Increase In Glomerular Filtration Research Articles

#503 The influence of the degree of liver cell failure on the functional state of the kidneys in patients with liver cirrhosis

Abstract Background and Aims Studying the influence of the severity of liver cirrhosis on the functional ability of the kidneys in patients without concomitant diseases (without diabetes mellitus and hypertension). Method The study included 38 patients with liver cirrhosis who were treated in the gastroenterology department of the Republican Scientific and Practical Center for Therapy and Medical Rehabilitation in Tashkent. The average age of patients was 54 ± 3.4 (from 33 to 65). The examined patients were divided into two groups, depending on the degree of hepatic cellular failure (according to the Child-Pugh classification) and the development of ascitic syndrome. In group 1 Liver cirrhosis without ascites (P-P class A) the number of patients was 20. In group 2 Liver cirrhosis with ascites (P-P class B) the number of patients was 18. When examining patients, we used: Clinical blood test; blood chemistry; determination of electrolytes, creatinine; general urine analysis; glomerular filtration level; Functional renal reserve (defined as the increase in glomerular filtration expressed as a percentage after the administration of Dopamine at a dose of 2-3 μg/kg/min. To assess portal hypertension, all patients underwent ultrasound examination of the organs abdominal cavity and duplex scanning of portal system vessels. Results The examined patients were analyzed for the functional state of the kidneys and its relationship with the main parameters of portal hypertension and hepatic cell failure. Comparative characteristics of the main indicators of renal function significant differences in functional parameters were revealed depending on degree of hepatic cell failure. In the group of patients with cirrhosis with ascites, there was a significant decrease in renal GFR to 77.5 ± 1.4 ml/min, in contrast to the unchanged level of GFR in the group of patients with cirrhosis without ascites—99.3 ml/min. In patients with cirrhosis without ascites, the glomerular filtration rate increases by against the background of dopamine administration was 13.5 ± 4.7% (which corresponds to the norm), in contrast to patients in the second group, where the average Renal Functional Reserve was 8.4 ± 2.8%. Changes in renal function were also characterized by a decrease in Fractional Excretion of Sodium (FENa). The reduction in FENa in the group of patients with persistent ascites. During a detailed assessment of the RFR in patients of the first group, the RFR was below normal only in 2.6 ± 2.5%, while in the second group the number of patients with the decrease in the RFR was 69.7 ± 8.1%. Study of functional renal reserve in a group of patients with cirrhosis with ascites revealed unchanged this indicator in only 10 (30.3 ± 8%). U 19 (57.5 ± 8.6%) of patients in this group, the RFR was less than 10%, and in 12.2 ± 5.7% cases of RFR was below 5%, which indicated pronounced intraglomerular hypertension and the risk of developing resistant ascites. Conclusion The present study indicates that Renal Functional Reserve (RFR) in patients with liver cirrhosis reflects the speed of effective renal plasma flow. A decrease in FPR in Child-Pugh class A liver cirrhosis was detected in 2.6% of cases, with hepatic cell failure, Child-Pugh class B in 69.7%.

PATHOPHYSIOLOGY OF MOLECULAR HYDROGEN INFLUENCE ON ACUTE KIDNEY DAMAGE IN HEMIC HYPOXIA

When hemoglobin is inactivated by nitrites, hypoxia of the renal tubules is not accompaniedby inhibition of renal blood circulation. At the same time, the fi ltration fraction of sodiumions and the load on the energy- dependent mechanisms of the proximal and distal tubules remain high, but since there is no energy, signifi cant reactions of damage to the proximalnephron and dysfunction of the distal tubules as reabsorption of sodium than in theproximal tubule are observed. To correct the detected disorders, it is advisable to usean antioxidant solution of negative redox potential with hydrogen saturation, whichcan penetrate into cells, reach mitochondria, penetrate areas of ischemia, edema andinfl ammation, improve energy supply by means of supplying additional electrons anddetecting neutralization of hydroxyl radical and peroxynitrite.Purpose – to determine the eff ect of an antioxidant solution of negative redox potentialwith molecular hydrogen saturation on the functional and biochemical processes of thekidneys in acute hemic hypoxia of moderate severity.Materials and methods. The experiments were performed on 30 white nonlinear malerats weighing 0.16-0.18 kg under the conditions of hyposodium diet. Simulation ofexperimental hemic hypoxia was performed by a single subcutaneous injection of 1%sodium nitrite solution at a dose of 50 mg / kg body weight, causing, respectively, theaverage severity of hemic hypoxia. An antioxidant solution of negative redox potentialwith hydrogen saturation 1.0-1.2 ppm and redox potential –297.3 ± 5.27 mV was obtainedusing a new generation generator Blue Water 900 (Korea). Experimental, physiological,biochemical, immunoenzyme, histoenzymo- chemical and statistical research methodswere used.Results. The development of acute hemic hypoxia of moderate severity was accompaniedby an increase in glomerular fi ltration, protein excretion, decreased distal reabsorptionof sodium ions. An increase in the concentration of tumor necrosis factor- alpha in bloodplasma was found and an increase in unlimited proteolysis in the kidneys was detected:by azocollagen lysis in the cortex, azocasein in the medullary substance and azoalbuminin the papilla. Moderate hemic hypoxia showed an increase in the concentration of lipidperoxidation products: malonic aldehyde and diene conjugates in the renal medulla andinhibition of succinate dehydrogenase activity in the proximal nephron (p <0.01). Theuse of a solution of negative redox potential with molecular hydrogen saturation hada corrective eff ect on the studied parameters.Conclusions. 1. In acute hemic hypoxia of moderate severity, a solution of negative redoxpotential with molecular hydrogen saturation due to its antioxidant, cytoprotective, energyproperties improves the condition of the proximal tubule, reduces the manifestations ofproteinuria (p <0,01), increases tubular type succinate dehydrogenase activity (p <0.02)in this part of the nephron. 2. The use of a solution of negative redox potential withmolecular hydrogen saturation due to its antioxidant, anti-infl ammatory, nephroprotectiveproperties has a protective eff ect on the kidneys and reduces elevated levels of tumornecrosis factor- alpha in blood plasma (p <0,01), lysis azocollagen, azoalbumin, azocaseinand lipid peroxidation products of malonic aldehyde (p <0.01) and diene conjugates inacute hemic hypoxia of moderate severity.

The study of the efficacy of combined medicines of quercetin and glucosamine derivatives in rats with the end-stage renal failure

Chronic kidney disease (CKD) is the most significant pathology among diseases of the urinary system, which leads to the inevitable development of renal failure. Currently, there are no effective treatments for the end-stage form of CKD in clinical practice.Aim. To study of the effect of combined medicines of quercetin with glucosamine derivatives in the experiment using various routes of administration on the course of the end-stage renal failure.Materials and methods. The study was performed on the model of adenine-induced nephropathy in rats. Test samples were administered intragastrically (80 mg/kg) and intramuscularly (30 mg/kg) for 4 weeks starting in 4 weeks after beginning of the experiment. Corvitin was used as a reference drug in the dose of 34 mg/kg. The efficacy of test drugs was assessed by indicators of the kidney functional state and nitrogen metabolism.Results. In 8 weeks after the pathology simulation under the influence of both test objects a positive effect on the course of renal failure was observed. In this case, an injection combination of quercetin with N-acetylglucosamine significantly (p<0.05) exceeded the efficacy of the oral combination. Under its influence, there was an increase in glomerular filtration and urinary excretion of creatinine and urea. It indicates the normalization of the kidney functional state and nitrogen metabolism. Moreover, this combination was significantly (p<0.05) superior to the Corvitin effect by the efficacy level.Conclusions. In conditions of the end-stage renal failure in rats the injection combination of quercetin with N-acetylglucosamine was highly effective. It allows considering this combination to be a promising medicine for treating CKD at the IV-V stages.

Non-steroidal anti-inflammatory drugs among chronic kidney disease patients: an epidemiological study

BackgroundNon-steroidal anti-inflammatory drugs (NSAIDs) should be avoided among chronic kidney disease (CKD) patients. Till now, limited data are available on NSAID use in Egypt, and we aimed to study the prevalence and pattern of NSAID use among CKD patients.MethodsA cross-sectional study was done among 350 CKD adult patients presented to the Main Alexandria University Hospital. Those with end-stage renal disease and diagnosed with acute renal injury and pregnant women were excluded. Demographic and clinical data were collected by interviewing eligible patients. Data about the pattern, history of drug-drug interactions, and knowledge about the NSAID side effects were also gathered.ResultsOf the enrolled patients, 57.1% were hypertensive, 46% were diabetics, 28% had osteoarthritis, and 18.3% had cardiovascular disease. CKD stages were 3.7%, 40.3%, and 56% in stages 2, 3, and 4, respectively. Almost two thirds (65.7%) were NSAID users. Among them, 82.6% were regular users. Headache was the most reported (68.7%) reason of use. The use of drugs which may have drug-drug interaction with the NSAIDs (as diuretics or renin-angiotensin-aldosterone system inhibitors) was reported in 36%. In multiple logistic regression, the odds of NSAID use decreased by 4% (odds ratio (OR) = 0.96, 95% confidence interval (CI) 0.93–0.99, p = 0.01) for every year increase in the patient’s age and decreased by 3% (OR = 0.97, 95% CI 0.95–0.99, p = 0.01) for every 1 ml/min/1.73 m2 increase in glomerular filtration rate.ConclusionDespite the hazards of NSAID use on the kidney, still high proportion of CKD patients are using them for a long period and they are simultaneously using other drugs with possible drug-drug interactions. This study provided important information that would decrease the gap in knowledge about the use of NSAID in Egypt. It is recommended that NSAIDs should be used with caution among CKD patients and patients should be advised about its adverse health consequences.

Effects of Acute Plasma Volume Expansion on Renal Perfusion, Filtration, and Oxygenation After Cardiac Surgery

Background In the present randomized study, we evaluated the differential effects of a colloid and a crystalloid fluid on renal oxygen delivery ( R D O 2 ), glomerular filtration (GFR), renal oxygen consumption ( R V ˙ O 2 ), and the renal oxygen supply–demand relationship (i.e. renal oxygenation) after cardiac surgery with cardiopulmonary bypass. Methods Thirty patients with normal preoperative renal function, undergoing uncomplicated cardiac surgery, were studied in the intensive care unit in the early postoperative period. Patients were randomized to receive a bolus dose of either a crystalloid (Ringers-acetate® 20 ml kg−1, n=15) or a colloid solution (Venofundin® 10 ml kg−1, n=15). Systemic haemodynamics were measured via a pulmonary artery catheter. Renal blood flow and GFR were measured by the renal vein retrograde thermodilution technique and by renal extraction of 51Cr-EDTA (=filtration fraction). Arterial and renal vein blood samples were obtained for measurements of renal oxygen delivery ( R D O 2 ) and R V ˙ O 2 . Renal oxygenation was estimated from the renal oxygen extraction. Results Despite an increase in cardiac index and renal blood flow with both fluids, neither of the fluids improved R D O 2 , because they both induced haemodilution. The GFR increased in the crystalloid (28%) but not in the colloid group. The crystalloid increased the filtration fraction (24%) and renal oxygen extraction (23%), indicating that the increase in GFR, the major determinant of R V ˙ O 2 , was not matched by a proportional increase in R D O 2 . Conclusions Neither the colloid nor the crystalloid improved R D O 2 when used for postoperative plasma volume expansion. The crystalloid-induced increase in GFR was associated with impaired renal oxygenation, which was not seen with the colloid. Clinical trial registration NCT01729364.

The Pathophysiological Hypothesis of Kidney Damage during Intra-Abdominal Hypertension.

The Pathophysiological Hypothesis of Kidney Damage during Intra-Abdominal Hypertension.

Effects of acute plasma volume expansion on renal perfusion, filtration, and oxygenation after cardiac surgery: a randomized study on crystalloid vs colloid

In the present randomized study, we evaluated the differential effects of a colloid and a crystalloid fluid on renal oxygen delivery (RD(O2)), glomerular filtration (GFR), renal oxygen consumption ((RV(O2))), and the renal oxygen supply-demand relationship (i.e., renal oxygenation) after cardiac surgery with cardiopulmonary bypass. Thirty patients with normal preoperative renal function, undergoing uncomplicated cardiac surgery, were studied in the intensive care unit in the early postoperative period. Patients were randomized to receive a bolus dose of either a crystalloid (Ringers-acetate 20 ml kg(-1), n=15) or a colloid solution (Venofundin) 10 ml kg(-1), n=15). Systemic haemodynamics were measured via a pulmonary artery catheter. Renal blood flow and GFR were measured by the renal vein retrograde thermodilution technique and by renal extraction of 51Cr-EDTA (=filtration fraction). Arterial and renal vein blood samples were obtained for measurements of renal oxygen delivery (RD(O2)) and RV(O2). Renal oxygenation was estimated from the renal oxygen extraction. Despite an increase in cardiac index and renal blood flow with both fluids, neither of the fluids improved RD(O2), because they both induced haemodilution. The GFR increased in the crystalloid (28%) but not in the colloid group. The crystalloid increased the filtration fraction (24%) and renal oxygen extraction (23%), indicating that the increase in GFR, the major determinant of RV(O2), was not matched by a proportional increase in RD(O2). Neither the colloid nor the crystalloid improved RD(O2) when used for postoperative plasma volume expansion. The crystalloid-induced increase in GFR was associated with impaired renal oxygenation, which was not seen with the colloid. NCT01729364.

Physical activity and kidney diseases

Regular physical activity (PA) in the early school years is recommended by several scientific associations for primary prevention of cardiovascular disease. Long-term observational studies have shown that subjects who exercise regularly have significantly less coronary heart disease (CHD) and a reduced risk of cardiovascular disease (CVD). Exercise reduces serum triglycerides, increases serum high density lipoprotein-cholesterol, lowers the blood pressure in patients with primary hypertension [1]. Regular exercise reduces the production of atherogenic cytokines and increases production of atheroprotective cytokines. It should be mentioned, however, that other factors may be associated with physical activity (e.g. a healthy diet, avoiding cigarette smoking, regular medical care) and may contribute to the improved health. No long term studies have been produced on the effects of PA during childhood on CHD and CVD in adult life but indirect evidence suggests that it may produce benefit. Regular exercise, on the other end, is associated with potential adverse effects (eg, musculoskeletal injuries, arrhythmias, myocardial infarction, and rhabdomyolysis); however, the absolute risk of kidney disease during exercise is low [2]. Consensus guidelines for the pre-participation physical evaluation (PPE) suggest a PPE for all children, even those who do not participate in organized sports, as an opportunity to promote health and fitness. PPE includes a medical and family history and a physical examination, with particular emphasis on the musculoskeletal and cardiovascular systems [3]. Exercise induces profound changes in the renal haemodynamics and in electrolyte and protein excretion. Proteinuria, hematuria and changes in serum electrolyte balance have been reported during intense PA; the increase in glomerular filtration may explain these transient alterations but the “nutcracker” compression on the renal vein may have a role. Haemoglobinuria and myoglobinuria may be observed under special exercise conditions [4]. PA does not worse nor reverse kidney disease but may reduce cardiovascular risk in chronic renal disease [5]. Children on dialysis and after a renal transplantation performing aerobic physical exercise show improvements in exercise tolerance, in quality of health and uraemic symptom scores; they gain weight loss, cardiovascular reactivity, avoiding an increase in blood pressure medication [6].

The protective role of coenzyme Q10 in renal injury associated with extracorporeal shockwave lithotripsy: a randomised, placebo‐controlled clinical trial

To determine the efficacy of coenzyme Q10 (CoQ10) in preventing renal injury in patients with lithiasis undergoing extracorporeal shockwave lithotripsy (ESWL). Prospective, randomised, double-blind, placebo-controlled clinical trial of 100 patients with renal lithiasis who were treated with ESWL. The patients were distributed randomly into two groups receiving either placebo or CoQ10 (200 mg/day), a powerful antioxidant with vasoactive properties, orally administered during the week before ESWL and for 1 week after. Renal dysfunction markers, vasoactive hormones, oxidative stress, plasma levels of several interleukins and vascular resistance index (VRI) using Doppler ultrasound were evaluated the week before ESWL, 2 h before ESWL and at 2 h, 24 h and 7 days after ESWL. There was a significant increase in glomerular filtration (P = 0.013), as well as a decrease in the albumin/creatinine ratio and the β2 -microglobulin level (P = 0.02) after 1 week of treatment in the CoQ10 group. These changes were maintained at the follow-up after ESWL. The administration of CoQ10 was associated with improvement in vasoactive hormone parameters, VRI and interleukin levels. These improvements were maintained until the end of the follow-up period. However, the administration of CoQ10 was not associated with significant changes in the oxidative stress parameters. Our results indicate that CoQ10 administration improves renal function and vasoactive and inflammation parameter values, allowing for preconditioning before the tissue insult caused by ESWL.

Polymyxin-B固定化ファイバーを用いた直接血液灌流療法(PMX-DHP)施行時における利尿機序の検討

In the present study, we applied direct hemoperfusion with polymyxin B-immobilized fiber(PMX-DHP) to patients who developed endotoxin shock after laparotomy, and examined the influence of PMX-DHP on the kidney function. Seven patients were enrolled in this study, whose conditions were matched to the following criteria: 1) endotoxin shock was highly suspected, 2) blood pressure became stable before PMX-DHP was indicated, 3) renal function(demonstrated with creatinine clearance(CCr) and fractional excretion of sodium (FENa)) was proven before the surgery. All patients underwent emergency surgery in Fuji City General Hospital because of perforative peritonitis. A 2-hour session of PMX-DHP was performed on the day of the laparotomy and the second 2-hour treatment was performed the following day. Urine was collected at 2 hours before starting PMX, during the treatment, and 2 hours after PMX-DHP, and urine volume(U-Vol), sodium and creatinine levels of urine were monitored. Sodium and creatinine levels in the serum were measured at the start and end of the PMX-DHP session. Average atrial natriuretic polypeptide (ANP) was obtained using a total of 8 samples from the 14 treatment sessions. Parameters of hemodynamics such as pulmonary capillary wedge pressure(PCWP) were monitored at the start and end of PMX-DHP session. Urine volume increased significantly during and after PMX-DHP. The change in urine volume correlated significantly with the change in CCr during PMX-DHP, and with the change in FENa after PMX-DHP. The change in FENa was significantly correlated with the changes in hemodynamic factors such as PCWP and with the change in serum ANP, but no significant correlation was observed between the change of CCr and the other parameters. In conclusion, the early increase in urine volume with PMX-DHP treatment might be attributable to the increase in glomerular filtration independently of systemic hemodynamic factors.

Renal agenesis and unilateral nephrectomy: what are the risks of living with a single kidney?

The long-term outlook for patients with unilateral renal agenesis or following unilateral nephrectomy in childhood is controversial. Animal studies suggest that the resultant compensatory increase in glomerular filtration might lead to progressive damage to the remaining renal tissue and may generate hypertension. Human studies addressing these concerns are limited in number and are difficult to interpret because they are small, retrospective, or cross sectional with significant variations in duration and completeness of follow-up. The published studies suggest that renal function remains stable for several decades in the majority of subjects. The clinical significance of mild-grade proteinuria and hypertension seen in some patients is unknown. Longitudinal studies are needed to understand the long-term effect and significance of the several pathophysiological changes observed in the solitary kidney.

L-arginine-induced glomerular hyperfiltration response: the roles of insulin and ANG II

Infusion of L-arginine produces an increase in glomerular filtration via kidney vasodilation, correlating with increased kidney excretion of nitric oxide (NO) metabolites, but the specific underlying mechanisms are unknown. We utilized clearance and micropuncture techniques to examine the whole kidney glomerular filtration rate (GFR) and single nephron GFR (SNGFR) responses to 1) L-arginine (ARG), 2) ARG+octreotide (OCT) to block insulin release, 3) ARG+OCT+insulin (INS) infusion to duplicate ARG-induced insulin levels, and 4) losartan (LOS), an angiotensin AT-1 receptor blocker, +ARG+OCT. ARG infusion increased GFR, while increasing insulin levels. OCT coinfusion prevented this increase in GFR, but with insulin infusion to duplicate ARG induced rise in insulin, the GFR response was restored. Identical insulin levels in the absence of ARG had no effect on GFR. In contrast to ARG infusion alone, coinfusion of OCT with ARG reduced proximal tubular fractional and absolute reabsorption potentially activating tubuloglomerular feedback. Losartan infusion, in addition to ARG and OCT (LOS+ARG+OCT), restored the increase in both SNGFR and proximal tubular reabsorption, without increasing insulin levels. In conclusion, 1) hyperfiltration responses to ARG require the concurrent, modest, permissive increase in insulin; 2) inhibition of insulin release after ARG reduces proximal reabsorption and prevents the hyperfiltration response; and 3) inhibition of ANG II activity restores the hyperfiltration response, maintains parallel increases in proximal reabsorption, and overrides the arginine/octreotide actions.

Physiology of pregnancy

Pregnancy initiates alterations to all body systems, which may take weeks to resolve after delivery. Understanding them is the key to managing pregnant women safely. Considerable adjustments to the reference ranges for many laboratory criteria result, and failure to appreciate these can cause diagnostic error or therapeutic disaster. The physiology of pregnancy is considered by system, emphasising the implication of the changes for clinical practice, and the relevance in relation to complications of pregnancy. The placenta creates a low resistance circulation, vasodilatation occurs peripherally and circulating volume increases. Increased heart rate, myocardial contractility and pre-load, and reduced after-load all influence cardiac performance in pregnancy, by expanding cardiac output. Oxygen consumption increases during pregnancy. Ventilation increases by 40%, such that the partial pressure of oxygen is unchanged (i.e. more oxygen is consumed but more is acquired). The partial pressure of carbon dioxide is reduced by this increase in ventilation. • There is a physiological rise in coagulation factors I (fibrinogen), V, V11, V111, IX and XII and a fall in some endogenous anticoagulants (antithrombin, protein S, activated protein C resistance). • The kidneys increase in length, and the renal calyces, renal pelvis and ureter dilate. Renal blood flow increases, leading to a 50% increase in glomerular filtration. Clinically there is a rise in creatinine clearance. Glycosuria is common in pregnancy. • 80% of pregnant women experience heartburn. • Liver function test results are lower in pregnancy because of haemodilution. Spider naevi and palmar erythema are common. Pruritus occurs in at least 20% pregnancies.

ARF in children with minimal change nephrotic syndrome may be related to functional changes of the glomerular basal membrane

Background: Acute renal failure (ARF) is a rare complication in children with minimal change nephrotic syndrome (MCNS). Several etiologic factors (renal vein thrombosis, side effect of such drugs as nonsteroidal anti-inflammatory drugs, and infections) have been described, but often such conditions are lacking, and hemodynamic derangements or changes in glomerular permeability are suspected. Methods: We assessed the role of alterations in renal perfusion and glomerular permeability by measuring clearances of inulin and para-aminohippurate before and during intravenous administration of a 20% albumin solution in patients with MCNS and oliguric ARF (serum creatinine > 1 mg/dL [88 μmol/L], urine output < 0.5 mL/kg body weight/h). Results: Eleven patients aged 2.5 to 15 years with biopsy-proven MCNS were studied. Before albumin administration, all patients had a significantly decreased glomerular filtration rate (GFR), whereas most renal plasma flow (RPF) values were within the normal range. This resulted in a significantly decreased filtration fraction (FF; GFR/RPF × 100), which was extremely low (<7%) in 4 patients. There was a heterogeneous response to albumin administration. Albumin infusion tended to increase RPF, but changes did not reach statistical significance. Some patients showed an increase in glomerular filtration, whereas in others, it decreased. In 7 patients, FF remained unchanged or decreased even further. Conclusion: Our data suggest that, although in some patients decreased intravascular volume may contribute to reduced renal function, changes in glomerular permeability may have a major role in ARF occurring in uncomplicated MCNS.

Chronic taurine treatment ameliorates reduction in saline-induced diuresis and natriuresis

Taurine is an osmolyte found in high concentration in the kidney. Both the modulation of tissue taurine stores and the exogenous administration of taurine are known to affect renal function. Therefore, it is likely that taurine therapy could benefit the dysfunctional kidney. To test this idea, the present study examined the effect of chronic taurine administration on the excretory responses to acute saline volume loading by the unilaterally nephrectomized (UNX) control and the UNX glucose-intolerant rat (ages 3 to 9 months). Sham-operated animals excreted similar amounts of the administered fluid and sodium loads with age. However, unilateral nephrectomy was associated with a significant reduction in the response to saline volume loading. This defect was prominent at a younger age (that is, 3 months) in the UNX glucose intolerant than the UNX control (6 months old) rat. Chronic taurine treatment ameliorated the reduction in saline-induced diuresis and natriuresis by both the UNX control and the UNX glucose intolerant rat. Both an increase in glomerular filtration and a reduction in tubular reabsorption of fluid and sodium caused this taurine-mediated improvement in renal excretory function. Taurine treatment protects the kidney of the UNX rat against an age-dependent decline in excretory efficiency.

Safety and availability of doxazosin in treating hypertensive patients with chronic renal failure.

Hypertension accelerates the progression of renal disease in patients with chronic renal failure. Doxazosin, an alpha1-antagonist, is an antihypertensive agent with a long half-life. In this study, 15 patients with chronic renal failure were treated only with doxazosin and diuretics for 6 months and their blood pressure, renal parameters and lipid profile were measured. The initial dose of doxazosin was 2 mg/day and it was titrated until blood pressure was normalized. The average dose was 5.6 mg/day. As expected, systolic and diastolic blood pressure were decreased with treatment (165/91 mmHg to 135/73 mmHg). The drop in blood pressure was associated with an increase in glomerular filtration and a decrease in plasma BUN and creatinine levels. Reduction in mean blood pressure and decrease in proteinuria had a significant positive correlation (r=0.048, p=0.007). Proteinuria was decreased from 1.8 mg/day to 1.3 mg/day with doxazosin treatment and triglycerides also decreased, while HDL-cholesterol was increased. No side effects were observed. These results indicate that doxazosin is an efficient depressor agent with renal protective actions and that higher doses of doxazosin can be safely given to patients with chronic renal failure.

Role of insulin-like growth factor (IGF)-1 in the modulation of renal haemodynamics in Type I diabetic patients.

We investigated in normotensive Type I (insulin-dependent) diabetic patients with normoalbuminuria the role of growth hormone-induced IGF-1 in the modulation of renal haemodynamics. We measured glomerular filtration (GFR) and renal plasma flow (RPF) at baseline and at 24 h after injection of different doses of growth hormone (0.1, 0.2, 0.4 U x kg(-1) x body weight(-1) in six patients with normal GFR under a euglycaemic clamp. We also examined a 24 h profile of plasma growth hormone and IGF-1 during usual insulin therapy in two other groups each with seven patients with a lower (from 93 to 114 ml x min(-1) x (1.73 m2)(-1) and higher (from 121 to 146 ml min(-1) x (1.73 m2)(-1) GFR. Plasma growth hormone concentrations peaked 2 h after its injection and plasma concentrations of IGF-1 peaked about 24 h after the growth hormone injection. There was a significant increase in GFR and RPF 24 h after the highest dose of the growth hormone injection (corresponding to the highest IGF-1 concentration), from baseline values of 115 +/- 24 and 536 +/- 141 ml x min(-1) x (1.73 m2)(-1) to 160 +/- 33 and 657 +/- 137 ml x min(-1) x (1.73 m2)(-1), respectively (p < 0.01 for GFR and p < 0.05 for RPF). No differences were observed in the 24 h profile of growth hormone and IGF-1 plasma concentrations between the two groups; growth hormone and IGF-1 concentrations were lower than those obtained after the injection of 0.4 U x kg(-1) x body weight(-1) of growth hormone. These results show that pharmacological growth hormone-induced IGF-1 concentrations are required to modify renal haemodynamics in Type I diabetic patients and suggest that, under the "physiological" conditions of diabetes, IGF-1 has no role as a mediator of glomerular hyperfiltration.

Albumin permeability in isolated glomeruli in incipient experimental diabetes mellitus.

The pre-clinical phase of diabetic nephropathy is characterised by increased glomerular filtration rate and episodes of microalbuminuria. The cause of the microalbuminuria has been variably ascribed to alterations of the size or charge selective barriers of the glomerulus or both or as a consequence of the haemodynamic changes. Our aim was to investigate very early albumin permeability alterations in isolated glomeruli which were not subject to perfusion pressure. Isolated glomeruli were studied from 120 male Wistar rats, divided into three groups: streptozotocin-treated, streptozotocin-treated with insulin pellet implants, and controls. From each group ten animals were killed at 7, 14, 28, and 56 days after induction. Study variables included blood pressure, proteinuria, iopamidol clearance, albumin permeability and glomerular area. Subsequently, albumin permeability, proteinuria, and iopamidol clearance were determined in an additional group of 40 diabetic animals studied at 24, 72, 96, and 120 h after induction. Albumin permeability increased steadily from induction in streptozotocin-treated animals, reaching a plateau at approximately 120 h. Glomerular filtration rate was shown to increase significantly at approximately 7 days and proteinuria correlated with it. Glomerular hypertrophy was observed both in streptozotocin-treated animals and in streptozotocin-treated rats with insulin pellet implants. Strict blood glucose control delayed the appearance of the permeability defect in isolated glomeruli and inhibited the increase in glomerular filtration in intact animals. It did not prevent glomerular hypertrophy. An albumin permeability defect exists early in isolated non-perfused glomeruli from streptozotocin-treated rats and seems to be independent of glomerular filtration rate alterations.

Circadian variations of renal sodium handling in patients with orthostatic hypotension

Sodium wasting during the night has been postulated as a potential pathophysiological mechanism in patients suffering from orthostatic hypotension due to severe autonomic deficiency. In this study, the diurnal variations in creatinine clearance, sodium excretion and segmental renal tubular handling of sodium were evaluated in 18 healthy subjects and 20 young patients with orthostatic hypotension (OH). In addition, 24-hour ambulatory blood pressure and the neuro-hormonal response to changes in posture were determined. The patients and their controls were studied on a free sodium intake. In a second protocol, 10 controls and 10 patients were similarly investigated after one week of a high salt diet (regular diet + 6 g NaCl/day). Our results demonstrate that, in contrast to normal subjects in whom no significant changes in glomerular filtration, sodium excretion and segmental sodium reabsorption were observed throughout the day, patients with OH were characterized by a significant increase in glomerular filtration rate during the nighttime (P = 0.03) and significant increases in urinary lithium excretion (P < 0.05) and lithium clearance (P = 0.05) during the night, suggesting a decreased proximal reabsorption of sodium. On a high sodium diet, the symptoms of orthostatic hypotension and the circadian variations in sodium reabsorption were significantly blunted. These results suggest that, while the patient is in a supine position the effective blood volume of those with OH becomes excessive due to the increased venous return. Hence, the kidney responds with an increase in glomerular filtration and a relative escape of sodium from the proximal tubular segments. These circadian variations in renal sodium handling may contribute to the maintenance of the orthostatic syndrome.

Drug interactions at the renal level. Implications for drug development.

The kidney plays a major role in the elimination of drugs. The purpose of this paper is to: (i) review the mechanisms of renal elimination; (ii) identify potential mechanisms for renal drug interactions; (iii) review in vitro and in vivo animal models for studying renal elimination mechanisms and identifying potential drug-drug interactions; (iv) review experimental designs used in identifying drug-drug interactions in humans with an emphasis on gaining information regarding the mechanism of the interaction; and (v) make recommendations regarding the potential for renal drug interactions in drug development. It is concluded that clinically significant drug interactions resulting in toxicity because of some mechanism at the renal level appear to be relatively rare and that in vitro screening should not be done on all drugs during drug development. Five potential mechanisms exist for drug interactions at the renal level: (i) a displacement of bound drug resulting in an increase in drug excretion via an increase in glomerular filtration; (ii) competition at a tubular secretion site resulting in a decrease in drug excretion; (iii) competition at the tubular reabsorption site resulting in an increase in drug excretion; (iv) a change in urinary pH and/or flow that may increase or decrease drug excretion depending on the pKa of the drug; and (v) inhibition of renal drug metabolism. The most well known renal drug interaction is competitive inhibition of tubular secretion, ultimately leading to an increase in plasma drug concentration. Only when renal clearance is a major contributor to the total clearance (> 30%) and plasma concentrations are greater than the Michaelis-Menten transport constant does the potential exist for clinically significant renal drug-drug interactions because only then does nonlinear pharmacokinetics become evident. The potential for drug interactions is small when renal clearance is less than 20 to 30% of the total clearance and/or when plasma concentrations are less than the Michaelis-Menten transport constant, unless the drug has a narrow therapeutic window.