Para-aminohippuric Acid Clearance Research Articles

Follow-up of kidney biopsies in normoalbuminuric patients with type 1 diabetes.

To study the development of diabetic glomerulopathy, we performed two kidney biopsies after 10.5 and 17 years of type 1 diabetes in 19 normoalbuminuric, normotensive adolescents (10 males). The biopsies were examined with light and electron microscopy. The glomerular filtration rate and effective renal plasma flow, determined with inulin and para-aminohippuric acid clearances, respectively, and ambulatory blood pressure were studied. Between the biopsies, significant increases occurred in glomerular volume, foot process width, mesangial matrix, and mesangial volume fraction/glomerulus. The metabolic control affected the basement membrane thickness, mesangial matrix, and mesangial volume fraction/glomerulus. The mesangial matrix and mesangial volume fraction/glomerulus were higher in female patients on the first biopsy, but on the second biopsy, the levels in males increased to those in females. The night-time systolic and mean arterial blood pressures from the first biopsy seemed to predict the mesangial matrix and mesangial volume fraction/glomerulus, foot process width, and slit pore length on the second biopsy. Despite normoalbuminuria and normal blood pressure, patients with type 1 diabetes have morphological changes of diabetic glomerulopathy that progress. The night-time blood pressure can be used to predict morphological changes of diabetic nephropathy in adolescents who are normoalbuminuric and normotensive.

Nimesulide, a cyclooxygenase-2 preferential inhibitor, impairs renal function in the newborn rabbit.

Tocolysis with nonsteroidal anti-inflammatory drugs (NSAIDs) has been widely accepted for several years. Recently, the use of the cyclooxygenase-2 (COX2) preferential NSAID nimesulide has been proposed. However, data reporting neonatal acute renal failure or irreversible end-stage renal failure after maternal ingestion of nimesulide question the safety of this drug for the fetus and the neonate. Therefore, this study was designed to define the renal effects of nimesulide in newborn rabbits. Experiments were performed in 28 newborn rabbits. Renal function and hemodynamic parameters were measured using inulin and para-aminohippuric acid clearances as markers of GFR and renal blood flow, respectively. After a control period, nimesulide 2, 20, or 200 microg/kg was given as an i.v. bolus, followed by a 0.05, 0.5, or 5 microg.kg(-1).min(-1) infusion. Nimesulide administration induced a significant dose-dependent increase in renal vascular resistance (29, 37, and 92%, respectively), with a concomitant decrease in diuresis (-5, -23, and -44%), GFR (-12, -23, and -47%), and renal blood flow (-23, -23, and -48%). These results are in contrast with recent reports claiming that selective COX2 inhibition could be safer for the kidney than nonselective NSAIDs. These experiments confirm that prostaglandins, by maintaining renal vasodilation, play a key role in the delicate balance regulating neonatal GFR. We conclude that COX2-selective/preferential inhibitors thus should be prescribed with the same caution as nonselective NSAIDs during pregnancy and in the neonatal period.

The adverse renal effects of prostaglandin-synthesis inhibitors in the newborn rabbit

Nonsteroidal anti-inflammatory drugs are frequently used during pregnancy (premature labor, polyhydramnios) and the immediate postnatal period (closure of patent ductus arteriosus). This article evaluates the renal effect of 3 nonspecific COX inhibitors (aspirin, indomethacin, and ibuprofen) in newborn rabbits. Five groups of anesthetized, ventilated, normoxemic 6-day-old rabbits (n = 52) were administered intravenous aspirin (40 mg/kg), indomethacin (2 mg/kg), and ibuprofen (0.02, 0.2, 2.0 mg/kg, respectively). Renal function and hemodynamics as assessed by inulin and para-aminohippuric acid clearances were measured before and in the hour after drug administration. In all groups of animals, the nonselective COX inhibitors induced an increase in renal vascular resistance and a consequent decrease in glomerular filtration rate and renal blood flow. Urine flow rate decreased significantly in all groups, except in the group receiving the lowest dose of ibuprofen. In newborn rabbits, aspirin, indomethacin, and ibuprofen induced intense renal vasoconstriction, which resulted in impaired renal function. This observation illustrates the major renal protective role played by the vasodilatory prostaglandins during the neonatal period, when the kidney is perfused at very low perfusion pressure. We conclude that all COX inhibitors should be administered with the same caution to the preterm neonate.

C(−260)T polymorphism in the promoter of the CD14 gene is not associated with coronary artery disease and myocardial infarction in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study

impact of renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary interventions. J Am Coll Cardiol 2002;39:1113–1119. 7. Rubenstein MH, Harrell LC, Sheynberg BV, Schunkert H, Bazari H, Palacios IF. Are patients with renal failure good candidates for percutaneous coronary revascularization in the new device era? Circulation 2000;102:2966–2972. 8. Rubenstein MH, Sheynberg BV, Harrell LC, Schunkert H, Bazari H, Palacios IF. Effectiveness of and adverse events after percutaneous coronary intervention in patients with mild versus severe renal failure. Am J Cardiol 2001;87:856–860. 9. Cannon CP, Weintraub WS, Demopoulos LA, Vicari R, Frey MJ, Lakkis N, Neumann FJ, Robertson DH, DeLucca PT, DiBattiste PM, Gibson CM, Braunwald E. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001;344:1879–1887. 10. Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med 1998;338:1488– 1497. 11. Januzzi JL, Snapinn SM, DiBattiste PM, Jang IK, Theroux P. Benefits and safety of tirofiban among acute coronary syndrome patients with mild to moderate renal insufficiency. Circulation 2002;105:2359–2364. 12. Toto RD. Conventional measurement of renal function utilizing serum creatinine, creatinine clearance, inulin and para-aminohippuric acid clearance. Curr Opin Nephrol Hypertens 1995;4:505–509. 13. Shaw RE, Anderson HV, Brindis RG, Krone RJ, Klein LW, McKay CR, Block PC, Shaw LJ, Hewitt K, Weintraub WS. Development of a risk adjustment mortality model using the American College of Cardiology-National Cardiovascular Data Registry (ACC-NCDR) experience: 1998-2000. J Am Coll Cardiol 2002;39:1104–1112.

Dynamic renal blood flow measurement by positron emission tomography in patients with CRF

Background: Positron emission tomography (PET) is a functional imaging device that allows dynamic regional blood flow measurements. We performed a study to test whether PET could detect acute changes in renal blood flow (RBF) in patients with chronic renal failure (CRF). Methods: RBF was measured by means of PET (PET-RBF) using oxygen 15-labeled water (H215O) in eight men with hypertension and moderate CRF before and 5, 40, 80, and 120 minutes after the injection of quinaprilat (10 mg intravenously). Effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) were measured simultaneously by para-aminohippuric acid (PAH-ERPF) and inulin clearances before and 20, 60, 100, and 140 minutes after quinaprilat injection. Results: Baseline RBF and ERPF were decreased in all patients (221 ± 20 mL/min/100 g and 225 ± 38 mL/min/1.73 m2, respectively). PET-RBF increased significantly after quinaprilat injection (+15%, +26%, +19%, and +23% versus baseline; P < 0.003). PAH-ERPF did not increase significantly (−6%, +12%, +20%, and +15% versus baseline; P = 0.15). GFR (50.1 ± 8.9 mL/min/1.73 m2 at baseline) did not change significantly after quinaprilat injection; however, filtration fraction (GFR-ERPF ratio) decreased significantly from 0.23% ± 0.02% to 0.20% ± 0.02% (P = 0.0004). Mean arterial pressure decreased significantly after quinaprilat injection (P < 0.005). Conclusion: This study dynamically measured RBF by means of PET in patients with CRF for the first time. It showed that RBF rapidly increased after quinaprilat injection. PET using H215O is a powerful method for the noninvasive measurement of dynamic changes in RBF that remain undetected by PAH clearance. Am J Kidney Dis 40:947-954. © 2002 by the National Kidney Foundation, Inc.

A trial to assess the clinical mechanistics of aspirin in healthy volunteers

The aim of this study was to assess the pharmacological effects of aspirin on prostanoid biosynthesis — as measured by plasma thromboxane B2 (TXB2) and prostaglandin E2 (PGE2) concentrations — and two physiological functions thought to be mediated via prostanoids, namely gastrointestinal mucosal integrity — as measured by faecal porphyrins — and renal blood flow — as measured by para-aminohippuric acid (PAH) and creatinine clearance. The trial was a randomized, double-blind, placebo-controlled crossover design, with each volunteer taking 750 mg aspirin (British Pharmacopoeia) or placebo, three times a day for 5 days, with an 18-day washout period between treatments. Faecal porphyrins were measured before the first dose and on days 2 to 5 inclusive of each dosing period; plasma TXB2 and PGE2 concentrations were measured before dosing and 0.5 hours after the final dose on day 5 of each of the dosing periods; PAH clearance was measured before dosing and at 90, 120 and 150 min after the start of the infusion of PAH on day 1 and day 5 of each dosing period; creatinine clearance was measured before dosing and prior to the final dose on day 5 of each dosing period.

The adverse renal effects of prostaglandin-synthesis inhibition in the fetus and the newborn

To summarize experimental animal data and to provide a limited literature review on the adverse renal effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the developing fetus and the maturing newborn. The experimental data were obtained from anesthetized, ventilated, six- to eight-day-old rabbits that received an intravenous bolus of either acetylsalicylic acid (ASA), ibuprofen (IBU) or indomethacin (INDO). In one set of experiments, ASA was also tested in 12-week-old (young adult) rabbits. Renal function was monitored with inulin and para-aminohippuric acid clearances measuring glomerular filtration rate (GFR) and renal blood flow. The renal vascular resistance was calculated. All three nonspecific cyclo-oxygenase-1 or -2 (COX-1/2) inhibitors caused remarkably similar reversible, oliguric, acute renal failure (ARF). In young adult animals, the side effects were attenuated. The underlying pathophysiology is related to the carefully maintained low GFR of the fetus and the newborn, dependent on a delicate interplay between vasoconstriction (angiotensin II) and vasodilation (prostaglandins [PGs]). When PG-synthesis is inhibited, the vasoconstriction is relatively unopposed, causing ARF. The renal effects of fetal exposure to NSAIDs are discussed, as are new insights into the role of COX-1/2 for a normal nephrogenesis. COX-nil or COX-inhibited animals have long lasting renal structural injury. Fetuses exposed in utero to significant amounts of NSAIDs have at birth various degrees of renal insufficiency and structural renal defects with a very high mortality. All NSAIDs, both specific and nonspecific COX inhibitors, have renal side effects in the immediate post-natal period and should, therefore, be given with the utmost caution. NSAIDs given during pregnancy for the prevention of toxemia, polyhydramnios and premature labour may affect fetal renal function and structure. In animal experiments, IBU was not less nephrotoxic than INDO, as suggested recently by human premature neonates.

The effects of losartan on renal function in the newborn rabbit.

The low GFR of newborns is maintained by various factors including the renin-angiotensin system. We previously established the importance of angiotensin II in the newborn kidney, using the angiotensin-converting enzyme inhibitor perindoprilat. The present study was designed to complement these observations by evaluating the role of angiotensin-type 1 (AT(1)) receptors, using losartan, a specific AT(1)-receptor blocker. Increasing doses of losartan were infused into anesthetized, ventilated, newborn rabbits. Renal function and hemodynamic variables were assessed using inulin and para-aminohippuric acid clearances as markers of GFR and renal plasma flow, respectively. Losartan 0.1 mg/kg slightly decreased mean blood pressure (-11%) and increased diuresis (+22%). These changes can be explained by inhibition of the AT(1)-mediated vasoconstrictive and antidiuretic effects of angiotensin, and activation of vasodilating and diuretic AT(2) receptors widely expressed in the neonatal period. GFR and renal blood flow were not modified. Losartan 0.3 mg/kg decreased mean blood pressure significantly (-15%), probably by inhibiting systemic AT(1) receptors. GFR significantly decreased (-25%), whereas renal blood flow remained stable. The decrease in filtration fraction (-21%) indicates predominant efferent vasodilation. At 3 mg/kg, the systemic hypotensive effect of losartan was marked (mean blood pressure, -28%), with decreased GFR and renal blood flow (-57% and -51%, respectively), a stable filtration fraction, and an increase in renal vascular resistance by 124%. The renal response to this dose can be considered as reflex vasoconstriction of afferent and efferent arterioles, rather than specific receptor antagonism. We conclude that under physiologic conditions, the renin-angiotensin is critically involved in the maintenance of GFR in the immature kidney.

Podocytopenia and disease severity in IgA nephropathy

IgA nephropathy is a common form of progressive glomerular disease, associated with proliferation of mesangial cells and mesangial deposition of IgA. The present study was designed to investigate functional and morphological covariates of disease severity in patients with IgA nephropathy. Glomerular hemodynamics, permselectivity and ultrastructure were studied in 17 adult patients with IgA nephropathy using inulin, para-aminohippuric acid (PAH) and 3H-Ficoll clearances and morphometric methods. A mathematical model of macromolecule permeation through a heteroporous membrane was used to characterize glomerular permselectivity. Controls consisted of 14 healthy living kidney donors and 12 healthy volunteers. The patients were heterogeneous in their disease severity, but as a group had a decreased glomerular filtration rate (GFR) and increased urinary protein excretion compared to controls [63 +/- 29 SD vs. 104 +/- 23 mL/min/1.73 m2, P < 0.001, and (median) 1.34 vs. 0.11 g/day, P < 0.0001, respectively). A multivariate analysis of structural and functional relationships revealed GFR depression to be most strongly correlated with the prevalence of global glomerular sclerosis (t = -4.073, P = 0.002). Those patients with the most severe glomerular dysfunction had a reduced number of glomerular visceral epithelial cells (podocytes) per glomerulus. The degree of podocytopenia was related to the extent of glomerular sclerosis and of impairment of permselectivity and GFR, with worsening injury below an apparent threshold podocyte number of about 250 cells per glomerulus. There were no corresponding correlations between these indices of injury and the number of mesangial and endothelial cells. Our findings show that podocyte loss is a concomitant of increasing disease severity in IgA nephropathy. This suggests that podocyte loss may either cause or contribute to the progressive proteinuria, glomerular sclerosis and filtration failure seen in this disorder.

Sodium and water homeostasis in children with shigellosis.

Studies in Bangladesh have shown that the mortality in shigellosis is significantly higher in hyponatraemic (HN) than in normo- (NN) or hypernatraemic children. The aim of this study was to describe the effect of shigellosis on renal haemodynamics and sodium and water homeostasis before treatment was started. Twenty-one moderately ill children infected with Shigella dysenteriae type I were studied. Eight of them had a serum sodium concentration below 130 mmol/L. Renal function was determined by glomerular filtration rate measured by clearances of inulin and iohexol. Effective renal plasma flow was estimated by clearance of para-aminohippuric acid. Plasma renin, aldosterone and anti-diuretic hormone were also studied. The HN children had significantly higher haemoglobin and haematocrit levels than the NN group. There was an inverse correlation between serum sodium and haemoglobin, and a direct correlation between serum sodium and urinary sodium and urinary chloride. Direct correlations were found between serum aldosterone and haemoglobin, plasma renin and systolic blood pressure and an inverse correlation between serum aldosterone and serum sodium. Clearances of inulin and iohexol were normal. Detectable levels of ADH were found in both groups, despite low serum osmolalities. The HN state seems to be triggered by multiple factors. The normal glomerular filtration rate excludes a volume expansion secondary to reduced renal function. Inappropriate or a physiological increase of anti-diuretic hormone secretion may be of importance. The higher sodium losses in stools of the HN children might also be a factor contributing to the HN.

Sodium and water homeostasis in children with shigellosis

Studies in Bangladesh have shown that the mortality in shigellosis is significantly higher in hyponatraemic (HN) than in normo‐ (NN) or hypernatraemic children. The aim of this study was to describe the effect of shigellosis on renal haemodynamics and sodium and water homeostasis before treatment was started. Twenty‐one moderately ill children infected with Shigella dysenteriae type 1 were studied. Eight of them had a serum sodium concentration below 130 mmol/L. Renal function was determined by glomerular filtration rate measured by clearances of inulin and iohexol. Effective renal plasma flow was estimated by clearance of para‐aminohippuric acid. Plasma renin, aldosterone and anti‐diuretic hormone were also studied. The HN children had significantly higher haemoglobin and haematocrit levels than the NN group. There was an inverse correlation between serum sodium and haemoglobin, and a direct correlation between serum sodium and urinary sodium and urinary chloride. Direct correlations were found between serum aldosterone and haemoglobin, plasma renin and systolic blood pressure and an inverse correlation between serum aldosterone and serum sodium. Clearances of inulin and iohexol were normal. Detectable levels of ADH were found in both groups, despite low serum osmolalities. Conclusion: The HN state seems to be triggered by multiple factors. The normal glomerular filtration rate excludes a volume expansion secondary to reduced renal function. Inappropriate or a physiological increase of anti‐diuretic hormone secretion may be of importance. The higher sodium losses in stools of the HN children might also be a factor contributing to the HN.

Erythropoietin enhances recovery after cisplatin‐induced acute renal failure in the rat

Erythropoietin (Epo) is a growth factor whose synthesis mainly takes place in the kidney. Epo has been shown to support the growth not only of erythroid progenitor cells but also of certain other cell types. We attempted to establish whether Epo enhances the recovery from acute renal failure induced by cisplatin. Sprague-Dawley rats were randomized into three groups. In the cisplatin group, animals received one intraperitoneal injection of cisplatin (6 mg/kg) and a daily injection of placebo for 9 days. In the cisplatin+Epo group, animals received intrapertoneal cisplatin and a daily injection of Epo (100 IU/kg) for 9 days. In the control group, animals received both placebo preparations alone. Para-aminohippuric acid and inulin clearances were determined after 4 and 9 days to evaluate renal blood flow and glomerular filtration rate. In addition, light microscopy and immunohistochemistry examinations were performed, and in situ proliferating cell nuclear antigen (PCNA) staining was done to estimate the degree of renal tubular cell regenerative activity. The potential role of epithelial growth factor (EGF) was evaluated by semi-quantitative assessment of EGF immunostaining. Renal blood flow and glomerular filtration rate decreased significantly in cisplatin and cisplatin+Epo groups versus control group at day 4. However, at day 9, they both were significantly greater in cisplatin+Epo-treated animals than in rats that had received cisplatin alone. Tubular cell regeneration was significantly enhanced at day 4 in cisplatin+Epo group, compared with cisplatin and control groups respectively. EGF immunostaining was not significantly different between the three groups. Epo significantly enhanced the rate of recovery from acute renal failure induced by cisplatin. PCNA staining indicated that Epo might act directly via stimulation of tubular cell regeneration.

Effect of 6 weeks of vitamin E administration on renal haemodynamic alterations following a single dose of neoral in healthy volunteers.

A single oral dose of cyclosporin-A (CsA) transiently reduces renal plasma flow (RPF) and glomerular filtration rate (GFR) in transplant patients and, in some patients, chronic administration of CsA leads to renal impairment and fibrosis. Based on experimental studies, several mediators including free radicals have been proposed to account for CsA-nephrotoxicity. We have previously reported that administration of the antioxidant vitamin E in a rat model of chronic CsA-nephrotoxicity reduces renal fibrosis and maintains renal function. In the present study, the effect on renal haemodynamics of a single dose of the new oral formulation of CsA (neoral) was assessed before and after 6 weeks of vitamin E (800 IU/day, 2-fold increase in serum vitamin E). GFR (inulin clearance) and RPF (para-amino hippuric acid clearance) were measured before and after a single dose of 5 mg/kg of neoral in 12 healthy subjects under standardised conditions. Although the mean area under the curve of the CsA levels was 21% lower after the vitamin E period, the peak CsA level at 120 min after neoral was similar both before and after vitamin E administration. At 120 min after neoral, a transient reduction in RPF and GFR was noted both before and after vitamin E administration. The nadir of the reductions in RPF (-81 +/-27 ml/min) and GFR (-14 +/- 6 ml/min) at 120 min compared with baseline tended to be lower before than after the treatment with vitamin E (-51 +/- 33 ml/min of RPF and -12 +/- 8, ml/min of GFR, respectively). Plasma and urine levels of F2-isoprostanes (free radical-catalysed vasoconstrictive prostanoids (F2-iso) at 120 min after the administration of neoral were not different from the pre-neoral levels. The findings demonstrate that a single oral dose of neoral causes transient, yet significant, reductions in RPF and GFR, and suggest that F2-iso might not be involved in the CsA-induced acute renal vasoconstriction. The tendency for a lower reduction in RPF and GFR following CsA during the vitamin E period in healthy humans warrants additional studies in transplant patients.

Mild to severe lithium-induced nephropathy models and urine N-acetyl-beta-D-glucosaminidase in rats.

Long-term treatment with lithium induces functional and/or structural disturbances in the kidneys. However, no procedure has been established for the early diagnosis of lithium intoxication. In this study, we prepared mild to severe lithium-induced nephropathy rat models and examined the usefulness of urine N-acetyl-beta-D-glucosaminidase (NAG) for the early diagnosis of lithium-induced renal insufficiency. Lithium was administered by repeated intraperitoneal injection (1, 2 and 4 mEq/kg/day for 10 days). We also measured the plasma creatinine and paraaminohippuric acid (PAH) clearance, and observed renal histological changes. Lithium pretreatment elevated the plasma creatinine level and decreased PAH clearance in a dose-dependent manner. The NAG level in the lithium 4 mEq/kg group was very high. The levels in the lithium 1 mEq/kg and 2 mEq/kg groups were almost the same and were higher than the control group. A histological examination of the kidney revealed glomerular congestion and/or atrophy and tubular expansion in all of the groups except the control group. These histological changes were dose-dependent. In conclusion, urine NAG may be useful in the early diagnosis of renal side effects caused by lithium therapy. When the urine NAG level becomes high in a patient taking lithium for bipolar disorder, the physician may need to consider lithium-induced renal insufficiency.

Effect of Antioxidants on Salt-Induced Hypertension and Renal Dysfunction.

43 We have demonstrated that the development of salt-dependent hypertension and renal dysfunction in the Dahl salt-sensitive (DSS) rat is accompanied by the accumulation of reactive oxygen species (ROS). To determine whether oxidative stress contributes to the development of progressive renal dysfunction, we examined the effect of dietary vitamin E, a natural antioxidant, on a model of salt-dependent hypertension. Dahl salt-resistant (DSR) and DSS rats were kept on 8% NaCl (HS) or 8% NaCl + 1000 U./kg chow of vitamin E (HSE) for 2 weeks. During this time blood pressure was monitored using the tail plethismography method. After 14 days on the diets, DSS rats on HS diet were hypertensive, as compared to the DSR rats (171.3 ± 7.4 vs. 138.4 ± 2.4 mmHg; p&lt;0.0001), whereas the animals on the HSE diet remained normotensive (125.1 ± 3.7 vs. 114.0 ± 5.4 mmHg). The animals were then instrumented for the evaluation of renal function, measured as clearance of para-aminohippuric acid (Cl PAH ) and clearance of inulin (Cl In ). As a measure of oxidative stress, kidney and blood samples were harvested for the determination of superoxide production and plasma 8-isoprostanes (8-IP), respectively. Results show that hypertensive DSS rats appear to have lower Cl PAH and Cl In , greater renal superoxide production, and greater plasma 8-IP concentration than the normotensive DSR rats (Cl PAH : 1.93 ± 0.15 vs. 4.11 ± 0.5 ml/min, p&lt;0.005; Cl In : 1.21 ± 0.19 vs. 2.05 ± 0.60 ml/min., p&lt;0.01; O - 2 : 664 ± 33 vs. 374 ± 13 nmol/mg protein/min, p&lt;0.05; and 8-IP: 1494.3 ± 93.4 vs. 386.6 ± 30.0 pM, p&lt;0.001). However, when DSR and DSS rats were kept on the HSE diet, no differences were observed (Cl PAH : 3.31 ± 0.34 vs. 3.29 ± 0.45 ml/min; Cl In : 1.89 ± 0.16 vs. 2.03 ± 0.08 ml/min.; O - 2 : 372 ± 10 vs. 344 ± 23 nmol/mg protein/min; and 8-IP: 276.1 ± 33.2 vs. 278.5 ± 28.3 pM). These results suggest that the incremental production of ROS during salt feeding in DSS rats plays a role in the development of hypertension and renal dysfunction in this model, and that the lipid-soluble antioxidant vitamin E can attenuate the production of ROS and prevent salt-induced hypertension and renal dysfunction.

Renal function of children exposed to cyclosporin in utero.

The use of cyclosporin (CsA) has improved graft survival in transplant (Tx) patients despite its potential nephrotoxicity. Children born to transplanted women may present with intrauterine growth retardation (IUGR). On the basis of potential reduced nephron mass both in IUGR and in newborn experimental animals exposed to CsA in utero, we investigated the renal function of children >1 year of age born to women under maintenance immunosuppression, including CsA. Fourteen children born to 12 Tx women (nine kidney, one pancreas-kidney, one heart, one liver) were investigated using inulin clearance (C(in)), para-aminohippuric acid clearance (C(PAH)), microalbuminuria, and electrolyte reabsorption rate. Gestational age of the 14 infants was 34+/-3 weeks and birth weight 2018+/-620 g. During pregnancy, CsA trough blood level was 234+/-115 microg/l and plasma creatinine range was 96-136 micromol/l. Two children were excluded from the study because renal investigation led to a diagnosis of hereditary nephritis (one Alport syndrome, one familial dominant focal segmental glomerulosclerosis) that was retrospectively completed in the mother. Renal function tests were finally performed in 12 children at 2.6+/-1.8 years of age: BP 94+/-7/55+/-5 mmHg, C(in) 117+/-28 ml/min/1.73 m(2), C(PAH) 545+/-124 ml/min/1.73 m(2), filtration fraction 0.23+/-0.03, microalbuminuria 4.2+/-3.5 mg/mmol. Electrolyte tubular reabsorption rates and urine concentrating capacity were normal. These results suggest that in children born to transplanted women taking CsA, renal function develops normally despite prolonged exposure in utero.

Endothelin antagonists in renal disease

and a beta blocker was added to the antihypertensive therapy. Approximately six months after surgery, the serum creatinine was 1.0 mg/dL, and proteinuria was virtually absent (0.12 g/day). The patient did well until one month before admission; the serum creatinine then rose slowly from 1.2 mg/dL to 2.0 mg/dL. On admission to the hospital, her blood pressure was 110/80 mm Hg; the renal graft was neither swollen nor tender. The CsA level was 169 ng/mL and her serum creatinine concentration was 2.1 mg/dL. Renal function, estimated by the plasma clearance of nonradiolabeled iohexol, was 49 mL/min/1.73 m; renal plasma flow, measured by the renal clearance of paraaminohippuric acid, was 208 mL/min/1.73 m. A percutaneous renal biopsy disclosed normal glomeruli and arterioles. Focal isometric vacuolization of proximal tubules was observed. Prominent tubular atrophy and striped interstiCASE PRESENTATION tial fibrosis were present. Mild focal collection of mononuclear A 43-year-old woman was admitted to the Ospedali Riuniti cells in the interstitium also was documented. Intense staining for endothelin-1 (ET-1) mRNA by in situ hybridization was Bergamo for a renal biopsy to evaluate a rising serum creatinine found in tubules but not in glomeruli, which were essentially 14 months after receiving a cadaveric renal allograft at the same negative for the ET-1 mRNA signal. High-intensity signal for institution. The patient initially had developed renal failure ET-1 mRNA was mainly observed in the epithelial cells of due to chronic glomerulonephritis (proliferative extracapillary tubules located in areas of interstitial fibrosis. Staining for glomerulonephritis) and hypertension, which required chronic MCP-1 mRNA also was selectively localized in tubules. In hemodialysis beginning 10 years ago. After receiving a kidney addition, the tubules stained markedly for RANTES mRNA, transplant 7 years ago, she received immunosuppressive treatwhich was also detected minimally in glomeruli. ment with cyclosporine (Sandimmune), azathioprine, and prednisone. The renal allograft functioned well initially; the serum creatiDISCUSSION nine concentration fell to 1.2 mg/dL on day 4 but rose to 2.1 mg/dL on day 22. The blood cyclosporine (CsA) level was 323 Dr. Ariela Benigni (Head, Department of Molecular ng/mL. A clinical diagnosis of acute graft rejection prompted Medicine, Mario Negri Institute for Pharmacological Rethe initiation of methylprednisolone pulse therapy. Her renal search, Bergamo, Italy): In the last 20 years, it has become function gradually recovered; beginning on the 34 postoperaclear that the endothelium participates directly in regutive day, the serum creatinine level stabilized at a baseline of lating vascular tone through the release of a wide variety 1.0 mg/dL to 1.2 mg/dL over the next 13 months. A CsA of vasoactive substances. The discovery of prostacyclin pharmacokinetic profile performed on day 32 documented an area-under-the-blood concentration-time curve (AUC) of 9722 in 1976 [1] was followed in 1980 by evidence that the ng/mL/h, a blood CsA trough level of 357 ng/mL, and a peak endothelium regulates vascular smooth muscle tone by blood CsA concentration of 1897 ng/mL (one hour after doselaborating potent endothelium-dependent vasodilators ing). Along with immunosuppressants given from the immedi[2]. Rubanyi and Vanhoutte reported in 1985 that hypate post-transplant period, a calcium-channel blocker also was oxia induces release of a diffusible vasoconstrictor subadministered to control blood pressure. Two months after stance from endothelial cells independent of prostaglandin transplantation, her blood pressure still was not well controlled, synthesis [3]. But it was not until 1988 that Yanagisawa and coworkers isolated from porcine aortic endothelial The Nephrology Forum is funded in part by grants from Amgen, cells an extremely potent vasoconstrictor that they idenIncorporated; Merck & Co., Incorporated; AstraZeneca LP; Dialysis tified as endothelin-1 (ET-1) [4]. Clinic, Incorporated; and R & D Laboratories.

Increased renal glomerular endothelin-1 release in gentamicin-induced nephrotoxicity.

Gentamicin-induced acute renal failure is characterized by a decrease in renal plasma flow and creatinine clearance. Endothelins (ET) are potent renal vasoconstrictors. The aim of this work is to assess the role of ET-1 in gentamicin-induced renal failure. Renal glomerular release of ET-1 was measured in rats with gentamicin-induced nephrotoxicity (100 mg/kg/day, s.c. for 2, 4 or 6 days). Glomeruli were isolated and incubated for 24 h in RPMI-1640. Glomerular supernatant and plasma concentration of ET-1 were measured by RIA. Renal failure was assessed by insulin, para-aminohippuric and creatinine clearance and histological studies. Gentamicin induced a dose number-dependent increase in plasma creatinine and a decrease in creatinine clearance. This was accompanied by a marked decrease in inulin and para-aminohippuric acid clearance, as well as by a marked tubular necrosis, without alterations in glomerular structures. Plasma ET-1 concentration and glomerular ET-1 release were also increased in gentamicin-treated rats. When 10-5 M gentamicin was added to control glomeruli, ET-1 production was not modified (36.4 +/- 2.2 vs. 35.2 +/- 1.7 pg/ml/24 h). All these results suggest that elevated ET-1 plasma levels and increased glomerular release of ET-1 could mediate, at least in part, the decrease in glomerular filtration rate observed in gentamicin-induced ARF.

Blood flow to the avian kidney: The use of transit‐time ultrasonic flow probes

A simplified model was used to assess blood flow to the kidney of the anaesthetised domestic fowl. The left kidney was intact and the right kidney consisted of the caudal division with associated vasculature. Transonic perivascular flow probes were placed around the right proximal ischiadic artery and renal vein. Snares around the caudal renal portal vein, common iliac vein and proximal ischiadic artery of the right kidney allowed manipulation of arterial and portal blood flow. Reduction of the pressure in the right renal artery to 50 mm Hg decreased right kidney arterial plasma flow and glomerular filtration rate (GFR). The plasma flow in the right renal vein and the clearance of para-aminohippuric acid by the right kidney remained unchanged. The true filtration fraction of the right kidney, determined from the ratio of GFR to the arterial flow increased slightly. Portal plasma flow and arterial plasma flow contributed 57% and 43%, respectively, to total renal plasma flow during normal arterial and portal flow. J. Exp. Zool. 284:15–22, 1999. © 1999 Wiley-Liss, Inc.

Blood flow to the avian kidney: The use of transit-time ultrasonic flow probes

A simplified model was used to assess blood flow to the kidney of the anaesthetised domestic fowl. The left kidney was intact and the right kidney consisted of the caudal division with associated vasculature. Transonic perivascular flow probes were placed around the right proximal ischiadic artery and renal vein. Snares around the caudal renal portal vein, common iliac vein and proximal ischiadic artery of the right kidney allowed manipulation of arterial and portal blood flow. Reduction of the pressure in the right renal artery to 50 mm Hg decreased right kidney arterial plasma flow and glomerular filtration rate (GFR). The plasma flow in the right renal vein and the clearance of para-aminohippuric acid by the right kidney remained unchanged. The true filtration fraction of the right kidney, determined from the ratio of GFR to the arterial flow increased slightly. Portal plasma flow and arterial plasma flow contributed 57% and 43%, respectively, to total renal plasma flow during normal arterial and portal flow. J. Exp. Zool. 284:15–22, 1999. © 1999 Wiley-Liss, Inc.