Ultrafiltration Coefficient Research Articles

The biophysical basis of hypofiltration in nephrotic humans with membranous nephropathy

Physiologic and morphologic techniques were used to elucidate the determinants of the glomerular filtration rate in 62 nephrotic patients with membranous nephropathy and 104 healthy controls. Renal plasma flow, glomerular filtration rate, afferent oncotic pressure and dextran sieving coefficients were determined. Mathematical models of glomerular filtration were then used to compute likely upper bounds for the ultrafiltration coefficient and pore area/length ratio (a measure of pore density). These upper bounds for each measure of intrinsic ultrafiltration capacity were both depressed by 75% in membranous nephropathy. A corresponding excess of ultrafiltration pressure (versus control), attributable solely to reduced intracapillary oncotic pressure was by 12 mm Hg. Glomerular morphometry revealed peripheral capillary filtration surface area to be enhanced in membranous nephropathy (3.27 x 10(5) vs. 2.03 x 10(5) micron2). However, there was a massive reduction in filtration slit frequency due to epithelial podocyte broadening (336 vs. 1204 slits/mm capillary length) as well as marked thickening of the glomerular basement membrane (1130 vs. 388 nm). We conclude that the latter two findings lower the ultrafiltration coefficient in membranous nephropathy by depressing the hydraulic permeability of the glomerular capillary wall. We propose that this abnormality is solely responsible for the hypofiltration observed in a majority of patients with this disease.

Pharmacologic manipulation of glomerular functionter

Normally, the glomerular filtration rate (GFR) is kept nearly constant. This is achieved by the autoregulation of the renal blood flow and by the tubuloglomerular feedback mechanism [1, 2]. Renal blood flow is in part autoregulated by changes in afferent arteriolar resistance. Thus, increases in systemic blood pressure will result in a constriction of the afferent arteriole whereas reductions in systemic blood pressure will induce a dilation of the afferent arteriole, rendering glomerular blood flow nearly constant. Nitric oxide and prostaglandins play an important role in this pressure-induced autoregulation [3]. Likewise, the tubuloglomerular feedback mechanism affects afferent arteriolar, but also efferent arteriolar resistance: a fall in GFR will lead to a diminished flow in the distal tubule and a decreased sodium and chloride content at the macula densa. As a result afferent arteriolar vasodilation and efferent arteriolar vasoconstriction will occur in order to restore glomerular filtration. On the other hand, if sodium delivery at the macula densa enhances, afferent vasoconstriction will ensue. Thus, the autoregulation of the renal blood flow and the tubuloglomerular feedback mechanism aim to keep GFR constant. Glomerular ultrafiltration is determined by four factors [2, 4–6]: (1) the glomerular plasma flow (Q A ); (2) the transcapillary hydrostatic pressure difference (ΔP), which is the difference between the hydrostatic pressure in the glomerular capillary and the hydrostatic pressure in Bowman's space, that is, in the proximal tubule; (3) the oncotic pressure in the glomerular capillary (Π GC ), which is the opposite force of ΔP; (4) the ultrafiltration coefficient of the glomerular basement membrane (K f ), being the product of the surface area for filtration and the effective hydraulic permeability of the capillary wall. Whereas throughout the capillary loops ΔP remains relatively constant, Π GC rises progressively as a result of filtration of protein-free fluid. Experimental studies in rats and primates have revealed that Π GC counterbalances ΔP before the end of the glomerular capillary, by which so-called filtration equilibrium ensues. It has not been elucidated whether in humans a filtration equilibrium normally exists also. Micropuncture studies in rats have demonstrated that Q A is the most important determinant of the glomerular ultrafiltration both in states of filtration equilibrium and filtration disequilibrium [4, 7]. In case of filtration equilibrium, a rise in Q A is followed by a proportional rise in glomerular ultrafiltration until filtration disequilibrium is reached. In case of filtration disequilibrium, a rise in Q A will be followed by a proportionally lesser rise in glomerular ultrafiltration. As a result the filtration fraction (FF), defined as the glomerular filtration rate divided by the glomerular blood (plasma) flow, will fall. In case of filtration equilibrium increments in ΔP will not affect GFR. On the other hand, an elevation in ΔP will induce a rise in glomerular ultrafiltration in cases of filtration disequilibrium, which will be associated with a rise in FF. Whenever pharmacological agents affect GFR, they will do so by affecting one or more of the above-mentioned determinants of the glomerular ultrafiltration. In humans the renal effects of pharmacologic agents are usually evaluated indirectly by utilizing clearance techniques to determine GFR, effective renal plasma flow (ERPF) and FF. Subsequently, observed changes in renal hemodynamics and FF are frequently used to deduce alterations in the tone of the renal resistance vessels and the determinants of glomerular ultrafiltration. By means of mathematical modelling, Carmines et al [8] pointed out that proportionally similar reductions in afferent and efferent arteriolar resistances will result in a fall in FF. Thus, changes in FF alone cannot be used to deduce alterations in the tone of the afferent and efferent arterioles, or in the determinants of glomerular ultrafiltration. This is especially so when the assumption holds true that filtration equilibrium does not exist in humans, since filtration disequilibrium implies that a rise in ERPF always will result in a proportionally lesser increase in GFR, and thus in a fall of the FF. However, if a pharmacological intervention results in opposite effects on GFR and ERPF, it must be assumed that changes in ΔP and K f have occurred. Since such changes in ΔP and K f may have additional or opposing effects on GFR and FF, the interpretation of observed modifications in FF and renal hemodynamics may not suffice to extrapolate changes in the determinants of glomerular ultrafiltration with certitude. Additional information may be obtained by simultaneous investigation of the urinary protein loss and/or dextran clearances.

New classification of hypertension based on renal mechanisms

The renal mechanisms of hypertension were reviewed, and new way to classify hypertension based on renal mechanisms was proposed. Theoretically, the pressurenatriuresis relationship can be affected in two different ways; either a parallel shift along the blood pressure axis toward a higher blood pressure level or a depression in the slope. The parallel shift of the pressure-natriuresis relationship induces non-sodium sensitive hypertension, while the depressed slope induces sodium sensitive hypertension. Since the degree of the shift of the pressure-natriuresis relationship is determined by the preglomerular vascular resistance from heart to glomeruli, non-sodium sensitive hypertension should be based on the increased preglomerular vascular resistance. On the other hand, the slope of the pressure-natriuresis relationship is determined by glomerulo-tubular balance of sodium, which is mainly controlled by the difference between the whole kidney ultrafiltration coefficient and the rate of tubule sodium reabsorption. Therefore, sodium sensitivity of blood pressure is based on a decrease in the whole kidney ultrafiltration coefficient (due to a decrease in either filtration surface area per glomerulus, hydraulic permeability of glomerular filtration barrier or the number of glomeruli) and/or an increase in tubule sodium reabsorption. In sodium sensitive states, whether whole kidney ultrafiltration coefficient is reduced or tubule sodium reabsorption is enhanced, the glomerular capillary hydraulic pressure rises to compensate for the impairments in sodium excretory capability. If there is a linkage between sodium sensitivity of blood pressure and glomerular hypertension as proposed, renal failure may be expected to be more common in sodium sensitive types of hypertension than in non-sodium sensitive types.(ABSTRACT TRUNCATED AT 250 WORDS)

Pathogenesis of glomerular injury in the fawn-hooded rat: effect of unilateral nephrectomy.

Fawn-hooded (FH) rats with congenital proteinuria and systemic and glomerular hypertension are very susceptible to renal damage at a young age. In this study, the effects of unilateral nephrectomy (UNX) on the function and structure of the remaining kidney in the FHH substrain were assessed. A long-term study was performed to determine the changes in systemic blood pressure, renal function, and proteinuria during the development of chronic renal failure in UNX-FHH and two-kidney (2K) FHH rats. Renal micropuncture and morphologic studies were performed at 4 wk after surgery. The long-term study showed that, after UNX, systolic blood pressure did not differ significantly (from that of 2K-FHH rats. After UNX, there was compensatory hyperfiltration, at about 70% of the 2K level, that could be maintained for 12 wk only. The subsequent fall in GFR was preceded by severe proteinuria. The mean survival time of UNX-FHH rats was only 35 wk. Micropuncture studies showed that the high mean glomerular capillary pressure of 2K-FHH rats was further elevated after UNX. The glomerular capillary ultrafiltration coefficient did not differ significantly between UNX-FHH and 2K-FHH rats. The weight of the remaining kidney and the mean glomerular tuft volume in UNX-FHH were, on average, 36 and 31% greater than in 2K rats. The results indicate that the FHH rat is extremely vulnerable to the adverse renal effects of UNX.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Study of High‐Flux Cuprammonium Rayon Hemodialysis Membranes

The aim of this crossover clinical study was to gain basic information on the hemocompatibility and effectiveness of recently developed high-flux membranes made of cuprammonium rayon with ultrafiltration coefficients of 10, 17, and 19 ml/mm Hg/h (S12W, SU12W, and SS12W dialyzers, respectively), and to identify any possible differences from a conventional membrane made of the same material with an ultrafiltration coefficient of 6 ml/mm Hg/h (C12W dialyzer). All the tested membranes led to an abrupt drop in leukocyte count in the initial phase of hemodialysis. In high-flux membranes, C5a anaphylatoxin would pass into the dialysate, but mean C5a anaphylatoxin concentrations in the dialysate were lower by orders of magnitude than its plasma concentrations, which behaved, in high- and low-flux membranes alike, typically of those made of nonsubstituted cellulose with no intermembrane differences. As judged by the concentrations of the thrombin-antithrombin III complex, the coagulation system was activated--again, without differences between membranes. The reduction rates for urea, creatinine, and phosphates were comparable for all the tested membranes. Compared with baseline, the post-dialysis serum concentrations of beta 2-microglobulin in high-flux membranes, unlike the low-flux membrane, were significantly lower. We conclude that there are no significant differences between the tested high- and low-flux membranes made of cuprammonium rayon in the monitored hemocompatibility parameters, and that high-flux membranes are capable of reducing serum beta 2-microglobulin concentrations.

Osmotic barrier properties of the rat peritoneal membrane.

In this study the osmotic barrier characteristics of the rat peritoneal membrane were investigated. Fluid movements between the peritoneal cavity and the blood were measured following instillation of isotonic saline (control) and hypertonic solutions of NaCl, glucose, sucrose, raffinose and myoglobin (test solutions). Moreover, 5 and 8% albumin in NaCl were investigated. Osmotic transients were assessed using a simple volume recovery technique. Peritoneal osmotic conductances (i.e. products of peritoneal hydraulic conductances [LpS] and solute reflection coefficients [sigma]) were calculated from the differences in the rates of peritoneal fluid loss and in osmotic pressures between test solutions and the isotonic saline control solution. The osmotic conductance to glucose was estimated to be 1.63 microliters min-1 mmHg-1 m-2 and that for albumin to be 59.6 microliters min-1 mmHg-1 m-2. Assuming an albumin sigma of 0.9, the sigma of glucose was estimated to be 0.025, in accordance with previous measurements for the cat peritoneal membrane. The osmotic conductances assessed here were compatible with an 'overall' peritoneal equivalent small pore radius of 47-48 A, but could also be fitted to a three-pore model of peritoneal permselectivity, including a transcellular (ultra-small pore) pathway and a large pore pathway. The great discrepancy between peritoneal sigma for small solutes and that for albumin obtained in this study indicates that small solute reflection coefficients are close to zero while that for albumin is not far from unity. Furthermore, the peritoneal hydraulic conductance (ultrafiltration coefficient) is large enough to allow for a substantial absorption of fluid directly into the plasma when the crystalloid osmotic pressures in blood and peritoneal dialysate are in equilibrium.

Role of endothelium-derived nitric oxide in control of renal microvasculature in aging male rats

The objective of this study was to evaluate the role of nitric oxide (NO) in the regulation of whole kidney and glomerular hemodynamics during aging. After 2 wk of oral treatment with N-nitro-L-arginine methyl ester (L-NAME; 4.5 mg.kg body wt-1.day-1) to inhibit NO synthesis, male rats, aged 3-5, 13-15, and 21-24 mo, were studied by micropuncture. Blood pressure increased by 50% in old (21-24 mo) rats with L-NAME but only 20-30% in the two younger groups. With L-NAME, renal vascular resistance increased fivefold in old rats but only twofold in younger groups. Glomerular capillary pressure increased 20-30% in younger L-NAME rats and 60% in older rats. Afferent and efferent resistances increased dramatically, and the glomerular capillary ultrafiltration coefficient decreased in all L-NAME-treated rats but most strikingly in the 21- to 24-mo-old group. Acute infusion of L-arginine significantly attenuated the effects of NO synthase inhibition on arterial pressure and renal hemodynamics in both young and old rats. This study confirms that NO synthesis blockade has a greater effect on renal hemodynamics in aging rats and implies that NO may play a progressively more important role in controlling renal function with advancing age.

Renal renin-angiotensin system in diabetes: functional, immunohistochemical, and molecular biological correlations

Recent evidence indicates a role for the renin-angiotensin system (RAS) in the pathogenesis of glomerular injury in diabetes. To further explore the RAS in diabetes, studies were conducted in nondiabetic control rats and in moderately hyperglycemic diabetic (DM) rats. In DM rats, both acute and chronic therapy with the specific angiotensin II (ANG II) receptor antagonist losartan did not affect glomerular hyperfiltration or hyperperfusion but selectively normalized the glomerular capillary hydraulic pressure and ultrafiltration coefficient. To determine the basis of intrarenal hemodynamic responsiveness to RAS inhibition, we conducted biochemical, molecular biological, and immunohistochemical studies to assess endogenous RAS activity. Values for plasma renin concentration and serum angiotensin-converting enzyme (ACE) activity in DM rats were normal. In contrast, intrarenal renin protein content, and renin and angiotensinogen mRNAs, were increased in DM rats, suggesting disproportionate activation of the intrarenal RAS. Total renal ACE activity was significantly reduced in DM rats, but immunohistochemical studies indicated redistribution of ACE in the diabetic kidney. Proximal tubule ACE activity was reduced, but ACE immunostaining intensity was enhanced in glomeruli and renal vasculature. Together, these observations indicate increased RAS activity in those sites (glomeruli and vasculature) most likely to regulate hemodynamic function, potentially explaining the prominent responses to pharmacological blockade of ANG II formation and/or action.

Effects of growth hormone and IGF-I on glomerular ultrafiltration in growth hormone-deficient rats.

In growth hormone deficient states glomerular filtration rate (GFR) and renal plasma flow rate (RPF) are both reduced. Studies were performed in growth hormone deficient rats to delineate the physiologic mechanisms by which growth hormone and IGF-I contribute to the regulation of glomerular function. Growth hormone deficient dw/dw rats received, for one week, subcutaneous infusions of vehicle, des(1-3)IGF-I or were injected i.m. with recombinant human growth hormone. Subsequent renal micropuncture and clearance studies revealed a low GFR and single nephron GFR (SNGFR) in vehicle treated growth hormone deficient animals. Glomerular function became normal with growth hormone or IGF-I treatment, respectively. Both treatments raised SNGFR by reducing arteriolar resistance and increasing the glomerular ultrafiltration coefficient. Furthermore, the two treatments also increased the glomerular tuft volume and the kidney weight which may contribute to the rise in SNGFR and GFR. It is concluded that, (1) in growth hormone deficiency glomerular function is reduced secondary to a high renal arteriolar resistance and a low ultrafiltration coefficient. Both result from a lack in IGF-I rather than the growth hormone deficiency state per se. (2) The growth hormone-IGF-I axis may contribute to the maintenance and physiologic regulation of GFR.

Bradykinin causes selective efferent arteriolar dilation during angiotensin I converting enzyme inhibition

We studied the effects of interruption of the renin-angiotensin system (RAS) in rats that were volume depleted by water deprivation for 48 hours (AWD) with/without furosemide (AWD + F), a condition known to activate RAS. Following baseline micropuncture, AWD rats (N = 6) were treated with a specific angiotensin II type 1 receptor antagonist (AIIRA; 4 mg/kg body wt bolus i.v. and then continuous infusion) and glomerular hemodynamics compared to those obtained during angiotensin I converting enzyme inhibitor treatment (ACEI; 24 mg/kg bolus i.v. and then continuous infusion). Systemic blood pressure decreased equally following AIIRA and ACEI. Single nephron glomerular filtration rate (SNGFR) increased from baseline following AIIRA (24 nl/min vs. 30, P < 0.025). While a decrease in efferent arteriolar resistance (RE) reduced glomerular capillary pressure (PGC; 67 mm Hg vs. 60, P < 0.05), this change in RE together with decrease in afferent arteriolar resistance (RA), enhanced glomerular plasma flow rate (QA; 80 nl/min vs. 111). Antagonizing angiotensin II receptor increased QA which, together with the tendency to increase glomerular capillary ultrafiltration coefficient, Kf, served to improve glomerular filtration. By contrast, although inhibition of the angiotensin I converting enzyme caused greater vasodilatation, no increase in SNGFR occurred. The lack of response in filtration after ACEI was due to a further fall in PGC to 52 mm Hg (P < 0.01 vs. AIIRA), reflecting profound reduction in RE. Since ACEI but not AIIRA potentiates bradykinin activity we examined effects of a specific bradykinin antagonist (Hoe).(ABSTRACT TRUNCATED AT 250 WORDS)

Continuous Veno-Venous Hemofiltration in Critically Ill Patients with Multiple Organ Failure

18 critically ill patients, with multiple organ failure (MOF) (from shock either septic, n = 15, or cardiogenic, n = 3), oliguria and increase in BUN and creatinine were treated with pump driven, high flux continuous veno-venous hemofiltration (CVVH). Replacement fluids were administered in predilution mode. All patients were under respiratory support and vasoactive drugs, and received early nutritional support (N input: 0.2-0.3 g/kg/day). Mean duration of treatment was 9.2 days and mean ultrafiltrate production was 21.4 l/day; treatment resulted in a significant reduction of both urea nitrogen and creatinine blood levels (-20 and -40% of initial values respectively) in spite of a very severe catabolism. The total amount of urea nitrogen removed through CVVH ranged from 15 to 73 g/day (mean 33.5), the median value of urea nitrogen clearance was 12.8 ml/min with a median ultrafiltration coefficient of 0.8. The mean duration of hemofilters was 69 hours (38-108); the efficacy of filters remained stable throughout the entire lifespan and changes were made in case of sudden decrease of ultrafiltration (< ml/min). No major complication was observed in over than 4000 hours of treatment. Pump driven, high flux CVVH proved effective in the control of water electrolyte balance and metabolic homeostasis in a group of critically ill, hemodynamically unstable, catabolic patients with MOF and acute renal failure. In no case we had to add intermittent hemodialysis or to use hemodiafiltration. The constant extracorporeal blood flow and the stable efficacy of hemofilters allowed an easy control of the overall effectiveness of this technique.

The Effect of Dialyzer Reprocessing on Performance and β2-Microglobulin Removal Using Polysulfone Membranes

Increased biocompatibility and lower cost are the two major arguments favoring routine dialyzer reprocessing. The impact of longer-term reprocessing is critical to the practical use of polysulfone membranes (PMs), because of the possibility of decreasing efficiency and performance, especially in the removal of beta 2-microglobulin (beta 2M), a protein that has been implicated in the development of dialysis-associated amyloidosis (DDA). In this study, we examine urea clearance (Kd), urea mass transfer coefficient (h0), ultrafiltration coefficient (K(uf)), and percent removal of beta 2M up to 24 uses. The study involved 11 patients on hemodialysis for 5.27 +/- 4.6 years, with a mean age of 62.5 +/- 9.7 years and average run-time treatment of 2.78 +/- 0.3 hours. PMs were tested after being reprocessed manually using bleach and formaldehyde. The efficacy of the dialyzer was examined on uses 1, 5, 10, 15, 20, and 24, and the percent removal of beta 2M was determined except in the twentieth use and corrected for ultrafiltration. The Kd obtained through 24 uses showed no significant change, although h0 was significantly increased in the fifteenth use, and K(uf) was significantly increased in the 10th and 20th use (P < 0.05). The percent removal of beta 2M increased significantly from 44.1 +/- 2.8 (mean +/- SEM) in the first use to 59.4 +/- 2.19 (P < 0.05) in the 10th use, and 62.1 +/- 4.07 and 63.1 +/- 4.27 in the 15th and 24th uses, respectively (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Leukotriene D4 is a mediator of proteinuria and glomerular hemodynamic abnormalities in passive Heymann nephritis.

We assessed the role of leukotrienes (LTs) in Munich-Wistar rats with passive Heymann nephritis (PHN), an animal model of human membranous nephropathy. 10 d after injection of anti-Fx1A antibody, urinary protein excretion rate (Upr) in PHN was significantly higher than that of control. Micropuncture studies demonstrated reduced single nephron plasma flow and glomerular filtration rates, increased transcapillary hydraulic pressure difference, pre- and postglomerular resistances, and decreased ultrafiltration coefficient in PHN rats. Glomerular LTB4 generation from PHN rats was increased. Administration of the 5-LO activating protein inhibitor MK886 for 10 d markedly blunted proteinuria and normalized glomerular hemodynamic abnormalities in PHN rats. An LTD4 receptor antagonist SK&F 104353 led to an immediate reduction in Upr and to reversal of glomerular hemodynamic impairment. Ia(+) cells/glomerulus were increased in PHN rats. In x-irradiated PHN rats, which developed glomerular macrophage depletion, augmented glomerular LT synthesis was abolished. Thus, in the autologous phase of PHN, LTD4 mediates glomerular hemodynamic abnormalities and a hemodynamic component of the accompanying proteinuria. The synthesis of LTD4 likely occurs directly from macrophages or from macrophage-derived LTA4, through LTC4 synthase in glomerular cells.

Glomerular hemodynamics in aortocaval fistula rats: role of renin-angiotensin system

To investigate intrarenal hemodynamics of aortocaval, arteriovenous (AV)-fistula rats and the effect of angiotensin-converting-enzyme (ACE) inhibition, micropuncture studies were obtained before and after administration of quinapril (100 micrograms.kg-1 x min-1), an ACE inhibitor. AV fistula produced by needle multipuncture was characterized by elevated left ventricular end-diastolic pressure (LVEDP), lower mean arterial pressure, and increased left and right ventricular weights. Effective renal plasma flow was lower in AV-fistula rats, and single-nephron glomerular filtration rate (SNGFR) and plasma flow (SNPF) were reduced. Single-nephron filtration faction (SNFF), stop-flow pressure, and glomerular pressure (PG) were increased. The lower SNGFR and SNPF and higher PG and SNFF were associated with higher afferent and efferent arteriolar resistances (RA and RE) and lower ultrafiltration coefficient (Kf). LVEDP correlated positively with with RA, RE, and SNFF (all P < 0.01) and negatively with SNGFR (P < 0.05) and SNPF (P < 0.01). After quinapril these variables returned toward normal. Thus this method for producing AV fistula was useful in creating mild and moderately severe cardiac failure (CHF). Intrarenal hemodynamics of AV were characterized by increased PG and SNFF and lower SNGFR and SNPF associated with increased RA and RE and lower Kf and SNPF correlated and with severity of CHF. Restoration of intrarenal hemodynamics to or toward normal with quinapril supports an important pathophysiological role of renin-angiotensin system in this CHF.

Renal response to angiotensin after short-term angiotensin converting enzyme inhibition.

In 13 normotensive subjects on a normal sodium diet, we studied hormonal, blood pressure, and renal vascular changes and dextran sieving profiles induced by infusion of exogenous angiotensin II (Ang II) (5 ng.kg-1.min-1). during baseline conditions and after 5 days of administration of the angiotensin converting enzyme inhibitor cilazapril. Cilazapril induced a renal vasodilative effect without affecting supine blood pressure and glomerular filtration rate. Fractional dextran clearances were significantly decreased for dextran of effective radius ranging from 3.0 to 4.0 nm. This shift was primarily related to an increase in glomerular capillary plasma flow, because no change was observed in the transcapillary glomerular pressure gradient, the ultrafiltration coefficient, or the membrane parameters. Ang II elicited a slight pressor response accompanied by hormonal, antinatriuretic, and renal hemodynamic changes that were similar during and before short-term angiotensin converting enzyme inhibition. Dextran sieving curves were unchanged by a low dose of Ang II. However, the transcapillary glomerular pressure gradient and the ultrafiltration coefficient were computed to increase by 19.4% and to decrease by 44.2%, respectively, whereas membrane parameters were unaffected. When superimposed onto short-term angiotensin converting enzyme inhibition, glomerular response to this unique dose of Ang II was similar to that induced by Ang II alone. These findings indirectly suggest that most, if not all, of the renal effects of cilazapril are mediated through suppression of Ang II formation.

Atrial Natriuretic Factor and Liver Disease

A working formulation for the role of ANF in the sodium retention of cirrhosis is summarized in Figure 4. Sodium retention is initiated early in cirrhosis, either as a result of hepatic venous outflow block or of primary vasodilation. The consequent intravascular volume expansion causes increases in ANF levels. At this stage of disease, the rise in ANF level is sufficient to counterbalance the antinatriuretic influences. However, this occurs at the expense of an expanded intravascular volume with the potential for overflow ascites. With progression of disease, disruption of intrasinusoidal Starling forces and loss of volume from the vascular compartment into the peritoneal compartment occur. This underfilling of the circulation may attenuate further increases in plasma ANF and promotes the activation of antinatriuretic factors. At this later stage of disease, elevated levels of ANF are insufficient to counterbalance antinatriuretic influences. Thus the role of ANF in cirrhosis is primarily beneficial in that it successfully attenuates the antinatriuretic forces in the compensated stage. Raised ANF levels have two potential deleterious effects. First, ANF may exacerbate arterial vasodilation, leading to further sodium retention. The primacy of vasodilatation has been proposed as an alternate formulation to the overflow and underfill hypotheses. Second, Epstein et al. found higher basal ANF levels in cirrhotic patients with edema than in those patients without edema. ANF is known to reduce plasma volume in anephric animals and to increase the ultrafiltration coefficients of isolated capillaries. Therefore it is conceivable that in the clinical setting in which antinatriuretic factors limit the renal responsiveness to ANF but in which ANF levels are elevated (i.e., cirrhosis, congestive heart failure, primary kidney disease), ANF itself may contribute to edema formation at the level of the peripheral microcirculation. In general, ANF likely has no primary role in the sodium retention in cirrhosis. In early compensated cirrhosis, ANF may maintain sodium homeostasis despite the presence of mild antinatriuretic factors. In late ascitic cirrhosis renal resistance to ANF develops, rendering it ineffective.(ABSTRACT TRUNCATED AT 400 WORDS)

Locally produced EDRF controls preglomerular resistance and ultrafiltration coefficient

During systemic acute blockade of endogenous endothelial-derived relaxing factor (EDRF) with N-monomethyl-L-arginine (NMA), a significant rise in arterial blood pressure (BP) occurred in the anesthetized rat. Renal vasoconstriction was also seen, with complex changes in glomerular hemodynamics; both preglomerular (RA) and efferent arteriolar (RE) resistances increased, producing a fall in glomerular plasma flow (QA) and a rise in glomerular blood pressure (PGC). The glomerular capillary ultrafiltration coefficient (Kf) was reduced. The net effect was a small fall in single-nephron glomerular filtration rate (SNGFR). To determine the effects of local EDRF blockade, two additional groups were studied with intrarenal administration of NMA; in the first series, one-tenth of the systemic dose was given, which produced no change in BP, a small renal vasoconstriction with an increase in RA, but no change in RE; thus PGC was unaffected. Kf fell, and a small reduction in SNGFR was seen. With a larger intrarenal dose of NMA (one-fifth systemic) a moderate rise in BP occurred, but only RA rose; RE and PGC were unaffected, and Kf and SNGFR fell. These observations suggest that locally produced EDRF controls RA and Kf and that a rise in RE and PGC is only seen with systemic EDRF blockade when a large rise in BP occurs.

The synergistic effects of cyclosporine and endothelin--demonstration of an important cardiodepressor action.

Cyclosporine represents the foundation for current immunosuppressive therapy following solid organ transplantation. CsA use is associated with renal insufficiency and systemic hypertension. We hypothesized that CsA would enhance the vascular actions of endothelin (ET). Three groups of anesthesized dogs (n = 15) were studied. Group 1 received CsA alone (1 mg/kg), group 2 received ET alone (1 ng/kg/min), and group 3 received combined CsA (1 mg/kg) and ET (1 ng/kg/min). The hemodynamic and renal effects were evaluated after 30 min. Combined treatment resulted in a profound reduction in mean arterial pressure (-62 +/- 14 mmHg (P < .05) and cardiac output (-2.2 +/- 0.4.1/min (P < .05). The reduction in mean arterial pressure and cardiac output were significantly greater than that observed with CsA or ET alone. Systemic vascular resistance was not significantly changed. Combined CsA and ET resulted in a significant reduction in renal blood flow (195 +/- 18 to 101 +/- 11 ml/mm P < .05) but without evidence of active renal vasoconstriction. The decline in GFR (31.8 +/- 5.6 ml/min to being unmeasurable) was of greater magnitude than the change in renal blood flow, suggesting enhanced afferent anteriolar vasoconstriction or an alteration in the ultrafiltration coefficient. These studies demonstrate an important and synergistic cardiodepressor effect when CsA and ET are combined.

A Three-Pore Model of Peritoneal Transport

The three-pore model of peritoneal transport treats the capillary membrane as a primary barrier determining the amount of solute that transports to the interstitium and the peritoneal cavity. According to the three-pore model, the principal peritoneal exchange route for water and water-soluble substances is a protein-restrictive pore pathway of radius 40-55 A, accounting for approximately 99% of the total exchange (pore) area and approximately 90% of the total peritoneal ultrafiltration (UF) coefficient (LpS). For their passage through the peritoneal membrane proteins are confined to so-called "large pores" of radius approximately 250 A, which are extremely few in number (0.01% of the total pore population) and more or less nonrestrictive with respect to protein transport. The third pathway of the three-pore model accounts for only about 2% of the total LpS and is permeable to water but impermeable to solutes, a so-called "water-only" (transcellular?) pathway. In contrast to the classical Pyle-Popovich (P&P) model, the three-pore model can predict with reasonable accuracy not only the transport of water and "small solutes" (molecular radius 2.3-15 A) and "intermediate-size" solutes (radius 15-36 A), but also the transport of albumin (radius 36 A) and larger molecules across the peritoneal membrane. The model operates with reflection coefficients(a) (sigma's) for small solutes < 0.1. These are approximately one order of magnitude lower than the sigma's in the P&P model. Furthermore, the peritoneal LpS is one order of magnitude higher than in the P&P model.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of mesangial cell in glomerular response to volume and angiotensin II

We have examined the physiological role of the mesangial cell in the regulation of glomerular hemodynamics utilizing mesangial cell lysis by the administration of antithymocyte antibody serum (ATS) 24 h before micropuncture evaluation. Plasma volume expansion (PVE) in normal NaCl-depleted rats increased single-nephron glomerular filtration rate (SNGFR) by 30% because of increases in single-nephron plasma flow (SNPF), whereas glomerular capillary hydrostatic pressure (PG) remained constant. SNGFR did not increase with PVE in NaCl-depleted ATS rats despite increases in SNPF, and PG increased significantly (51 +/- 2 to 67 +/- 3 mmHg) because of afferent arteriolar dilation, whereas efferent resistance remained elevated. Angiotensin II (ANG II) infusion in normal rats decreased SNGFR because of reductions in SNPF and the glomerular ultrafiltration coefficient (LpA), whereas the hydrostatic pressure gradient (delta P) increased. In ATS rats ANG II infusion did not change SNGFR, LpA, or delta P. These in vivo studies suggest that the mesangial cell plays an important role in the regulation of LpA, efferent arteriolar resistance, and the regulation of PG, whereas this cell exerts little effect on the afferent arteriole.