A critique of the overfill hypothesis of sodium and water retention in the nephrotic syndrome
1998; Elsevier BV; Volume: 53; Issue: 5 Linguagem: Inglês
10.1046/j.1523-1755.1998.00864.x
ISSN1523-1755
AutoresRobert W. Schrier, Robert G. Fassett,
Tópico(s)Renal function and acid-base balance
ResumoA critique of the overfill hypothesis of sodium and water retention in the nephrotic syndrome. Recent reviews have claimed that the majority of patients with the nephrotic syndrome have plasma volume expansion (that is, they are overfilled). Here we attempt to re-establish balance to the debate on body fluid volume status in nephrotic patients by: (a) discussing the conflicting literature on plasma volume measurements in the nephrotic syndrome; (b) providing alternate explanations for data purporting to support an overfill hypothesis in the nephrotic syndrome; (c) emphasizing secondary neurohumoral responses that support underfilling at least as frequently as overfilling; and (d) emphasizing the clinical importance of fluid assessment in the individual patient with the nephrotic syndrome particularly in relation to diuretic use. A critique of the overfill hypothesis of sodium and water retention in the nephrotic syndrome. Recent reviews have claimed that the majority of patients with the nephrotic syndrome have plasma volume expansion (that is, they are overfilled). Here we attempt to re-establish balance to the debate on body fluid volume status in nephrotic patients by: (a) discussing the conflicting literature on plasma volume measurements in the nephrotic syndrome; (b) providing alternate explanations for data purporting to support an overfill hypothesis in the nephrotic syndrome; (c) emphasizing secondary neurohumoral responses that support underfilling at least as frequently as overfilling; and (d) emphasizing the clinical importance of fluid assessment in the individual patient with the nephrotic syndrome particularly in relation to diuretic use. A recent scholarly review has emphasized that, “edema formation in the majority of patients with the nephrotic syndrome can be best explained by an overfill mechanism”1.Palmer B.F. Alpern R.J. Pathogenesis of edema formation in the nephrotic syndrome.Kidney Int. 1997; 51: S21-S27Google Scholar. There can be little doubt that some patients with nephrotic syndrome, particularly those with associated renal failure, become volume expanded and hypertensive concomitantly with an associated suppression of the renin-angiotensin-aldosterone system2.Meltzer J.I. Keim H.J. Laragh J.H. Sealey J.E. Jan K. Chien S. Nephrotic syndrome: Vasoconstriction and hypervolemic types indicated by renin-sodium profiling.Ann Intern Med. 1979; 91: 688-696Crossref PubMed Scopus (126) Google Scholar. These patients have been referred to as having hypervolemic nephrotic syndrome (that is, their circulations are overfilled). Patients with chronic renal failure of various etiologies without nephrotic syndrome also retain sodium and water, develop hypertension and respond favorably to loop diuretics. These patients, however, demonstrate substantial renal dysfunction. Patients with the nephrotic syndrome generally do not have the signs of volume expansion3.Eisenberg S. Blood volume in patients with acute glomerulonephritis as determined by radioactive chromium tagged red cells.Am J Med. 1959; 27: 241-245Abstract Full Text PDF PubMed Scopus (11) Google Scholar, nor the very low renin and high atrial natriuretic peptide (ANP) levels seen in acute glomerulonephritis4.Rodriguez-Iturbe B. Colic D. Parra G. Gutkowska J. Atrial natriuretic factor in the acute nephritic and nephrotic syndromes.Kidney Int. 1990; 38: 512-517Abstract Full Text PDF PubMed Scopus (21) Google Scholar. What has been suggested in patients with nephrotic syndrome is that intrarenal mechanisms enhance tubular sodium reabsorption, mainly in the distal tubule, and this effect predominates over extrarenal volume regulatory mechanisms. These patients, therefore, become plasma volume expanded (overfilled) in the presence of preserved renal function as assessed by a normal, or near normal, glomerular filtration rate (GFR). The purpose of this article is not to provide another comprehensive review of the nephrotic syndrome, but rather to critically assess some of the published results that have been used to support the “overfill” hypothesis. Alternative interpretations of these results are entertained in an effort to provide some perspective about whether the “majority” patients with the nephrotic syndrome are indeed plasma volume expanded. One group of investigators has performed several studies over the past 18 years that suggest that plasma volume is consistently expanded in children and adults with nephrotic syndrome, including those with minimal change disease5.Geers A.B. Koomans H.A. Roos J.C. Boer P. Dorhout Mees E.J. Functional relationships in the nephrotic syndrome.Kidney Int. 1984; 26: 324-330Abstract Full Text PDF PubMed Scopus (59) Google Scholar, 6.Dorhout Mees E.J. Roos J.C. Boer P. Yoe O.H. Simatupang T.A. Observations on edema formation in the nephrotic syndrome in adults with minimal change lesions.Am J Med. 1979; 67: 378-384Abstract Full Text PDF PubMed Scopus (93) Google Scholar, 7.Geers A.B. Koomans J.C. Roos J.C. Dorhout Mees E.J. Preservation of blood volume during edema removal in nephrotic subjects.Kidney Int. 1985; 28: 652-657Abstract Full Text PDF PubMed Scopus (26) Google Scholar, 8.Walle J.V. Donckerwolcke R. Boer P. van Isselt H.W. Koomans H.A. Joles J.A. Blood volume, colloid osmotic pressure and F-cell ratio in children with the nephrotic syndrome.Kidney Int. 1995; 49: 1471-1477Abstract Full Text PDF Scopus (36) Google Scholar, 9.Joles J.A. Rabelink T.J. Braam B. Koomans H.A. Plasma volume regulation: Defences against edema formation (with special emphasis on hypoproteinemia).Am J Nephrol. 1993; 13: 399-412Crossref PubMed Scopus (34) Google Scholar, 10.Dorhout Mees E.J. Geers A.B. Koomans H.A. Blood volume control and sodium retention in the nephrotic syndrome: A controversial pathophysiological concept.Nephron. 1984; 36: 201-211Crossref PubMed Scopus (57) Google Scholar. There have been, however, studies by other investigators who have demonstrated a decrease in blood volume in patients with the nephrotic syndrome11.Yamauchi H. Hopper J. MCCormack K. Blood volume and fainting in nephrosis.Clin Res. 1960; 8 (abstract): 195Google Scholar, 12.Yamauchi H. Hopper J. Hypovolemic shock and hypotension as a complication of the nephrotic syndrome.Medicine. 1964; 60: 242-254Google Scholar, 13.Garnett E.S. Webber C.E. Changes in blood volume produced by treatment in the nephrotic syndrome.Lancet. 1967; 2: 798-799Abstract PubMed Google Scholar, 14.Kumagai H. Onoyama K. Iseki K. Omae T. Role of renin angiotensin aldosterone on minimal change nephrotic syndrome.Clin Nephrol. 1985; 23: 229-235PubMed Google Scholar, 15.Metcoff J. Janeway C.A. Studies on the pathogenesis of nephrotic edema.J Pediatr. 1961; 58: 640-685Abstract Full Text PDF Scopus (19) Google Scholar, 16.Usberti M. Gazzotti R.M. Poiesi C. D’Avanzo L. Ghielmi S. Considerations on the sodium retention in nephrotic syndrome.Am J Nephrol. 1995; 15: 38-47Crossref PubMed Scopus (35) Google Scholar. If overfill mechanisms predominate, then the majority of patients with nephrotic syndrome should have expanded plasma volumes. In this regard, however, an analysis of 217 nephrotic patients from 10 studies found that only 25% had expanded plasma volumes10.Dorhout Mees E.J. Geers A.B. Koomans H.A. Blood volume control and sodium retention in the nephrotic syndrome: A controversial pathophysiological concept.Nephron. 1984; 36: 201-211Crossref PubMed Scopus (57) Google Scholar. This analysis does not, therefore, support the overfill hypothesis for the majority of patients with nephrotic syndrome. Interestingly, the results of these 10 studies mimic a Gaussian distribution with 33% of patients demonstrating a reduced plasma volume, 42% a normal plasma volume, and 25% an increased plasma volume. It is, therefore, possible that plasma volume measurements are not sufficiently sensitive to distinguish between overfill and underfill mechanisms in the nephrotic syndrome. Measurements used to assess plasma volume in the nephrotic syndrome have frequently utilized albumin as a tracer. Since the initial whole body disappearance of albumin in humans is biphasic and rapid, the “uncritical use of albumin as a plasma volume marker is not justified”17.Bent-Hansen L. Initial plasma disappearance and distribution volume of [131I] albumin and [125I] fibrinogen in man.Acta Physiol Scand. 1989; 136: 455-461Crossref PubMed Scopus (28) Google Scholar. Thus, a larger tracer such as fibrinogen could produce more reliable results, but this technique has not yet been used in the nephrotic syndrome. In general, the reproducibility of current techniques to measure plasma volume varies by ± 10%, a range where renal sodium excretion is clearly regulated by extrarenal mechanisms. Since nephrotic patients are edematous, should plasma volume measurements be normalized per kilogram of dry or wet weight? Depending on the approach chosen, a given absolute plasma volume measurement could be considered to be increased (adjusted for dry weight) or decreased (adjusted for wet wt). To date there is insufficient information to choose between these two possibilities. Posture has also been found to be a determinant of plasma volume measurement. Specifically, nephrotic patients with normal plasma volume measurements in the supine position have been found to have an exaggerated fall in plasma volume in the orthostatic as compared to the recumbent positions18.Eisenberg S. Postural changes in plasma volume in hypoalbuminemia.Arch Int Med. 1963; 112: 140-145Crossref Scopus (33) Google Scholar,19.Fawcett J.K. Wynn V. Effects of posture on plasma volume and some blood constituents.J Clin Pathol. 1960; 13: 304-310Crossref PubMed Scopus (108) Google Scholar. This hypovolemic effect has been suggested to explain the occurrence of oliguric acute renal failure and hypovolemic shock, which has been observed in some patients with nephrotic syndrome20.Chamberlain M.J. Pringle A. Wrong O.M. Oliguric renal failure in the nephrotic syndrome.Q J Med. 1966; 138: 215-235Google Scholar, 21.Jennette J.C. Falk R.J. Adult minimal change glomerulopathy with acute renal failure.Am J Kidney Dis. 1990; 16: 432-437Abstract Full Text PDF PubMed Scopus (99) Google Scholar, 22.Lowenstein J. Schacht R.G. Baldwin D.S. Renal failure in minimal change nephrotic syndrome.Am J Med. 1981; 70: 227-233Abstract Full Text PDF PubMed Scopus (123) Google Scholar, 23.Imbasciati E. Ponticelli C. Case N. Acute renal failure in idiopathic nephrotic syndrome.Nephron. 1981; 28: 186-191Crossref PubMed Scopus (27) Google Scholar, 24.Hulter H.N. Bonner JR, E.L. Lipoid nephrosis appearing as acute oliguric renal failure.Arch Intern Med. 1980; 140: 403-405Crossref PubMed Scopus (27) Google Scholar. Studies assessing plasma volumes in nephrotic patients should therefore be measured in both the supine and upright positions. Plasma volume expansion, as would occur with primary renal sodium and water retention, would be expected to suppress the renin-angiotensin-aldosterone system (RAAS). Moreover, glomerular diseases that cause the nephrotic syndrome might also be associated with the syndrome of hyporeninemia and hypoaldosteronism. However, in a review of nine studies, elevated plasma renins were found in approximately 50% of the cases10.Dorhout Mees E.J. Geers A.B. Koomans H.A. Blood volume control and sodium retention in the nephrotic syndrome: A controversial pathophysiological concept.Nephron. 1984; 36: 201-211Crossref PubMed Scopus (57) Google Scholar. The postural position must also be considered when measuring plasma renin, since increased RAAS activity may only be demonstrable when the patient is in an upright position. Angiotensin converting enzyme inhibitors (ACEI), which are often used in nephrotic patients, have been shown to significantly decrease plasma aldosterone concentration, yet a natriuresis did not occur Figure 1). This led the authors to conclude that aldosterone was not important in the sodium retention of the nephrotic syndrome, thus supporting the “overfill” hypothesis25.Brown E.A. Markandu N.D. Sagnella G.A. Jones B.E. MacGregor G.A. Lack of effect of captopril on the sodium retention of the nephrotic syndrome.Nephron. 1984; 37: 43-48Crossref PubMed Scopus (38) Google Scholar. This conclusion, however, was premature. Specifically, ACEI lowered blood pressure, and thus renal perfusion pressure, by a mean of 10 mm Hg in the nephrotic patients Figure 1). This hemodynamic effect could by itself cause an antinatriuretic response and thus override any natriuretic response secondary to the fall in plasma aldosterone. To test this possibility, studies were performed in five nephrotic patients using competitive inhibition of aldosterone with spironolactone26.Shapiro M.D. Hasbargen J. Hensen J. Schrier R.W. Role of aldosterone in the sodium retention of patients with the nephrotic syndrome.Am J Nephrol. 1990; 10: 44-48Crossref PubMed Scopus (29) Google Scholar. In order to ensure competitive inhibition of any elevation of endogenous aldosterone, large doses of spironolactone (200 mg orally twice daily) were used. A control group of six normal subjects were also studied using the same dose and duration of treatment of spironolactone. In order to avoid any differences in sodium balance, both the patients and control subjects received a constant high sodium intake for four days prior to and four days during spironolactone therapy. The results demonstrate a natriuretic response to spironolactone only in the nephrotic patients Figure 2). Since the natriuretic response to spironolactone is dependent on an intact adrenal gland, it is reasonable to conclude that aldosterone was contributing to sodium retention in these nephrotic patients. These results, therefore, support the underfill rather than the overfill hypothesis of sodium retention in nephrotic patients. The earlier finding in experimental nephrotic syndrome that adrenalectomy diminishes sodium retention27.Kalant N. Gupta D.D. Despointes R. Giroud C.J.P. Mechanisms of edema formation in experimental nephrosis.Am J Physiol. 1962; 202: 91-96Google Scholar is also compatible with these spironolactone results26.Shapiro M.D. Hasbargen J. Hensen J. Schrier R.W. Role of aldosterone in the sodium retention of patients with the nephrotic syndrome.Am J Nephrol. 1990; 10: 44-48Crossref PubMed Scopus (29) Google Scholar.Figure 2Sodium excretion of both nephrotic patients and controls on a constant sodium intake of 285 ± 6 mEq/day before and after spironolactone (200 mg, po., b.i.d.) was given. Reprinted with permission from Williams & Wilkins (Shapiro MD, Hasbargen J, Hensen J, Schrier RW: Role of aldosterone in the sodium retention of patients with the nephrotic syndrome. Am J Nephrol 10:44–48, 199026.Shapiro M.D. Hasbargen J. Hensen J. Schrier R.W. Role of aldosterone in the sodium retention of patients with the nephrotic syndrome.Am J Nephrol. 1990; 10: 44-48Crossref PubMed Scopus (29) Google Scholar).View Large Image Figure ViewerDownload (PPT) It is also important to emphasize that assessment of the RAAS activity can only be undertaken in relationship to sodium balance. Thus, plasma renin and/or aldosterone concentration in an edematous nephrotic patient with a large positive sodium balance should be suppressed, which means that the “normal” level is relatively increased. Since most of the plasma renin and aldosterone concentrations reported in patients with nephrotic syndrome have not been correlated with total body sodium balance, plasma concentrations in nephrotic patients that fall within the normal range for control subjects should not be used in support of the overfill hypothesis. Moreover, similar plasma concentrations of renin and aldosterone before and after a steroid-induced natriuresis do not negate the role of the RAAS since, because of changes in total body sodium balances, these hormonal concentrations are not comparable. The renal interstitial edema and the resultant effect on the RAAS is another changing variable before and after edema remission in nephrotic patients. Plasma and urinary catecholamine concentrations have been found to be increased in patients with the nephrotic syndrome28.Kelsch R.C. Light G.S. Oliver W.J. The effect of albumin infusion upon plasma norepinephrine concentration in nephrotic children.J Clin Lab Med. 1972; 79: 516-525PubMed Google Scholar, 29.Oliver W.J. Kelsch R.C. Chandler J.P. Determination of increased catecholamine excretion in the nephrotic syndrome.Proc Soc Exp Biol Med. 1967; 125: 1176-1180Crossref PubMed Scopus (14) Google Scholar, 30.Rahman S.N. Abraham W.T. Van Putten V.J. Hasbargen J.A. Schrier R.W. Increased norepinephrine secretion in patients with the nephrotic syndrome and normal glomerular filtration rates: Evidence for primary sympathetic activation.Am J Nephrol. 1993; 13: 266-270Crossref Scopus (37) Google Scholar, a finding more compatible with the underfill rather than the overfill hypothesis of sodium and water retention. Recent studies examining catecholamine kinetics in control subjects and nephrotic patients have also shown an increased turnover in nephrotic patients Figure 3). The results are, however, more variable in experimental models of the nephrotic syndrome. The demonstration that renal denervation ameliorates sodium and water retention in an experimental model of nephrotic syndrome supports a role of the sympathetic nervous system in the associated edema formation Figure 4)31.DIBona G.F. Herman P.J. Sawin L.L. Neural control of renal function in edema-forming states.Am J Physiol. 1988; 254: R1017-R1024PubMed Google Scholar. In the same model renal denervation also reversed the resistance to atrial natriuretc peptide31.DIBona G.F. Herman P.J. Sawin L.L. Neural control of renal function in edema-forming states.Am J Physiol. 1988; 254: R1017-R1024PubMed Google Scholar. This increased renal sympathetic tone is most compatible with hypovolemia in this model of nephrotic syndrome. A recent study has also shown that nephrotic rats have a central defect in cardiac baroreflex function that is specific for efferent renal sympathetic nerve activity32.DIBona G.F. Jones S.Y. Sawin L.L. Reflex influences on renal nerve activity charactaristics in nephrosis and heart failure.J Am Soc Nephrol. 1997; 8: 1232-1239PubMed Google Scholar and is reversed with an angiotensin II receptor antagonist33.Sanchez-Palacios M.E. DIBona G.F. Intracerebroventricular losartan enhances suppression of renal sympathetic nerve activity during volume expansion in nephrotic rats.J Invest Med. 1997; 45 (abstract): 213AGoogle Scholar. It has been suggested, therefore, that the activation of the renin-angiotensin-aldosterone system secondary to an underfilled circulation may impair baroreceptor integrity32.DIBona G.F. Jones S.Y. Sawin L.L. Reflex influences on renal nerve activity charactaristics in nephrosis and heart failure.J Am Soc Nephrol. 1997; 8: 1232-1239PubMed Google Scholar. These human and experimental studies in the nephrotic syndrome support an underfilled circulation with associated stimulation of the sympathetic nervous system. On the other hand, puromycin-induced nephrotic rats demonstrated a persistent defect in renal sodium excretion in the isolated perfused kidney34.Firth J.D. Raine A.E.G. Ledingham J.G.G. Abnormal sodium handling occurs in the isolated perfused kidney of the nephrotic rat.Clin Sci. 1989; 76: 387-395Crossref PubMed Scopus (16) Google Scholar. Moreover, bilateral renal denervation in rats with adriamycin-induced nephrotic syndrome did not correct the impaired response to volume expansion35.Valentin J.-P. Qiu C. Muldowney WP Ying W.-Z. Gardener D.G. Humphreys M.H. Cellular basis for blunted volume expansion natriuresis in experimental nephrotic syndrome.J Clin Invest. 1992; 90: 1302-1312Crossref PubMed Scopus (84) Google Scholar. The results from the latter two studies are most compatible with overfill edema.Figure 4Renal denervation in nephrotic rats (DNX) ameliorates the sodium and water retention compared to sham (SHAM) operated rats. Sodium and water excretion in denervated rats was similar to controls. Reprinted with permission from the American Journal of Physiology (DiBona GF, Herman PJ, Sawin LL: Neural control of renal function in edema-forming states. Am J Physiol 254:R1017—R1024, 198831.DIBona G.F. Herman P.J. Sawin L.L. Neural control of renal function in edema-forming states.Am J Physiol. 1988; 254: R1017-R1024PubMed Google Scholar).View Large Image Figure ViewerDownload (PPT) Plasma volume expansion should suppress and plasma volume depletion should increase the non-osmotic release of arginine vasopressin (AVP). Several studies support a role for AVP in the water retention found in the nephrotic syndrome36.Usberti M. Federico S. Meccariello S. Cianciaruso B. Balletta M. Pecoraro C. Sacca L. Ungaro B. Pisanti N. Andreucci V.E. Role of plasma vasopressin in the impairment of water excretion in nephrotic syndrome.Kidney Int. 1984; 25: 422-429Abstract Full Text PDF PubMed Scopus (67) Google Scholar,37.Apostol E. Ecelbarger C.A. Terris J. Bradford A.D. Andrews P. Knepper M. Reduced renal medullary water channel expression in puromycin aminonucleoside induced nephrotic syndrome.J Am Soc Nephrol. 1997; 8: 15-24PubMed Google Scholar. Usberti et al demonstrated a direct correlation between the decrement in plasma volume and plasma AVP concentrations in patients with the nephrotic syndrome Figure 5)36.Usberti M. Federico S. Meccariello S. Cianciaruso B. Balletta M. Pecoraro C. Sacca L. Ungaro B. Pisanti N. Andreucci V.E. Role of plasma vasopressin in the impairment of water excretion in nephrotic syndrome.Kidney Int. 1984; 25: 422-429Abstract Full Text PDF PubMed Scopus (67) Google Scholar. Elevated plasma vasopressin concentrations have also been observed in puromycin-induced nephrotic syndrome in the rat37.Apostol E. Ecelbarger C.A. Terris J. Bradford A.D. Andrews P. Knepper M. Reduced renal medullary water channel expression in puromycin aminonucleoside induced nephrotic syndrome.J Am Soc Nephrol. 1997; 8: 15-24PubMed Google Scholar. An argument for overfill edema secondary to an intrarenal sodium retaining defect in nephrotic patients is the finding that plasma volume expansion with saline, hyperoncotic or isoncotic albumin or head-out water immersion (HWI) improves, but does not normalize sodium excretion in the nephrotic patient. The authors reason that if underfill is the primary reason for sodium and water retention in nephrotic syndrome, normalizing plasma volume should totally correct the perturbation in renal sodium and water excretion. While this may seem like a reasonable conclusion, there is an alternative explanation. It has been known for many years that prior sodium restriction blunts and prior sodium excess enhances the natriuretic response to volume expansion38.Strauss M.B. Landin E. Smith W.P. Bleifer D.J. Surfeit and deficit of sodium: a kinetic concept of sodium excretion.Arch Intern Med. 1958; 102: 527-536Crossref Scopus (118) Google Scholar. Thus, one might expect a blunted natriuretic response to volume expansion in nephrotic patients whose circulation is underfilled. This alternative interpretation for the failure to totally normalize sodium excretion during volume expansion in the nephrotic patient is, therefore, also reasonable. On the other hand, patients with nephrotic syndrome who are overfilled or volume expanded would also not be expected to normally excrete a sodium load because of primary renal sodium retention. An intrarenal defect has indeed been shown with toxic experimental nephrotic syndrome in the rat39.Ichikawa I. Rennke H.G. Hoyer J.R. Badr K.F. Schor N. Troy J.L. Lechene C.P. Brenner B.M. Role of intrarenal mechanisms in the impaired salt excretion of experimental nephrotic syndrome.J Clin Invest. 1983; 71: 91-103Crossref PubMed Scopus (196) Google Scholar. This defect has been localized to the collecting duct using micropuncture techniques in superficial nephrons Figure 6. Studies in humans with nephrotic syndrome also support enhanced collecting duct sodium reabsorption, since the action of aldosterone on the collecting duct can be reversed by high dose spironolactone. This effect of aldosterone, however, is presumably due to underfilling activating the RAAS, thus resulting in secondary, not primary, renal sodium retention. There are compensatory mechanisms whereby interstitial edema may not accompany a lowered plasma albumin concentration and capillary oncotic pressure. Specifically, increased transcapillary transport of fluid is initially accompanied by a rise in interstitial pressure and increased lymphatic flow, which can counterbalance the effect of the lowered capillary oncotic pressure of the nephrotic syndrome, thereby avoiding edema formation. Moreover, as transport of fluid into the interstitium occurs in association with hypoalbuminemia, the interstitial oncotic pressure falls in parallel with the plasma oncotic pressure. A new steady-state may, therefore, occur without a decrease in the average 12 mm Hg transcapillary oncotic gradient (plasma vs. interstitial oncotic pressure: 24 minus 12 mm Hg). There is also evidence that the capillary permeability to protein may decrease in response to hypoalbuminemia, thereby further protecting plasma oncotic pressure40.Fadnes H.O. Protein concentration and hydrostatic pressure in subcutaneous tissue of rats in hypoproteinemia.Scand J Clin Lab Invest. 1975; 35: 441-446Crossref PubMed Google Scholar. Studies in nephrotic patients that demonstrate equivalent changes in plasma and interstitial protein concentration during both relapse and remission also support the conclusion that compensatory mechanisms are adequate to avoid hypoalbuminemia-induced edema Figure 7)41.Koomans H.A. Kortlandt W. Geers A.B. Dorhout Mees E.J. Lowered protein content of tissue fluid in patients with the nephrotic syndrome observations during disease and recovery.Nephron. 1985; 40: 391-395Crossref PubMed Scopus (45) Google Scholar. Such a conclusion is supported by the report that patients with analbuminemia do not develop anascara42.Bennhold H. Klaus D. Scheurlen P.G. Volume regulation and renal function in analbuminemia.Lancet. 1960; 2: 1169-1170Abstract Scopus (19) Google Scholar, 43.Scheurlen P.G. Klaus D. Flussigkeitshaushalt und volumenregulation bei extremem serumalbuminmangel (analbuminamie).Klinishe Wochenschrift. 1960; 38: 123-126Crossref PubMed Scopus (8) Google Scholar, 44.Keller H. Morrell A. Noseda G. Riva G. Analbuminamie.Schweiz med Wschr. 1972; 102: 33-35PubMed Google Scholar, 45.Waldmann T.A. Gordon R.S. Rosse W. Studies on the metabolism of the serum proteins and lipids in a patient with an-albuminemia.Am J Med. 1964; 37: 960-968Abstract Full Text PDF PubMed Scopus (48) Google Scholar. Thus, an intrarenal sodium-retaining defect independent of plasma oncotic pressure could account for volume expansion (overfill) in the hypoalbuminemic nephrotic patient. Such reasoning must, however, reckon with the observation that several circumstances that cause hypoalbuminemia without renal involvement can be associated with anasarca. Specifically, protein-losing gastroenteropathy or dermopathy as well as Kwashiorkor's syndrome can be associated with severe hypoalbuminemia and profound edema. These clinical states that occur in the absence of primary renal sodium retention suggest that the compensatory responses to a lowered capillary oncotic pressure do not always prevent interstitial edema formation in extreme cases (such as plasma albumin concentration < 2.0 g/dl). It is also important to point out that analbuminemic patients generally do have mild edema and also may hyperexcrete a sodium load, thus providing another mode of protection against edema formation42.Bennhold H. Klaus D. Scheurlen P.G. Volume regulation and renal function in analbuminemia.Lancet. 1960; 2: 1169-1170Abstract Scopus (19) Google Scholar. It has been suggested that compensatory mechanisms to prevent interstitial edema may already be overwhelmed in the nephrotic patient, and this may explain why comparable volume expansion causes hypertension in normoalbuminemic patients with renal disease but not hypoalbuminemic nephrotic patients1.Palmer B.F. Alpern R.J. Pathogenesis of edema formation in the nephrotic syndrome.Kidney Int. 1997; 51: S21-S27Google Scholar,46.Koomans H.A. Boer W.H. Dorhout Mees E.J. Renal function during recovery from minimal lesion nephrotic syndrome.Nephron. 1987; 47: 173-735Crossref PubMed Scopus (34) Google Scholar. The proposed explanation is that nephrotic patients have exhausted their compensatory capillary reserve mechanisms against edema, and therefore the administered fluid moves rapidly into the interstitium rather than remaining in the intravascular compartment and causing hypertension. An alternative or additional explanation is that the nephrotic patient's vascular compartment is underfilled in comparison to the normoalbuminemic chronic renal failure patient. Thus, for the same volume load, the nephrotic patients are less likely to become plasma volume expanded and hypertensive. An additional caveat must be stated about toxic models of the nephrotic syndrome induced by either adriamycin or puromycin. In addition to the glomerular capillary leak of protein, numerous tubular defects have now been observed, suggesting that extrapolation of results from these toxic models to humans should be made with caution. In summary, the purpose of this editorial is not to provide a comprehensive review, but rather to give some pause to the conclusion that the “majority” of nephrotic patients are overfilled (that is, plasma volume expanded) due to primary renal sodium retention. While overfill edema may occur in the nephrotic syndrome, there are a number of caveats before the “majority” of nephrotic patients are considered to have overfill edema. Given these caveats raised in this critique, at the present time it may be more appropriate to state that “some” rather than the “majority” of patients with the nephrotic syndrome have plasma volume expansion secondary to primary renal sodium retention, which causes overfill edema. The clinical implications of the so-called overfill versus underfill edema of nephrotic syndrome are substantial. If the majority of nephrotic patients with a normal GFR are indeed plasma volume expanded, the edema can be beneficially treated aggressively with diuretics without potential complications. The diuretics would override the primary renal sodium retention and the discussed compensatory mechanisms of hypoalbuminemia will prevent edema formation. On the other hand, if the majority of these patients are underfilled, diuretic treatment must be more judiciously undertaken to avoid further depletion of intravascular volume and even acute renal failure. The assessment of intravascular volume of an individual patient with the nephrotic syndrome is thus difficult, but critical in the decision of whether it is safe to aggressively use diuretics. In Table 1 factors are detailed that may assist in this clinical decision. In closing, a historical event is probably worth remembering. Specifically, in earlier studies plasma volume depletion was not detectable with chronic thiazide treatment; thus, it was concluded for quite some time that the drug's antihypertensive effect was independent of a negative sodium balance. We now know that this is not the case, since once the diuretic is discontinued the patients uniformly retain sodium. Therefore, an assumed sensitivity of plasma volume measurements misled investigators for quite some time. It is certainly worth emphasizing that conclusions based on plasma volume measurements in nephrotic patients and extrapolation of results from toxic animal models of nephrotic syndrome with multiple tubular defects to humans must be made with caution. We believe that further studies in patients with nephrotic syndrome are necessary to better understand the mechanisms of the sodium and water retention and edema formation.Table 1Table 1. Factors that may give guidance as to whether in an individual patient with the nephrotic syndrome has overfill of underfill edema Open table in a new tab
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