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Kidney International, Vol. 45 (1994),pp.266—281 NEPHROLOGY FORUM

Mechanisms and management of nephrotic edema

Principal discussant: MICHAEL H. HUMPHREYS

University of California San Francisco, San Francisco, California

showed a normal heart size and regular rhythm; heart sounds were distant through a thickened chest wall, but no murmurs or gallops were Editors heard, The abdomen was nontender without evidence of hepatic or JORDAN J. COHEN splenic enlargement. The stool was guaiac positive. The extremities JOHN T. HARR1NGTON showed no clubbing, but massive anasarca was present, with pitting edema of all extremities as well as the abdominal and thoracic wall. The NICOLAOS B. MADIAS penis and scrotum were edematous, and paraphimosis was evident, Neurologic examination was normal except for a slowed relaxation Managing Editor phase of the deep-tendon reflexes. CHERYL J. ZUSMAN Laboratory values on admission were: hematocrit, 29.5; white blood cell count, 16,700/mm3 with a left shift; and a platelet count of 212 x 103/mm'. The serum sodium concentration was 145 mEq/liter; potas- sium, 4.3 mEq/liter; chloride, 121 mEq/liter; total CO2. 16 mmol/liter; State University of New York at Stony Brook BUN, 65 mg/dl; and serum creatinine, 5.5 mgldl. The serum albumin and concentration was 0.6 g/dl; calcium, 6.9 mg/dl; phosphorus, 5.4 mg/dl; and magnesium, 1.8 mg/dl. The erythrocyte sedimentation rate was 139 Tufts University School of Medicine mm/hr, and the serum cholesterol was 554 mg/dl. Urinalysis disclosed a specific gravity of 1.015, a pH of 6, and 4+ protein; microscopic examination revealed 30—40 red blood cells/high-power field and many hyaline and granular casts as well as oval fat bodies. A 24-hour creatinine clearance test yielded a value of 8 mI/mm; the protein Case presentation excretion rate was 8.7 g/24 hr. A chest radiograph showed bilateral pleural effusions and a mild increase in interstitial markings. Arterial A 61-year-old Chinese man was admitted to Moffitt Hospital, Uni- blood gas measurements obtained with the patient breathing room air versity of California San Francisco, 3 years ago with a chief complaint were: pH, 7.47; pCO2, 24 mm Hg; and p02, 105 mm Hg. An electro- of swelling, a 17 lb weight gain, and progressive dyspnea on exertion for cardiogram showed normal sinus rhythm with diffuse low voltage. the 2 weeks prior to admission. Serum complement levels, antinuclear antibody, rheumatoid factor, The patient had noted pedal edema 7 months before admission.hepatitis B surface antigen, and antistreptococcal serologies all were Evaluation at that time disclosed a serum creatinine of 4 mg/dl; diuretics normal or negative. An abdominal ultrasound examination revealed were prescribed and he was seen by several nephrologists, the last ofnormal-sized kidneys without evidence of hydronephrosis; a renal MRI whom treated him with oral prednisone, 60 mg daily; this medication scan showed patent renal veins without evidence of thrombosis. was quickly tapered after 3 weeks. When the swelling and dyspnea The patient was believed to have idiopathic nephrotic syndrome. Oral persisted, the patient was referred to UCSF for evaluation. prednisone was tapered further and discontinued, and his diuretic A diagnosis of Graves' disease had been made in the past, and he was regimen was changed to intravenous furosemide, 80 mg every 8 hours, treated with 1311 ablation; subsequently he developed hypothyroidism and oral metolazone, 5 mg twice daily. Further diagnostic evaluation and was given thyroid replacement medication daily. He also had a included a rectal biopsy that was negative for amyloid. Thoracenteses history of anemia but no complaints of gastrointestinal dysfunction or established that the pleural effusions were transudative in nature. bleeding. He had no history of hepatitis, tuberculosis, hypertension, Gastroscopy revealed reflex esophagitis and several punctate gastric diabetes, or heart disease. The patient smokes one-third of a pack ofulcers. Thyroid function studies indicated that he was hypothyroid, and cigarettes per day, drinks alcohol only occasionally, and has never usedthe thyroxine dosage was increased; a cosyntropin stimulation test intravenous drugs. He is a retired laundry worker who lives with his revealed a normal cortisol response without evidence of adrenal insuf- wife. Medications at the time of admission included bumetanide, 1.5mg ficiency. daily; hydrochlorothiazide, 50 mg daily; prednisone, 10 mg daily; A percutaneous renal biopsy on the 11th hospital day showed levothyroxine, 0.075 mg daily; and iron sulfate tablets, intermittently. moderate diffuse thickening of the glomerular capillary walls without Physical examination revealed a well-developed Asian man in noproliferation or sclerosis; immunofluorescent staining was strongly obvious distress. His blood pressure was 110/78 mm Hg, heart rate, 104 positive for IgG and complement, with lesser staining for 1gM. Electron beats/mm; respiratory rate, 20 beats/mm; and temperature, 37.5°C. The microscopy revealed numerous densely packed, moderately sized, jugular venous pressure was estimated at 8 cm. His tongue was swollen, epimembranous deposits distributed diffusely and uniformly throughout and the thyroid was not palpable. Both lungs were dull to percussion at the glomerular capillary walls; diffuse fusion of epithellal cell foot the bases and breath sounds were decreased. Cardiac examinationprocesses was evident. The pathologic diagnosis was membranous glomerulonephritis. The patient was treated with intravenous methylpredalsolone, 1 g Presentation of this Forum is made possible by grants from Merckdaily for 3 days, followed by oral prednisone, 30 mg each day for one month. Prednisone then was stopped and chlorambucil, 10 mg dally, Sharp & Dohme International; Dialysis Clinic, Incorporated; Marion Merrell Dow, Incorporated; and Mead-Johnson Pharmaceuticals; and begun. He was readmitted to the hospital 2 months later because of by a gift from R & D Laboratories. symptomatic anemia; his hematocrit was 18.7%. At that time, he had only 1 + pedal edema, and he was taking furosemide, 20mg twice daily; © 1994 by the International Society of Nephrology the BUN and serum creatinine were 35 and 4.2 mg/dl, respectively, and

266 Nephrology Forum: Mechanisms and management of nephrotic edema 267 the creatinine clearance was 12 mI/mm. A 24-hour urine collection Glomerular Disease contained 18 g of protein. No evidence of gastrointestinal bleeding was found; the anemia was attributed in part to marrow suppression by chlorambucil, and this drug was discontinued. He received another / course of intravenous methyiprednisolone followed by oral prednisone, Proteinuria Increased Fractional which was finally discontinued 2 months after the second hospital Albumin Catabolism admission. When last seen 4 months ago, the creatinine clearance was 57 mI/mm; urinary protein, 7.2 g/24 hi; serum albumin, 3.4 gIdl; and serum cholesterol, 226 mg/dl. Only trace edema was present. / Hypoalbuminemia Discussion DR. MICHAEL H. HUMPHREYS (Chief, Division of Nephrol- ogy, San Francisco General Hospital, and Professor of Medi- / Plasma Oncotic Secondary Renal cine, University of California San Francisco, San Francisco, Pressure Sodium Retention California): This patient illustrates many of the key issues regarding the development and management of nephrotic edema. Although gratifying in this case, response of the under- p lying disease to treatment was the subject of a previous Ne- Capillary Plasma Volume phrology Forum [1], and I shall not consider it further today. Filtration Rather, I shall focus on abnormalities in sodium handling in the nephrotic syndrome, addressing first the mechanisms governing fluid distribution across peripheral capillaries and the normal defenses against edema, and then reviewing the evidence for or EDEMA against the two major hypotheses that have been offered to account for the development of edema in proteinuric condi- tions. In the process I shall discuss the roles of known sodium-Fig. 1. Overview of the development of edema in nephrotic syndrome from underfihl mechanisms. In this model, nephrotic kidneys respond regulating systems in the context of these two hypotheses. Inormally to signals such as sympathetic nerve activity, the renin- shall then review some recent studies in experimental nephroticangiotensin system, and aldosterone, which are activated as a result of syndrome that suggest the possible cellular basis for nephrotica diminished plasma volume. These mechanisms then mediate second- sodium retention, and I shall conclude with a brief discussion ofary sodium retention. some issues in the practical management of nephrotic edema. Let us begin, then, by looking at normal defenses against edema formation. The Starling equation relates the distributionfiltration [3]. These mechanisms in aggregate prevent the devel- of fluid on two sides of a membrane to the hydrostatic andopment of edema in day-to-day life in normal individuals. By oncotic pressure differences across the membrane: the same token, the occurrence of edema indicates that these J, = —oir defenses have been disrupted at the local capillary level. In LP addition, reduced renal sodium excretion relative to intake also where J,. is the flow of fluid across the membrane; P and T,must be a major factor in states of generalized edema formation. thetransmembrane hydrostatic and oncotic gradients, respec- tively; L, the hydraulic conductivity of the membrane; and o Underfihl edema in the nephrotic syndrome the Staverman reflection coefficient for plasma protein, chiefly Hypoalbuminemia is a hallmark of the nephrotic state, so albumin. This relationship determines the balance of extracel-much attention has been focused on the role of reduced plasma lular fluid between the plasma compartment and the interstitialoncotic pressure in the edema of nephrotic syndrome (Fig. 1). space across peripheral capillary beds [2]. Increases in hydro-Hypoalbuminemia results both from a loss of albumin into the static pressure, such as those that occur in the feet when oneurine, and from an increase in the fractional catabolic rate of changes from a lying to a standing position, favor the increasealbumin [4]. Because albumin is the major contributor to plasma in filtration of plasma water across capillaries. Normally, thisoncotic pressure, a reduction in its concentration in plasma also increase in capillary filtration does not lead to the accumulationlowers plasma oncotic pressure. This in turn alters the Starling of excess interstitial fluid as edema because efficient mecha-forces governing the distribution of fluid between the plasma nisms remove the ifitered fluid, on the one hand, and retard itsand interstitial compartments: interstitial fluid volume increases formation, on the other. The increased filtration leads to anat the expense of plasma volume and, when the rate of capillary increase in the flow of lymph and the return of fluid from thefiltration exceeds the ability of the mechanisms I have described lymphatic system to the circulation. Because the filtered fluid iseither to return it to the circulation or to retard its further low in protein content, the concentration of albumin in theformation, edema develops. Just as in any condition of hypo- interstitial fluid, normally about one-half that of the serumvolemia, the reduction in plasma volume then activates renal albumin concentration, falls. This decrease increases the on-sodium-conserving mechanisms. Renal sodium excretion is cotic pressure gradient between plasma and interstitium, areduced below that required to maintain sodium balance at the change that retards further filtration. The increased filtrationgiven level of intake, and sodium is retained. This sodium rate also increases interstitial hydrostatic pressure, therebyretention contributes directly to extracellular fluid volume offsetting the increase in capillary hydrostatic pressure thatexpansion and edema formation, and exacerbates the hypoalbu- results from upright posture, thus also retarding further fluidminemia. This hypothesis places primary emphasis on reduced 268 Nephrology Forum: Mechanisms and management of nephrotic edema serum albumin concentration and plasma volume in the processwith Heymann nephritis, a model of human membranous ne- of edema accumulation. According to this hypothesis, thephropathy, had plasma and extracellular fluid volumes no kidneys, functionally normal with respect to sodium metabo-different than did normals despite a reduction in plasma oncotic lism, respond appropriately to sodium-conserving stimuli acti-pressure from 20 mm Hg to 9 mm Hg [13]. Administration of vated by reduced plasma volume. I shall first review the dataalbumin concentrates does not appreciably mobilize edema supporting or refuting a critical role for each of the elements influid in many nephrotic subjects [14, 151, although sodium this proposed pathophysiologic scheme of nephrotic edemaexcretion can increase transiently in some [16—18]. Finally, formation. patients with minimal-change nephropathy who are treated with Serum albumin concentration. A linchpin of the underfillcorticosteroids undergo a diuresis and natriuresis well before hypothesis is that a reduction in serum albumin concentration isthe serum albumin concentration starts to increase; this finding critical to the development of the edema. Support for thissuggests that correction of the hypoalbuminernia might not be concept stems from the clinical observation that virtually allimportant in the steroid-induced natriuresis [19, 20]. In aggre- nephrotic patients with edema are hypoalbuminemic. However,gate, then, a compelling role for reduced plasma albumin several lines of evidence suggest that hypoalbuminemia is not aconcentration and oncotic pressure in the sodium retention of critical element in edema formation. Patients with analbumine-nephrotic syndrome is difficult to demonstrate. mia (from congenital absence of the albumin gene) generally Plasma volume. Another critical concept in the underfill have no gross abnormality in sodium homeostasis [5—7]; plasmahypothesis of nephrotic edema formation is that plasma volume oncotic pressure is partially maintained by the presence of othercontraction is the proximate stimulus for renal sodium reten- plasma proteins. Further, in analbuminemic rats, the transcap-tion. This concept derives closely from the importance of the illary oncotic gradient does not markedly differ from normal [8].hypoalbuminemia: the reduction in plasma oncotic pressure Nor does capillary filtration differ markedly from normal [5],that accompanies the hypoalbuminemia alters the Starling equa- and edema is only an occasional finding [6, 7]. The gradienttion in a manner that favors the transfer of plasma water into the between plasma and interstitial fluid albumin or oncotic pres-interstitium. Early observations suggested that hypovolemia sure also has been examined when plasma albumin concentra-was indeed a prominent feature of the nephrotic state, even to tion has been reduced by plasmapheresis in animals withthe point of producing circulatory collapse and acute renal normal kidneys. Manning and Guyton found that reduction offailure [21]. However, the basis for the renal failure in many of plasma total protein concentration from 6.9 g/dl to 4.6 gldl,these cases might be due to factors other than hypovolemia and corresponding to a reduction in plasma oncotic pressure fromrenal hypoperfusion [15]. The technique of plasma volume 21.6 mm Hg to 13.3 mm Hg, did not affect arterial pressure ormeasurement in hypoalbuminemic subjects came into question blood volume [9]. Additional plasmapheresis, which reducedfollowing the observation that postural reductions in plasma oncotic pressure to less than 6 mm Hg, reduced arterialvolume were exacerbated in hypoalbuminemic patients [22, 23]. pressure and blood volume, and increased plasma renin activityA survey of clinical measurements of plasma volume in ne- (PRA) [9]; the pattern of renal hemodynamic function wasphrotic patients found a lack of uniformity in the results: consistent with renal hypoperfusion [10]. Wraight observed thatalthough some observations did indicate a significant reduction the transcapillary escape rate of albumin, a measure of itsin plasma volume, a majority of patients were found to have permeability across peripheral capillary beds, decreased whennormal plasma volume measurements, and some actually had plasma albumin was lowered by plasmapheresis from 2.12 g/dlincreased plasma volume [24]. This same group also published to 1.36 g/dl in rats [11]. Such a result would favor the mainte-in 1984 an extensive review on the role of plasma volume in nance of a normal or near-normal oncotic gradient across thenephrotic edema formation [151. They performed a detailed capillary wall in hypoalbuminemic states. A similar approach incritique of the technique of plasma volume measurement, and dogs, however, failed to demonstrate a decrease in the trans-they concluded that methodologic considerations could intro- capillary escape rate of albumin after plasmapheresis, but didduce an error of only a few percent in the measurement, an show that reduction of plasma oncotic pressure to 9 mm Hg didamount not adequate to account for the wide range of measure- not decrease blood volume or increase PRA or plasma aldoste-ments observed in clinical studies including the preponderance rone concentration [12]. A further reduction in oncotic pressureof normal or increased values in nephrotic patients [15, 25]. to 7.3 mm Hg led to transient sodium retention and elevations inResults of plasma volume measurements in animals with exper- PRA and plasma aldosterone concentration [12]; this result wasimental nephrotic syndrome likewise do not demonstrate a similar to the findings of Manning and Guyton [9, 10]. As is truereduced plasma volume [13, 26]. in analbuminemic rats, the transcapillary oncotic gradient was If reduced plasma volume were a critical factor in nephrotic preserved during plasmapheresis by a parallel reduction insodium retention, one would expect that correction of the tissue oncotic pressure as plasma oncotic pressure fell, excepthypovolemia by plasma volume expansion would lead to natri- at the very lowest levels of plasma oncotic pressure, when theuresis. Indeed, early studies showing a benefit of plasma interstitial fluid oncotic pressure no longer declined [121. Theexpansion therapy on natriuresis in nephrotic subjects provided data thus suggest that hypoalbuminemia in humans or animalsinitial support for underfill mechanisms [17, 18]. This viewpoint with normal kidneys does not necessarily result in fluid reten-is also supported by more recent data [16] and by the studies by tion and plasma volume contraction unless plasma oncoticUsberti et al, who showed that impaired water excretion in a pressure falls dramatically to less than 8 mm Hg or so. group of nephrotics with reduced plasma volume was improved Numerous clinical and experimental observations call intoby infusion of hyperoncotic albumin, which reduced the plasma question a key role for hypoalbuminemia in the pathogenesis ofADH concentration [27]. They concluded that hypovolemia in nephrotic edema. Kaysen and associates demonstrated that ratsthese subjects led to nonosmotic stimulation of ADH secretion, Nephrology Forum: Mechanisms and management of nephrotic edema 269 which was corrected by the volume expansion [27]. Othervations is unclear, however. Although these maneuvers can studies evaluating the response to plasma volume expansionincrease sodium excretion, the relationship of the suppression have indicated that expansion does not uniformly lead toof PRA to the natriuresis is not established. As I already natriuresis [14, 28]. Several studies have shown that centralmentioned, Peterson et al observed that head-out water immer- blood volume expansion produced by head-out water immer-sion resulted in blunted natriuresis in nephrotics [32]. Although sion could induce natriuresis in nephrotic subjects [29—33].PRA was not measured in these studies, it is likely that it These studies did not always establish whether the natriureticdecreased, as reported by others [30, 31, 33]. Dietary salt response was as potent as expected in normal individuals orloading was successful in suppressing PRA in 2 nephrotic was blunted; in the study by Krishna and Danovitch, thepatients, but sodium retention and weight gain were the same as magnitude of the natnuresis during immersion significantlyin 8 other subjects whose PRAs were not suppressed [40]. correlated with the initial plasma volume [30]. This associationInfusion of the angiotensin II receptor antagonist saralasin into suggested that diminished plasma volume contributed to6 nephrotic patients failed to increase sodium excretion; indeed, blunted natriuresis in some patients [30]. More recently, Peter-at the higher infusion rates, sodium excretion was actually son and colleagues used the same technique and also found adecreased, perhaps because of a concomitant fall in GFR [41]. blunted response by nephrotic subjects compared to normals;Brown and associates identified a group of 12 nephrotic patients these observations suggested that, despite equivalent degrees ofin whom PRA inversely correlated with serum albumin concen- central blood volume expansion, the nephrotic patients hadtration [42]. This finding would be expected if hypoalbuminemia impaired natriuresis [321. Remission of steroid-responsive ne-leads to hypovolemia, which then stimulates renin secretion. phrotic syndrome also has not been associated with an increaseHowever, blockade of the renin-angiotensin system with cap- in plasma volume [24]. topril in 8 nephrotic patients with elevated PRA did not alter Thus, as is the case with hypoalbuminemia, the evidencesodium retention or lead to natriuresis as it did in normal supporting a key role for plasma volume contraction in the subjects [27]. This observation suggests that sodium retention development of nephrotic edema is lacking. The reason for thein the nephrotic patients was not under control of the renin- preservation of plasma volume in many nephrotic patients, despite the marked reduction in plasma albumin concentrationangiotensin system. and oncotic pressure, is that interstitial oncotic pressure is The response of PRA to steroid therapy of the nephrotic reduced in parallel, thus maintaining the transcapillary oncoticsyndrome likewise calls into question the importance of this system in nephrotic edema formation. In a group of patients gradient 1T[34—36].Only when plasma oncotic pressure is profoundly reduced (below 8 mm Hg) is the gradient seriouslywith minimal-change nephropathy with normal or low PRA, affected, and it is at this level that evidence of hypovolemia canDorhout Mees and associates observed no overall change in appear [9, 10, 34]. PRA after steroid-induced remission, although PRA tended to The renin-angiotensin-aldosterone system. Because underfillincrease while blood pressure fell significantly; these changes states of any cause initiate sodium retention through commonare not consistent with underfill mechanisms [24]. In contrast, pathways, these pathways also have been studied intensively toBrown et al found that PRA fell from high levels in selected evaluate their roles in nephrotic edema; the renin-angiotensin-patients with minimal-change lesions during remission, but then aldosterone system is foremost among them. Aldosterone ini-rebounded to elevated values. These investigators concluded tially was isolated from the urine of children with nephroticthat elevated renin and aldosterone levels were not related to syndrome [37], thus suggesting its importance in this condition.nephrotic sodium retention [19], although the fall in PRA and Plasma renin activity, the focus of much attention, has beenplasma aldosterone did correlate with steroid-induced natriure- measured in many series. Unfortunately, the results are incon-sis. Koomans and colleagues also observed reductions in PRA clusive: although elevated in some patients, values are normaland plasma aldosterone concentration in patients with minimal- in others and suppressed in still others [14, 16, 19, 20, 23, 24, 27,change nephropathy undergoing steroid-induced remission, but 28, 30, 31, 33]. Medina and colleagues suggested that low levelsconcluded that the changes in PRA were a consequence of of PRA could reflect a depletion of renin substrate [38]. Thisimproved filtration and delivery of sodium to the macula densa possibility was evaluated directly by Boer and associates, whowith suppression of renin secretion, rather than a result of found that renin substrate concentration was normal or elevatedcorrection of a diminished plasma volume [20]. Using data from in 25 of 27 cases of nephrotic syndrome [39]. In these patients,their studies of PRA, Meltzer and colleagues identified two PRA was low or normal in 24 of the 27, indicating that substratetypes of nephrotic patients. The first group was a vasoconstric- depletion did not lead to spuriously low values of PRA, andtor type with high PRA, plasma volume contraction, and implying that variations in PRA in nephrotic patients reflectedelevated hematocrit consistent with hemoconcentration; mini- factors other than volume status. mal-change nephropathy was evident on renal biopsy. The Since static measurements of PRA by itself do not give muchsecond type comprised hypervolemic patients characterized by insight into the role of the renin-angiotensin system in nephroticincreased plasma volume, reduced hematocrit, and a sup- edema, the functional responsiveness of this system has beenpressed PRA; they had membranous or membranoproliferative studied during volume expansion with albumin infusions ornephropathy and reduced GFR [43]. These authors suggested head-out water immersion. Albumin infusion regularly sup-that measurement of PRA could help delineate two different presses PRA, usually without regard to the initial magnitude ofpathophysiologic mechanisms of nephrotic edema. On the other the PRA [14, 16, 27]. Central blood volume expansion producedhand, Geers and associates examined the relationships among by head-out water immersion also suppresses PRA in nephroticplasma volume, PRA, and renal function in a large group of patients [30, 31, 33]. The functional significance of these obser-patients with both minimal-change lesions and a variety of other 270 Nephrology Forum: Mechanisms and management of nephrotic edema glomerular abnormalities [44]. Their failure to find any signifi-steroid treatment and before proteinuria or sodium retention cant differences between patients with minimal-change ne-had resolved [48]. The same investigators also measured plasma phropathy and those with histologic lesions fails to confirm thenorepinephrine; in nephrotic children excreting less than 1 hypothesis of Meltzer et al. mEq/day of sodium, the concentration was elevated over that in In aggregate, there seems to be no consensus regarding thenormal children, but plasma norepinephrine was no different in role of PRA in nephrotic edema formation or in the resolution ofnephrotics excreting more than 10 mEq/day of sodium [49]. the edema. This should not be surprising, as renin secretionPlasma volume expansion successfully lowered norepinephrine might be under the direct influence of local, intrarenal pathwayslevels in nephrotic children [16, 49]. Subsequent measurements related to the intrinsic renal disease as well as systemic factorsof plasma norepinephrine have yielded conflicting results. reflecting blood volume status; the latter might be more impor-Dorhout Mees and colleagues found no difference in either tant in minimal-change nephropathy. supine or upright levels between normal subjects and patients Similar ambiguity attends the role of aldosterone in thewith nephrotic syndrome [15, 23]. On the other hand, a prelim- pathogenesis of nephrotc edema. In many of the PRA studies Iinary report of norepinephrine kinetics in supine nephrotic just reviewed, either plasma aldosterone concentration or uri-patients found a greater rate of norepinephrine secretion com- nary aldosterone excretion also was measured [14, 16, 19, 20,pared with controls, and this increased norepinephrine secre- 27, 29, 31, 33]. However, as was true with PRA, no consensustion led to a marginally greater plasma norepinephrine concen- exists that aldosterone levels are increased in nephrotic sub-tration. However, nephrotic patients had insignificant increases jects nor that mineralocorticoid effects are important in ne-in these variables with upright posture as opposed to greater, phrotic sodium retention. Brown and associates administeredsignificant increases in the normal subjects [50]. the converting enzyme inhibitor captopril to a group of ne- An important role for renal nerves in nephrotic sodium phrotic patients with initially elevated PRA and plasma aldo-handling has been shown in studies examining the response of sterone [28]. Captopril lowered plasma aldosterone concentra-rats with experimental nephrosis to oral and intravenous so- tion and blood pressure, but did not cause natriuresis or preventdium loading [51]. Conscious nephrotic rats had blunted natri- further weight gain. This same group examined the relationshipuresis to oral sodium loads that was corrected by renal dener- between plasma aldosterone and sodium excretion in a group ofvation. Compared with normals, efferent sympathetic renal patients with minimal-change disease during steroid-inducednerve activity was higher in nephrotic rats, and decreased less remission; the observation that plasma aldosterone fell asafter intravenous volume expansion [51]. On the other hand, we diuresis and natriuresis developed suggested that the hormonewere unable to demonstrate improvement in volume expansion could have participated in the initial sodium retention [19].natriuresis in anesthetized, nephrotic rats [52]. Koomans et al also found a reduction in plasma aldosterone These studies indicate some variability in the extent of concentration, albeit a statistically insignificant one, during thesympathetic nerve activation in nephrotic syndrome and, like induction of remission by steroid administration, but theythe other measures that have been used to assess arterial argued that this reduction was not the basis for the natriuresisunderfilling, indicate that the available data do not permit a [20]. On the other hand, Shapiro et al administered the aldoste-conclusion that nephrotic edema arises from underfill mecha- rone antagonist spironolactone to a group of 5 nephrotic pa-nisms. tients with membranous nephropathy or focal glomerulosclero- sis [45]. These patients were in positive sodium balance while Overflow mechanisms of nephrotic edema ingesting a high-sodium diet, but went into negative sodium balance when treated with spironolactone. The authors con- Because of the difficulties in painting a uniform picture of an cluded that aldosterone was an important factor in nephroticunderfill state in most nephrotic patients, it is not surprising that sodium retention. However, the plasma aldosterone concentra-researchers have developed an alternative hypothesis. In con- tions did not differ in the patients compared with a group oftrast to underifil edema, this hypothesis regards sodium reten- normal subjects treated in a similar manner. This similaritytion leading to edema as a result of a primary intrarenal suggests the possibility of increased sensitivity to aldosterone inabnormality. In addition to being supported by the data I the nephrotics via an as-yet-unexplained mechanism [45]. Thatreviewed that are inconsistent with underfill mechanisms, the rats with experimental nephrosis develop edema that is main-overflow hypothesis is also buttressed by direct observations tained despite adrenalectomy [26] indicates that sodium reten-indicating the presence of an intrarenal sodium handling defect. tion in these animals does not require aldosterone. The resulting overflow edema is summarized in Figure 2. The sympathetic nervous system. The sympathetic nervousAccording to this hypothesis, proteinuric renal disease leads to system is another homeostatic system activated during hypo-increased reabsorption of filtered sodium, chiefly in the distal volemia. Other states of pathologic sodium retention, namely,nephron, through mechanisms that have been only partially congestive heart failure and cirrhosis of the liver, are associatedidentified. In addition, decreased GFR from glomerular injury with heightened sympathetic nervous system activity [46, 47],also can contribute to sodium retention [53]. With continued thought to reflect the functional response to an underfilledingestion of sodium in excess of renal excretory ability, extra- circulation. If underfill mechanisms also operate in nephroticcellular fluid and blood volume expand. In the context of the sodium retention, sympathetic activation likewise should exist.Starling equation, increased capillary filtration takes place Oliver et al measured urinary catecholamine excretion in aprimarily by an increase in P to the point that the defenses are group of nephrotic children. Catecholamine excretion wasovercome and edema accumulates. elevated in a manner roughly paralleled by the sodium avidity of Direct evidence supporting this form of nephrotic edema these patients, but fell to normal levels within a few days offormation began to accumulate with the observation that in Nephrology Forum: Mechanisms and management of nephrotic edema 271

Glomerular Disease 90

80

70

Proteinuria Hypoalbuminemia 60 5o z0

Ce 40 Primary Renal E Sodium Retention Ci, a.30

20

4' Plasma Volume 10 0 0 Base 1 2 3

Capillary Filtration Time of immersion, hours 4' Fig. 3. Response of plasma ANP concentration to head-out water immersion in normal subjects and in patients with nephrotic syndrome. Plasma ANP concentration was lower in nephrotic patients (solid circles) than in normals (open circles) at the outset, but rose to levels * slightly higher than in normals after 3 hours of immersion. Despite this, nephrotic patients had a blunted natriuretic response. *,significantly EDEMA greater than time 0; +,significantlyless than value in normals, P <.05. (From Ref. 32.) Fig. 2. Representation of nephrotic edema formation from overflow mechanisms. In this model, hypoalbuminemia is not a critical compo- nent of sodium retention; rather, proteinuric renal disease leads to heightened sodium reabsorption through a primary, intrarenal mecha- nism, the basis for which is not currently understood, but which isnephrotic sodium handling, reduced GFR, and increased distal independent of the renin-angiotensin system and other pathways ofsodium reabsorption. The reduction in GFR presumably results secondary sodium retention. from structural glomerular damage but could also reflect hypo- perfusion: Shapiro et al showed that impaired water excretion in a group of nephrotic patients could be related to a reduced dogs with unilateral glomerulonephntis, abnormal sodium han-GFR [59]. Water immersion improved renal water excretion in dling occurred only in the affected kidney [54]. Induction ofa manner that correlated best with the observed increase in unilateral proteinuria by the intrarenal administration of amino-GFR [59]. The mechanism underlying heightened reabsorption nucleoside of puromycin also led to sodium retention by thein the distal nephron is not known with certainty, but it could proteinuric kidney [55, 56]. The mechanism leading to thisrelate to impaired action of atrial natnuretic peptide (ANP). unilateral sodium retention might relate to the reduced GFR In addition to exhibiting blunted volume-expansion natriure- resulting from puromycin administration [55, 56]. However,sis, it was quickly observed that nephrotic animals and most micropuncture experiments indicated that, despite reducednephrotic patients have appropriately elevated plasma ANP GFR, delivery of filtrate to the distal nephron was similar inconcentrations after volume expansion [16, 31, 32, 52, 60]. Thus control and nephrotic kidneys; this observation led to thethe nephrotic state was defined as a condition of ANP resis- conclusion that increased sodium reabsorption in the late distaltance. In the study by Peterson and colleagues, a 3-hour period nephron was responsible for the unilateral sodium retentionof head-out water immersion in a group of nephrotic patients [56].Thisconclusion agrees with the earlier experiments bycaused plasma ANP concentration to increase from 14 3 Bernard and associates, who also found evidence for increasedpg/mi to 75 19pg/mi, a value slightly higher than that in distal sodium reabsorption in rats with Heymann nephritis [57],normal control subjects (Fig. 3) [32]. Yet increases in both and with clinical studies by Grausz et a! 20 years ago, whofractional and absolute rates of sodium excretion were mark- concluded that reabsorption in the proximal tubule was de-edly blunted in the nephrotic patients, so it is likely that these creased in sodium-retaining nephrotic patients, thus indicatingpatients had renal resistance to ANP [32]. This suggestion is that increased distal reabsorption must have occurred [58].further supported by experiments of ANP infusion into ne- Thus, two intrarenal mechanisms might participate in abnormalphrotic rats: the natriuretic response to the infusion was blunted 272 Nephrology Forum: Mechanisms and management of nephrotic edema

A ADA without marked reduction in GFR in the early stages; later, GFR falls, and focal glomerulosclerosis develops [66]. Rats with adriamycin-induced nephrosis had blunted natriuresis in response to volume expansion despite plasma concentrations of ANP that were actually higher than those seen in normal rats undergoing the same volume-expansion protocol (Fig. 5). The blunted natriuretic response was accompanied by a parallel 6 blunting of the increase in urinary cyclic guanosine-3' ,5'-mono- phosphate (cGMP) excretion (UCGMPV) (Fig. 5); UCGMPV is a 4 useful index for the renal actions of ANP [67]. Thus, blunted natriuresis in response to volume expansion in these nephrotic animals was related to ANP resistance, which in turn was 2 ** linked to an abnormality in cGMP metabolism [52]. The cellular basis for nephrotic ANP resistance was explored 0 in additional experiments by our group. Figure 6 is a schematic view of ANP's effects on its target cell, in this case an epithelial B Saline cell in the inner medullary collecting duct (IMCD), a recognized site of ANP action [68]. The secreted peptide must reach its receptors via a blood-borne route. Once there, it interacts with 8 its receptor. Although several classes of receptors for ANP have been described [69], those in the IMCD are primarily of the biologically active type containing guanylate cyclase activ- 6 ity in the intracellular domain of the receptor [70]. Interaction of ANP with these receptors activates the guanylate cyclase to 4 increase the production of cGMP. The intracellular second messenger, cGMP, then causes, either directly or through I2 intermediary steps, a luminal membrane amiloride-sensitive sodium channel to close, thereby inhibiting sodium reabsorp- tion [68]. The signal is terminated by cleavage of cGMP to 0 5'GMP, chiefly by the action of a specific cGMP phosphodies- 0 40 60 80 100 terase (PDE). The ANPresistancein nephrosis could result from a failure of normally secreted peptide to gain access to its Time, minutes receptors in the IMCD, impaired binding to these receptors, Fig.4. Natriuretic effect of intravenous ANP infusion in rats 21 days impaired generation of cGMP, or accelerated breakdown of after one kidney was rendered proteinuric by the intrarenal administra- tion of adriamycin (ADR). Proteinuric kidneys (solid circles) had an normally produced cGMP. absent natruretic response to the infusion, whereas control kidneys To test these various possibilities, we measured ANP-depen- (open circles) in the same animals exhibited the expected natriuresis dent cGMP accumulation in vitro in glomeruli and IMCD cells (top panel). Injection of the saline vehicle alone did not alter ANPisolated from normal and nephrotic rats (Fig. 7). We observed responsiveness (bottom panel). (From Ref. 64.) blunted cGMP accumulation in both tissues in response to increasing concentrations of ANP. Thus ANP resistance in vivo was unlikely to result from impeded access of the peptide to its or absent compared with the response in normal animalsreceptors [52]. Binding of ANP to IMCD cells did not differ [61—63]. This blunted ANP responsiveness resided within thebetween normals and nephrotics, as previously shown by kidney; rats with unilateral proteinuria from administration ofPerico et al [64]. Therefore, we examined the effect of PDE adriamycin into one renal artery exhibited resistance to sys-inhibition on ANP-dependent cGMP accumulation in vitro. In temic ANP infusion in the proteinuric kidney, while the non-the presence of the nonselective PDE inhibitor 3-isobutyl-l- proteinuric, contralateral kidney was normally responsive tomethylxanthine (IBMX), basal cGMP accumulation both by ANP [64] (Fig. 4). The resistance to ANP did not appear to beisolated glomeruli and IMCD cells increased, and the difference due to altered binding of the peptide to its receptors in the innerbetween normal and nephrotic tissues in response to ANP was medulla [64], but was improved by renal denervation [611. Thisno longer observed. These results were extended by using a latter observation suggests that ANP resistance is related to thespecific cGMP PDE inhibitor zaprinast (M&B 22,948) (Fig. 7). heightened efferent renal sympathetic nerve activity in ne-The effect of this compound on basal cOMP accumulation was phrotic animals [511. This conclusion was strengthened by themodest, and ANP increased cGMP accumulation in a dose- finding that stimulation of renal nerves in normal rats blunteddependent manner. However, as with IBMX, the difference the renal response to ANP infusion [65]. The possibility thatbetween normal and nephrotic rats was no longer apparent [52]. this ANP resistance in nephrotic patients could account for the In aggregate, these results suggest that the abnormality in blunted response to volume expansion was, therefore, annephrotic cGMP metabolism could be related to heightened attractive idea to pursue. We have measured the renal responseactivity of cGMP PDE. This possibility was further supported to volume expansion in rats with high-grade proteinuria fromby experiments measuring cGMP accumulation in response to adriamycin administration [52]. This agent produces proteinuriasodium nitroprusside, which stimulates a soluble guanylate Nephrology Forum: Mechanisms and management of nephrotic edema 273

A B 100 Infusion I* 15 75

10 * . 50 - T*

— T — 5 /1\T*'A Fig. 5. Effect of intravenous normal saline 25 volume expansion (2% body weight over 5 mm [shown by the black bar]) on sodium excretion (A) and cyclic GMP excretion (B) in normal F' and nephrotic rats. Nephrotic rats (triangles) 0 had a blunted natriuretic response that was 0 10 20 30 40 50 0 10 20 30 40 50 accompanied by a smaller increase in UCOMPV in response to the volume expansion Time, minutes compared to normal rats (circles). (From Ref. 52 with permission of the American Society of S • normal A A nephrotic Clinical Investigation.)

increase in UCGMPV after volume expansion by nephrotic kidneys [52]. Thus, this cGMP PDE inhibitor was able to correct not only ANP resistance shown by nephrotic cells in vitro, but it also corrected the blunted volume-expansion natriuresis in nephrotic rats in vivo. These results raise the possibility that abnormal sodium metabolism in nephrosis is related to a specific cellular alteration in the ANP signaling pathway, namely, an increase in cGMP PDE activity that blunts the cellular actions of cGMP normally produced in response to ANP's interaction with its biologically active receptor. This possibility was extended by preliminary data from our group, which showed that rats with Heymann nephritis also had cellular resistance to ANP that was corrected by zaprinast [71]. This latter observation implies heightened cGMP PDE activity in this form of proteinuric renal disease also. Not all results support the argument that increased activity of cGMP PDE ultimately accounts for abnormal nephrotic sodium Na metabolism. Abassi et al measured UCGMPV during ANP infu- Fig. 6. Schematic representation of the steps in ANP signaling in a cell sion and found no difference between normal rats and rats with from the inner medullary collecting duct. adriamycin-induced nephrosis [72]. However, data were ex- pressed per unit of GFR; since the nephrotic rats had lower GFR, absolute UCGMPV by nephrotic animals was only 55% the cyclase not linked to the ANP receptor. If cells from nephroticvalue in normals, a reduction qualitatively similar to the differ- animals had heightened activity of cGMP PDE, cGMP accumu-ence observed by Valentin and associates after volume expan- lation in response to this compound should also be blunted.sion in rats in which differences in GFR were much smaller [521. This was indeed the case and, as with ANP-dependent cGMPWoolf et al infused ANP into a heterogeneous group of ne- accumulation, the difference between accumulation by normalphrotic patients and found no difference in either the natriuresis and nephrotic glomeruli and IMCD cells in response to nitro-or the increase in UCGMPV from normal subjects [73]. In this prusside was abolished by IBMX and zaprinast [52]. To test thegroup of nephrotic patients, only 3 of 6 actively retained sodium physiologic relevance of these in-vitro findings, we infusedon a dietary intake of 150 mmoLlday; the normal natriuretic zaprinast continuously into one renal artery of normal andresponse of the group as a whole suggests that they did not have nephrotic rats in a dose that had no effect on basal sodiumANP resistance. However, the peak UCGMPV by the nephrotic excretion or UCGMPV. In nephrotic rats, volume expansionpatients of only 56% of normals during ANP infusion again produced the same blunted natriuretic response by contralat-suggested blunted responsiveness to the peptide [73]. eral, noninfused kidneys as previously observed. Nephrotic kidneys infused with zaprinast exhibited a natriuretic response Underfihl versus overflow that was indistinguishable from the response by normal rat Given this wealth of contradictory clinical and experimental kidneys, however. The zapnnast infusion also normalized thedata, how can one develop a unifying scheme of nephrotic 274 NephrologyForum; Mechanisms and management of nephrotic edema

Glomeruli IMCD cells

1500 T 600 1200 . /1 /1* 900 400 /*I A 600 . T—_ /1 A L 200 300 0 0 C) + zaprinast +zaprinast 1500 0 4 600 C-) 1200 Fig. 7. ANP-dependent cGMP accumulation 900 400 by isolated glomeruli (left) and IMCD cells I (right) from normal (circles) and nephrotic 600 TI (triangles) rats. Nephrotic tissues had a 200 markedly blunted response compared to 300 'I normals (top panels). Addition of the specific cGMP phosphodiesterase inhibitor zaprinast 0 0 (M&B 22,948, iO M) did not alter basal C —11 —9 —7 —5 C —11 —9 —7 levels appreciably, but normalized responsiveness by the nephrotic cells (bottom log ANP,M panels). Asterisks indicate nephrotic values significantly less than normals (P <.05or • —. normal A — A nephrotic greater). (Modified from Ref. 52.) edema formation? As I said earlier, one important issue lies inmality were activated. Although the concept of a widespread the credibility of plasma volume measurement in nephroticpermeability defect in minimal-change nephropathy has been a syndrome; in addition to artifacts introduced by differences incontroversial one [78], such an abnormality could help explain posture and in the transcapillary escape rate of albumin, there iswhy most data indicating underfill mechanisms have been also some ambiguity in the proper reference to express theobtained in patients with this form of nephrosis. result. Because nephrotic patients are by definition edematous, The sodium-retaining pathways activated by an underfilled so-called "dry weight" can be determined only after the fact, ifcirculation could themselves possibly initiate an intrarenal at all, and thus an appropriate reference is difficult to identify [9,sodium reabsorptive abnormality characterized by renal resis- 74]. Even so, the differences in clinical and experimentaltance to ANP similar to the scheme I have outlined. Cells of the studies are such that instead of facing an "either/or" situation,IMCD exhibit specific binding and/or physiologic actions to a we could be dealing with one that is "both. .. and";that is,number of neurohumoral compounds involved in epithelial features of both underfill and overflow mechanisms mightsolute and water transport; in addition to ANP, these include contribute to the pathogenesis of edema in nephrotic patientsvasopressin [79], angiotensin II [80], endothelin [81], aldoste- [9, 74]. In this formulation, a common thread of all nephroticrone [82], ct-adrenergic agonists [83], and adenosine [841. Acti- states could be an intrarenal sodium handling abnormality, onevation of one or more of these regulatory systems by an perhaps related to ANT' resistance. This abnormality leads tounderfilled circulation could lead to the development of tubular positive sodium balance and edema formation on an overflowresistance to ANPthroughthe mechanism I described. Figure 8 basis, but can be modified in its manifestations by underfillis a schematic representation of how overflow and underfill features, which would result from the severity of the hypoalbu-mechanisms each might bring about ANP resistance through an minemia; patients with plasma oncotic pressures less than 8 mmincrease in cGMP PDE activity. Hg would be particularly likely to exhibit evidence of underfill. Thus, it seems possible that underifil and overflow mecha- Additionally, some have suggested that nephrotic patients havenisms interact with each other in the production of nephrotic a widespread abnormality in capillary permeability that couldedema. The extent of this interaction will determine the char- lead to reductions in plasma volume [27, 75]. Drawing on theacteristics of sodium and volume regulation in individual pa- initial hypothesis of Shalhoub that minimal-change nephropathytients. It is clear that more work is required to elucidate the reflects a disorder of T-cell function [76], Lagrue et al found thatnature of this interaction. cultures of lymphocytes from nephrotic patients, when stimu- lated with concanavalin.A, released a substance resembling a Management of nephrotic edema cytokine into the medium that increased vascular permeability Given these complexities regarding the pathophysiology of when tested in a skin extravasation bioassay [77]. Underfillnephrotic edema formation, it is no surprise that its manage- manifestations could predominate in individual patients to thement is frequently problematic. Table 1 lists measures that can extent that the one or more factors responsible for this abnor-be employed in the treatment of nephrotic edema, Dietary Nephrology Forum: Mechanisms and management of nephrotic edema 275

Underlill mechanisms

tRenal nerve activity

Angiotensin II

Vasopressin Overflow mechanisms

Endothelin r cGMP Phosphodiesterase $1 / activity Fig. 8. Hypothetical scheme whereby both underfihl and overflow mechanisms result in ANP resistance in IMCD cells. An underfilled circulation could activate a number of neural and humoral pathways, a few of which are depicted here, to act on the IMCD cell to 3 increase cGMP phosphodiesterase activity, thereby producing ANP resistance. Overflow J mechanisms could have the same result, although the signal responsible for increasing H cGMP PDE activity has not yet been ANP resistance identified.

Table 1. Approaches in the management of nephrotic edema increases the risk of thromboembolic complications, especially Dietary sodium restriction with prolonged bed rest [85]. Support stockings are also of some Bed rest use; by favoring the distribution of blood to the central blood Support stockings volume, they may alleviate some of the stimuli for sodium Head-out water immersion Plasma volume expansion retention [86] in a manner analogous to the effects of head-out Diuretic administration water immersion. As I said earlier, this maneuver increases Plasma ultrafiltration sodium excretion in nephrotic patients through central blood volume expansion, stimulation of ANP release, and suppres- sodium restriction is a mainstay in the approach to all condi-sion of PRA and plasma aldosterone [29—33]. It, too, is of only tions of generalized edema formation. Many nephrotic patientslimited practicality as a diuretic technique; moreover, sodium in the active stages of sodium retention will excrete less than 10excretion decreases to basal values immediately alter patients mEq of sodium per day. Because reduction of sodium intake toare removed from the immersion tank, and it is possible that this level or less is extremely difficult to achieve outside aeven more avid sodium retention during the time out of the tank metabolic ward, sodium restriction to the more modest levelsoffsets the natriuresis occurring as a result of the immersion. achievable in the outpatient setting is usually helpful only in Plasma volume expansion, usually with hyperoncotic albu- slowing the rate of edema formation rather than in leading to itsmin concentrates, is an oft-tried approach to nephrotic edema. resolution. However, many nephrotic patients with edema willThe data I summarized earlier indicate that results with this be less sodium avid, as illustrated in some of the clinical studiesapproach are variable, with less than one-half of patients I discussed earlier [19, 20, 27, 30, 45, 73]. In these patients, rates of sodium excretion match levels easily achieved withresponding [16—20, 27, 28]. However, volume expansion ther- apy might play an adjunctive role in the diuretic management of modest sodium restriction, and positive sodium balance occurs only when they are challenged with excessively high sodiumnephrotic patients who have resistant edema; plasma expansion intakes. Therefore, dietary sodium restriction to about 50restored responsiveness in a group of such patients [87]. The mEq/day should be a reasonable goal in all patients. major drawback with this approach is that the infused albumin Bed rest is another measure of general benefit in edematousis rapidly excreted into the urine [88] by an apparent increase in disorders, presumably because it alleviates orthostatic activa-glomerular pore size [89]. This makes albumin administration tion of the renin-angiotensin and sympathetic nervous systemsan expensive therapy with only short-lasting benefit, and there- that accompany upright posture, and facilitates the transfer offore it should be reserved for patients with only the most interstitial fluid to the vascular compartment to expand centralresistant, severe, symptomatic edema. blood volume. But bed rest obviously is of limited practical Diuretics are of course the cornerstone of management of utility, and its benefits must be balanced against its risks;nephrotic edema. Loop diuretics are generally employed be- hypercoagulability is a feature of most nephrotic patients andcause less potent agents can have blunted or absent diuretic 276 Nephrology Forum: Mechanisms and management of nephrotic edema action, although Shapiro and associates showed that the aldo-accumulation in response to ANP in glomeruli isolated from sterone antagonist spironolactone exerted at least a short-termthese rats to be the same as that in normals when incubated in natriuretic effect in a group of nephrotic patients on a high-the presence of IBMX, but they did not study glomeruli without sodium diet [45]. Diuretic efficacy in nephrotic patients resultsthis PDE inhibitor, so a difference might have been missed. On from factors determining pharmacokinetics and pharmacody-the other hand, abnormal binding of ANP in renal medulla of namics. Brater has suggested that the ratio of urinary sodiumrats with heart failure has been demonstrated [101], and blunted excretion to urinary diuretic excretion is a useful indicator ofANP-dependent cGMP accumulation by glomeruli from rats diuretic potency [90], and in micropuncture studies, Kirchner,with aortocaval fistula was shown in another study [102] using Voelker, and Brater showed that the reduced ratio in nephrotican assay system that included 0.5 mM IBMX. Finally, Abraham rats was related to a blunted effect of intravenous furosemide onet al have observed an appropriate level of cGMP excretion loop chloride reabsorption [91]. These authors proposed thatrelative to plasma ANP concentration in patients with heart furosemide resistance in nephrotic syndrome was caused byfailure [103]; this finding disputes the cellular mechanism I binding of the diuretic to tubular fluid albumin. The addition ofalready described for nephrotic ANP resistance. Only further albumin to tubular fluid of normal rats reproduced the nephroticstudy will clarify the contributions of these various mecha- defect [92], and agents such as sulfisoxazole, which competednisms, including altered ANP binding and opposing effects of with furosemide for albumin binding, restored responsivenessantinatriuretic systems as well as cellular changes such as [93]. If these observations hold true in humans with nephrosis,increased PDE activity, to ANP resistance in these various as seems likely, higher doses of furosemide to overcomephysiologic and pathophysiologic responses. binding of the drug to tubular fluid albumin likely will be DR. MARTIN G. COGAN (Chief, Division of Nephrology, Ft. required to achieve a desired diuretic effect [90]. ContinuousMiley VA Hospital, San Francisco): Have you attempted to infusion of the loop diuretic bumetanide in patients with chronicinfuse an analogue of cGMP such as dibutyryl-cGMP to see renal insufficiency has greater diuretic potency than does thewhether you can overcome the resistance that you described? same total dose of drug given intermittently [94]. It is possible DR. HUMPHREYS: That, too, is an important experiment to that continuous infusion also is more potent in nephroticcarry out. We have not yet had the opportunity to do it, but we patients with preserved GFR as well, although this point has notinterpret the normalization of both volume-expansion natriure- been specifically addressed. Impaired absorption of orally ad-sis and UGMpV by zaprinast when infused intrarenally as ministered diuretics because of edema of the bowel wall mightsuggesting that blunted responsiveness in nephrotic rats is reduce the drug's bioavailability and limit its diuretic effect [95].related to diminished cGMP action. Finally, ultrafiltration has been suggested as an alternative DR. HARLAN E. Ivus (Chief, Division of Nephrology, Moffitt- approach in diuretic-resistant nephrotic patients with massiveLong Hospital, San Francisco): How would you square the edema [96]. This technique is offered to hospitalized patients inobservation that denervation improves responsiveness to ANP the critical care setting, many of whom have acute renal failurewith the data showing that in-vitro tissues maintain a blunted [97], and obviously can be recommended only in the mostresponse to ANP? Is it possible that the half-life of PDE is long exceptional cases. It has been suggested that renal failure inenough that the defect is still present long after the tissues are some nephrotic patients develops from intrarenal edema caus-removed? ing a reduction in GFR [98]. Although such cases are difficult to Da. HUMPHREYS: We have no direct information on that recognize, ultrafiltration might have some utility in their man-point. The in-vitro results were obtained on relatively fresh agement. tissue isolated the same day as the incubation, so the defect lasts at least a few hours. We are interested in culturing these Questions and answers IMCD cells to see whether the evidence for increased cGMP DR. FLOYD C. RECTOR, JR. (Chairman, Department of Med-PDE activity is demonstrable after several days. With respect icine, University of California San Francisco, San Francisco,to the role of the renal nerves, renal denervation failed to California): A variety of models of hypovolemia involve acti-improve volume expansion natriuresis in our study in anesthe- vation of the sympathetic nervous system and the remn-angio-tized rats [52], but it did restore responsiveness in nephrotic tensin-aldosterone axis. Have you had the opportunity to lookrats studied in the conscious state [511. Whether other factors at the effects of any of these models, such as chronic saltcould explain this difference is not currently known. depletion, on the activity of the cGMP phosphodiesterase? DR. R. CURTIS Moiuus, JR. (Professor of Medicine, Pediat- DR. HUMPHREYS: That's a very good question. One wouldrics, and Radiology, University of California San Francisco): predict that any circumstances that led to activation of theIn that regard, has anyone measured cGMP excretion by pathways outlined on the left side of Figure 8 might be accom-denervated nephrotic kidneys in response to ANP infusion? panied by ANP resistance. No studies have specifically ad- DR. HUMPHREYS: Not that I'm aware of. Infusion of ANP dressed this issue. As with any natriuretic stimulus, the magni-increases UCGMPV by normal kidneys that have been dener- tude of the response to ANP is conditioned by the levels ofvated, but I don't believe anyone has examined the response of counterregulatory systems like renal sympathetic nerves anddenervated nephrotic kidneys. angiotensin II [65, 99]. However, I am not aware of any data DR. HENRY HULTER (Division of Nephrology, San Francisco suggesting that this blunted action is related to the cellularGeneral Hospital, San Francisco): You mentioned that cQMP mechanism that I outlined. Abassi et al demonstrated reducedappears to work in the IMCD by an action on the sodium excretion of cGMP in rats with high-output heart failure [100];channel. Are there data on the integrity of the sodium channel these findings are similar to our observations in experimentalin nephrotic animals? Could there be an abnormality at this nephrotic syndrome in rats [52]. Abassi's group found cGMPlevel that accounts for blunted natriuresis? Nephrology Forum: Mechanisms and management of nephroric edema 277

DR. HUMPHREYS: I am not aware of any information onreduced plasma and blood volumes in the majority of nephrotic amioride sensitivity of IMCD cells in nephrotic animals, and itpatients, and because, in those patients who are hypovolemic, certainly is possible that an abnormality there could contributea reduced transcapillary oncotic gradient might be the chief to nephrotic sodium retention. However, the normalization ofcontributor. It does appear, however, that most patients with the volume expansion response with zaprinast leads me tofunctional evidence of hypovolemia have minimal-change ne- conclude that the major abnormality resides in the cGMPphropathy. This observation leaves open the possibility that a system. diffuse capillary leak exists in these patients. DR. JOHN T. HARRINGTON (Chief of Medicine, Newton- DR. ANTHONY A. PORTALE (Chief, Division of Pediatric Wellesley Hospital, Newton, Massachusetts): As you noted,Nephrology, Moffitt-Long Hospital): Along the same lines, Kirchner and associates showed that sulfa compounds competecould you comment on the quantitative contribution of in- with furosemide for binding sites in the tubular lumen ofcreased renal albumin catabolism in the hypoalbuminemia of proteinuric rats [91]. Has anyone tried to apply this observationnephrotic syndrome? clinically by using other such drugs? I'm thinking specifically DR. HUMPHREYS: It is clear that increased albumin catabo- about whether thiazide diuretics might have some effect. lism, primarily in the kidneys, must contribute to nephrotic DR. HUMPHREYS: I believe the only agent that group hashypoalbuminemia, because patients with end-stage renal dis- evaluated is furosemide. Although one could try administeringease treated with continuous ambulatory peritoneal dialysis drugs that compete with furosemide for binding to tubularlose amounts of albumin via the dialysate that are comparable albumin, I think Brater simply recommends using higher dosesto those excreted in the urine by nephrotic patients, yet they of furosemide to enhance diuretic efficacy in nephrotic patientsmaintain normal or near-normal serum albumin concentrations [90]. [105]. In individual nephrotic patients, the serum albumin DR. IVES: Many of the PDE inhibitors also have activityconcentration is determined by the interplay of several factors, against adenosine receptors. Is it possible that some of theincluding urinary albumin loss, albumin catabolism, hepatic actions of these agents in the glomerulus and IMCD cell couldalbumin synthesis, and albumin distribution between vascular be explained by blockade of adenosine receptors at these sites?and extravascular compartments, so it is difficult to offer a DR. HUMPHREYS: I must confess I do not know whetherquantitative assessment of one factor without a knowledge of zaprinast has been tested for effects at adenosine receptors, butthem all. Today's patient is a good example: on initial presen- it shares structural similarity with other methylxanthines. Astation, absolute proteinuria was moderate for nephrotic patients you know, adenosine's effects on tubular transport are complexwhen considered by itself, but when considered in the context and poorly understood [104], and zaprinast could conceivablyof his low filtered load because of the very low serum albumin influence adenosine-mediated effects on sodium excretion.concentration and low GFR, it is massive. Later in his course, However, I think the in-vitro results would be more difficult toGFR and serum albumin concentration were much higher, yet ascribe to an adenosine receptor effect. protein excretion was about the same. DR. WILLIAM P. MULDOWNEY (Staff Nephrolo gist, Santa DR. MARTHA L. GRABER (Division of Nephrology, Mof- Clara Kaiser Permanente Medical Center, Santa Clara, Cali-fitt-Long Hospital): Has anyone examined the role of the fornia): Patients markedly differ in the degree of edema thatrenin-angiotensin-aldosterone system in the blunted response to develops as a consequence of the nephrotic syndrome. How doANP in the nephrotic animal? you reconcile your model with this observation? DR. HUMPHREYS: Not specifically. In most experimental DR. HUMPHREYS: That's a good point. I believe that ne-models of nephrosis, it is difficult to document unequivocal phrotic patients exist along a continuum: at one end, avidinvolvement of this system. This finding is in contrast to the sodium retention dominates, perhaps through the combinationsituation in congestive heart failure, another circumstance of of underfihl and overflow mechanisms I mentioned earlier, andANP resistance, but one in which activation of the renin- edema formation can be disabling. Toward the other end, lessangiotensin axis is regularly demonstrable, and in which angio- pronounced or absent underfill, and a milder degree of cellulartensin antagonists and converting enzyme inhibitors improve resistance to ANP, may permit a new steady state to developANP resistance [106, 107]. with less severe edema formation. Certainly, nephrotic patients DR. JOSHUA LIPSCHUTZ (Fellow in Nephrology, University of exhibit a range of sodium avidity, as I pointed out: some excreteCal(fornia San Francisco): What is the effect of converting less than 10 mEq of sodium per day, and others demonstrateenzyme inhibitors on the ANP resistance of heart failure, and positive sodium balance only when challenged with a very highhave ACE inhibitors been tried in nephrotic syndrome? sodium intake. DR. HUMPHREYS: In two separate studies of experimental Da. DAVID J. MENKE (Staff Nephrologist, San Franciscoheart failure in rats, treatment with an oral converting enzyme Kaiser Permanente Medical Center): In the hypovolemic formsinhibitor restored both the hemodynamic [106] and the renal of nephrosis, you pointed out that some people have postulated[107] actions of ANP infusion, although the basis for this has a diffuse leakiness of capillaries because hypoalbuminemianot yet been established. With respect to nephrotic syndrome, alone can't explain the low plasma volume. Do you think suchI mentioned the study by Brown et al [28], which concluded that a process could be involved? As you showed, hypoalbuminemiainterruption of the renin-angiotensin system by converting by itself does not adequately account for the changes leading toenzyme inhibition did not modify sodium retention in their sodium retention. nephrotic patients. However, the decrease in blood pressure DR. HUMPHREYS: Although there was initial interest in thiscaused by the treatment could have blunted a natriuretic effect. possibility, little attention has been paid to it lately. I believeCaptopril treatment of rats wit puromycin aminonucleoside this is because researchers have been unable to demonstratenephrosis also failed to influence sodium retention [1081. 278 NephrologyForum: Mechanismsand management of nephrotic edema

Da. HARRLNGTON: You hinted that endothelin and other such phosphodiesterase inhibitors in the management of nephrotic compounds could have a role in triggering nephrotic ANPsyndrome! Would you care to comment on the treatment, a resistance. What evidence is there indicating an endothelinrather short course of treatment at that? abnormality? What are endothelin levels in the various forms of DR. HUMPHREYS: I share with you a sense of amazement that nephrotic syndrome, and what happens with diuretic treat-he could recover so much renal function and clear the severe ment? edema he had on initial presentation with the interrupted DR. HUMPHREYS: I am not aware of any information on thisprotocol he received. As I said at the outset, this is a subject issue. worthy of its own Nephrology Forum, which Dr. Ponticelli DR. HULTER: Peterson et a! used a low ANP level asalready has given [1]. Perhaps he should be invited back for a evidence for an underfilled circulation in nephrotic patientsreturn visit! [32].Hasa low ANP level been a general observation? How does it correlate with other markers of underfilling such as PRA Reprint requests to Dr. M. Humphreys, Division of Nephrology, San andaldosterone concentration? Francisco General Hospital, Building 100, Room 350, San Francisco, DR. HUMPHREYS: Unfortunately, resting plasma ANP levels California 94110, USA show no consistent pattern in nephrotic subjects. Many patients have levels no different than those in normals, and ANP does Acknowledgments not clearly correlate with PRA. Experimental nephrosis in the The author wishes to acknowledge the contributions of Drs. David G. rat also seems to lead to no difference in ANP concentrationGardner and Jean-Pierre Valentin in the development of some of these ideas. This work was supported in part by grant DK 31623 from the [52, 60]. National Institutes of Health. DR. COGAN: It has become clear than ANP is a member of a larger family of natriuretic peptides and, as you alluded, there References also are numerous receptors. Have you had an opportunity to look at other natriuretic peptides and their possible roles in 1. PONTICELLI C: Nephrology Forum: Prognosis and treatment of nephrotic sodium retention? membranous nephropathy. Kidney mt 29:927—940, 1986 DR. HUMPHREYS: As you know, most attention with respect 2. STARLING EH: The fluids of the body. The Herter Lectures (1908), Chicago, W.T. Kerner & Co. 1909 to the kidney has focused on urodilatin, an ANP family member 3. MANNING Rb, GUYTON AC: Control of blood volume. Rev differing from ANP by an N-terminal extension of four amino Physiol Biochem Pharmacol 93:70—114, 1982 acids, which is thought to be synthesized exclusively in the 4. KAYSEN GA: Albumin metabolism in the nephrotic syndrome: the kidney [1091. Urodilatin might be more closely related to the effect of dietary protein intake. Am J Kidney Dis 12:461—480, 1988 regulation of sodium excretion than is ANP. We have studied 5. BENNHOLD H, KLAUS F, SCHEURLEN PU: Volume regulation and renal function in analbuminemia. Lancet 2:1169—1170, 1960 this compound only to the extent that we have shown that it 6.DAMMACCOF, MIGLIETTA A, D'ADDABBO A, FRATELLO A, exhibits similar binding characteristics to renal receptors and MOSCHETTA R, BONOMO L: Analbuminemia: Report of a case and leads to similar cGMP accumulation as ANP [110]. We also review of the literature. Vox Sang 39:153—161, 1980 have documented that glomeruli and IMCD cells isolated from 7. RUSSI E, WEIGAND K: Analbuminemia. KIm Wochenschr 61:541— 545,1983 nephrotic rat kidneys have blunted cGMP accumulation in 8. J0LE5 JA, WILLEKES-KOOLSCHIJN N, BRAAM B, KORTLANDT W, response to urodilatin just as they do for ANP [111]. However, KOOMANS HA, DoRilouT MEES EJ: Colloid osmotic pressure in we have not otherwise examined the role of this agent in young analbuminemic rats. Am J Physiol 257:F23—F28, 1989 experimental nephrosis. Greenwald and colleagues reported 9. MANNING 1W, GUYTON AC: Effects of hypoproteinemia on fluid that kidneys of nephrotic rats had increased amounts of ANP- volumes and arterial pressure. Am J Physiol 245:H284—H293, 1983 10. MANNING RD: Effects of hypoproteinemia on renal hemodynam- like compound [112], although how such an increase might ics, arterial pressure, and fluid volume. Am J Physiol 252:F91— relate to nephrotic sodium retention is not clear. F98, 1987 Da. HULTER: Now that mRNA for ANP has been found in 11. WRAIGHT EP: Capillary permeability to protein as a factor in the renal tissue [113], has anyone investigated whether there are control of plasma volume. J Physiol (Lond) 237:39—47, 1974 12. JOLES JA, KOOMAN5 HA, KORTLANDT W, BOaR P, DORIIOUT differences in expression in proteinuric states? Do the data you MEES EJ: Hypoproteinemiá and recovery from edema in dogs. Am presented suggest any kind of a local, intrarenal phenomenon in J Physiol 254:F887—F894, 1988 nephrotic ANP resistance? 13. KAYSEN GA, PAUKERT TF, MENKE DJ, COUSER WG, HUM- DR. HUMPHREYS: No information is yet available on ANP PHREYS MH: Plasma volume expansion is necessary for edema message levels in nephrosis; as you know, the signal was formation in the rat with Heymann nephritis. Am J Physiol 248:F247—F253, 1985 vanishingly low and could only be demonstrated by polymerase 14. KOOMANS HA, GEERS AB, MEIRACKER AH v o, Roos JC, BOER chain reaction amplification (113]. I do not yet see how the P, Dosnour MEES EJ: Effects of plasma volume expansion on model presented of ANP resistance could relate to altered renal renal salt handling in patients with the nephrotic syndrome. Am J synthesis of urodilatin or other ANP-like compounds, unless Nephrol 4:227—234, 1984 15. DORHOUT MEES EJ, GEaRS AB, KOOMANS HA: Blood volume cellular resistance led to a compensatory increase in the syn- and sodium retention in the nephrotic syndrome: A controversial thesis of such a peptide. Although it will be of interest to pathophysiological concept. Nephron 36:201—211, 1984 examine this possibility, it suggests that the cellular resistance 16. TULASSAY T, RASCHER W, LANG RE, SEYBERTH HW, SCHARER to ANP develops from some other consequence of the ne- K: Atrial natnuretic peptide and other vasoactive hormones in nephrotic syndrome. Kidney mt 3 1:1391—1395, 1987 phrotic state. 17. EDER HA, LAUSON HD, CHINARD FP, GREIF RL, COTIAS GC, DR. IvEs: My comment diverges from the topic of your talk, VAN SLYKE DD: A study of the mechanisms of edema formation in but the clinical response of this patient to the therapy he patients with the nephrotic syndrome. J Cue Invest 33:636—656, received is truly remarkable and might obviate the need for any 1954 Nephrology Forum: Mechanisms and management of nephrotic edema 279

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