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The relation between surface area and body weight changes dramatically in infancy. In 31 healthy infants of 27 to 40 weeks' gestation, variations in glomerular filtration rate were reduced more than twofold by choosing glomerular filtration rate/kg body weight rather than glomerular filtration rate/m2. The former provides the most useful and practical index of renal function in the neonate.
Clearance of technetium-99m-labelled diethylenetriaminepenta-acetic acid was used to measure total and individual kidney glomerular filtration rates in 48 girls with covert bacteriuria. The mean (+/- SD) of the total rates of 18 girls with scarred kidneys (99 +/- 24 ml/min/1.73 m2) was significantly (0.005 greater than p greater than 0.002) lower than that in 30 girls with unscarred kidneys (119 +/- 18 ml/min/1.73 m2). This reduction in glomerular filtration was related to the loss of kidney substance associated with scarring rather than to vesicoureteric reflux. The glomerular filtration rate was unrelated to the duration of bacteriuria. These findings suggest that in girls aged 4 and over neither vesicoureteric reflux nor covert bacteriuria contributes to the progression of kidney damage.
It has been assessed whether an internal dose of cadmium (Cd), as reflected by a Cd concentration in urine not yet sufficient to induce a significantly increased urinary excretion of various plasma proteins (microproteinuria defined as beta 2-microglobulin in urine greater than 300 micrograms/g creatinine, or retinol-binding protein in urine greater than 300 micrograms/g creatinine, or albumin in urine greater than 15 mg/g creatinine, or a combination of these), may affect the filtration reserve capacity of the kidney. The last was determined by measuring the difference between the baseline creatinine clearance and the maximal creatinine clearance after an acute oral load of protein (400 g of cooked red meat). In total 215 men were examined of whom eventually 87 Cd exposed workers (concentration of Cd in urine greater than 2 micrograms/g creatinine) from zinc/cadmium smelters and 92 control workers (concentration of Cd in urine less than 2 micrograms/g creatinine, absence of microproteinuria, normal fasting serum creatinine) were retained for data analysis performed separately for workers aged less or more than 50 years. Microproteinuria was present in 20 Cd workers, all older than 50. This study confirmed the previous observation that the age related decline of the baseline glomerular filtration rate (GFR) is accelerated in male workers with Cd induced microproteinuria; the same observation was made for the maximal GFR. It was found, however, that a renal Cd burden that had not yet caused microproteinuria did not impair the filtration reserve capacity of the kidney. This study therefore validates the previous estimate of the threshold effect concentration of Cd in urine (10 micrograms/g creatinine) that is intended to prevent the occurrence of microproteinuria in male Cd workers. It should be kept in mind, however, that because of the likely interference of the healthy worker effect, this conclusion may not be directly extrapolated to the general population.
Two economical membrane filtration techniques are described: (1) vacuum filtration through a single funnel into several sterile containers and (2) pressure filtration using an inexpensive combination of pressure source, vessel, and valve.
The development of filtration rate and perfusion rate in superficial nephrons has been studied in 17- to 60-day-old rats with micropuncture and microsphere techniques. Recordings have also been made of total renal blood flow (RBF), cardiac output (CO), arterial blood pressure, and hematocrit. Sincle-nephron glomerular filtration rate (SNGFR) as well as glomerular perfusion rate (GPR) and RBF described a similar developmental pattern with a slower rise from 17 to 30 days of age and a faster rise thereafter. No plateau was observed. The quotient between SNGFR and GPR was constant from at least 22 days of age. Since the hematocrit was also constant after 22 days this implies a constant filtration fraction. On the basis of those findings it is suggested that GPR is the main determinator for the development of GFR. The fraction of cardiac output perfusing the kidneys increased continuously in 17- to 60-day-old rats, suggesting that the increase in RBF and GPR is due to intrarenal factors: renal vasodilatation and increase in renal vascular volume.
We have developed microtechniques that allow the determination of compartmental fluid distribution and glomerular filtration rate in chick embryos during three significant developmental periods: phase 1, the developmental period when the mesonephros alone is functioning; phase 2, periods of simultaneous meso/metanephric kidney function; and phase 3, the period during late development when the metanephros completely replaces the degenerated mesonephros. Water content of tissues is greater in younger embryos (89.4 +/- 0.2%, day 10) compared with older animals (78.3 +/- 0.5%, day 18). Although all major tissue components show an absolute increase in mass during this period, the embryo proper increases at five times the rate of the extraembryonic tissues. Glomerular filtration rate increases during development from 0.61 +/- 0.08 ml/h at day 10 to 2.31 +/- 0.11 ml/h at day 18. Glomerular filtration rate scales to body mass with an allometric exponent identical to adult birds only if total tissue mass (embryo + membranes) is considered. Our data suggest that significant errors in allometry will be encountered when scaling measurements are made on embryonic or fetal amniotes without taking into consideration the extraembryonic tissues.
We evaluated the glomerular filtration rate (GFR) during the second postpartum week in 22 healthy women who had completed an uncomplicated pregnancy. We used physiological techniques to measure GFR, renal plasma flow, and oncotic pressure and computed a value for the two-kidney ultrafiltration coefficient (K(f)). We compared these findings with those in pregnant women previously studied on the first postpartum day as well as nongravid women of reproductive age. Healthy female transplant donors of reproductive age permitted the morphometric analysis of glomeruli and computation of the single-nephron K(f). The aforementioned physiological and morphometric measurements were utilized to estimate transcapillary hydraulic pressure (Delta P) from a mathematical model of glomerular ultrafiltration. We conclude that postpartum day 1 is associated with marked glomerular hyperfiltration (+41%). A theoretical analysis of GFR determinants suggests that depression of glomerular capillary oncotic pressure, the force opposing the formation of filtrate, is the predominant determinant of early elevation of postpartum GFR. A reversal of the gestational hypervolemia and hemodilution, still evident on postpartum day 1, eventuates by postpartum week 2. An elevation of oncotic pressure in the plasma that flows axially along the glomerular capillaries to supernormal levels ensues; however, GFR remains modestly elevated (+20%) above nongravid levels. An analysis of filtration dynamics at this time suggests that a significant increase in Delta P by up to 16%, an approximately 50% increase in K(f), or a combination of smaller increments in both must be invoked to account for the persistent hyperfiltration.
Although the regulation of cyclooxygenase-2 (COX-2) expression in the kidney cortex has been extensively characterized, the physiological control mechanisms of COX-2 expression at the level of the kidney and at the level of the tubular cells are not well understood. Based on the current hypothesis that tubular salt transport might be a crucial regulator of COX-2 expression, this study aimed to determine the impact of salt delivery to the tubules (glomerular filtration) for the regulation of COX-2 in the kidney cortex in vivo. To this end, glomerular filtration of the right kidney was abrogated by the ligation of the right ureter of male Sprague-Dawley rats. After 1 wk of ligation, the animals were treated with subcutaneous infusions of furosemide (12 mg x kg(-1) x day(-1)) or with a low-salt or a high-salt diet (0.02% wt/wt; 8% wt/wt), and COX-2 as well as renin mRNA expression were determined in the ligated and the nonligated contralateral kidney. During ureteral ligation, hydronephrosis developed with a reduction of medullary mass, while the cortex was preserved. Expressions of the Na-K-2Cl cotransporter isoforms A and B were both reduced in the hydronephrotic cortex to 70 and 35% of the corresponding contralateral intact kidney. Despite the abrogation of glomerular filtration, detected by inulin clearance measurements, renocortical COX-2 mRNA abundance was stimulated by furosemide treatment (3.2-fold) or low-salt diet (2.9-fold) to similar degrees compared with the intact contralateral kidney (2.7-fold for both treatments), whereas a high-salt diet did not significantly suppress COX-2 mRNA in the macula densa region of either kidney. Renin mRNA expression was regulated strictly in parallel in both kidneys, a low-salt diet or furosemide treatment stimulating and a high-salt diet suppressing it. We conclude from these findings that salt delivery to the tubules is not an essential requirement for the upregulation of COX-2 by salt deficiency or by loop diuretics in the rat kidney cortex nor is it for chronic stimulation of renin mRNA expression.
A method for estimating glomerular filtration rate (GFR) has been developed that is based on an analysis of the total area under the plasma radioactivity-time curve after a single intravenous injection of [125I]iothalamate. Glomerular filtration rates obtained by this method (method A) and those obtained with two widely used single-injection techniques, the slope-intercept method (method B), and the two-compartment method (method C), were compared with GFRs obtained by standard inulin clearance techniques in 14 dogs. Method B consistently over. estimated inulin clearances more than 30%. Method C also overestimated inulin clearance considerably in dogs with an increased extracellular fluid volume, but was fairly reliable in normal dogs. Glomerular filtration rates obtained by the new method (method A) were in excellent agreement with inulin clearances in all dogs, regardless of the state of body hydration. The mean inulin clearance for all 14 experiments was 72.7+/-6.0 SE ml/min, while GFRs obtained by method A averaged 75.1+/-6.0 ml/min. The data from this study suggest that method A is a reliable means for estimating GFR that is especially useful in chronic experiments.
Factors that determine and cause an increased glomerular filtration rate in superficial nephrons (sngfr) in the mature, growing rat were examined in 39 Munich-Wistar rats, ranging from 93 to 335 g in body weight, from 40 to 140 days in age, and in sngfr, from 15 to 78 nl/min. Hydrostatic pressure gradient (delta P) from glomerular capillary (PG) to Bowman's space (Pt) was measured in surface glomeruli and pertinent oncotic pressures (pi) by microprotein methods. Isoncotic plasma expansion (PV) prevented filtration-pressure equilibrium (EFP) and permitted calculation of glomerular permeability coefficient (LpA) where sngfr = EFP-LpA, and EFP = delta P - pi. Increased sngfr correlated best with nephron plasma flow (rpf) (r = 0.81, P less than 0.001) and LpA (r = 0.71, P less than 0.001). The rpf increased because of parallel reductions in afferent and efferent resistances (slope = 0.89 +/- 0.09, r = 0.86, P less than 0.001), which also produced a constancy of PG and deltaP with growth. The ratio of rpf to LpA remained constant with growth permitting EFP to remain relatively unchanged (r = 0.14, P greater than 0.4). The increase in LpA should permit filtration-pressure equilibrium to persist in the hydropenic rat in spite of increases in rpf with growth. deltaP was constant with increasing age and therefore did not contribute to the increase in sngfr.
Renal blood flow (RBF) and glomerular filtration rate (GFR) autoregulation during changes in renal artery pressure (RAP) were examined in dogs fed a "normal" diet (group 1, n = 10) and in renin-depleted dogs (group 2, n = 11) which received a high-sodium diet and deoxycorticosterone acetate (DOCA) injections for a minimum of 21 days prior to the study. Renal venous plasma renin activity was undetectable in group 2 by radioimmunoassay of angiotensin I and did not increase even when RAP was reduced to less than 70 mmHg. Autoregulation of RBF was not impaired by renin depletion. However, GFR autoregulation, which was very effective in group 1 dogs, was markedly impaired in group 2. Average GFR in group 2 decreased progressively to 58 +/- 7% of the control value as RAP was reduced in steps from the control value of 137 +/- 3 to 69 +/- 1 mmHg. In normal dogs, the filtration fraction either increased slightly or did not change when RAP was reduced in steps, whereas in renin-depleted dogs the filtration fraction decreased progressively during reductions in RAP. Thus, chronic sodium loading and DOCA administration causes renin depletion and dissociates the autoregulation of RBF and GFR. These data are consistent with the hypothesis that the renin-angiotensin system participates in the control of GFR, possibly by an efferent arteriolar mechanism.
Sodium balance may affect the response of single-nephron filtration rate (SNFR) to changes in renal arterial pressure (deltaRAP) when the SNFR is measured in the absence of orthograde fluid delivery from the proximal tubule. This thesis was tested in sodium-depleted and -expanded dogs given furosemide, Doca, and low- or high-salt diets, respectively. After 7 days of treatment, renal renin content was significantly greater in the sodium-depleted group (delta = 23.5 +/- 7.4 DU [dog units]/g kidney). Glomerular filtration rate and renal plasma flow were similar in both groups following changes in RAP of 29 +/- 4 and 29 +/- 3 mmHg in the sodium-depleted and -expanded groups, respectively. SNFR at high RAP was not different from SNFR at low RAP in the sodium-depleted group (delta = -0.2 +/- 4.9 nl/min) and slightly, but significantly, greater in the sodium-expanded group (delta = 7.6 +/- 2;1 nl/min). However, the response of SNFR was similar to that of whole-kidney filtration rate. Furthermore, the autoregulatory response (deltaSNFR/deltaRAP) was not significantly different between the groups but was significantly greater than the response calculated for RAP below the range studied. It is concluded that an autoregulatory response of SNFR, in the absence of orthograde fluid delivery from the proximal tubule, is observed in both sodium-depleted and -expanded dogs.
This study was designed to investigate the role of intrarenally formed angiotensin II (ANG II) in controlling glomerular filtration rate (GFR) during reduction of renal artery pressure (RAP). The experimental design prevented renin released by the kidney from entering the systemic circulation and therefore prevented changes in circulating ANG II from influencing GFR control. In dogs with only a functional intrarenal renin-angiotensin system (RAS), GFR and renal blood flow (RBF) were not significantly altered by RAP reduction to 70 mmHg. After blockade of intrarenal ANG II formation with SQ 14225, reduction of RAP to 70 mmHg decreased GFR and filtration fraction to 75.6 +/- 7.0 and 59.0 +/- 4.1% of control, respectively, while RBF remained at 129.3 +/- 8.8% of control. Calculated efferent arteriolar resistance decreased considerably more when RAP was reduced after SQ 14225, whereas preglomerular resistance decreased to about the same level as observed prior to SQ 14225 infusion. After return of endogenously produced ANG II by recirculation of the renal venous blood or after infusion of ANG II (following SQ 14225) at a rate that restored RBF to the control level (with RAP held at 70 mmHg in each case), GFR, filtration fraction, and calculated efferent resistance were restored to control levels, but preglomerular resistance did not change. These results suggest that intrarenal ANG II formation plays an important role in maintaining GFR during reductions in RAP by constricting efferent arterioles.(ABSTRACT TRUNCATED AT 250 WORDS)
Atrial natriuretic factor (ANF) is a peptide originally found to be present in extracts of mammalian atria that possess marked natriuretic and diuretic qualities. A number of mechanisms have been suggested to explain these properties. Recently, it has been suggested that ANF may enhance glomerular filtration. In this report, we describe a series of experiments designed to investigate if atriopeptin II, a 23-amino acid synthetic analogue of ANF, increases glomerular filtration rate (GFR) and, if so, the mechanism for this increase. We used the isolated perfused glomerulus technique (n = 6), which allows a single isolated glomerular unit to be perfused and the determinants of single-nephron GFR (SNGFR) to be measured. Two periods were performed in each experiment, the control followed by the experimental. The only difference between the two periods was the addition of atriopeptin II to the experimental perfusate at a final concentration of 5 X 10(-7) M. There was indeed a significant increase in the SNGFR (78 +/- 27 to 108 +/- 29 nl/min, P less than 0.01). This increase was associated with a significant increase in the glomerular capillary hydrostatic pressure (PGC) from 31 +/- 3 to 35 +/- 3 mmHg (P less than 0.05). The filtration fraction also increased in each experiment (from 0.16 +/- 0.3 to 0.25 +/- 0.03, P less than 0.005). Neither the afferent flow nor the efferent arteriolar flow changed, although there was a tendency for both to decrease.(ABSTRACT TRUNCATED AT 250 WORDS)
A parallel network model was developed to examine the effects of a distribution of capillary lengths on the filtration of macromolecules by the glomerulus. When networks having different distributions of capillary lengths (but similar values of single nephron glomerular filtration rate) were compared, the filtrate-to-plasma concentration ratio (theta s) for neutral macromolecules was found to increase as the vessel lengths became less uniform. Because anatomical studies have demonstrated that the glomerulus is in fact a heterogeneous network, this implies that the conventional modeling assumption of identical capillaries in parallel leads to an overestimation of effective pore sizes. However, simulations employing various pore-size distributions demonstrated that the expected errors in estimating membrane-pore parameters are generally negligible. Furthermore, the dependence of theta s on hemodynamic inputs such as glomerular plasma flow rate and transmembrane hydraulic pressure difference was insensitive to the assumed distribution of capillary lengths. We conclude that models based on dimensionally uniform capillary networks remain valid for interpreting clearance data for macromolecules.
Age-related changes in the function of individual nephrons were investigated by micropuncture experiments measuring single-nephron filtration rates (SNGFR) and proximal reabsorptions in 10-, 20-, and 30-mo-old rats. The animals were female WAG/Rij rats with low incidence of chronic progressive nephropathy, no loss of nephrons, and renal hypertrophy of both kidneys in the oldest animals. Mean SNGFR values per gram kidney weight were 41.4 +/- 1.1, 37.1 +/- 1.5, and 32.2 +/- 1.1 nl.min-1.g kidney wt-1 (n = 41) in the 10-, 20-, and 30-mo-old animals, respectively. This age-related decrease in filtration was no longer apparent when SNGFR values were expressed per nephron (means 24.3 +/- 0.7, 23.7 +/- 0.9, and 24.4 +/- 0.9 nl/min. Individual filtered loads of sodium, potassium, calcium, and magnesium and their absolute reabsorption by the proximal tubule were not different in the three age groups; however, absolute and fractional reabsorptions of phosphate decreased significantly in the 30-mo-old rats. These results indicate that, with the exception of phosphate, individual filtrations and proximal reabsorptions are well maintained in aging rats free of disease. This may be related to the observed renal hypertrophy.
Arginine decarboxylase is present in the kidney and metabolizes the amino acid, arginine, to agmatine. Agmatine increases filtration rate in single nephrons (J. J. Lortie, W. F. Novotny, O. W. Peterson, V. Vallon, K. Malvey, M. Mendonca, J. Satriano, P. Insel, S. C. Thomson, and R. C. Blantz. J. Clin. Invest. 97:413-420, 1996). Experiments were conducted to determine whether exogenously administered agmatine exerts these effects via interaction with nitric oxide synthase (NOS) and whether this interaction depends upon alpha 2-adrenergic receptors. Agmatine microperfused (1 microM) into the urinary space of surface glomeruli of the rat increased nephron filtration rate from 33 +/- 4 to 40 +/- 5 nl/min with complete recovery within 10 min. When NG-monomethyl-L-arginine (L-NMMA), a nonselective NOS inhibitor, was systemically infused, agmatine no longer increased single-nephron glomerular filtration rate (SNGFR). BHT-933, an alpha 2-adrenergic agonist, did not increase SNGFR and was unaffected by concurrent L-NMMA. In vitro incubation of freshly harvested glomeruli with agmatine resulted in significant increases in the generation of cGMP, effects similar to carbachol, and blocked by nitro-L-arginine methyl ester (L-NAME) but not yohimbine, an alpha 2-adrenergic antagonist. Agmatine exerts effects on glomerular ultrafiltration via a constitutive NOS-dependent mechanism, and this does not require the participation of alpha 2-adrenoreceptors.
In the middle of the twentieth century, the suspicion that deep and superficial nephrons might serve different functions created a demand for measurement of single-nephron glomerular filtration rate (SNGFR). Rather unexpectedly, the answer came from Odd E. Hanssen (1917-1964), a Norwegian physician working on his own in the Department of Pathological Anatomy, University of Oslo, with minimal support and no interaction with renal physiologists. In 1963, after nearly 10 years of work, he presented the ferrocyanide method, allowing simultaneous estimates of SNGFR in a large number of nephrons in all layers of the kidney. This review first describes his early visions of the method and the elaborate and extremely time-consuming studies in mice to verify the technique. As a byproduct came valuable information on the relationship between nephron size and SNGFR, glomerular intermittency, and the emptying of the tubules on filtration stop. Hanssen died from a cerebral hemorrhage in 1964, and for several years the method seemed entirely forgotten. Fortunately, Andrew Baines took up the use of ferrocyanide in 1963-1964 while working on his thesis in Toronto, but his first publication came in 1969 from Saclay, France, in collaboration with Christian de Rouffignac. Modifications allowing determination of absolute SNGFR were worked out by de Rouffignac and by Jaime Coehlo in New York. Thereafter, the "Hanssen method" spread rapidly, and in the early 1980s about 50 reports had been published from 17 laboratories in 9 countries. The distribution of SNGFR in mammals, birds, and fish was described, as well as the response to water and salt loads, vasoactive substances, hormones, varying perfusion pressure, blood loss, etc. Finally, after mentioning two recent methods inspired by the Hanssen technique but using other filtration markers, the review concludes that most of our present knowledge on SNGFR distribution and regulation has been obtained by the method developed by Hanssen 40 years ago.