PAH Clearance Research Articles

Urineless estimation of glomerular filtration rate and renal plasma flow in the rat

A simple method to perform serial renal clearance studies without urine collection in rats is described. This was applied to nonradiolabelled para-aminohippurate sodium (PAH) and iothalamate sodium (IOT) which were used respectively to estimate renal plasma flow (RPF) and glomerular filtration rate (GFR). Under isoflurane-anesthesia the jugular vein and carotid artery of Fischer 344 rats were cannulated, and a loading dose followed by a continuous infusion of PAH and IOT was administered. Steady state was reached after 30 min, and four arterial blood samples were collected over the next 30 min for analysis by HPLC (day 0). The clearances of PAH and IOT were calculated according to Fick's principle as estimates of RPF and GFR from the ratio of the infusion rates to the median solute concentrations. Three days later the femoral artery and vein were cannulated, and the same study was repeated (day 3). There was no significant difference in renal clearances of PAH and IOT between days 0 and 3. The described method gives values that compare well with others in the literature based on other methods and presents an accurate and simple way of detecting changes in renal function before and after a potentially nephrotoxic treatment regimen.

Effects of Extracorporeal Shock Wave Lithotripsy to One Kidney on Bilateral Glomerular Filtration Rate and PAH Clearance in Minipigs

Purpose This study examined the acute time course of effects of extracorporeal shock wave lithotripsy (ESWL) 1 1 Dornier Medical Systems, Marietta, Georgia. on renal hemodynamics in anesthetized minipigs with and without pretreatment with verapamil. Materials and Methods We applied ESWL (2000 shocks, 24 kV, unmodified Dornier HM3), to the right kidneys of isoflurane-anesthetized female pigs. Urine flow and renal hemodynamics were monitored from each kidney via ureteral balloon catheters. Arterial blood pressure and bilateral urine flow, glomerular filtration rate (GFR, inulin clearance) and renal plasma flow (RPF, para-aminohippurate clearance) were monitored for 45 minutes before ESWL, and at 1, 4 and 24 hours after ESWL. Results Treatment with ESWL consistently caused unilateral hematuria and subcapsular renal hematomas in the shocked kidneys and significantly reduced GFR and RPF in those kidneys at 1 and 4 hours after ESWL. Urine flow was reduced through 24 hours in the shocked kidneys. Renal plasma flow, but not GFR, was significantly reduced in the contralateral (unshocked) kidneys at 1 and 4 hours after ESWL to the other kidneys. Verapamil blunted the ESWL-induced reductions of urine flow, GFR and RPF in the shocked kidneys and eliminated the reduction of RPF in the unshocked kidneys. Conclusions These experiments demonstrate that ESWL to 1 kidney acutely impaired hemodynamics in both kidneys and that verapamil attenuated the response in the shocked kidneys and eliminated it in the contralateral unshocked kidneys.

Effects of Extracorporeal Shock Wave Lithotripsy to One Kidney on Bilateral Glomerular Filtration Rate and PAH Clearance in Minipigs

Effects of Extracorporeal Shock Wave Lithotripsy to One Kidney on Bilateral Glomerular Filtration Rate and PAH Clearance in Minipigs

Effects of atrial natriuretic peptide on acute renal impairment in patients with heart failure after cardiac surgery

To investigate the effects of IV infusion of atrial natriuretic peptide (human ANP 1-28) on renal function in patients with acute heart failure and renal impairment after cardiac surgery. Pharmocodynamic dose-effect investigation. Cardiothoracic Intensive Care Unit of a university hospital. Twelve patients (mean age 68 years, range 44-78 years) treated with inotropic drugs and an intra-aortic balloon pump (n = 8) were studied 1-3 days after cardiac surgery. Patients had acute renal impairment, defined as a rise in serum creatinine of more than 50% compared to preoperative values. Patients were receiving dopamine and furosemide infusion to increase urine flow. Baseline measurements of glomerular filtration rate (GFR) and renal blood flow (51Cr-EDTA and PAH clearance) were first performed during two 30-min periods. ANP was then administered for two consecutive 30-min periods (25 and 50 ng/kg per min), followed by two control periods. Mean arterial pressure decreased by 6% at the highest ANP dose. Urine flow, GFR and RBF increased 62%, 43% and 38%, respectively, while renal vascular resistance decreased 30%. At this dose level, circulating ANP concentrations were on the average eight fold higher than preinfusion levels. ANP improved renal function and decreased elevated renal vascular resistance in patients with renal dysfunction after cardiac surgery. The improvement in renal blood flow and glomerular filtration rate may be of potential therapeutic value to prevent or treat exaggerated renal vasoconstriction in patients with acute renal impairment following cardiac surgery.

Mechanisms of hyperuricemia in cyclosporine-treated renal transplanted children.

Mechanisms of hyperuricemia were investigated in 19 pediatric renal transplant recipients 6 months after transplantation. 51Cr-EDTA, PAH, lithium and sodium clearances, 24-hour urinary creatinine and urate excretions were measured. Ten patients had hyperuricemia. The hyperuricemic patients had lower EDTA, PAH, and urate clearances (mean 69.5 vs. 92.5, p < 0.05, 234 vs. 421, p < 0.05 and 4.3 vs. 10.6 ml/min/1.73 m2, p < 0.001, respectively). Serum urate concentration correlated with cyclosporine dose (r = 0.46, p < 0.05) and inversely with urate (r = -0.88, p < 0.001), and lithium (r = -0.55, p < 0.05) clearances. Urate clearance showed a significant positive correlation with lithium clearance (r = 0.66, p = 0.01) and an inverse correlation with fractional proximal tubular reabsorption (r = -0.63, p = 0.02). Results were not influenced by diuretic administration. Our data support increased proximal tubular urate reabsorption rather than decreased secretion as the mechanism in cyclosporine-induced hyperuricemia.

MR Velocity Mapping Measurement of Renal Artery Blood Flow in Patients with Impaired Kidney Function

Renal blood flow (RBF) was measured in 9 patients with chronic impaired kidney function using MR velocity mapping and compared to PAH clearance and 99mTc-DTPA scintigraphy. An image plane suitable for flow measurement perpendicular to the renal arteries was chosen from 2-dimensional MR angiography. MR velocity mapping was performed in both renal arteries using an ECG-triggered gradient echo pulse sequence previously validated in normal volunteers. Effective renal plasma flow was calculated from the clearance rate of PAH during constant infusion and the split of renal function was evaluated by 99mTc-DTPA scintigraphy. A reduction of RBF was found, and there was a significant correlation between PAH clearance multiplied by 1/(1-hematocrit) and RBF determined by MR velocity mapping. Furthermore, a significant correlation between the distribution of renal function and the percent distribution of RBF was found.

Stimulatory effect of insulin on tubular sodium reabsorption in normotensive subjects with a positive family history of hypertension

Insulin resistance and hyperinsulinaemia has been suggested as a pathogenetic mechanism in hypertension. In this investigation the renal response to insulin was studied in normotensive subjects with a positive family history of hypertension in two generations (n = 14), in one weight-matched (n = 11) and one lean (n = 13) control group. During hyperinsulinaemia (euglycaemic hyperinsulinaemic clamp technique) we determined renal haemodynamics (clearances of 51Cr-EDTA and PAH) and urinary sodium excretion. Lithium clearance was used to estimate the segmental tubular reabsorption of sodium. In subjects with a positive family history of hypertension, hyperinsulinaemia did not influence renal plasma flow (RPF) or glomerular filtration rate (GFR) but urinary sodium excretion decreased by 50%. Estimated proximal tubular sodium reabsorption was unaffected by insulin while estimated distal fractional sodium reabsorption increased, P < 0.01. At the end of the clamp a low-dose infusion of angiotensin II (0.1 ng/kg per min) was superimposed. GFR and RPF then decreased significantly concomitant with urinary excretion of sodium. In control subjects hyperinsulinaemia caused an unchanged GFR in both groups, increased RPF in the lean control group and 15-25% reduction in sodium excretion. No alteration was seen in estimated proximal tubular sodium reabsorption, but estimated distal tubular sodium reabsorption increased (P < 0.05) in the lean control group. Angiotensin II elicited a further increase in distal fractional tubular sodium reabsorption in both groups (P < 0.05). In normotensive subjects with a positive family history of hypertension, in contrast to control subjects without such history, hyperinsulinaemia caused a marked decrease in urinary sodium excretion in presence of unchanged RPF and GFR indicating a renal tubular effect of insulin located at distal site of the renal tubules. Angiotensin II caused further sodium retention, probably due to an effect on renal haemodynamics.

Kidney size is a determinant of structural/functional injury following shock wave treatment of pigs

It has been suggested that kidney size is a risk factor for increased shock wave lithotripsy- (SWL) induced damage. This relationship was investigated in pigs of two different ages; ten weeks of age (group 1) and five weeks of age (group 2). Each pig received 2000 shocks, 24 kV to the right kidney. Glomerular filtration rate (GFR), PAH clearance and extraction were measured 1 h before and 1 and 4 h after SWL treatment. The kidneys were harvested at the end of the clearance study. Values for GFR, PAH clearance, and extraction were reduced in the shocked kidney of both groups 1 h post-SWL. Calculated values for true renal plasma flow showed a greater reduction in the treated kidneys of group 2 versus group 1. The degree of subcapsular hemorrhage and intraparenchymal bleeding and tubular disruption was more extensive in group 2 versus group 1 treated kidneys. The data document the degree of structural and functional injury induced by SWL and support the hypothesis that the effect of SWL is greatest in kidneys having the least mass. [Work supported by NIH Grant No. P01 DK 43881.]

Antioxidants Attenuate Endotoxin-Gentamicin Induced Acute Renal Failure in Rats

The synergistic mechanism by which endotoxin enhances the nephrotoxic potential of gentamicin is unknown. In this study, we attempted to shed light on this mechanism by injecting rats with endotoxin plus gentamicin. Renal injury was assessed by measuring creatinine, inulin and PAH clearance, NADH levels and electrolyte reabsorption, for 24 hr following this injection. Gentamicin alone (20 mg/100 g) induced no renal injury, while endotoxin without gentamicin (0.075 mg/100 g) induced mild injury. However, endotoxin plus gentamicin resulted in acute renal failure. In an attempt to halt the progressive renal dysfunction, the antioxidants NAO (5 mg/100 g), Vitamin E (0.2 mg/100 g per day) and dimethylthiourea (DMTU-50 mg/100 g) were administered, or early endotoxin tolerance was induced before injecting the rats with endotoxin plus gentamicin. The reduction in renal function was markedly slower in rats administered with antioxidants compared with untreated rats. Similar results were obtained with endotoxin tolerance. These data suggest that NAO, vitamin E, DMTU and endotoxin tolerance are potentially beneficial in arresting progressive renal damage associated with endotoxin plus gentamicin.

Ibopamine in Patients with Congestive Heart Failure and Different Degrees of Renal Function.

Following a 1-week placebo run-in phase, 20 patients with congestive heart failure (New York Heart Association class II) were treated orally for 7 days with 100 mg ibopamine t. i. d. Ten subjects had a normal renal function, whereas 10 patients suffered from chronic renal insufficiency (mean creatinine clearance 36 plus minus 3.9 ml min(minus sign1)). Ibopamine significantly increased stroke volume and cardiac output, but only 45 and 90 min after administration. After 7 days of ibopamine treatment, urine output rose significantly in both patient groups by about 400--500 ml per 24 h. The glomerular filtration rate (inulin clearance) and urine osmolality remained nearly unchanged, whereas renal plasma flow (PAH clearance) increased on ibopamine administration. Urinary sodium and potassium excretion were slightly but insignificantly elevated. Pharmacokinetic parameters of ibopamine were unaltered in impaired renal function, both on the first and seventh treatment day. Maximum plasma levels of the active metabolite epinine were achieved after 45 min and were higher on the first as compared with the seventh treatment day in both groups. In conclusion, ibopamine caused a relevant increase in stroke volume and cardiac output associated with a rise in renal perfusion and urine output in patients with normal and with impaired renal function. Ibopamine is an orally active derivative of dopamine and is used for treatment of patients with congestive heart failure, who frequently have an impaired renal function. Therefore, in the present study, the hemodynamic effects and kinetic behavior of ibopamine should be investigated in patients with different degrees of renal function.

AN IMPROVED GLOMERULAR FILTRATION RATE IN CARDIAC TRANSPLANT RECIPIENTS WITH ONCE-A-DAY CYCLOSPORINE DOSING1,2

We tested the hypothesis that there would be a difference in the unwanted side effects of cyclosporine (CsA) when heart transplant patients received CsA once a day versus half the dose twice a day. Eight stable cardiac transplant patients (>6 months posttransplant) were administered their dose of CsA either as a once-a-day dose or half the dose b.i.d. for 21 days in a random fashion. After 21 days the patients were crossed over to the other regimen. Patients underwent inulin and PAH clearances at CsA trough on each arm of the study. Each patient collected several 24-hr urines for determination of creatinine clearance, and had ambulatory blood pressure monitoring done during each arm of the study. Serum chemistries and lipid profiles were performed at the end of each arm of the study. The CsA dose was 1.9-7.2 mg/kg/day. All patients were hypertensive and on calcium channel antagonists. Once-a-day CsA dosing resulted in a 29% decrease in trough CsA levels. A significant increase in glomerular filtration rate, as estimated by the clearance of inulin, (65.16±24.4 q. day vs. 54.62±19.0 b.i.d. (ml/min)P<.02) and a significant increase in renal plasma flow, as estimated by the clearance of PAH, occurred with once-a-day dosing when compared with b.i.d. dosing (P=.02). Creatinine clearances were not different between the 2 arms of the study and significantly overestimated glomerular filtration rates (P=.01). CsA dosing b.i.d. resulted in significantly higher nocturnal blood pressures (91.2±8.3 b.i.d. vs. 86.4±8.1 q. day, mmHg,P=.015) when compared with once-a-day dosing. A significant increase in LDL cholesterol and a significant decrease in HDL cholesterol were noted during the b.i.d. dosing arm when compared with q. day CsA dosing. We conclude that in stable heart transplant patients once-a-day CsA dosing results in better GFR and renal plasma flow, a lower nocturnal blood pressure, and an improved lipid profile when compared with dosing CsA twice a day.

AN IMPROVED GLOMERULAR FILTRATION RATE IN CARDIAC TRANSPLANT RECIPIENTS WITH ONCE-A-DAY CYCLOSPORINE DOSING1,2

We tested the hypothesis that there would be a difference in the unwanted side effects of cyclosporine (CsA) when heart transplant patients received CsA once a day versus half the dose twice a day. Eight stable cardiac transplant patients (> 6 months posttransplant) were administered their dose of CsA either as a once-a-day dose or half the dose b.i.d. for 21 days in a random fashion. After 21 days the patients were crossed over to the other regimen. Patients underwent inulin and PAH clearances at CsA trough on each arm of the study. Each patient collected several 24-hr urines for determination of creatinine clearance, and had ambulatory blood pressure monitoring done during each arm of the study. Serum chemistries and lipid profiles were performed at the end of each arm of the study. The CsA dose was 1.9-7.2 mg/kg/day. All patients were hypertensive and on calcium channel antagonists. Once-a-day CsA dosing resulted in a 29% decrease in trough CsA levels. A significant increase in glomerular filtration rate, as estimated by the clearance of inulin, (65.16 +/- 24.4 q. day vs. 54.62 +/- 19.0 b.i.d. (ml/min) P < .02) and a significant increase in renal plasma flow, as estimated by the clearance of PAH, occurred with once-a-day dosing when compared with b.i.d. dosing (P = .02). Creatinine clearances were not different between the 2 arms of the study and significantly overestimated glomerular filtration rates (P = .01). CsA dosing b.i.d. resulted in significantly higher nocturnal blood pressures (91.2 +/- 8.3 b.i.d. vs. 86.4 +/- 8.1 q. day, mmHg, P = .015) when compared with once-a-day dosing. A significant increase in LDL cholesterol and a significant decrease in HDL cholesterol were noted during the b.i.d. dosing arm when compared with q. day CsA dosing. We conclude that in stable heart transplant patients once-a-day CsA dosing results in better GFR and renal plasma flow, a lower nocturnal blood pressure, and an improved lipid profile when compared with dosing CsA twice a day.

Renal allograft histology and correlation with function in children on triple therapy

Histopathological findings of 13 LRD and 17 CAD renal allografts of paediatric recipients were prospectively semiquantitatively scored and correlated with clinical and functional parameters 18 and 36 months after transplantation. The most common findings at 18 months were diffuse interstitial fibrosis (incidence 57%), glomerular mesangial matrix increase (91%), arteriolar intimal proliferation (70%), and tubular atrophy (83%). Most changes were mild and most biopsies were scored normal or borderline (Banff classification). At 18 and at 36 months 30% of grafts showed mild chronic rejection (CR). Only two grafts showed grade II CR at 18 months and one graft grade III CR at 36 months. Progressive CR was not seen. Donor source or recipient age had no effect on graft histology. Vascular-interstitial cyclosporin (CsA) nephrotoxicity was not found. On the contrary, cumulative CsA dose (mg/kg/day) showed an inverse correlation with arteriolar intimal proliferation (P < 0.001). 51Cr-EDTA and lithium clearances showed inverse correlations with diffuse interstitial fibrosis and lymphocytosis. PAH clearance did not correlate with interstitial or vascular changes. The results indicate good prognosis in children on triple immunosuppression (with CsA administered in three doses/day to pre school children) regardless of donor source.

Renal and hemodynamic effects of diltiazem after elective major vascular surgery--a potential renoprotective agent?

A postoperative study was done of the effects of an infusion of diltiazem (DTZ), 1 microgram.kg-1.min-1 after a bolus dose of 0.28 mg.kg-1 on renal function and hemodynamics in 10 patients who were operated with insertion of an abdominal aortic graft. Urine flow, glomerular filtration rate (GFR) by inulin clearance, and renal plasma flow (RPF) by PAH clearance and fractional excretion of electrolytes and osmols were measured for three periods of 20 min during infusion of DTZ, in the morning after surgery. Systemic hemodynamic studies were conducted and serum levels of catecholamines were measured. GFR increased during the initial period of DTZ infusion. There were no significant changes during the study period in any of the other parameters, compared to baseline, except for a decrease in heart rate from 84 to 77 beats per minute. The absence of a sustained increase in GFR and a natriuretic and diuretic effect may possibly be ascribed to a preexisting nonconstricted status of the renal vasculature. The authors conclude that the dose of DTZ used in this study can be safely used for further investigations to elucidate the effects of peroperative infusion of DTZ on renal function in connection with major vascular surgery.

Ifosfamide Metabolite Chloroacetaldehyde Causes Fanconi Syndrome in the Perfused Rat Kidney

Renal proximal tubule dysfunction has been reported in patients treated with the chemotherapeutic agent ifosfamide. The present study investigated whether ifosfamide or its metabolites acrolein and chloroacetaldehyde would impair function in the isolated perfused rat kidney. Renal function was monitored before and after these chemicals were added to a modified Krebs-Ringer-bicarbonate perfusion medium containing 6.6 g/dl albumin and a mixture of substrates. No functional changes were observed when ifosfamide (470 μM) or acrolein (470 μM) was added to the perfusate. Addition of chloroacetaldehyde (210 μM) resulted in significant decreases in the fractional reabsorption of sodium (from 92 to 32%), glucose (from 97 to 46%), inorganic phosphate (from 88 to 22%), and inorganic sulfate (from 94 to 86%). There were no changes in glomerular filtration rate. PAH clearance also significantly decreased from 4.1 to 0.7 ml/min per gram of kidney weight, indicating impairment of proximal tubule organic acid secretion. This impairment was associated with a significant decline in the extraction ratio for PAH, suggesting abnormal PAH uptake at the basolateral membrane. These results show that chloroacetaldehyde causes generalized renal proximal tubule dysfunction and that it may be the ifosfamide metabolite responsible for nephrotoxic side effects,

Effects of atrial natriuretic peptide on acute renal impairment in patients with heart failure after cardiac surgery

To investigate the effects of IV infusion of atrial natriuretic peptide (human ANP 1–28) on renal function in patients with acute heart failure and renal impairment after cardiac surgery. Pharmocodynamic, dose-effect investigation. Cardiothoracic Intensive Care Unit of a university hospital. Twelve patients (mean age 68 years, range 44–78 years) treated with inotropic drugs and an intra-aortic balloon pump (n=8) were studied 1–3 days after cardiac surgery. Patients had acute renal impairment, defined as a rise in serum creatinine of more than 50% compared to preoperative values. Patients were receiving dopamine and furosemide infusion to increase urine flow. Baseline measurements of glomerular filtration rate (GFR) and renal blood flow (51Cr-EDTA and PAH clearance) were first performed during two 30-min periods. ANP was then administered for two consecutive 30-min periods (25 and 50 ng/kg per min), followed by two control periods. Mean arterial pressure decreased by 6% at the highest ANP dose. Urine flow, GFR and RBF increased 62%, 43% and 38%, respectively, while renal vascular resistance decreased 30%. At this dose level, circulating ANP concentrations were on the average eight fold higher than preinfusion levels. ANP improved renal function and decreased elevated renal vascular resistance in patients with renal dysfunction after cardiac surgery. The improvement in renal blood flow and glomerular filtration rate may be of potential therapeutic value to prevent or treat exaggerated renal vasoconstriction in patients with acute renal impairment following cardiac surgery.

A non-radioactive iothalamate and p-aminohippuric acid high-performance liquid chromatographic method for simultaneously measuring glomerular filtration rate and renal blood flow in the rat.

A high-performance liquid chromatographic (HPLC) assay method has been developed for the quantitative determination of iothalamate and p-aminohippuric acid (PAH) concentrations in serum and urine samples in the male rat. Glomerular filtration rate (GFR) was measured as clearance of iothalamate, while effective renal blood flow (ERBF) was measured as clearance of PAH. The method is simple, rapid and sensitive and detects iothalamate and PAH in rat serum and urine following administration of bolus doses and continuous infusions of iothalamate and PAH. Samples of serum and urine were deproteinized with two volumes of acetonitrile containing the internal standard, and an aliquot chromatographed on a C18 reversed-phase column. The mobile phase was comprised of 0.1 M sodium phosphate with 1.2 mM tetrabutylammonium phosphate: methanol, 85:15 (v/v), at a flow rate of 1.0 mL/min. The analytical column eluate was monitored with a UV detector at 254 nm with quantitation achieved using peak-height ratios. The precision of the method was 6.6 and 3.6% for iothalamate in serum and urine, and 5.6 and 4.9% for PAH in serum and urine, respectively. The lower limit of quantitation was 0.63 microgram/mL for iothalamate and 1.25 microgram/mL for PAH in serum, and 3.1 microgram/mL for iothalamate and 1.5 microgram/mL for PAH in urine. Recovery of iothalamate from serum and urine was 99.9 and 93.5%, respectively. Recovery of PAH from serum and urine was 99.8 and 92.6%, respectively. The present study demonstrated that non-radioactive iothalamate and PAH can be measured simultaneously using a HPLC assay to measure GFR and ERBF in the male rat.

Effect of age on renal blood flow during exercise

The present study examined the effect of age on the control of renal blood flow (RBF; PAH clearance) and renal vascular conductance (RVC = RBF/mean arterial pressure) during and after a bout of dynamic exercise in a warm environment. Six healthy fit older men (O; 67 +/- 1 years) and 6 young men (Y; 24 +/- 2 years) were matched for body size, adiposity, and maximal oxygen uptake (VO2max). Subjects exercised at approximately 50% of VO2max for 90 minutes in an environment of 30 degrees C, 60% humidity on each of 4 consecutive days, with data collected on days 1 and 4. There was no effect of repeated days of exercise on RBF or RVC, despite a 4% expansion of blood volume in Y (< 1% in O). On each day, resting RBF was significantly lower in O (e.g., Y = 1127 +/- 67, O = 852 +/- 114 mL/min on day 1; p < 0.05). During exercise, Y decreased RBF to a significantly (p < 0.05) greater extent [-508 (-45%) and -365 (-36%) mL/min on days 1 and 4, respectively] than the O [-98 (-12%) and -83 (-12%) mL/min]. RVC followed a similar pattern, decreasing by 52% and 37% during exercise for Y vs only 15% and 13% for O. The relationships between delta RBF and HR and delta RBF and plasma norepinephrine concentration were independent of age, implying similar sympathetic control during exercise. During recovery, RBF and RVC increased as expected in Y, but continued to decrease in O, falling significantly below exercise values (p < 0.05). Compared to young men, fit healthy older men redistribute less blood flow away from the kidneys during dynamic exercise in the heat, an effect which appears to result from the existence of a smaller resting RBF rather than differential sympathetic control. On the other hand, chronological age seems to be associated with altered control of RBF and RVC during recovery from exercise.

Models used to assess renal function

AbstractThe kidney as a primary excretory organ is a major route of elimination for numerous xenobiotic agents. In the process, it is liable to the hemodynamic and injurious actions of drugs due to their concentration in the kidney. In this brief review, a number of methods for assessing kidney function (e.g., serum creatinine, enzymuria, inulin, and PAH clearances, etc.), with their advantages and limitations, are described. Various acute and chronic animal models (rats and dogs) commonly used in performing safety evaluation of drugs are described; several antihypertensive drugs are cited as examples. These models can be modified with varying number of measurements, depending on the pharmacological activity of test drugs, animal species, specific issues (e.g., vascular vs. tubular effects), pathophysiological conditions, etc.

Effects of atrial natriuretic peptide on renal function after cardiac surgery and in cyclosporine-treated heart transplant recipients

The study investigated the effects of intravenous infusion of atrial natriuretic peptide (human ANP 99–126) on renal function and central hemodynamics after coronary artery bypass grafting (CABG), and the ability of ANP to reverse the acute nephrotoxic effects of cyclosporine after heart transplantation. Ten patients with an EF > 0.5 and normal renal function were studied 2 to 4 hours after CABG surgery. Furthermore, six heart transplant recipients receiving cyclosporine for immunosuppression who developed renal dysfunction 2 to 4 days after transplantation were studied. Standard urinary clearance of 51Cr-EDTA and PAH was used to study the effects of ANP on glomerular filtration rate (GFR) and renal blood flow (RBF). Baseline measurements were first performed during two 30-minute periods. Incremental infusion rates of ANP were then administered for three consecutive 30-minute periods (25, 50, and 100 ng/kg/min), followed by two 30-minute post-ANP control periods. Marked increases in urinary flow (UF), GFR, filtration fraction (FF), and fractional urinary excretion of Na + were observed in the CABG patients with increasing doses of ANP, while RBF was unchanged. Mean arterial pressure decreased by around 15% at the highest ANP dose. In the heart transplant recipients, baseline GFR was markedly reduced compared to pretransplantation values (−65%). UF, GFR, and RBF increased 240%, 69%, and 53%, respectively, while renal vascular resistance decreased 45% during the highest dose of ANP infused. At this ANP dose level, circulating ANP concentrations were sixfold to eightfold higher than the preinfusion control level. The study shows that ANP may improve renal function in uncomplicated CABG patients and may counteract cyclosporine-induced renal vasoconstriction in heart transplant recipients. In particular, the latter effect may be of potential therapeutic value in preventing acute renal failure after heart transplantation.