the high concentration group had higher plasma potassium concentrations at day 90 and patients in the low group experienced a slight increase in GFR. In moderate to severe chronic renal insufficiency the same degree of blood pressure control was achieved on low as well as moderate daily doses of enalapril. This was irrespective of concomitant antihypertensive treatment.

Body water handling in response to hypertonic-saline induced diuresis in fasting northern elephant seal pups ( Mirounga angustirostris)

During natural fasting conditions in postweaned northern elephant seal (NES) ( Mirounga angustirostris) pups, urinary water loss is minimized and percent total body water (TBW) is maintained constant. However, following infusion of hypertonic saline, glomerular filtration rate (GFR) and urine output increased in fasting pups. Therefore, we quantified the magnitude of the hypernatremia-induced diuresis relative to the animal's total body water (TBW) pool and the percentage of filtered water reabsorbed. Following a 24 h control period, naturally fasting NES pups ( n=7) were infused (4 ml min −1) with hypertonic saline (16.7%) at a dose of 3 mmol NaCl kg −1 body mass. Total body water was estimated prior to infusion by tritium dilution, GFR was estimated by standard creatinine clearance, and urine output (V) was measured for 24 h during the control and post infusion periods. Percentage of filtered water reabsorbed was calculated as (1−(V/GFR))×100. Twenty-four hours following the infusion, GFR (control: 69±12 ml min −1 and post-infusion: 118±19 ml min −1; mean±S.E.) increased 77±28% above control and the percentage of filtered water reabsorbed was decreased 0.4±0.1%. The increase in urine output (control: 218±47 ml d −1 and post-infusion: 883±92 ml d −1) accounted for 1.7±0.2% of the pups’ TBW. The hypernatremia-induced diuresis was accompanied by the loss of body water indicating the lack of water retention. Although the 77% increase in GFR was only associated with a 0.4% decrease in the percentage of filtered water reabsorbed, this decrease was significant enough to result in a 4-fold increase in urine output. Despite the observed diuresis, fasting NES pups appear to possess an efficient water recycling mechanism requiring only a small percentage of body water to excrete an excess salt load. This water recycling mechanism may allow pups to avoid negative perturbations in body water as they initiate feeding in a marine environment following the fast.

Anesthetic Considerations for Bariatric Surgery

According to the National Institutes of Health, obesity is a major health problem with clearly established health implications, including an increased risk for coronary artery disease, hypertension, dyslipidemia, diabetes mellitus, gallbladder disease, degenerative joint disease, obstructive sleep apnea, and socioeconomic and psychosocial impairment (1). The risk of developing one or more of these obesityrelated conditions is based on body mass index (BMI), with 25–30 kg/m 2 being low risk and 40 kg/m 2 being very high risk (2). The prevalence of obesity in the 18- to 29-yr-old group increased from 12% in 1991 to 18.9% in 1999 (3). Bariatric surgery encompasses a variety of surgical weight loss procedures used to treat morbid obesity. Obesity is clinically expressed in terms of BMI or Quetelet’s index (4), which is derived by dividing weight by the square of height to estimate the degree of obesity. Thus, BMI body weight (kg)/height 2 (m 2 ). Morbid obesity is a BMI more than 35 kg/m 2 , and super morbid obesity is BMI more than 55 kg/m 2 . The indications for surgical treatment of severe obesity, as outlined in the 1991 National Institutes of Health Consensus Development Conference Panel, include an absolute BMI more than 40 kg/m 2 or BMI more than 35 kg/m 2 in combination with lifethreatening cardiopulmonary problems or severe diabetes mellitus (1). Patients seeking surgical weight loss must have proven attempts at medically supervised weight loss. Documentation of loss of 5% to 10% excess body weight or weight gain after at least 6 mo of diet modification, exercise, and medical therapy or nonimprovement in comorbid conditions during this period indicates failure. Studies have shown that weight loss of 5%–10% of initial body weight improves glucose intolerance and Type II diabetes, hypertension, and dyslipidemia (5–7). The average expenditure is approximately $7000 per year per patient on weight loss programs and equipment. Unfortunately, long-term weight loss is the exception, and most patients regain weight, sometimes more than they initially lost.

Long-term functional outcome of kidneys in children with urolithiasis after ESWL treatment.

The aim of this study was to determine the long-term functional outcome of kidneys in children with urolithiasis treated by means of extracorporeal shock wave lithotripsy (ESWL). The effectiveness and safety of this method in the management of pediatric urinary stone disease was also studied. This prospective study enrolled 84 children, 33 boys (age: 9.1 +/- 3.8 yrs) and 51 girls (age: 9.6 +/- 3.9 yrs), with urolithiasis who were treated using a second-generation "Siemens" Lithostar lithotriptor, in the period between 1988 and 1998. Dynamic kidney scintigraphy using (99 m)Tc-DTPA was done prior to, immediately following ESWL treatment, three months later, and again after an observation period of 12 - 67 months (38 +/- 13 months). Immediate fragmentation rate was 90 %, while the calculus clearance rate was 61 %. Glomerular filtration rate (GFR), measured by clearance of (99 m)Tc-DTPA, immediately after an ESWL treatment of 107 +/- 6 ml/min was significantly lower compared to the pretreatment value of 118 +/- 7 ml/min, but returned three months later to 121 +/- 6 ml/min, and to 131 +/- 10 ml/min at the end of the observation period. A separate analysis was performed on three groups of patients treated by ESWL: with acute calculous disease, chronic calculous disease, and chronic calculous with partial stasis. ESWL treatment in children with acute obstruction was associated with an immediate increase in GFR; however, in chronic calculous disease a decrease in GFR was found. A return of GFR to the pretreatment level was observed at the three-month control in these patients. In patients with acute stone obstruction, at 3 and 12 - 67 months after ESWL treatment, GFR of the treated kidney was found to be significantly increased compared to the pretreatment level. In contrast, in children with chronic calculous disease this increase was modest. This study has demonstrated ESWL to be an effective treatment option for urinary calculi management, which can be safely performed in a pediatric population without long-term effects on the growing kidneys.

Renal denervation abolishes the protective effects of ischaemic preconditioning on function and haemodynamics in ischaemia-reperfused rat kidneys.

Studies were conducted to investigate the role of renal sympathetic nerves in the process of acquiring ischaemic tolerance in ischaemic preconditioned ischaemia-reperfused rat kidneys. Two periods of 3-min occlusion of bilateral renal arteries was performed prior to 30-min bilateral ischaemia and 90-min reperfusion in acute renal denervated or innervated kidneys. The glomerular filtration rate (GFR), fractional excretion of sodium (FENa) and lithium (FELi), and renal blood flow (RBF) were assessed in reperfused kidneys. Ischaemic preconditioning significantly improved values for all these parameters as compared with no treated ischaemia-reperfused kidneys. Denervation caused slight increase in GFR, diuresis and natriuresis without improving RBF after reperfusion. However, protecting effects of ischaemic preconditioning on renal function were disappeared in denervated kidneys, while in innervated kidneys the effects of ischaemic preconditioning were maintained. These results clearly showed that ischaemic preconditioning pre-treatment protects kidneys against ischaemia-reperfusion injury, and the effects are, at least in part, mediated by sympathetic nerves, as the protective effects were abolished by denervation.

Effect of acute iNOS inhibition on glomerular function in tubulointerstitial nephritis

Tubulointerstitial nephritis (TIN) is characterized by progressive inflammatory infiltrate of the renal interstitium, induction of cortical tubular inducible nitric oxide synthase (iNOS) and reductions in glomerular filtration rate (GFR). These studies were designed to examine the changes in glomerular hemodynamics 7 and 21 days after induction of TIN and to evaluate the effect of acute iNOS blockade on glomerular function in the early stages of this model. TIN was induced by immunizing Brown Norway rats with renal tubular antigen in complete Freund's adjuvant (RTA/CFA). Control rats were immunized with CFA alone. Micropuncture and morphologic studies were performed 7 and 21 days after immunization. Histology revealed minimal peritubular and interstitial inflammation in the RTA/CFA group one week after immunization while extensive interstitial inflammation with few preserved superficial nephron was observed three weeks after RTA/CFA immunization. Micropuncture studies on day 7 in the RTA/CFA group revealed a significant reduction in single nephron GFR due to a profound reduction in nephron plasma flow and in the ultrafiltration coefficient. Studies performed on day 21 revealed that single nephron GFR (SNGFR), nephron plasma flow (SNPF) and the ultrafiltration coefficient had returned to the normal baseline value despite the severe reduction in GFR. To assess the role of increased nitric oxide production secondary to iNOS induction on the glomerular hemodynamic changes observed in the early stages of the disease, the iNOS blocker (l-N(6)-iminoethyl lysine, L-NIL) was administered IV (1 mg/h) in RTA/CFA rats and CFA rats. L-NIL had no effect in CFA rats but produced significant increases in GFR, SNGFR and SNPF in RTA/CFA rats. These results demonstrate that TIN is associated with a progressive reduction in GFR, which is likely the result of functional vasoconstriction and decreases in the ultrafiltration coefficient in the early stages of the disease and on a significant reduction in the number of functioning nephron in the later stages. Induction of iNOS with increased NO production actively participates in the functional changes observed in the early stages of the disease most likely by inhibiting normal endothelial NOS activity.

Diurnal variations of glomerular filtration rate and albuminuria in diabetic nephropathy

The aim of our study was to evaluate the diurnal variation in glomerular filtration rate (GFR), and the potential mechanisms responsible for such variations in GFR and albuminuria in diabetic nephropathy. In three 24-hour urine samples, divided into a night- and daytime portion, diurnal variation in albuminuria (ELISA) was assessed. Furthermore, during recumbency changes in albuminuria, GFR (51Cr-EDTA plasma clearance) and arterial blood pressure (TM2420) from nighttime (00:00 to 05:00 hours) to subsequent daytime (08:00 to 13:00 hours) were examined in 20 type 1 diabetic patients with diabetic nephropathy. The 24-hour urine collections showed an average rise in albuminuria from night- to daytime of 51% (95% CI; 16 to 95; P < 0.01). During recumbency a non-significant rise was recorded from night- to daytime in albuminuria (22%, -8 to 61, P=0.15), simultaneously with an increase in GFR of 9.0% (3.4 to 14.5, P < 0.005) and mean arterial blood pressure (MABP) of 8.0% (4.3 to 11.7, P < 0.0001). No diurnal variation in fractional clearance of albumin was found. Significant associations between MABP and albuminuria were demonstrated during night- (R2=0.50; P < 0.001) and daytime (R2=0.48; P < 0.005). A linear regression analysis between diurnal variations in MABP and GFR showed that an increase in MABP (of 10%) from night- to daytime was associated with a significant increase in GFR (of 8.0%, 0.2 to 4.1, P < 0.02). Our study revealed diurnal variations in GFR, albuminuria and MABP in diabetic nephropathy, with lowest values during sleep at night. The observed diurnal variation in albuminuria seems to be explained partly by mechanisms related to orthostasis, and partly by the diurnal variation in GFR and serum albumin concentration. The diurnal variation of blood pressure seems to play a role for the diurnal changes in GFR and albuminuria.

RAT RENAL FUNCTION FOUR DAYS AFTER BILE-DUCT LIGATION: EFFECTS OF INDOMETHACIN AND VASOACTIVE AGENTS

The purpose of this study was to assess the effects of the cyclooxygenase inhibitor, indomethacin, and some vasoactive agents on the renal functional parameters during the early liver injury induced by four days bile duct ligation (BDL). Wistar rats with four days-BDL and control-sham operated were used. Renal function was measured in anesthetized rat treated with a single dose of indomethacin (control, 0.3, 1.0, 3.0 mg/kg b.w.; i.v.) one hour before clearance studies. Sulindac effects were also evaluated (5 mg/kg b.w., i.p). Isolated rat kidney preparations from control and BDL donor rats were used to study renal vascular response to noradrenaline, carbachol or sodium nitroprusside. The bile duct ligation promoted a diminished renal cortical plasma flow (RCPF) on the fourth day post surgery accompanied with a diminution in the glomerular filtration rate (GFR), increased filtration fraction and increased fractional excretion of water and sodium. Indomethacin 0.3 mg/kg induced an increase in GFR and RCPF, maintaining the high filtration fraction in BDL rats. The other doses did not alter these parameters as compared with bile duct ligated rats without treatment, but indomethacin 3 mg/kg caused a significant increase in filtration fraction. Indomethacin induced dose-dependent diminution in natriuresis in sham and BDL groups. Sulindac did not modify hemodynamic parameters, but induced antinatriuresis and antidiuresis in both experimental groups. Maximal vascular responses to noradrenaline measured in isolated rat kidneys were statistically diminished in BDL-rats as compared with controls (C, n = 7; 35.0 ± 2.3 mmHg ml−1 min; BDL-rats, n = 5; 23.8 ± 0.7 mmHg ml−1 min; p<0.02), without changes in EC15. Maximal relaxation induced by sodium nitroprusside in the phenylephrine (PHE)-pre-constricted renal vasculature in control preparations did not differ from that observed in BDL group (C: n = 6; 49.5 ± 2.3%). Values of EC50 were 1.26 ± 0.07 µM (n = 6) in control preparations and 0.34 ± 0.03 µM (n = 4) in kidneys from BDL-rats (p<0.001). Carbachol induced a biphasic relaxation of PHE-pre-constricted renal vasculature. No differences in maximal responses were found. EC50 value of the second phase in BDL group was significantly decreased compared to control preparations (C: n = 6, 0.47 ± 0.05 µM; BDL: n = 6, 0.22 ± 0.03 µM; p<0.001). The present results show that the altered renal function after a short time post bile duct ligation is determined, at least in part, by increased release of arachidonic derivatives in vascular bed and tubular cells. At this stage of liver injury, the alteration in the renal vascular response to different vasoactive agents is remarkable.

Long-term follow-up of renal function in recipients and donors following pediatric kidney transplantation.

Of 125 children undergoing kidney transplantation (tx), 87 received their grafts from living donors. Renal function of recipients (R) and donors (D) was assessed by glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) determined by clearances of inulin and para-aminohippuric acid. Rs were investigated yearly and Ds on alternate years. Within 5 months of tx, absolute GFR and ERPF (ml/min) were significantly lower in R than in D, and the differences in absolute GFR and ERPF between D and R were directly related to the difference in body surface area (BSA) between the two subjects. R and D pairs were repeatedly followed for 4, 6, and 8 years and the absolute GFR of R did not change during follow-up, while relative GFR decreased. Relative GFR decreased most in R, with the greatest difference in BSA between D and R at tx. In the donors, however, both absolute and relative GFR increased significantly up to 8 years. In conclusion, renal function of the two kidneys from the donor, i.e., the grafted kidney in the R and the single native kidney of the D, differed. The native kidney showed a capacity to increase its absolute and relative function with time. The grafted kidney, however, did not show an increase in absolute GFR, resulting in decrease in relative GFR, and the greater difference in BSA between D and R at tx, the greater fall in relative GFR of the R.

Role of nNOS in regulation of renal function in angiotensin II-induced hypertension.

Previous studies have indicated that in normotensive rats, NO produced by neuronal NO synthase (nNOS) plays an important role in modulating tubuloglomerular feedback (TGF)-mediated afferent arteriolar constriction. It has also been shown that in angiotensin (Ang) II-infused hypertensive rats, there is a reduced ability of nNOS-derived NO to counteract this vasoconstriction. The present study was performed to (1) assess in vivo renal functional responses to intrarenal nNOS inhibition in control and Ang II-infused rats and (2) determine whether changes in renal function following nNOS inhibition are mediated by unopposed stimulation of Ang II receptor subtype 1 (AT(1)). Wistar rats were infused with either saline (SAL) or Ang II (80 ng/min) by osmotic minipumps implanted subcutaneously. Mean arterial blood pressure of SAL- and Ang II-infused rats on day 13 after implantation averaged 121+/-4 (n=28) and 151+/-5 (n=30), respectively (P<0.05). There were no differences in glomerular filtration rate (GFR) (0.68+/-0.09 versus 0.59+/-0.09 mL. min(-1). g(-1)), renal plasma flow (RPF) (2.66+/-0.31 versus 2.34+/-0.39 mL. min(-1). g(-1)), and absolute sodium excretion (0.37+/-0.07 versus 0.42+/-0.09 micromol. min(-1). g(-1)). Intrarenal infusion of SAL did not change GFR, RPF, and sodium excretion in either SAL-infused (n=7) or Ang II-infused rats (n=8). Acute intrarenal administration of the nNOS inhibitor S-methyl-L-thiocitrulline (L-SMTC; 0.3 mg/h) decreased GFR, RPF, and sodium excretion in SAL-infused rats (n=9) by 29+/-4%, 38+/-4%, and 70+/-4% compared with control values (P<0.05). The pretreatment by the AT(1) receptor antagonist candesartan (750 ng IR) in SAL-infused rats (n=7) effectively prevented the decrease in RPF (-3+/-3%) elicited by nNOS inhibition and resulted in an increase in GFR (+25+/-12, P<0.05) and a concomitant greater increase in sodium excretion (84+/-12%, P<0.05) compared with control values. In contrast, in Ang II-infused rats (n=10) intrarenal inhibition of nNOS by L-SMTC did not cause significant decreases in GFR, RPF and sodium excretion (-2+/-2%, -15+/-10%, and -14+/-10%, respectively). These results suggest that in normotensive rats nNOS-derived NO counteracts Ang II-mediated vasoconstriction in the pre- and postglomerular microcirculation. Furthermore, Ang II-infused rats exhibit an impaired ability to release NO by nNOS. Decreased nNOS activity is likely to account at least partially for the enhanced TGF responsiveness in Ang II-infused rats and thus may contribute to the maintenance of hypertension in this model.

Arterial pressure control at the onset of Type I diabetes: the role of nitric oxide and the renin-angiotensin system

Little is known about how hyperglycemia in diabetes directly affects renal and cardiovascular function. Therefore, we modified the streptozotocin-model of Type I diabetes in rats to enable chronic cardiovascular study at the earliest stages of diabetes, before there was time for development of vascular structural changes. We showed that the onset of diabetic hyperglycemia increased total peripheral resistance, decreased skeletal muscle blood flow, increased thromboxane production, and caused a transient increase in plasma renin activity (PRA). Mean arterial pressure (MAP) also increased, but the amplitude was modest. Moreover, we measured significant increases in glomerular filtration rate (GFR) and renal plasma flow, and also showed that endothelially mediated vasodilation in skeletal muscle was not impaired. We then tested the hypothesis that nitric oxide (NO) was playing an important role in counteracting a pressor response to the onset of diabetes. Our results showed that induction of diabetes in rats with chronic NO synthase inhibition caused a marked and progressive increase in MAP. In addition, PRA increased progressively under those conditions and the increase in GFR was prevented. This suggests that NO may work to keep arterial pressure in control at the onset of hyperglycemia very early in the development of diabetes, possibly by facilitating renal vasodilation and by suppressing activity of the renin-angiotensin system. However, the mechanisms for these interactions and the role of renal vascular resistance and other factors in mediating the hypertensive response remain unknown.

Effects of the angiotensin converting enzyme inhibitor benazepril in cats with induced renal insufficiency.

To determine effects of the angiotensin converting enzyme inhibitor benazepril in cats with induced renal insufficiency. 32 cats. Renal mass was surgically reduced, and cats were assigned to 1 of 4 eight-cat groups. Group 1 received placebo, whereas groups 2, 3, and 4 received benazepril hydrochloride orally once daily for approximately 6.5 months at the following doses: group 2, 0.25 to 0.50 mg/kg of body weight; group 3, 0.50 to 1.00 mg/kg; and group 4, 1.00 to 2.00 mg/kg. Arterial blood pressures, glomerular filtration rate (GFR), and renal plasma flow were determined before treatment and during the treatment period. Other determinants of renal hemodynamics were measured by use of micropuncture techniques. Renal biopsy specimens were examined microscopically. Compared with cats that received placebo, mean systolic arterial blood pressure was significantly less and GFR significantly greater in cats that received benazepril. Glomerular capillary pressure and the ratio of efferent to afferent arteriolar vascular resistance were also significantly less in treated cats. However, histologic differences in renal specimens were not detected. Treatment with benazepril sustained single nephron GFR in remnant nephrons of cats with induced renal insufficiency. Administration of benazepril was also associated with a small but significant reduction in degree of systemic hypertension and an increase in whole kidney GFR. Benazepril may be an effective treatment to slow the rate of progression of renal failure in cats with renal disease.

Renal hemodynamic response to maximal vasodilating stimulus in healthy older subjects

It is still unclear whether age per se is associated with preservation of renal functional reserve, that is, of the increase in glomerular filtration rate (GFR) induced by appropriate vasodilating stimulus. To gain insights into this issue, we evaluated the renal response to a maximal vasodilating stimulus, represented by the combined infusion of mixed amino acid solution (AA) and dopamine at renal dose (D), in 10 young subjects (median age of 30 years, range of 19 to 32) and in 11 subjects of older age (median age of 67 years, range of 65 to 76). Two further age-matched groups of young (N = 15) and older (N = 11) living kidney donors underwent renal needle biopsy immediately before nephrectomy to perform semiquantitative scoring (0 to 3) of arteriosclerosis in intrarenal arteries. All of the study subjects were nonsmokers with healthy status proven by extensive diagnostic evaluation excluding any risk factor of renal dysfunction. Basal renal plasma flow (RPF) and GFR were proportionally lower in older subjects (RPF, 361 +/- 29 vs. 618 +/- 34 mL/min/1.73 m(2), P < 0.001; GFR, 79 +/- 4 vs. 127 +/- 5.8 mL/min/1.73 m(2), P < 0.001). After AA + D, a significant increase of RPF and GFR was observed in both groups, but the older subjects exhibited a smaller percentage increment (RPF, 25.5 +/- 4.8 vs. 42.4 +/- 5.8, P < 0.05; GFR, 19.6 +/- 5.7 vs. + 33.8 +/- 6.4, P < 0.05). Furthermore, the maximal vasodilating stimulus was not able to restore renal hemodynamics in older subjects to the level measured in young controls at baseline. Renal vascular resistances were higher (P < 0.05) in the older subjects both at baseline (0.19 +/- 0.02 vs. 0.09 +/- 0.004 mm Hg/mL/min) and after AA + D (0.14 +/- 0.01 vs. 0.06 +/- 0.004). Light microscopy examination detected the presence of a greater degree of arteriosclerosis at the level of interlobular and arcuate arteries (0.89 +/- 0.15 vs. 0.45 +/- 0.08) and interstitial fibrosis/tubular atrophy (1.18 +/- 0.13 vs. 0.53 +/- 0.13) in older than in young subjects. Therefore, aging has adverse effects on renal function despite the absence of any risk factor for renal disease, including chronic smoking: (1) GFR and RPF are lower, and (2) the renal response to maximal vasodilating stimulus is impaired. These aging-related alterations of renal hemodynamics are possibly due to organic lesions in renal vasculature.