View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Kidney International, Vol. 34 (1988), pp. 825—831 Atrial natriuretic peptide and the renal response to hypervolemia in nephrotic humans Cit&IG PETERSON, BERIT MADSEN, ANDREW PERLMAN, ALEX Y.M. CHAN, and BRYAN D. MYERS Department of Medicine, Division of Nephrology, Stanford University Medical Center, Stanford, California, USA Atrial natriuretic peptide and the renal response to hypervolemia inresponsiveness suggested a specific defect of ANP action on the nephrotic humans. To elucidate the abnormality of body fluid homeo- tubule [6]. stasis that attends the nephrotic syndrome, we compared the atrial hormonal and renal excretory and vasomotor responses to water To elucidate the possible contribution of ANP to body fluid immersion of nephrotic patients (N =10)with those of healthy controls homeostasis, we subjected nephrotic subjects and healthy vol- (N =9).Nephrotics exhibited depressed baseline levels of atrialunteers to water immersion, a maneuver that leads to atrial natriuretic peptide (ANP, P <0.05)and lower rates of urine flow and distention [8], enhanced release of ANP [9] and an ensuing sodium excretion (P <0.01).Although immersion-induced hypervol diuresis and natriuresis [8—12]. We used a differential solute 19vs. 606 emia increased plasma ANP to equivalent levels (75 pg/clearance technique to compare the renal vasomotor and excre- ml), the disparity in corresponding urinary flow (5 1vs. 13 2ml! mm, P <0.01)and sodium excretion (171 42vs. 540 65sEq/min, tory responses to the transient hypervolemia in the two groups. P <0.01)grew larger. In contrast, immersion caused an equivalent Our findings suggest that renal cortical vessels of nephrotic reduction of renal vascular resistance by 16 and 17%, respectively (P < subjects are normally responsive, but that their tubules exhibit 0.01).Despite higher renal plasma flow and lower oncotic pressure of plasma, the glomerular filtration rate remained constant during immer- insensitivity to immersion-induced natriuretic influences, in- sion in both groups. Similar constancy of fractional clearances ofcluding enhanced release of endogenous ANP. An inability to dextrans of graded size suggests that immersion may have lowered the mount a normal diuretic and natriuretic response to transient glomerular transcapillary hydraulic pressure difference (i.P). We con- hypervolemia may contribute to the enlargement of interstitial clude that renal vasomotor responsiveness to hypervolemia is pre-fluid volume that typifies the nephrotic syndrome. served in nephrotics, but that the mediatory role of ANP in this response is uncertain. By contrast, diminished responsiveness of the distal nephron to the natriuretic action of endogenous ANP could Methods contribute to edema formation in the nephrotic syndrome. Study populations Ten patients referred consecutively to us because of the development of a nephrotic syndrome and aged 16 to 54 years The mechanism by which nephrotic subjects form edemacomprised the experimental population. In each instance daily remains an enigma. It has been proposed that renal sodium andurinary protein losses in excess of 4 g were accompanied by water retention is a consequence of the hypoalbuminemia thathypoalbuminemia and edema. Renal biopsy revealed a variety attends massive urinary losses of protein. According to thisof underlying glomerular diseases, including lupus-associated theory, lowered plasma oncotic pressure permits extracellularproliferative glomerulonephritis (N =2),membranous glomer- fluid to be translocated from the vascular to the interstitialulopathy (N =3),and minimal change glomerulopathy with or compartment. An ensuing reduction of "effective" plasmawithout focal and segmental glomerulosclerosis (N =5).Nine volume is then postulated to result in a series of neurohormonalhealthy volunteers who ranged in age from 19 to 51 years served adaptations which stimulate renal sodium retention [1—31.as a control group. All denied a history of renal disease, Among these adaptations may be depression of the ambientdiabetes or hypertension, and were found at the time of levels of the atrial natriuretic peptide (ANP). A second expla-examination to be normotensive and to have a negative dipstick nation is that intrinsic injury to the nephron leads to a primarytest for urinary protein. enhancement of tubular sodium reabsorption that is indepen- dent of events in the systemic circulation [4, 5]. In keeping with Study protocol this possibility, infusion of exogenous ANP into nephrotic rats has been associated with a blunted diuretic and natriuretic The study protocol, approved previously by the institutional response to the peptide [6, 7]. Preservation of vasomotorreview board at Stanford University Medical Center, was described in detail and informed consent to perform the study was obtained from each patient and volunteer. Ambient levels of plasma ANP were determined in a clinical research center. Received for publication December 30, 1987 Each subject remained seated in a chair for at least one hour and in revised form August 5, 1988 before blood was sampled. Blood was placed immediately in a © 1988 by the International Society of Nephrology chilled heparinized tube containing 1 mg/mI of disodium ethyl- 825 826 Peterson et a!: Nephrotic response to hypervolemia enediamine tetraacetrate (EDTA) and 500 KIU/mI of Aprotininsecond and third hours of water immersion, a period which has (Sigma Chemicals Co., St. Louis, Missouri, USA). Plasma wasbeen shown to be associated with peak volume expansion and a separated by centrifugation at 2500 rpm for 15 minutes andcorresponding maximal renal response to the hypervolemia [8— stored at —70°C until the day of assay. These determinations12]. Urinary losses were replaced quantitatively throughout by were made at 0.900 hours following a light breakfast, and in theintravenous infusion of 0.45% saline in 2.5% dextrose solution. case of the proteinuric patients, after discontinuation of antihy-The following were determined in duplicate before the priming pertensive and diuretic drugs for the four days preceding theinfusion, during the baseline clearances, at hourly intervals study. during the three hour period of water immersion, and again one Each patient and volunteer was then subjected to differentialhour after immersion; heart rate, arterial blood pressure (cal- solute clearances and head-out water immersion. A primingculated as diastolic pressure plus one-third of pulse pressure), infusion containing 10% inulin (60 mg/kg), 20% para-aminohip-hematocrit (Hct), plasma protein concentration and oncotic puric acid (PAH, 8 mg/kg), and 10% dextran 40(130 mg/kg) waspressure, and plasma levels of ANP. administered. Thereafter, inulin and PAH were infused contin- uously at a rate calculated to maintain their respective plasma Laboratory procedures concentrations constant at 20 and 1.5 mg/dl. During a 60-minute Plasma and urinary concentrations of inulin and PAH were equilibration period, a solution of 0.45% saline in 2.5% dextrose analyzed using techniques that have been described previously was infused at 10 ml per kg body weight to promote a diuresis.[21]. Separation of dextran 40 in protein-free filtrates of plasma Four accurately-timed urine collections were then obtained byand urine into narrow fractions was achieved by high perfor- spontaneous voiding. Peripheral venous blood was drawn from mance liquid chromatography using a pump (#2010, Varian, an indwelling cannula to bracket each urine collection. ThePalo Alto, California, USA) and two Micropak TSK columns in average inulin clearance for the four collection periods was series (SW 3000 and SW 4000, Toyosoda, Tokyo, Japan). The equated with the glomerular filtration rate (GFR). Renal plasmacolumns were calibrated with three, narrowly dispersed dex- flow (RPF) was calculated by dividing the corresponding PAHtrans and an inulin preparation, all of known molecular weight clearance by an estimate of the renal extraction ratio of PAH(70, 40, 10 and 5.5 kilodaltons, respectively). Blue dextran was (EpAH). In the healthy volunteers, we used a ratio of 0.85 [13,used to identify the void volume. Dextran concentration was 14]. However, EPAH has been shown to be moderately de-measured using an "on-line" refractive index detector (#RS-3, pressed in patients with proteinuric glomerular diseases [15—Varian). An integrator (#4270, Spectraphysics, San Jose, Cal- 18], To define a representative value of EPAH for the experi-ifornia, USA) was used to devide the chromatogram into four mental group, we determined this quantity directly in sevenslices per minute at a chart speed of 0.25 cm/mm during the 30 nephrotic subjects, two of whom were members of the experi-minute run. The integrated area of each slice was equated with mental population. All were undergoing catheterization to ex-the dextran concentration at the corresponding retention time. clude a renal vein thrombosis and had been shown by biopsy toMolecular radius (r) was computed from the linear relationship have either membranous (N =4),lupus related (N =1),or focalbetween retention time and molecular weight (MW), where: sclerosing glomerulopathy (N =2).Renal and peripheral ve- nous blood was sampled simultaneously during an infusion of r 0.33 x (MW)°463 (2) PAH, identical to that used during the clearance studies. EPAH was depressed uniformly, varying between 0.58 and 0.80 andThe fractional clearances (0) of each