Peripheral Microvascular Parameters in the Nephrotic Syndrome

Home , Oncotic pressure, Starling equation

Kidney International, Vol. 54 (1998), pp. 1261–1266

Peripheral microvascular parameters in the nephrotic syndrome

DAVID M. LEWIS,JOHN E. TOOKE,MARTIN BEAMAN,JOHN GAMBLE, and ANGELA C. SHORE

Renal Unit, Royal Devon and Exeter Hospital, and Department of Vascular Medicine, University of Exeter, Exeter; and Department of Physiology, Charing Cross & Westminster Medical School, London, England, United Kingdom

Peripheral microvascular parameters in the nephrotic syndrome. findings in several studies that plasma volume is not Background. Peripheral edema, in combination with severe necessarily reduced, and indeed is normal or elevated in the proteinuria and low serum albumin levels, is pathognomonic of majority of subjects [3]. In addition, renal sodium and water the nephrotic syndrome, yet the exact mechanism of its formation is unknown. Two of the most important of the factors in Starling’s handling mechanisms have been shown to be impaired in forces controlling fluid filtration across the capillary have hitherto the nephrotic state in experimental models [4], and humans not been studied in nephrotic subjects. [5]. The “overflow” hypothesis regards the primary intra- Methods. The hydrostatic capillary pressure at the finger nail- renal deficits in sodium/water excretion to be causing fluid fold in actively nephrotic subjects and age and sex matched retention, a tendency towards increased plasma volume, controls was studied, using direct puncture of the apex of the capillary under video microscopy, and a servonulling apparatus to and overflow edema formation [6, 7]. At a microvascular give a direct measurement of capillary pressure. Capillary filtra- level, an increase in capillary hydrostatic pressure is hy- tion capacity (CFC) at the calf was measured noninvasively by a pothesized as the factor causing extravascular fluid accu- modern derivative of the technique of mercury strain gauge mulation and edema formation. plethysmography. Fifteen nephrotic subjects with a variety of Microvascular fluid exchange is governed by the so-called underlying pathological lesions, and age matched controls were studied. Starling’s forces. Expressed in equation form for a single Results. Contrary to the assumption of the “overflow” hypoth- capillary the flow of fluid across the capillary wall, a esis of edema formation, there was no evidence of capillary semi-permeable membrane, is related to the balance of hypertension. The capillary pressure showed no difference be- hydrostatic and oncotic forces acting across the capillary. tween nephrotic subjects and controls: median (range) of 17.6 ϭ ϭ Ϫ Ϫ ␴ ␲ Ϫ ␲ (12.0 to 24.2) compared with 17.3 (9.0 to 21.6) mm Hg, P NS. Jv LpS {(Pc Pi) ( p i)} CFC was significantly higher in nephrotic subjects than controls Ϫ Ϫ [5.23 (3.28 to 8.52) ϫ 10 3 versus 3.55 (2.43 to 5.28) ϫ 10 3 where Jv is the fluid flux or net rate of fluid movement, Lp ml/min/100 g/mm Hg, P Ͻ 0.01]. is the hydraulic conductivity and S the surface area of the ␴ Conclusions. An increase in CFC provides a potentially novel capillary wall; LpS is hydraulic conductance; is the mechanism contributing at least in part to the formation of reflection coefficient for protein; Pc and Pi are the capillary peripheral edema in the nephrotic syndrome. ␲ and interstitial hydrostatic pressures, respectively; and p ␲ and i are the osmotic pressures of plasma and interstitial fluid, respectively. The mechanisms of edema formation in the nephrotic The Starling equation applies to a single short section of syndrome are not resolved at a microvascular level. The capillary. For a whole organ, including human limbs, the early underfill theory suggested a physiological process of capillary filtration coefficient or capacity (CFC) represents renal salt and water retention, secondary to hypovolemia the sum of the product of the average hydraulic conductiv- from reduced serum colloid osmotic pressures due to ity of the walls of the exchange vessels within the tissue and ⌺ hypoalbuminemia [1]. The stimulus for edema formation their total exchange area (LpS) [8]. would initially be low serum oncotic pressure and subse- A number of the factors in this equation have been quently salt and water overload [2]. However, an alterna- measured in the nephrotic state. Colloid osmotic pressure tive “overflow” hypothesis was developed based on the of plasma and interstitial fluid drops in parallel until profoundly low levels of serum albumin are reached, an important anti-edema mechanism [9]. Interstitial hydro- Key words: capillary pressure, capillary filtration capacity, nephrotic, static pressure was elevated in edematous areas as would be edema, glomerulonephritis, diuretics, Starling forces. expected [10]. However, the rate limiting factor for micro- Received for publication January 23, 1998 vascular fluid exchange, capillary filtration capacity, has not and in revised form May 13, 1998 been measured, nor has capillary hydrostatic pressure. Accepted for publication May 13, 1998 The currently favored overflow theory suggests an ele- © 1998 by the International Society of Nephrology vated capillary hydrostatic pressure as the driving force

1261 1262 Lewis et al: Microvascular studies in nephrotic syndrome

Table 1. Characteristics of nephrotic subjects and controls. Results are expressed as median (range)

Nephrotic patients with All nephrotic capillary pressure Controls for capillary patients Controls P measurement pressure group P Female/male number 8/7 8/7 2/6 2/6 Age years 57 (21–79) 56 (21–77) NS 53 (27–69) 57 (27–70) NS Body mass index kg/m2 27 (23–34) 24 (20–35) NS 27 (23–34) 23 (19–32) NS Mean arterial pressure 103 (77–131) 104 (86–124) NS 102 (98–131) 97 (91–122) NS mm Hg 24 Hour urinary protein g 7.1 (3.8–22.4) — 7.1 (3.8–22.4) — Urine protein/creatinine ratio — 67 (38–125) — NR 0–125 Serum creatinine 142 (64–604) 79 (70–120) Ͻ0.01 143 (64–280) 86 (77–110) Ͻ0.05 NR 45–120 ␮mol/liter Serum albumin 24 (15–29) 41 (38–44) Ͻ0.01 24 (17–29) 40 (35–44) Ͻ0.01 NR 30–48 g/liter Time edematous weeks 8 (1–24) None 8 (2–20) None Diuretics 10 None 6 None Abbreviations are: NR, normal range; NS, not significant. resulting in peripheral edema formation. Alternatively, place in a resting supine position in a temperature con- systemic changes in capillary permeability to water [11] and trolled environment (22 Ϯ 1°C) after acclimatizing supine albumin [12] have been postulated in the nephrotic syn- for 30 minutes. Brachial arterial blood pressure was deter- drome, with increased peripheral transcapillary escape mined from five measurements by an automated blood rates or gastrointestinal loss of albumin [13]. The aims of pressure recorder (Dynamap 845; Critcon Inc., Tampa, FL, the present study were (1) to test the overflow hypothesis, USA) and skin temperature measured at the finger nailfold that the capillary hydrostatic pressure of peripheral capil- or calf by thermocouple (Fluke 52; RS Components, Corby, laries is increased in the nephrotic syndrome; (2) to test the UK). Capillary pressure and filtration coefficient measure- hypothesis that peripheral capillary fluid leakiness is in- ments were undertaken at separate times but under the creased in the nephrotic syndrome; and (3) to assess same experimental conditions. whether capillary pressure and capillary filtration capacity Ten patients were treated with loop diuretics that were are altered by diuretic therapy. omitted on the day of study. One nephrotic patient had received a short course of nifedipine and this was discon- METHODS tinued two days before study. The group of patients in Fifteen subjects (8 females, aged 21 to 79 years) were whom capillary pressure measurements were made did not recruited. All were clinically and biochemically nephrotic contain any with a diagnosis of amyloid, myeloma or light with varying degrees of edema. Details of subjects and chain disease. controls are given in Table 1. Underlying renal pathologies The study was approved by the local Medical Research were as follows: three minimal change glomerulonephritis Ethics Committee and participants gave written informed (MCGN), one later developing focal segmental glomerulo- consent. sclerosis (FSGS), four membranous glomerulonephritis, one myeloma, two amyloid, three proliferative glomerulo- Measurement of capillary pressure nephritis, one light chain disease, and one undiagnosed (failed renal biopsy). Capillary pressure was measured in The method of capillary pressure measurement has been eight subjects, the estimation not being possible in the described in detail elsewhere [14]. Briefly, a scalpel blade remainder because of: poorly visible capillaries (N ϭ 1); was used to carefully remove the upper dead layer of Raynaud’s phenomenon, which may have a confounding opaque stratum corneum from two fingers of the left hand influence on capillary pressure (N ϭ 2); or inability to without inducing bleeding or inflammation. The finger schedule the examination before commencing disease mod- under study was held in a plasticine mould to minimise ifying treatment (N ϭ 4). Control subjects were matched movement and a Granuflex ring (Squibb, Hounslow, Mid- for age (Ϯ 5 years), sex and in the case of premenopausal dlesex, UK) placed around the nailfold to retain a pool of females, menstrual cycle phase. Controls for capillary pres- 0.9% saline to aid visualization of the capillary and measure studies were also matched for nailfold skin tempera- surement of atmospheric pressure. Nailfold capillary pres- ture as capillary pressure is known to be related to this sure was measured following direct cannulation of the apex variable. of the capillary loop by glass micropipette held in a Subjects were asked to refrain from taking caffeine or micromanipulator. An electronic resistance feedback ser- smoking for two hours before the tests. Investigations took vonulling system allowed dynamic pressure recording, Lewis et al: Microvascular studies in nephrotic syndrome 1263 which was filtered, digitized and stored on computer for later off-line analysis. Previous work has shown capillary pressure determina- tions to be highly reproducible both between capillaries across the nailfold (coefficient of variation 5.4%) in nine capillaries measured at the same visit in five individuals, and within the same individual over time (coefficient of variation 9.6%) for six measurements over six months [15]. For capillary pressure studies, previous control population data have shown a population SD for capillary pressure of 2.5 mm Hg. Based on this 16 subjects in each group would be required to have a 90% power to showa3mmHg difference in capillary pressure between groups at a signif- icance level of 5%. The capillaries of the finger nailfold belong to the same class of continuous capillaries as found in skin, connective tissues and skeletal muscle. Develop- mentally this area is an outgrowth of the dorsal skin of the hand. During the measurements pitting edema was observed in the tissues of the distal phalanx of adjoining fingers. Nevertheless, it is important not to assume that the measurements of the capillary pressure at the finger nailfold are necessarily representative of all edema forming regions.

Measurement of capillary filtration capacity Mercury-in-silastic strain gauge plethysmography was used to measure calf capillary filtration capacity (CFC), as Fig. 1. Capillary pressure in patients with nephrotic syndrome and age- ϭ described by Gamble, Gartside and Christ [16]. This and sex-matched controls. P NS. method measures changes in calf volume in response to a series of small pressure increments in a thigh occlusion cuff. The technique has a number of theoretical advantages microvascular wall. Although no net filtration was taking over single step techniques [8]. A multiple inlet thigh place, this did not preclude simultaneous movement of occlusion cuff was rapidly inflated by electric pump, with fluid into and out of the capillary. Calf tissue compliance pressure regulated by a multiple resistance air bleed valve. was calculated from the gradient of the regression line of Serial pressure increments of 8 to 12 mm Hg were made at the venous compliance volumes plotted against cuff pres- five minute intervals to increase lower limb venous pressure. sure. Calf swelling rate was recorded by a mercury-in- Using this technique to measure capillary filtration coef- silastic strain gauge mounted in a temperature compensat- ficient in four normal individuals, studied four to six times ing holder applied to the upper calf. Once ambient venous over 10 months, the mean intra-individual coefficient of pressure was exceeded, each increase in cuff pressure variation was 9.1 Ϯ 5.6% (mean Ϯ SD) and for Pvi was produced a characteristic response. This comprised an 10.7 Ϯ 4.7%. initial rapid calf volume increase, which was due to filling of capacitance vessels (the venous compliance) and could be Statistical analysis modeled with a negative exponential curve with a time Data are presented in the text as median (range), constant of approximately 15 seconds. The concurrent assuming a non-parametric distribution. Comparison be- linear phase to the response reflected the fluid flux across tween groups was made using Mann-Whitney U-test. Cor- the capillary bed. Traces were recorded on microcomputer relations were examined by the two-tailed Spearman rank for later analysis. Values for fluid flux were obtained from test. the gradient of the linear phase of each volume response curve at a period greater than five time constants from the RESULTS increase in cuff pressure. The slope of the regression line of Capillary pressure showed no difference between ne- fluid flux and corresponding cuff pressure was calculated to phrotic subjects and controls: 17.6 (12.0 to 24.2) compared give the CFC. The horizontal intercept was the isovolumet- with 17.3 (9.0 to 21.6) mm Hg, P ϭ NS (Fig. 1). CFC was ric venous pressure (Pvi), defined as the pressure at which significantly higher in nephrotic subjects than controls: 5.23 Ϫ Ϫ there was neither net fluid filtration nor absorption at the (3.28 to 8.52) ϫ 10 3 versus 3.55 (2.43 to 5.28) ϫ 10 3 1264 Lewis et al: Microvascular studies in nephrotic syndrome

DISCUSSION

This study has demonstrated an increase in calf capillary filtration capacity in patients with active nephrotic syndrome, as demonstrated by a multi-step strain gauge plethysmography technique, providing a novel explanation for edema formation in this condition. There was no difference in finger nailfold capillary pressure in the subset in whom measurement was possible, a finding that is at odds with the overflow theory of edema formation. Cardiac edema is typically associated with central venous pressure elevation and the traditional model of the pathogenesis suggests that the principal change in Starling’s forces is an elevation of capillary hydrostatic pressure. Indeed, in established peripheral edema states of acute nephritis and cardiac failure [17, 18] finger nailfold capillary pressure has been shown to be significantly elevated, albeit with a less accurate method. It is possible that nephrotic patients with severely diminished renal function and hypertension might have elevated capillary pressures. In the nephrotic syndrome two models of edema formation have evolved. The underfill model assumes intravascular depletion due to fluid flux from plasma caused by depleted plasma oncotic pressure. The relative hypovolemia produced would stimulate a secondary, physiological, renal fluid retention. This hypothesis has been disputed because Fig. 2. Capillary filtration capacity in patients with nephrotic syndrome of lack of agreement in studies of plasma volume, as and age- and sex-matched controls. P Ͻ 0.01. summarized by Dorhout Mees, Geers and Koomans [3]. More recently, generalized salt and water overload has been attributed to an intrinsic renal defect causing fluid ml/min/100 g/mm Hg, P Ͻ 0.01 (Fig. 2). Pvi was significantly retention (overflow model), and an increase in capillary lower in nephrotic subjects 14.0 (1.8 to 38.4) versus 24.9 hydrostatic pressure has been proposed to explain the (17.7 to 35.6) mm Hg P Ͻ 0.01. Calf tissue compliance 5.3 production of peripheral edema. Ϫ (2.8 to 7.1) ϫ 10 2 versus 4.1 (2.5 to 10.2) ml/mm Hg and Referring back to the Starling equation, the microvascu- mean arterial blood pressure 102 (77 to 131) versus 104 (86 lar basis of edema formation can be considered from to 124) mm Hg were the same for both groups (P ϭ NS). changes of the various forces. Our data suggest that, CFC results for the nondiuretic treated subgroup alone contrary to the overflow theory, an elevation of capillary showed this group to have a significantly higher results pressure was not involved in edema formation at least at compared to their respective age and sex matched controls: the time of study, although it could be argued that in the Ϫ Ϫ 5.17 (4.04 to 6.84) ϫ 10 3 versus 2.92 (2.63 to 4.02) ϫ 10 3 current study patients were examined at a time of re- ml/min/100 g/mm Hg, P Ͻ 0.05. CFC for the diuretic established steady state equilibrium, with edema accumu- Ϫ treated subgroup was 5.52 (3.28 to 8.52) ϫ 10 3 ml/min/100 lation at an end. This would be compatible with normal g/mm Hg. Excluding subjects with myeloma, amyloid or capillary pressure, but only if other factors were abnormal light chain disease, nephrotic subjects had a CFC of 5.18 to maintain the edematous state. Increased fluid flux across Ϫ (3.20 to 8.14) ϫ 10 3, and controls of 3.55 (2.63 to 5.28) ϫ the capillary due to increased hydraulic conductance, in Ϫ 10 3 (P Ͻ 0.01). There was no significant difference keeping with our findings, could contribute both to forma- between capillary pressure in this subgroup and their tion and maintenance of peripheral edema. Plasma and ␲ ␲ controls, or any significant correlation at a level of signifi- interstitial colloid osmotic pressures ( p and I) fall in cance of 5% between serum albumin concentration or parallel as a function of dilution and washout in the urinary albumin loss and CFC or capillary pressure. There interstitium [9], and hence would not contribute to edema.

were no evident differences in microvascular parameters Interstitial pressure (Pi) is known to have a nonlinear between the groups of nephrotic subjects with different relationship with interstitial volume [19], and for the degree histological diagnoses, neither was there any correlation of edema seen in the subjects described here the interstitial between CFC and renal function as measured by serum pressure would be expected to be elevated from the normal creatinine concentrations. mildly negative pressures described in most subcutaneous Lewis et al: Microvascular studies in nephrotic syndrome 1265 tissues and species examined [20]. This, and the limited smaller capillary surface area per unit volume than in a compliance of the interstitium found in the early stages of nonedematous state. The assessment of dry weight in edema formation, provide an anti-edema mechanism. This edematous nephrotic subjects is complicated by the under- would oppose fluid flux due to the increased CFC observed lying loss of dry body wt [3], probably due largely to loss of in the present study, once the level of edema has reached a muscle mass. This would increase the ratio of other tissues, steady state. Only after the orientation of the interstitial including bone, to the muscle capillary bed and tend to proteoglycan structures has been deranged by significant result in an underestimation of CFC, independent of volume increase does the pressure volume curve adopt a changes in hydraulic conductance. As both factors may lead flat alignment and present relatively less impediment to to underestimates of CFC, they cannot explain our findings fluid flux from the capillary. Specific impairment of lym- of an increase in CFC in the nephrotic individuals. How- phatic drainage exacerbates the edema rather than being ever, they do raise the possibility that our values may the primary cause [21]. underestimate the true values. The possibility of a circulating factor altering peripheral Diuretics have been implicated in alteration of albumin capillary permeability in renal disease could be hypothe- permeability in a rat model [30]. It is unknown whether the sized. Various factors largely peculiar to MCNS or the use of loop diuretics in human subjects alters peripheral related FSGS, such as an altered charge on albumin and vascular leakiness. Ten of the subjects in this study had erythrocytes [22, 23], have implications for capillary func- ingested loop diuretics by mouth the day before the tests. It tion. Circulating factors affecting glomerular permeability was felt unethical to omit them for a longer period before have been proposed for some time [24]. Serum or plasma study in patients with active and significant fluid retention. from patients with focal segmental glomerulosclerosis Nevertheless, analyzing the CFC results for the nondiuretic (FSGS) have produced proteinuria in animal models [25], treated subgroup alone shows this group to have a signifi- and plasma protein adsorption decreases proteinuria in cantly higher results compared to their respective age and recurrent disease after renal transplantation [26]. Vascular sex matched controls. A number of the nephrotic subjects permeability factor (vascular endothelial growth factor) is a had renal impairment, shown by an elevated serum creati- disulfide-linked dimeric glycoprotein of about 40 kD that nine concentration. However, there was no correlation promotes fluid and protein leakage from blood vessels [27]. between serum creatinine and CFC. The possibility of It has become a candidate agent in changes of glomerular comparison with subjects with impaired renal function and possibly systemic permeability in the nephrotic syn- (rather than normal control subjects) was addressed. The drome, but it appears to be implicated predominately in possibility of introducing other factors that might effect minimal change nephrotic syndrome (MCNS) and possibly endothelial function such as hypertension, medications and IgA nephropathy [28, 29]. Few studies discuss these factors underlying renal disorders, as well as uremia per se was felt with regard to other renal pathologies, but those that do to be too great to use such a control group. In fact, the tend to consider nephrotic syndrome secondary to MCNS degree of dysfunction present in the nephrotic subjects may and/or FSGS as a separate entity to other nephrotic states not be as high as suggested by the data in Table 1: only two [25]. Our study shows no clear trend in the small number of subjects had a serum creatinine greater than 200 ␮mol/liter. subjects with minimal change disease. A unifying hypothe- In conclusion, active nephrotic syndrome is associated sis of circulating agent(s) altering vascular permeability in with an increase in systemic CFC, providing a potentially the nephrotic state remains unproven at present. novel mechanism for the edema formation characteristic of With regards to methodology, the changes in CFC this condition. In contrast, no evidence for capillary hyper- observed in our study imply an alteration of capillary tension was obtained. We are unable to exclude the possi- hydraulic conductivity, or of the functional capillary surface bility that an elevation in capillary pressure may play a role area available for exchange. Back perfusion of all available in the initiation of edema formation; further studies are capillaries in this technique due to venous distension would required to delineate the relative importance of these argue against an increased capillary surface area being an microvascular parameters at different stages of the disease explanation of the findings [16], although the surface area process. for exchange may not be identical to the number of perfused capillaries: for example, there may be an increase ACKNOWLEDGMENTS in membrane porosity per unit surface area of capillary wall. Hence, both the effective area of exchange and Lp are This work was partially funded by the Wellcome Trust, reference subject to variation. While there is no evidence of increased numbers 032627/Z/90/Z/1.27/LA and 039501/Z/93/Z/DG. A portion of this paper was presented at the 1996 meetings of the Renal Association (UK) total capillary surface area in the lower limb of nephrotic in Oxford and the EDTA in Amsterdam. subjects, such an increase cannot be ruled out. The pres- ence of edema in the limb being measured would decrease Reprint requests to Dr. David M. Lewis, Renal Unit, Manchester Royal the ratio of capillary volume/tissue volume that might result Infirmary, Oxford Road, Manchester, M13 9WL England, United Kingdom. in an underestimation of CFC due to a proportionately E-mail: [email protected] 1266 Lewis et al: Microvascular studies in nephrotic syndrome

REFERENCES silastic strain gauge plethysmography for microvascular permeability assessment in man. J Physiol (Lond) 464:407–422, 1993 17. MACLEOD M: Systemic capillary pressure in acute glomerulonephritis 1. SQUIRE JR: The nephrotic syndrome. Adv Intern Med 7:201–241, 1955 estimated by direct micropuncture. Clin Sci 19:27–33, 1960 2. BERNARD DB, ALEXANDER EA: Edema formation in the nephrotic 18. FAHR G, ERSHLER I: Studies of the factors concerned in edema syndrome: Pathophysiologic mechanisms. Cardiovasc Med 4:605–625, formation. II. The hydrostatic pressure in the capillaries during edema 1979 formation in right heart failure. Ann Intern Med 15:798–810, 1941 3. DORHOUT MEES EJ, GEERS AB, KOOMANS HA: Blood volume and 19. GUYTON AC: Interstitial fluid pressure: II. Pressure-volume curves of sodium retention in the nephrotic syndrome: A controversial patho- interstitial space. Circ Res 16:452–460, 1965 Nephron physiological concept. (review) 36:201–211, 1984 20. LEVICK JR: Capillary filtration-absorption balance reconsidered in 4. ICHIKAWA I, RENNKE HG, HOYER JR, BADR KF, SCHOR N, TROY JL, light of dynamic extravascular factors. Exp Physiol 76:825–857, 1991 ECHENE RENNER L CP, B BM: Role for intrarenal mechanisms in the 21. BEACH RE, WALDEN C, BOUDREAUX JP, DUBOSE TD: The role of impaired salt excretion of experimental nephrotic syndrome. J Clin lymphatic flow in edema formation of nephrotic syndrome. Am J Med Invest 71:91–103, 1983 Sci 297:339–342, 1989 5. PERICO N, REMUZZI G: Renal handling of sodium in the nephrotic 22. GHIGGERI GM, GINEVRI F, CANDIANO G, OLEGGINI R, PERFUMO F, syndrome. Am J Nephrol 13:413–421, 1993 QUEIROLO C, GUSMANO R: Characterization of cationic albumin in 6. HUMPHREYS MH: Mechanisms and management of nephrotic edema. minimal change nephropathy. Kidney Int 32:547–553, 1987 Kidney Int 45:266–281, 1994 23. LEVIN M, SMITH C, WALTERS MD, GASCOINE P, BARRATT TM: 7. SCHRIER RW: Pathogenesis of sodium and water retention in high- Steroid-responsive nephrotic syndrome: A generalised disorder of output and low-output cardiac failure, nephrotic syndrome, cirrhosis, membrane negative charge. Lancet 2:239–242, 1985 and pregnancy. (First of two parts) N Engl J Med 319:1065–1072, 1988 24. SHALHOUB RJ: Pathogenesis of lipoid nephrosis: A disorder of T-cell 8. MICHEL CC, MOYSES C: The measurement of fluid filtration in human function. Lancet 2:556–559, 1974 limbs, in Clinical Investigation of the Microcirculation, edited by TOOKE 25. SAVIN VJ, SHARMA R, SHARMA M, MCCARTHY ET, SWAN SK, ELLIS E, JE, SMAJE LH, Boston, Martinus Nijhoff, 1987, pp 103–126 LOVELL H, WARADY B, GUNWAR S, CHONKO AM, ARTERO M, 9. FAUCHALD P, NODDELAND H, NORSETH J: Interstitial fluid volume, VINCENTI F: Circulating factor associated with increased glomerular plasma volume and colloid osmotic pressure in patients with nephrotic permeability to albumin in recurrent focal segmental glomeruloscle- syndrome. Scand J Clin Lab Invest 44:661–667, 1984 rosis. N Engl J Med 334:878–883, 1996 10. NODDELAND H, RIISNES SM, FADNES HO: Interstitial fluid colloid 26. DANTAL J, BIGOT E, BOGERS W, TESTA A, KRIAA F, JACQUES Y, DE osmotic and hydrostatic pressures in subcutaneous tissue of patients LIGNY BH, NIAUDET P, CHARPENTIER B, SOULILLOU JP: Effect of with nephrotic syndrome. Scand J Clin Lab Invest 42:139–146, 1982 plasma protein adsorption on protein excretion in kidney-transplant 11. MELTZER JI, KEIM HJ, LARAGH JH, SEALEY JE, JAN KM, CHIEN S: recipients with recurrent nephrotic syndrome. N Engl J Med 330:7–14, Nephrotic syndrome: Vasoconstriction and hypervolemic types indi- 1994 cated by renin-sodium profiling. Ann Intern Med 91:688–696, 1979 27. ROBERTS WG, PALADE GE: Increased microvascular permeability and 12. GEERS AB, KOOMANS HA, BOER P, DORHOUT MEES EJ: Plasma and endothelial fenestration induced by vascular endothelial growth fac- blood volumes in patients with the nephrotic syndrome. Nephron tor. J Cell Sci 108:2369–2379, 1995 38:170–173, 1984 28. YOSHIZAWA N, KUSUMI Y, MATSUMOTO K, OSHIMA S, TAKEUCHI A, 13. SCHULTZE G, AHUJA S, FABER U, MOLZAHN M: Gastrointestinal KAWAMURA O, KUBOTA T, KONDO S, NIWA H: Studies of a glomerular protein loss in the nephrotic syndrome studied with 51Cr-albumin. permeability factor in patients with minimal-change nephrotic syn- Nephron 25:227–230, 1980 drome. Nephron 51:370–376, 1989 14. SHORE AC, SANDEMAN DD, TOOKE JE: Capillary pressure, pulse 29. BAKKER WW, BEUKHOF JR, VAN LUIJK WH, VAN DER HEM GK: pressure amplitude and pressure waveform in healthy volunteers. Vascular permeability increasing factor (VPF) in IgA nephropathy. Am J Physiol 268:H147–H154, 1995 Clin Nephrol 18:165–167, 1982 15. SANDEMAN DD, SHORE AC, TOOKE JE: Relation of skin capillary 30. LEHOUX S, SIROIS MG, SIROIS P, PLANTE GE: Acute and chronic pressure in patients with insulin-dependent diabetes mellitus to diuretic treatment selectively affects vascular permeability in the complications and metabolic control. N Engl J Med 327:760–764, 1992 unanesthetized normal rat. J Pharmacol Exp Ther 269:1094–1099, 16. GAMBLE J, GARTSIDE IB, CHRIST F: A reassessment of mercury in 1994