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Home , Minimal change disease, Nephrotic syndrome

Kidney International, Vol. 33 (/988), pp. 1184—1202 FORUM

Extrarenal complications of the

Principal discussant: DAVID B. BERNARD

The University Hospital and Boston University Sc/zoo!ofMedicine, Boston, Massachusetts

present and equal. The temperature was 100°F. The was 110/70 mm Hg in the right arm with the patient supine and standing. The Editors patient had no skin , peteehiae, clubbing, or . Examina- JORDANJ. COHEN tion of the head and neck revealed intact cranial nerves and normal fundi. Ears, nose, and throat were normal. The jugular venous pressure Jot-IN T. HARRtNOTON was not increased. No lymph glands were palpable in the neck or JEROME P. KASSIRER axillae, and the trachea was midline, cardiac examination was normal. NICOLA05 E. MAmAs Examination of the lungs revealed coarse rales at the right base but no other abnormalities. Abdominal examination revealed aseites, but no Editor abdominal guarding, tenderness, or rigidity. The and spleen were Managing not palpable and no masses were present. The contained 4± CHERYL J. ZUSMAN ; microscopic examination revealed free fat droplets, many oval fat bodies, and numerous fatty casts. Five to 10 red blood cells were seen per high-power field, but no casts were present. A Universityof'Chicago Pritzker School of Medicine 24-hr urine collection contained 8 g of protein. The BUN was 22 mg/dl; , 2.0 mg/dl; and were and normal. Serum total calcium was 7.8 mg/dl, and the phosphorus was 4.0 Taf is University School of' Medicine mg/dl. was 35% and the count 15,000 cells/mm3. The erythroeyte sedimentation rate was 82 mm in the first hour. Total protein was 4.3 g/dl; , 1.3 g/dl; alpha-I globulin, 0.2 g/dl (normal, 0.15—0.40 gAll); alpha-2 globulin, 1.41 g/dl (normal, 0.40—0.90 g/dl); beta globulin, 0.96 g/dl (normal, 0.50—1.10 gAll); and gamma globulin, 0.42 g/dl (normal, 0.60—1.60 g/dl). The tgG was 596 Case presentation mg/dl (normal, 750—1650 mg/dl); IgA, 70 mg/dl (normal. 80—390 mg/dl); and 1gM, 160 mg/dl (normal, 60—270 mg/dl). Total was 420 A65-year-old white man was referred to The University Hospital for mg/dl (normal, 150—280 mg/dl) and 364 mg/dl (normal, management of complications of the nephrotic syndrome. He had gone 40—20(1 mg/dl). The HDL cholesterol was 22 mg/dl (normal, 30—70 mg/dl) to a private physician 3 months carlier complaining of scveral months of and the LDL cholesterol 109 mg/dl (normal, 62—185 mg/dl). chest x-ray ankle swelling; he was found at that time to have nephrotic syndrome. revealed an interstitial infiltrate at the right base and bilateral pleural The 24-hour urinary protein excretion was 18.2 g, and a cffusioos. showed membranous nephropathy. The plasma creatinine was 1.5 treatment was initiated and and a low-salt mg/dl; the BUN, 20 mg/dl; and the calculated creatinine clearance, 110 were continued. was tapered. l'he pneumonia cleared up mI/mm. An extensive search failed to disclose a secondary cause for the rapidly, but increasing doses of diuretics, and eventually salt-poor glomerular lesion. Renal ultrasound examination revealed normal-sized albumin infusions, were needed to promote a diuresis; the , kidneys, and a renal venogram demonstrated patent renal veins. Treat- however, did not resolve. Further investigation revealed a 25 hydroxy- ment was started with prednisone, 120 mg every other day, together level of 4 ng/ml (normal, 10—15 ng/ml) with a 1,25 dihydroxy- with . Two months later he still had severe edema. Urinary vitamin D level of 33 pg/mI (normal, 20—76 pg/mI). The PTH (C- protein excretion was 12 g/24 hr and the serum creatinine had increased terminal) was 227 pg/mI (normal, up to 340 pg/nil). Plasma zinc was 36 to 1.9 mg/dl. The was 2.0 g/dl and total protein was 5 ,ag/dl (normal, 60—130 jig/dO; transferdn, 135 mg/dl (normal, 200—400 gAll. The hematocrit was 35%, and the white blood cell count was 7500 mg/dI); and serum was normal (101 jig/dI). The patient was cells/mm3. The prednisone dose was reduced to 100 mg every othcr discharged after 2 weeks for followup in renal clinic. day. A low-salt diet was instituted, and metolazouc was added to the regimen. He was examined 2 weeks later because of persistent edema and a 3-day history of productive cough with fever and chills. He Discussion had no chest pain or hemoptysis. He had not lost any weight since his last visit. He was transferred to The University Hospital for continuing DR. DAVtDH.BERNARD (Director,Clinical Renal Unit, The management. Uttis'ersity Hospital, and Associate Profrssor of' Medicine, Physical examination revealed an ill-looking white man who was Evans Memorial Department of Clinical Research and Depart— taehypoeic and pale but mentally alert. He was 20 kg above his usual weight, and 4± edema of the legs was present. Respiratory rate was ,'nent of' Medicine, Boston University Sc/tool o,f Medicine, 30/mm; the pulse was 100 beats/mm and regular. All pulses were Boston, Massachusetts): Thecase under discussion aptly dem- ons(rates an important aspect of severe nephrotic syndrome, namely i(s association with many extrarenal metabolic compli- Presentation of the Forum is made possible by grants from Pfizer, cations. These complications account for much of the morbidity Incorporated; Merck Sharp & Dohme; Sandoz, Incorporated; and E. R. of the disease, and some are so serious that they threaten the Squibb & Sons, Incorporated. life of the patient, even when renal function is normal. Compli- © 1988 by the International Society of Nephrology cations arc frequently detectable, at least initially, by biochem-

1184 Nephrologv Forum: Lxtrarenal complicationsofthe nephrotic syndrome 1185

Increased glomerular permeability

Urinary losses of 4, Increased filtration of Altered turnover carrying -l , metals plasma proteins ' rates of and vitamins immunoglobulins

Alterations in Reduced cellular Increasedi coagulation immunity - I factors Thromboembolism Lipiduria — Increased tubular _.. reabsorption of ______filtered protein ______I Hyperlipoproteinemia I

Tubular Increased hepatic synthesis of damage Tubular catabolism of albumin ______1 Fig. 1. Pathophvsiology ofnephrotic syndrome. All Tubular abnormalities originate from increased glomerular dysfunction permeability to plasma proteins; hypoalbuminemia Edema initiates the major manifestations.

Intravascular pool/plasma Hepatic albumin Extrarenal Glomerular Tubular Urinary synthesis concentration catabolism filtration catabolism excretion albumin turnover in normal l5Og/4.Og/dl Fig. 2. Daily Normal l-2g l-2g 0 individualsand patients with nephrotic syndrome. Values for albumin filtration by the are derived from animal studies. Note that in nephrotic syndrome lCl-12g the rates of albumin synthesis and absolute catabolism are normal or are increased 75 g/2.0 g/dl ______20 g 5 g 5 g slightly. Yet each day a greater-than- normal fraction of intravascular albumin is catabolized. Albumin catabolism by renal tubular epithelium is increased; it is presumed that a portion of filtered albumin log returned is returned to the body pool. From Ref. I to body pool by permission. ical testing rather than by clinical examination, are usuallyextrarenal locations [2]. A small amount, about 10%, is catab- ignored in discussions of treatment and prognosis, and repre-olized in the , presumably by tubular reabsorption of sent an area of much controversy [11. Figure 1 represents thefiltered albumin. many metabolic manifestations of nephrotic syndrome. The How is this state altered in nephrotic syndrome? Hypoalbu- figure illustrates that the common pathophysiologic defect thatminemia can result from a decreased rate of albumin synthesis, initiates these varied manifestations is an increased glomerularan increased rate of albumin catabolism, changes in albumin permeability to plasma proteins, and that the proximate causedistribution, decreased intake of dietary protein, or loss of of the major derangements is hypoalbuminemia. albumin from the body. In nephrotic syndrome, several of these factors appear to be at work. Clearly, the loss of albumin in the Patho genesis of hypoalbuminemia in nephrotic syndrome urine is important. However, protein loss is by itself an inade- Most patients with nephrotic syndrome, like the patient wequate explanation for hypoalbuminemia in most patients with are discussing today, develop hypoalbuminemia at some stagenephrotic syndrome because the rate of hepatic albumin syn- during the course of their disease. In general, the greater thethesis normally can increase by at least threefold and should magnitude of the , the lower the serum albumineasily be able to compensate for the usual urine losses [2]. concentration. A convenient way of exploring the mechanismStudies in humans and in animal models of nephrotic syndrome of hypoalbuminemia in nephrotic syndrome is to comparedemonstrate that the rate of albumin synthesis is at the upper albumin metabolism in the normal individual and in the patientlimit of normal or slightly above normal as long as dietary with nephrotic syndrome (Fig. 2). In the normal person, albu-protein is adequate [3, 4]. In patients on low-protein diets, min production by the liver is 12—14 g/day (130—200 mg/kg);however, synthesis rates can be below normal [4]. Studies using production equals the amount catabolized, predominantly inturnover techniques [5], liver perfusion methods [6], isolated (1igfmin x100gBW) losses, andtheserumalbuminconcentrationtypicallyremains patients aresimilartourinaryproteinlossesinnephrotic daily extrarenalalbuminlossesfromtheperitoneuminsuch undergoing continuousambulatoryperitonealdialysis(CAPD): albumin synthesisisnotlowinabsoluteterms,itrelative perhaps evenwithintheliveritself[9].Althoughhepatic tions, buttoareductioninextravascularpoolsofalbumin, albumin synthesis.Interestingly,therateofhepatic min messengerRNA[8]giveevidenceofincreasedhepatic liver mierosomalpreparations[7],andmeasurementsofalbu- (p.g/min x100g8W) Filtered load 1186 tubular uptakeandcatabolism asthenephrotiestateworsens increase asproteinuriaincreases; thesefindingssuggestmore uptake andbreakdownoffilteredalbumin.Severalstudies both be thekidney,catabolismpresumablyresultingfromtubular patients withnephroticsyndrome,thisfractionisintherange of pool iscatabolizedinthenormalpersoneachday.Inmany often isincreased,particularlyifproteinintakepoor13, 141. quently arenormal[3,131,therateoffractionalcatabolism has beenexamined.Althoughabsolutecatabolicrates fre- albumin levelstowardsnormal[12]. hepatic albuminsynthesis[4]andmayevenrestoreserum high-protein diettopatientswithnephroticsyndromeincreases due tosomekindofnutritionaldeficiency,becausefeedinga restored tonormal.Thefactthatthisdoesnothappenmightbe towards nearlymaximumlevels,plasmaalbuminmightbe is inadequate;presumably.ifhepaticsynthesiswereincreased response innephroticsyndrometorenalalbuminlossesclearly normal orisonlyslightlyreduced1111.Thus,theliver's albumin synthesisincreasesgramfortocompensate syndrome [101.YetinpatientsundergoingCAPD,hepatic to theserumalbuminlevel.Agoodanalogyispatient synthesis seemsnottoberelatedplasmaalbuminconcentra- (gtmin x100gBW) Excretion Sieving coefficient nephrcctomized, albumincatabolism decreasesby50%[5]; [3, 14].Ifratswithexperimental nephroticsyndromeare in humansandanimalsdemonstrate thatalbumincatabolicrates 16% to50%,Themajorsiteofincreasedcatabolismappears to As Figure2illustrates,5%to12%oftheintravascularalbumin Number ofanimals Reabsorption Animal group: The rateofalbumincatabolisminnephroticsyndromealso (92) x (%) serum controlsper100gBW Controls and

14 — Nephrologv Forum: 0.5 mlAnti-GBM11.0 1+ '.j

1+

13 ° ( k, 9k 0'pI 0, IfLn Pb' U, Exiratenni

1+ —. per 100gBW Ui

a Pflo ml

I+a Ni Anti-GBMI 1.0mlAnti-GBM 8 , La NJ 0 p.Ni romp/a that permittedtubularabsorptiveratesforalbumintoincrease did becomesaturatedwhentheproteinloadexceededphysio- uptake [181.Althoughalow-capacitysystemwaspresentthat cataholized, hutissimplyexcretedintheurine[171.Inarecent that anyincreaseinfilteredproteincannotbeabsorbedand virtual saturationatphysiologiclevelsoffilteredalbuminand argued thattherenaltubularalbumintransportmechanismisat minemia innephroticsyndromeiscontroversial,Somehave increased inresponsetoglomerularproteinuria[16]. lysozymal activity(cathepsinBandL)intubularcellsis distal cellsofratswithexperimentalnephroticsyndrome[15]; albumin andglobulinhavebeendemonstratedinproximal morphologically, proteinabsorptiondropletscontainingboth gastrointestinal tracthasbeen showntooccurinsomestudies lost fromthetotal-bodyprotein pool.Lossofalbuminfronithe re-used, somemaybecatabolized withintherenaltubulesand metabolized albuminmaybe returnedtothecirculationhe some oftheconstituentamino acidsoftheabsorbedandlocally syndrome usuallyismuchlessthanthisamount.Although the dailyurineproteinexcretioninpatientswithnephrotic probably isanimportantsiteofalbumincatabolism,because [201. Ifthesefiguresareevenclosetobeingcorrect,thekidney close agreementwiththecalculationsderivedfromratstudies level offilteredalbuminwasabout25to60g/day,afinding in study inhumanswithnephroticsyndromeconcludedthat the each dayinhumannephroticsyndrome[191.Oneclearance nephrotic ratssuggestthat10to60gofalbumincouldbefiltered the dataonalbuminsievingcoefficientsofglomeruli from control inabout50%oftheanimals.Extrapolationtohumans of creased inmanyanimals,absorptionwas10timesgreaterthan absolute tubularabsorptiveratesforalbuminwerenotin- ture studyofnephrotoxicnephritis(Fig.3)showthatalthough as thefilteredloadrose.Furthermore,datafromamicropunc- logic levels,ahighcapacity-lowaffinitysystemalsowaspresent Maack demonstratedadualtransportsystemforalbumin study ofisolatedperfusedproximaltubules,however,Parkand per 100jBW I ations qJthenephrotic The contributionofrenalalbumincatabolismtohypoalbu- - a' _____coP 1+ 1+ —

4 0) r 0, NiCO0 NJ ______- given inp.g/minascorrectedfor100gbody Values foramountsfilteredandexcretedare Fig. 3.Filtrationandabsorptionofalbumin. proximal transittimesantireducedGFRs. Ref. 19.5Referstoanimalswithprolonged (arrows andnumbersleftoftubules).From tubules) andaspercentageoffilteredload absolute amount(arrowsandnumbersrightof weight. Albuminabsorptionislistedas syndrome Nephrology Forum:Extrarenalcomplicationsof the nephrotic syndrome 1187

[211 but not others [221 and seems unlikely to be a major factorBecause many carried in the blood are bound to albumin, in the pathogenesis of hypoalbuminemia. hypoalbuminemia can result in higher circulating levels of free Figure 2 displays a model of albumin metabolism in nephroticdrug when usual doses of the are administered. The high syndrome. Hypoalbuminemia occurs because of increased lossincidence of toxic reactions with clofibrate in patients with of albumin in the urine and, in some instances, because of annephrotic syndrome is an example of reduced drug binding in increased rate of albumin degradation by the kidney. Suchhypoalbuminemic plasma. Such complications are avoidable if losses occur in conjunction with a rate of hepatic synthesis that,the drug is given at a dosage of about one-half the usual dose although not reduced in absolute terms, is not increased enough[32]. The use of warfarin, a drug tightly bound to albumin, also to maintain the plasma level. When proteinuria is modest, therequires close monitoring because of unpredictable effects on catabolic rate of albumin is not markedly increased, the rate ofcoagulation factors [33]. Hypoalbuminemia also might play a albumin synthesis is nearly normal, and hypoalbuminemia thenrole in the platelet hyperaggregability in nephrotic syndrome may be caused by urine protein losses and inadequately in-[34]. Because albumin normally binds arachidonic acid, thus creased synthesis. At higher rates of albuminuria, however,limiting its conversion to thromboxane A, by platelets, hypoal- albumin catabolism increases as large amounts of filtered albu-buminemia might allow increased platelet arachidonic acid min are absorbed and degraded by the tubules. Under thesemetabolism to take place, and platelet hyperactivity may result circumstances, protein loss and protein catabolism both con-[34]. Hypoalbuminemia also plays a key role in the pathogene- tribute importantly to the pathogenesis of hypoalbuminemia. Insis of nephrotic hyperlipoproteinemia and edema. the most severe cases, absolute albumin turnover rates can exceed 50% of the intravascular pool per day. The influence of Edema formation dietary protein intake on plasma albumin concentration is an As in the patient under discussion, swelling of the lower limbs important issue that requires further study. In one recent studyor weight gain frequently is the reason the patient with ne- [12], despite massive proteinuria, plasma albumin concentra-phrotic syndrome seeks medical advice. Indeed, edema, the tions were in a nearly normal range (> 3 g/dl). The authorsclinical expression of an expanded extracellular fluid compart- report this to be their usual experience because they alwaysment, is present in almost all patients at some time during the offer'.. . appropriateprotein and calorie supplementa-course of the disease. The fact that hypoalbuminemia plays tion to their patients. On the other hand, other studiessome role in edema formation in nephrotic syndrome is sug- have demonstrated that catabolic and excretion rates increasegested by the usual appearance of edema after the plasma pan passu with high protein intake and that the final serumalbumin concentration falls below 2.5 g/dl. For progressive albumin concentration is unaffected or even slightly lower [4,extracellular fluid expansion to develop, the kidneys must 13]. For the moment it seems advisable for us to encourageconcomitantly retain salt and ; the pathophysiology of this high-protein diets (1.5—2.0 g/kg/day in adults; up to 5.0 g/kg/dayrenal avidity requires explanation as we consider the mecha- in growing children) in nephrotic subjects with very low plasmanisms of edema formation. albumin concentrations (below 2.0—2.2 g/dl). According to the traditional view, lowering of the plasma albumin concentration is the initiating step in renal Consequences of hypoalbuminemia retention [35]. Hypoalbuminemia results in a reduction in the Hypoalbuminemia has many deleterious effects. Althoughcolloid of the blood, favoring movement of blood volume is normal in most cases, patients with nephroticwater from intravascular to interstitial space and producing syndrome are remarkably sensitive to any further losses ofhypovolemia. then activates volume sensors and blood volume. Shock and pre-renal azotemia can occur follow-baroreceptors which, via a variety of intrarenal and extrarenal ing minimal losses of fluid during minor surgical procedures,neurohumoral and hemodynamic mechanisms, signal the kid- with the use of diuretics, or even spontaneously [23]. Severalney to retain salt and water [35]. In this way, sodium retention instances of renal failure have occurred, probably as ais viewed as the expected and physiologically appropriate result of prolonged or critical hypoperfusion [24]. Severe renalresponse by the kidney to the reduced circulatory volume, and failure also has been described in the absence of impressiveit protects the organism from progressive contraction of plasma tubular or interstitial changes on renal biopsy; this complicationvolume. has been attributed either to hemodynamic factors or to edema For unequivocal confirmation of this hypothesis, the follow- of the renal interstitium [25, 26]. Patients with nephrotic syn-ing must be true: blood and plasma volumes must be reduced drome also are prone to develop acute renal failure fromduring the accumulation of edema; maneuvers that increase nonsteroidal antiinflammatory drugs. The fall in glomerularplasma volume into the normal range in edematous patients filtration rate induced by these agents usually is reversible [27,with nephrotic syndrome must induce a natriuretic response; 281, but that is not always the case [29]. In fact, these agentsand functional evidence of hypovolemia can be demonstrated, have been used to cause permanent renal failure (a "medicalsuch as circulatory and humoral changes. In recent years, nephrectomy"), when obliteration of renal function in severeseveral studies have failed to confirm these critical predictions, nephrotic syndrome is necessary to prevent life-threateningand the classic theory, albeit logical and convenient, has been metabolic complications [301. Some studies have suggested thatbrought into question. Furthermore, in many instances of the agent sulindac is less likely to be as harmful in this regardsevere hypoalbuminemia in experimental animals and humans, [28]. edema is not present [36, 37]. This observation suggests not Hypoalbuminemia also has an important pharmacologic con-only that renal sodium retention in nephrotic syndrome might sequence, namely the potential for enhanced drug toxicitybe occurring via some other mechanism, but also that an because of a reduced availability of drug binding sites [31].edema-preventing mechanism must be present to obviate 1188 NephrologvForo;n:Lxtrareno/romp/wa/ionsqf tIw nep//runc syndrome edema despite hypoalbuminemia [36, 37]. Indeed, an alternate favoring the notion that some stimulus apart from hypovolemia hypothesishas been advanced to explain sodium retention, had been responsible for renal sodium avidity [50, 511. namely,that renalsodium retention is primary and is the Finally, functional evidence of hypovolemia also cannot he consequenceof intrarenal rather than systemic factors [38—4l].demonstrated consistently in nephrotie syndrome. For exam- The major reason for concluding that a primary reduction inple. plasma renin activity and aldosterone concentrations or renalsodiumexcretion might he a better explanation for sodiumexcretion rates in patients with nephrotic syndrome are vari- avidity in nephrotic syndrome is the lack of consistent reduc-able: plasma renin activity and plasma aldosterone concentra- tionsin blood and plasmavolumesin patientswithnephrotie tions or excretion rates are high in fewer than 50% of the eases syndrome.In one analysis ol' more than 250 patients with[39, 41, 431. Also, no close correlation exists between changes nephrotic syndrome, measured blood volume was reduced in in plasma renin activity or aldosterone and blood volume [39, only 30% and was normal or increased in the rest [39]. Recent 41]. Other humoral markers of hypovolemia, such as norepi- studies have found low blood volumes to he even less common nephrine and vasopressin levels, also are normal in nephrotic [4l—45]. Furthermore, when blood and plasma volumes were syndrome [43]. At a clinical level, changes in blood pressure in measured in the edematous patients again after they had nephrotie patients during relapse and remission also argue undergone remission and lost their edema, intravascular vol- against significant hypovolemia. Many patients have elevated ume frequently was unchanged or even lower after edemapressures during relapse that return to normal following reniis- resolved [39, 46]. Some have suggested that two groups ofsion [39, 41. 52]. nephrotie patients exist, separable according to their blood Taken together, these data suggest that the commonly held volume levels: those with low blood volumes, generally repre- view that hypovolemia in nephrotie syndrome is responsible for sented by patients who have minimal-change disease with renal sodium retention and edema cannot he supported in many normal renal function, and those who have normal or elevated eases. If renal retention of sodium is the primary initiating blood volumes, generally represented by patients who havefactor, blood volume would become expanded, and this de- both reduced renal function and structural renal disease [471. rangement would elevate blood pressure and suppress plasma Othershave not found it possible to consistently separate their renin activity and aldosterone levels. Edema would develop by patients in this way [39, 41, 43]. In summary then, it is fairly"overflow"; that is. the expanded plasma volunie would leak well accepted now that the majority of patients with nephrotic into the interstitiuni under the influence of altered local Starling syndrome have blood and plasma volumes that are normal or l'orees. high, a finding in clear conflict with traditional concepts of Although this scenario has considerable experimental sup- edema formation in this disorder. port, pathophysiologie mechanisms in some patients with ne- 'l'he conclusion that hypovolemia usually is not present and phrotie syndrome and edema still can be fitted more conve- thus not the stimulus to renal sodium retention in nephroticniently into the traditional view. I believe that no single syndronie is confirmed by the variable natriuresis noted inmechanism can he invoked to explain all eases of renal sodium response to volume expansion. Despite substantial volume retention in nephrotic patients. Perhaps different mechanisms expansion produced by hyperoncotic plasma infusion, an ade- are operative in different patients, or several mechanisms might quate diuresis and natriuresis occurs in only about one-half ofbe at play in any one patient at different times, depending on patients 1481. In one study, patients with nephrotic syndrome factors such as the specific underlying glomerular lesion, the and edema were given 41) g of salt-poor albumin each day for 3 stage of evolution of the sodium retentive process. dietary salt consecutive days. Whereas plasma volumes were shown tointake, the posture of the patient, the presence and severity of have increased into a normal or above-normal range in allassociated heart or liver disease, and a host of additional patients, urine sodium excretion remained below daily intake, factors. and all patients gained weight [49]. The renal effects of neck-out Two studies of puromycin aminonueleoside (PAN)-indueed immersion in a water bath for several hours, a well-established nephrotie syndrome have produced direct evidence of renal method of inducing central volume expansion, also have been sodium retention from one or more local intrarenal causes 153, examined in patients with nephrotie syndrome [50, 51]. An54]. In each study, one kidney of each animal was perfused with increase in urinary sodium excretion occurs in all patients,PAN and the other not, so that unilateral proteinuria was although individual responses vary widely. In one study, de-produced and hypoalbuminemia did not develop. Most interest- spite the existence ol' normal or high blood volumes beforeingly. sodium excretion was normal or high from the non- immersion in 7 of 8 subjects, peak response in sodium excretion perfused, control kidneys, but was reduced significantly in the varied from 55 to 488 zEq/niin [50]. These data suggest thatPAN-pert'used. proteinurie kidneys. Proteinuria occurred when volume expansion alone is unable to overcome antinatriuretic plasma protein concentration, and presumably blood volume, inlluenees in all cases and that other factors are involved.was normal, and when systemic factors that might stimulate Another interesting observation in the water-immersion studies secondary renal sodium retention should have been absent. is that whereas free-water clearance increased markedly in the 'Thus the renal sodium retention seems to have been a primary first 2 hours, sodium excretion increased later. 'l'his suggests phenomenon due to intrarenal influences. These elegant studies that volume expansion during the early immersion period led to offer the first strong evidence for the presence of an intrarenal increased delivery of fluid to the distal hut that distal factor or factors that promote sodium retention by proteinurie sodium chloride reabsorption had remained high, thus generat- kidneys. A recent study in which a small group of patients with ing increased free water, Only towards the end of the immersion minimal-change disease was studied before, during, and after period, when volume expansion presumably had been present the onset of -induced remission lends support to the for several hours, did the urinary sodium excretion peak,notion of a primary intrarenal defect in sodium excretion [41]. /Veplzrologv Fonuzi: Evtrarenal uo,uplica lons (fthenephrotic syndrome 1189

20 ' Glomerular disease // /// Increased filtration 15 / of plasma proteins Renal sodium retention E // E / 10 / Tubular Albuminuria / catabolism/1 / 0 of Plasma volume / albumin expansion / Hypoalbuminemia F- // 0.*o0 / 0 o0 80 Increased capillary 0 Reduced plasma hydrostatic pressure onCotic pressure 0 5 10 15 20 25 Plasma COP, mm Hg Fig.5.Relations/zipbetzz'eenplasmaand tissue—fluid oncorim pressure (COP)in /2 patients zit/t thenep/troticsyndrome, at the first visit (0) Water movement from andduring the j/1owup ofó patients with partial or complete recoz'erv intravascular to interstitial/ (•i.Dashedline refers to the line of identity. From Ref. 59. space

I plasmaCOP is about 24 mm Hg (range, 22—25 mm Hg), and Edema interstitial COP is about 12 mm Hg (range, 10—13 mm Hg), creating a transcapillary COP gradient of approximately 12 mm Fig. 4. New conceptsof the pathophzvsiologv of edema formationin nephroriesyndrome. Hg [45. 59, 60]. In nephrotic syndrome, the COP of interstitial fluid falls virtually in parallel with the COP of the plasma as hypoalbuminemia develops. Thus, the net transcapillary COP gradient is maintained in the normal range, and any anticipated At the time of remission, defined as the day on which urinedriving force for fluid movement out of the intravascular space sodium excretion approximated sodium intake, no changesis dissipated. Studies of the same patients during relapse and were noted in plasma albumin concentration (which was low) orremission showed almost equivalent changes in the COP of blood volume (which was normal); further, blood pressure fell.interstitium and plasma (Fig. 5) at all levels of serum albumin An intrarenal defect in sodium excretion that was removed at [59].Thisvirtually constant transcapillary difference in oncotic the initiation of the natriuresis seems the best explanation forpressure, maintained despite considerable reductions in plasma these observations [41]. The intrarenal factors responsible foralbumin concentration, permits blood volume to be maintained sodium retention could relate to a reduction in glomerularand edema formation to be avoided, as long as the plasma COP filtration rate or to increased tubular reabsorption. For exam-is greater than 10—12 mm Hg. When COP falls below this level ple, one recent study concluded that changes in glomerular(usually reflected by a plasma albumin of under 2 g/dl). this filtration were most important [43], whereas others have re-compensatory mechanism no longer works, the transcapillary ported defects in the atrial release of [55]orrenal response to COP gradient falls, and fluid moves into and accumulates in the [561 atrial natriuretic peptide. On the other hand, in a recentinterstitial space. In one study, edema of the legs was noted report of children with nephrotic syndrome in relapse, plasmawhen the plasma COP dropped below 16,5 mm Hg, whereas levels of atrial natriuretic peptide were considered to be normalgeneralized edema occurred only when COP fell below II mm and to rise appropriately in response to hyperoncotic albuminHg [60]. The reduction in interstitial COP is thought to arise by infusion [57].Furtherelaboration of the potential mechanismsacceleration of lymphatic flow, which returns interstitial protein is needed. In the meantime, a new diagram summarizing currentto the vascular compartment [45, 59]. It is assumed that this concepts of the events leading to edema formation in nephroticphenomenon, called "protein washout." is triggered by a slight syndrome must be developed, and I oiler one in Figure 4. rise in interstitial volume and hydrostatic pressure induced by When it became clear that blood and plasma volumes werethe initial transudation of fluid out of the circulation. Body usually normal in patients with nephrotic syndrome, severalalbumin pools are redistributed so that a greater fraction than investigators began to explore the mechanisms responsible fornormal is located in the vascular compartment; blood volume is the maintenance of euvolemia in the presence of hypoalbumin-maintained and edema is prevented. emia. The normal levels were a surprising finding, given tradi- A further aspect of this edema-preventing and blood-volume- tional concepts of the factors controlling fluid movement frommaintaining mechanism is the relationship that arises between intravascular to interstitial compartments. Using a techniqueblood volume and extracellular fluid changes as fluid retention described in the 1970s [58], careful studies of interstitial tissueoccurs, In normoalbuminemic patients retaining fluid because colloid osmotic pressures (COP) were carried out in normalof renal failure, blood volume rises steadily as extracellular fluid individuals and in patients with nephrotic syndrome duringvolume increases by the time extracellular fluid volume has relapse and remission [44, 45, 59, 60]. In normal humans,increased by 30%, blood volume has increased by the same 1190 Nephrology Forum: Ex/rarenalcomplications (fi/u' nephroiicsyntho,ne percentage [42]. Above this level of extracellular fluid expan- 4 LCAT sion, blood volume increases no further. In patients with IHOL NASCENT HDL nephrotic syndrome and hypoalbuminemia, blood volume in- APO CII creases much less, by under 10%, with evet, greater increases in (Liver) extracellular fluid volume: the curve relating extracellular fluidLIVER — IDL______LDL volume and blood volume is almost flat at all levels of extracel- >VLDI" (circulation) 6 lular fluid [42, 52]. Thus the blood volume is substantially 5 increased in overhydrated norinoalbuminemic patients but is maintained in the normal range in nephrotic patients whether hydration is increased or not. Some have considered this Fig. 6.Normalunidirectionalmetabolicpathwayoflipoproteins. homeostatic mechanism an important one that protects against Defectsat sites I to 6 result in hyperlipoproteinemia. HDL =high- significant intravascular volume expansion and hence alsodensity ; LCAT lecithin-cholesterol acyltransferase; protects against severe , so common in compara-VLDL very-low-density lipoprotein; LPL ; bly fluid-expanded patients with renal failure. This differenceAPO-Cli =apolipoproteinC-Il; IDL =intermediate-densitylipopro- tein; LDL =low-densitylipoprotein; CE =-cholesterolester; TG = probably can be explained by the protein-washout phenome- triglyceride.From Ref. I by permission. non. In normoalbuminemic patients with renal failure, protein washout begins with the initial increase in extracellular fluid volume; the increased fluid thus is retained initially in theLevels of triglyceride are more variable and in many patients do circulation. In patients with nephrotic syndrome, protein wash-not increase at all, except when the nephrotic state is very out already has occurred, even prior to significant body fluidsevere [62, 64]. Plasma levels of free fatty acids are within expansion; as extracellular fluid increases with renal fluidnormal limits in nephrotic syndrome, although a smaller-than- retention, most of the retained fluid immediately translocatesnormal fraction is bound to plasma albumin [62]. The very-low into the interstitium, and the blood volume does not increasedensity (VLDL), intermediate-density (IDL), and low-density further. In the patients with the lowest plasma albumin concen-(LDL) lipoproteins also increase early in nephrotic syndrome trations, in whom a transcapillary COP gradient cannot be[62—67]; the data on high-density lipoproteins (HDL) are less maintained, blood volume actually can be below normal. Thisclear. Abnormalities in the composition of the lipoprotein unusual state is likely to occur only when the plasma albuminmolecule also are present in nephrotic syndrome. Greater-than- falls below 1.5gldl;in such instances fluid retention may notusual amounts of cholesterol and triglyceride are present in restore blood volume to normal. VLDL, IDL, and LDL, and an alteration in the specific type These new observations have important implications for theand quantity of the various apoprotein moieties of the lipopro- treatment of edema in nephrotic syndrome. Previously it hadtein molecule also has been described [I, 671. Finally, the been assumed that edema was a prerequisite for maintaining aplasma level of certain apolipoproteins is also increased [68, normal blood volume in nephrotic subjects, but that seems not69]. These abnormalities return to normal fairly promptly when to be the case, Blood volumes are normal even in the absencethe syndrome remits [I]. of edema in these patients [42, 44, 521. Interestingly, when Plasma lipids as well as lipoproteins can be increased because edema is eliminated with diuretics, but hypoalbuminemia per-of an increased rate of synthesis, a decreased rate of removal, sists, the tissue fluid COP remains low and the blood-volume-increased mobilization from fat stores, or combinations of these maintaining mechanism is preserved [44]. In most cases, edemafactors, Figure 6 illustrates the normal pathway of lipoprotein can be resolved quite safely in nephrotic subjects, and oftenmetabolism. Newly synthesized triglyceride (site I) originates quite vigorously, without endangering the circulation. In onefrom the liver as VLDL and is then hydrolyzed by an enzyme report, a mean removal of 7.4 liters of fluid by ultrafiltrationsystem of lipoprotein lipase (LPL; site 2) situated in over 2 days, which reduced the interstitial volume by 20%,extrahepatic tissues such as adipose tissue, muscle, and vascu- produced no changes in blood volume or creatinine clearancelar endothelium. Under the influence of LPL, are [61]; in another study, the removal via diuretic therapy of moreremoved progressively from VLDL, leaving behind smaller than 13 liters of fluid from edematous nephrotic patients re-remnants of intermediate density lipoprotein (IDL), and na- sulted in their becoming free of edema while maintaining normalscent HDL. Lipoprotein lipase requires a peptide, apolipopro- blood volume [441.Plasmarefilling from interstitial fluid follow-tein-CII (apo-CIl), to be activated; this peptide is transported ing diuresis seems to occur quite rapidly, although it slowsby 1-IDL and transferred to VLDL during the catabolic process down as hydration becomes normal. The rate of weight loss(site 3). The lipoprotein lipase reaction also is stimulated by the thus should be reduced as edema diminishes, and the patientglycosaminoglycan, heparan sulfate [70]. Nascent HDL is cat- should be monitored carefully for evidence of postural hypo-alyzed to HDL by the enzyme lecithin-cholesterol acyl trans- tension. ferase or LCAT (site 4). Intermediate-density lipoprotein is converted to LJJL in the liver and probably within the circula- Pathophysiologyof andhyperlipoproteinemia tion as well (site 5) and is then taken up by peripheral tissues As in the patient under discussion today, virtually all bloodand by the liver (site 6). The uptake of IDL by the liver is a key lipid and lipoprotein fractions are elevated in nephrotic syn-step in the lipoprotein synthetic pathway, because it has the drome [1]. Blood levels of total serum cholesterol and phospho-important role of suppressing de-novo synthesis of hepatic lipids almost always are increased and continue to rise as thelipids [701. High-density lipoprotein (site 3) is made by the liver severity of nephrotic syndrome worsens [621. Total cholesterol,as well as during the LPL reaction; it shuttles apo-CIl to VLDL free cholesterol, and cholesterol esters all are increased [63].and carries cholesterol to the liver for excretion. Defects at any Nephiology Forwn: Extrarenalcomplicationsof thenephrolic syndrome 1191 site (I to 6) in this pathway can result in an accumulation ofreduced levels in children with nephrotic syndrome from other lipoproteins in the circulation; in nephrotic syndrome, defectsglomerular lesions [79]. It is also possible that increased liver have been described at almost every location, but the primarysynthesis of HDL might compensate better for urine losses in cause of hyperlipoproteinemia appears to be an increased ratesome instances than in others. of hepatic synthesis of lipoproteins [69, 71—73]; a reduction in catabolic removal plays an additional role [72,74]. Consequences of hyperlipidemia Hepaticsynthesis of lipoproteins (site 1) is markedly in- The most important consequence of hyperlipidemia is its creased in humans and in animal models of the disease. Bothpotential for inducing cardiovascular disease. Even though the lipid and protein moieties of the lipoprotein fractions arepatients with nephrotic syndrome have several risk factors, affected, and these alterations probably form the main basis forincluding hypertension, hypercoagulability, and hyperlip- hyperlipidemia [69, 71—73].Apart from this defect, some studiesidemia, the incidence of ischemic heart disease in these patients also have shown a decrease in the rate of removal of theis uncertain—in part because such patients form a heteroge- lipoproteins from the circulation [72,74].In theory, defects inneous group. Two factors seem important in determining the enzymes LPL or LCAT, abnormal HDL physiology, orwhether a particular nephrotic patient is at high risk of devel- defective removal of LDL all could prevent or reduce theoping . The first is the duration and persistence subsequent removal of VLDL. Although initial measurementsof hyperlipidemia. In this regard, most nephrotic patients found of LPL activity (site 2) in nephrotic syndrome produced normalto have heart disease have had persistent proteinuria and results [751,laterstudies have shown LPL activity to benephrotic syndrome for years rather than months [81]. Coro- reduced by 30% to 60% of normal, a defect that clearly wouldnary disease appears to be unusual, for example, in patients retard VL])L removal [76]. The reasons for reduced LPLwith minimal-change disease, in which the lipid abnormality activity are not known. Some believe it is a consequence ofordinarily is short-lived and intermittent. On the other hand, a hypoalbuminemia [73, 74]. Because free fatty acids released byrecent study of childhood nephrotic syndrome found in a the action of LPL on VLDL normally are rapidly bound tosignificant number of cases that cholesterol, triglycerides, and albumin, hypoalbuminemia would permit a greater accumula-lipoproteins had remained increased even during remission and tion of free fatty acids in adipose tissue, a state known to retardeven when remission had been prolonged [79]. Thus, at least LPL activity. Others believe that LPL is inhibited by a circu-some nephrotic children may have prolonged hyperlipidemia, lating plasma factor, or that its action is retarded by a deficiencyeven after clinical remission, and be at increased risk of of apo-CII or other activator peptides (such as heparan sulfate)developing premature atherosclerosis. that arises from changes in synthesis rates and urine losses [70, The second factor relates to the presence of increased levels 76]. of the possibly protective lipoprotein HDL in these patients. Studies in nephrotic syndrome also have shown a reductionRecent studies of the relationship between serum cholesterol in the activity of the enzyme LCAT (site 4), an abnormality thatlevels and morbidity or mortality from cardiovascular disease would reduce HDL production [77].ThisLCAT deficiencysuggest that the critical factor might be not the absolute level of would limit the availability of co-peptides for enzyme actiontotal cholesterol, but either the level of associated HDL cho- and would reduce the amount of cholesterol that could belesterol or the ratio of HDL cholesterol to total and LDL removed from peripheral tissue, such as vascular endothelium.cholesterol levels [82]. In patients with nephrotic syndrome, if The reasons for low LCAT levels in nephrotic syndrome areHDL cholesterol were elevated, the risk of vascular disease unclear. Such reductions simply might be due to urine loss;might not be increased. As I mentioned, HDL levels are high in alternatively, in the presence of hypoalbuminemia, lysolecithinsome patients and low in others; these observations suggest that (produced during the process of cholesterol esterification bythe cardiovascular risk probably also varies. Studies of HDL LCAT) cannot be removed at an optimally steady rate, and thissubfractions are also important in assessing cardiovascular risk. might cause the LCAT reaction to slow down [77]. Observations suggest that the HDL2 rather than the HDL3 Conflicting data exist regarding HDL levels in humans andfraction is most closely associated with an increased cardiovas- animals with nephrotic syndrome, and several recent studiescular risk [12]. In one recent report of patients with nephrotic have failed to resolve the issue. Some have shown clearlysyndrome, although total cholesterol and total HDL levels were reduced levels [65,66,77]; others report HDL levels to benormal, HDL2 was decreased in males and was trending down normal or elevated [12, 68, 76, 78, 79]. Because HDL hasin females [121. In the largest study of patients with nephrotic approximately the same molecular dimensions as does albumin,syndrome, HDL cholesterol levels were normal or high, and the one would expect HDL to be lost in the urine in nephroticincidence of cardiovascular disease was not increased [83]. In syndrome; indeed, studies have confirmed its presence therecontrast, other, smaller studies have reported a higher risk for [80]. The amount lost via this route varies, however. In onecardiovascular disease [811. On balance, it seems likely that study, patients with minimal-change disease showed low urinesome, but not all, nephrotic patients are at risk for ischemic and high blood levels of HDL, whereas in patients with ne-heart disease. Patients with nephrotic syndrome who have high phrotic syndrome from other causes, considerable amounts oflevels of HDL cholesterol and normal HOL-to-total cholesterol HDL were found in the urine, and blood levels were reducedratios, whatever their underlying disease, are likely to be at [781. Indeed, in support of this suggestion, the patient we arelower risk. On the other hand, if HDL levels are reduced (or discussing today had low levels of HDL in the plasma inperhaps even normal in the presence of increased total choles- association with membranous nephropathy as a cause of ne-terol), and particularly if the nephrotic state persists over some phrotic syndrome. A recent study in children confirmed in-years, the risk of developing cardiovascular disease is probably creased HDL levels in patients with minimal-change disease butincreased. Current data suggest that the risk of vascular disease 1192 NephrologyForum.• E-trarenai complications of thenephroticsyndrome is not markedly increased in patients with nephrotic syndrome,nephrotic syndrome demonstrated reduced .splenic function, and routine manipulation of plasma lipids does not seem justi-which returned to normal with remission and correlated closely fied in all cases; however, it might be justified in patients withwith infectious episodes [98]. persistent, severe nephrotic syndrome. Certainly, lipid-lowe- Several mechanisms have been suggested to account for ring agents can lower cholesterol, LDL, and triglycerides andthese abnormalities of cellular immunity. Because normal lym- produce either no change or an increase in HDL levels inphocytes are inhibited in their response to mitogenic stimulants patients with nephrotic syndrome [84, 85]. by plasma from nephrotic patients, the appearance of a new, or The hypothesis recently has been advanced that hyperlipid-loss of a physiologic circulating serum factor that affects T-cell emia in nephrotic syndrome has another consequence, namelyfunction has been postulated [96]. One study in children sug- glomerular injury [86—89]. It originally was proposed that fil-gested a close correlation between abnormal lymphocyte pro- tered lipoproteins might accumulate in the mesangium andliferative responses and transferrin deficiency; the markedly promote sclerosis [86]. Subsequently, free and esterifled cho-abnormal in-vitro lymphocyte transformation response to con- lesterol was found in the glomeruli of nephrotic rats, and a closecanavalin A was corrected when transferrin was added [99]. correlation was noted between plasma cholesterol levels andTransferrin, the iron-binding protein, is necessary for in-vitro the number of sclerosing glomerular lesions [87]. The authorsgrowth of lymphocytes and in the proliferation of T-cell lines called this lesion "atherosclerosis of the glomerular mesan-[991. Other studies have suggested that deficiency of zinc might gium" [87]. In 2 preliminary reports, the incidence of renalplay a role [100]. Zinc is important for the normal biologic failure and of focal glomerular sclerosis in the rat remnantactivity of thymic hormones [lOll; thus zinc deficiency, com- kidney model was markedly reduced by treatment with lipid-mon in nephrotic patients, might impair normal immune re- lowering agents [88, 89]. This exciting new work suggests thatsponses. Others have suggested that increased production of lipid accumulation in the glonierular mesangium might play anprostacyclin in nephrotic syndrome is the cause of the inade- important role in progressive glomerular damage and renalquate response of lymphocytes to mitogens [102] because the failure; therapeutic normalization of plasma lipids might evendefect was correctable with indorriethacin [103]. Finally, one prove to be of value in slowing the rate of renal failure, butgroup found that although plasma from patients with nephrotic much more work is needed to establish this point. It certainlysyndrome inhibited the normal lymphoproliferative response to seems as if the relationship is not a simple one, however. In amitogens, removal of the lipoprotein fraction completely nor- recent preliminary report, comparable degrees of hyper-malized this response. This observation suggests that hyperlip- cholesterolemia produced significant glomeruloscierosis in theidemia is responsible for the abnormal cellular immunity in Wistar but not in the PVG strain of rat [90], It seems likely thatnephrotic syndrome [104]. hyperlipidemia alone is not responsible for the glomerular Complement levels are not reduced by the nephrotic syn- damage, but that unless both hyperlipidemia and mesangial celldrome per se, and may even be increased [105]. One study dysfunction are present, as in the Wistar rat, glomerulosclerosisreported a potentially important complement abnormality in will not result. nephrotic syndrome, namely, significantly depressed levels of serum factor B [106]. Factor B, or C3 proactivator, a compo- Immune status nent of the alternate complement pathway, was reduced during Patientswith nephrotic syndrome have low serum levels ofrelapse, probably because of urine losses, and increased gamma globulin and IgG (often affecting the various IgG sub-towards normal when remission occurred [1061. Of particular classes differently). Three mechanisms seem responsible: lossimportance was the observation that during relapse the serum of IgG in the urine, an increase in catabolic rate, and a reducedof these patients had a reduced capacity to opsonize F. coil and rate of synthesis [3, 91, 92]. Immunoglobulin synthesis bythat this capacity could be restored to normal by the addition of pokeweed mitogen-stimulated lymphocytes, defective duringpure factor B to nephrotic serum, These defects in immune relapse, returns to normal in remission [91]. responseresponses probably explain nephrotic patients' high suscepti- to administered is reduced [931. Also, IgA levels arebility to . decreased in nephrotic syndrome, whereas 1gM usually is increased, particularly in patients with minimal-change disease Increased susceptibility to infection and normal renal function [94]. Indeed, 1gM can remain ele- Before the era of and , infection was the vated for several years after remission has occurred. Themost common cause of death in patients with nephrotic syn- reason and significance of this finding is unknown. Levels ofdrome. The organisms most frequently encountered were IgE also are elevated in cases of minimal-change disease,Streptococcuspneumoniae andEscherichia coil; infections of perhaps because an atopic tendency exists in these patientsthe lungs (as in the patient being discussed today) and perito- [95]. neum were the most common sites. Many factors, as 1 already Important defects in cell-mediated immunity also occur inhave outlined, are responsible for this high susceptibility to nephrotic syndrome [96, 97]. The total number of circulatinginfection, including insufficient immunoglobulin production, T-lymphocytes is reduced, T-cell subsets often are abnormal,inadequate antibody responses, inadequate opsonization, and the blastogenic response by lymphocytes to the mitogens con-defective cell-mediated immunity. Immunosuppressive therapy canavalin A and phytohemagglutinin is reduced, and delayedcan contribute of course. is a particular problem. In cutaneous hypersensitivity reactions frequently are abnormal.one large review, approximately 6% of children with nephrotic These abnormalities generally revert to normal following remis-syndrome suffered one or more episodes [107]. It has been sion of nephrotie syndrome, although less frequently if cyclo-suggested that low levels of complement and immunoglobulin in phosphamide has been given [97]. One study in children withthe ascitic fluid, together with a generalized reduction in ascitic Nephrology Forum: Extrarenal complications of the nephrolic syndrome 1193 bactericidal activity, account for the tendency for peritonitis to Table 1.Bone in nephrotic syndromea occur. Osteoma- The incidence of fatal infection in nephrotic syndrome has Osteo- lacia plus fallen considerably. This reduction is partly due to the avail- Normal malacia resorption ability of highly potent antibiotics, and partly-—at least in (%) (%) (%) (%) children—to the high incidence of steroid-responsive, minimal-Nephrotic syndrome with normal 76 17 7 change disease. However, a risk of serious infection always is renal function present in nephrotic syndrome, and aggressive antibiotic ther-Nephrotic syndrome with azotemia 35 25 40b apy should be instituted at the first suspicion of an infection.Azotemia without nephrotic 53 34 13 syndrome Prophylactic measures, such as , should be applied in patients with nephrotic syndrome and severely a Datafrom Ref. 112. bp=< .05,group II versus Ill. depressed immunoglobulins, particularly in young children, and especially when early remission is not anticipated. Although the initial antibody response to pneumococcal vaccine is favorable,reduced and the PTH levels to be normal or increased [109, 110, by one year 50% of patients have failed to maintain adequate115, 118]. antibody concentrations against several pneumococcal capsular The impact of these abnormalities on the skeleton remains types [108]. Despite this figure, it is currently recommendedunclear. A few children in the one- to two-year age group with that all nephrotic children over 2 years of age, and many adultsnephrotic syndrome have developed rickets, and they have with severely depressed immunoglobulins, be vaccinated withexhibited bone healing after receiving large doses of vitamin D the 23-valent pneumococcal vaccine [1081. [119]. Evidence of bone disease or vitamin deficiency has been found in children with nephrotic syndrome [115]. In this study, Calcium and hone metabolism although 1 ,25(OH)2D levels were normal, bone densitometry , hypocalciuria, reduced intestinal absorptionshowed values below 90% of normal in 6 of 9 children. In of calcium, blunted calcemic response to parathyroid hormoneanother report, and proximal myopathy occurred in (PTH), and the presence of osteomalacia and/or hyperparathy-one child who had low levels of total calcium, ionized calcium, roidism have been demonstrated in patients with nephrotic25-OH-D, and l,25(OH)2D [1181. All biochemical abnormalities syndrome [109, 110]. Although hypocalcemia initially was at-were corrected, and the weakness and myopathy disappeared tributed to hypoalbuminemia, studies of ionized calcium levelswith oral vitamin D therapy. in many patients show low levels [110—112]. Reduced blood No clinical or radiologic evidence of bone disease has been levels of vitamin D and its metabolites are found in manyreported in adults with nephrotic syndrome. Histomorpho- nephrotic patients; a vitamin D-deficient state explains thesemetric studies conflict: some find no bone disease [1161, and abnormalities in calcium metabolism [111, 113. 114]. Initialothers find evidence of osteomalacia and hyperparathyroidism studies in nephrotic syndrome revealed low blood levels of[110]. One important study examined bone histology and cal- 25-hydroxyvitamin D (25-OH-D) [109—ill, 113]. The detectioncium metabolism in two sets of patients with nephrotic syn- of this vitamin D metabolite in the urine led some workers todrome—one with normal, the other with reduced renal func- assume that the low blood level was due to its urinary excretiontion—and compared the findings with those from a group of with the vitamin D carrier protein [1131. Later, reduced levelsnon-proteinuric azotemic patients with comparable levels of of 1,25 dihydroxyvitamin D [1 ,25(OH)2D] were found in some renal functional impairment [112]. Table 1 summarizes the data studies [109, 110, 114], although not in all [I 15J. Since thesefrom the study. In patients with normal renal function, ionized original observations, additional studies have examined thecalcium was reduced in 5 of 9 patients and 25-OH-D levels were status of calcium and vitamin D metabolism in nephroticlow, but l,25(OH)2D and PTH levels were normal. Bone syndrome, and its impact on the skeleton, but no consistenthistology, normal in 76% of the patients, showed osteomalacia pattern has emerged [112, 115, 116]. Although virtually allin 17% and bone resorption in 7%. However, when renal studies agree that plasma levels of 25-OH-D are reduced infunction began to decline, 1,25(OH)2D levels fell, mineraliza- nephrotic syndrome, and often 25,26-OH-D and 24,25-OH-D astion was markedly decreased, and bone resorption became well, the data relating to l,25(OH)2D are controversial; someabnormal in 40% of patients; this percentage was significantly authors have found levels to be low; others, as in today'sgreater than the 13% incidence found in a group with compara- patient, report them to be normal; and some believe that theyble degrees of renal failure in the absence of nephrotic syn- are low predominantly in patients receiving glucocorticoidsdrome [112]. Thus in the presence of nephrotic syndrome and [114, 1161. Some have argued that because the assay fornormal renal function, bone disease is not common, but when I ,25(OH)2D measures both free and bound vitamin, no conclu-renal function declines, severe osteodystrophy is likely to sions can be drawn about the significance of the findingsresult. Studies are needed to confirm this finding and to deter- because only the free amount is physiologically important. Inmine the dose, timing of administration, and preparation of one recent study of nephrotic patients, a free 1,25 index" wasvitamin D that could prevent this . It is possible significantly lower than control, even in patients with normalthat patients with nephrotic syndrome from a glomerular lesion renal function [117]. Even the data regarding blood levels oflikely to produce progressive renal failure, as in the patient we ionized calcium and PTH conflict. Some authors report normalare discussing today [120], should have the biochemical abnor- levels of both despite low blood levels of vitamin D metabolitesmalities corrected. Certainly, vitamin D therapy can effectively and suggest that unbound (free) levels of vitamin D must benormalize blood levels. In one study, treatment with vitamin D3 normal [114, 116]. Yet others report the ionized calcium to befor 4 to 52 weeks elevated 25-OH-D in 8 of 9 patients and raised 1194 NephrologvForum: Extrarenal complications of the nephrotic syndrome

Table 2. Hemostatic factors in nephrotic syndrome Promotes Promotes Coagulation factor Abnormality clotting bleeding Zymogens Reduced: II. IX, Xl. Xl! + Increased: Vii, X + Cofactors Increased: V and Vtt1 + Fibrinogen Increased + Coagulation inhibitors Reduced: lI1 + Increased: alpha-2 + Fibrinolytic system Reduced: plasminogen + Increased antiplasmins: alpha-2 macroglobulin, + alpha-2 antiplasmin + Reduced antipiasmins: alpha-I and alpha-2 antitrypsin + Platelets Thrombocytosis + Increased adhesiveness + tncreased aggregation' + Most common defects.

I ,25(OH)2D in 5 of 9 patients, at least while renal functiondecreased (antithrombin Ill, alpha 1-antitrypsin); evidence of remained normal [1211. increased (reduced alpha-i and alpha-2 antitrypsin) or reduced (reduced plasminogen and increased alpha-2 macroglobulin and Abnormalitiesof coagulation alpha-2 antiplasmin) activity of the fibrinolytic system is pres- Thromboembolismis one of the most serious complicationsent. Finally, several studies have demonstrated marked platelet of nephrotic syndrome. The most frequent site of ishyperactivity [34, 122, 125]. The platelet count is often in- the renal vein, with a reported incidence (documented bycreased, and platelet adhesiveness and aggregation (both spon- venography) varying from 2% to 62%, with an average of abouttaneously and in response to stimulants) is much exaggerated. 35%. Approximately 40% of these patients have pulmonarySome believe that hypoalbuminemia plays a role in the platelet emboli, although death from this cause is rare. Clinical evidencehyperactivity [341; others blame hyperlipoproteinemia [1261 or of is present in 4% to 8% of cases.complex alterations in other plasma proteins [1271. Beta- Noninvasive studies (ventilation/perfusion scans) reveal thatthromboglobulin, a protein released by platelets on aggregation, approximately 20% of adults with nephrotic syndrome haveoften is elevated in the serum of patients with nephrotic evidence of pulmonary embolic disease, although no more thansyndrome [128], one-half have clinical evidence of pulmonary emboli and/or The major coagulation abnormalities in the nephrotic state deep-vein thrombosis [122]. The magnitude of the problem isinclude increased levels of factors V, VIII, and plasma fibrin- now thought to be similar in children [123]. Thrombotic com-ogen; a decreased level of antithrombin III; thrombocytosis; plications also can involve major arteries such as the pulmo-and an increased level of platelet aggregation. Although it is not nary, axillary, renal, aortic, femoral, coronary, and mesenteric,yet possible to attribute the clotting tendency in nephrotic and the axillary and subclavian veins [124]. syndrome to hypercoagulability, certain of the defects do seem Profound changes occur in nephrotic syndrome in the pro-to be better predictors of thromboembolism than others. The teins concerned with initiating both coagulation and fibrinolysisfollowing derangements may be useful clinically: a low level of [122, 125]. This defect arises because of widespread alterationsantithrombin III (below 75%), which correlates closely with a in synthesis, turnover, and urine losses that affect many pro-clotting tendency [129]; an increased alpha-2 antiplasmin, teins in nephrotic syndrome. The majority of patients withwhich may be the most reliable marker of renal-vein thrombosis nephrotic syndrome have a hypercoagulable state. Deficient[1301; and an increased level of beta-thromboglobulin, which hemostasis is infrequent. The role of this hypercoagulable statemay be a sign of platelet aggregation [128]. in the thromboembolic complications has not been established, Many studies lack the longitudinal approach needed to estab- however, A causal relationship between the hypercoagulabilitylish the particular defects that best identify patients at higher and the development of thrombosis has not been demonstratedrisk of thromboembolism. When this information becomes [122, 125]. available, studies will be necessary to assess the value of Table 2 summarizes the numerous defects in hemostasis thatprophylactic anticoagulation in these high-risk patients. In the occur in nephrotic syndrome. Alterations in the concentrationsmeantime, anticoagulation with warfarin seems indicated, for as of almost every coagulation factor and clotting inhibitor as welllong as the nephrotic syndrome persists, in all patients who as defects in platelets and the fibrinolytic system can occurdevelop thromboembolic disease and in those at high risk [122, 125]. The situation is confusing and complicated; somebecause of unavoidable immobilization (for example, patients coagulation factors seem increased (V, VII, VIII, X, andwith pelvic or limb fractures). Although prophylactic anticoag- fibrinogen) and others decreased (11, IX, XI, XII); some clottingulation for all patients with nephrotic syndrome cannot be inhibitors are increased (alpha-2 macroglobulin) and otherssupported, some believe it is reasonable to consider such Nephrology Forum: Extrarenal complications of the nephrotic syndrome 1195 therapy in patients whose plasma albumin is below 2 g/dl, andand degradation of protein as an interesting way of explaining perhaps in those with membranous nephropathy [122, 123].the discrepancy between moderate protein losses and remark- Simple prophylactic measures of encouraging leg exercises,able reductions in serum albumin. I have a problem with that avoiding volume depletion, avoiding immobilization, and avoid-now. If it is true in nephrotic syndrome that plasma proteins are ing femoral artery or vein punctures should always be applied.filtered, reabsorbed by the tubules, and then degraded, one would predict that hypoalbuminemia occasionally might occur Miscellaneous before proteinuria appeared in patients who develop recurrent Several other complications of a metabolic nature can occurnephrotic syndrome. In fact, these two events, at least from in nephrotic syndrome [I]. Low levels of the metals copper,clinical observations, tend to be simultaneous. One also might iron, and zinc occur in nephrotic patients [131], as do theirpredict, based on these principles, that we might see an carrier proteins ceruloplasmin [64] and transferrin [132, 133],occasional patient with glomerular disease who has hypoalbu- probably from loss in the urine. Today's patient had low zincminemia with only minimal proteinuria. Yet we do not recog- and transferrin levels. The significance of these low levels isnize such a phenomenon. Would you comment on this apparent unknown; iron deficiency is rare [132, 133] but, as I discusseddiscrepancy? before, transferrin and/or zinc deficiency can produce defective DR. BERNARD: The easiest way for me to answer your cellular immunity [99, 100]. Urinary loss of thyroxine-bindingquestion is to emphasize that the pathophysiology of hypoalbu- globulin alters blood levels of hormones and mayminemia in nephrotic syndrome is undoubtedly multifactorial. confuse interpretation of thyroid function tests, although theClearly, the plasma albumin concentration can vary from pa- patients remain euthyroid [I, 134]. Protein malnutrition cantient to patient, and from time to time in a single patient, arise from combinations of poor intake, massive urinary losses,depending on the net balance between the rate of hepatic and increased catabolism; such protein deficits can be devas-synthesis of albumin, dietary intake of protein, urine losses of tating in growing children [119]. Finally, dysfunction of renalalbumin, and the rates of catabolism of albumin by renal and tubular cells, presumably related to resorption of filtered pro-extrarenal sources. Diet in fact might be a critical factor; as I tein, can lead to features of proximal tubular dysfunction andmentioned earlier, some British nephrologists claim that with can manifest with glycosuria, aminoaciduria, phosphate andaggressive protein and calorie supplementation, hypoprotein- wasting, and hyperchloremic acidosis [1]. emia is unusual, even in the presence of heavy proteinuria [12]. Conversely, in the presence of an inadequate diet, it should be Questions and answers possible to develop hypoalbuminemia with only minimal pro- DR. NlcoLAos F. MADIAS (Chief, Division of Nephrology,teinuria, if rates of hepatic synthesis are low and renal catabolic New England Medical Center, Boston, Massachusetts):rates are high. As far as the first part of your question is Shouldn't we be able to advance our understanding of theconcerned, I don't believe we know for sure exactly what pathophysiology of edema formation in nephrotic syndrome byhappens to plasma albumin concentration just before the onset comparing the findings of studies such as those you described inof a relapse in recurrent nephrotic syndrome. That would be a nephrotic syndrome with similar studies carried out in otherdifficult study to do because the timing of a relapse is, of course, hypoalbuminemic states such as protein-losing enteropathy orunpredictable. Certainly by the time most patients have devel- malnutrition? Have such studies been done? oped heavy proteinuria they also have hypoalbuminemia. But I DR. BERNARD: I am not aware of any studies in hypoalbu-agree that at least theoretically it might be possible for minemic states, other than nephrotic syndrome, that havehypoalbuminemia to occur before proteinuria. simultaneously examined plasma volume, plasma oncotic pres- DR. KA5sIRER: But you haven't fully addressed my question sure, and interstitial oncotic pressure, together with urinaryabout renal degradation of filtered proteins. When the glomeruli sodium excretion rates. Such studies certainly would be inter-begin to leak, presumably the tubules have the "first crack" at esting. However, at least one piece of indirect evidence relatingthe filtered protein, and if that is the case, then those proteins to non-nephrotic hypoalbuminemnia indicates that a renal sodi-would be lost to the circulation. In principle, hypoalbuminemia um-retentive defect unrelated to hypoalbuminemia is critical inmight develop in some instances even without overt protein- edema formation in nephrotic syndrome: the lack of edema inuria. patients with analbuminemia [37]. Such patients have markedly DR. BERNARD: We should consider two additional factors. reduced plasma oncotic pressures, as low as 10 to 14 mm Hg,First, it is presumed that at least some of the albumin metabo- but no clinical water or disturbance [37]. Further-lized by the renal tubules is converted into its constituent amino more, even in nephrotic syndrome, hypoalbuminemia is notacids, which are then returned to the circulation to rejoin the always associated with edema. We all have seen patients withbody pool of protein [135]. So not all is lost. Presumably the no edema in the presence of severe hypoalbuminemia, andproportion of filtered and reabsorbed protein that is returned to experimentally severe proteinuria and hypoalbuminemia arethe circulation and that which is locally catabolized and perma- not inevitably associated with edema [36]. These facts stronglynently lost from the body pool vary under different circum- argue that a renal defect in sodium excretion unrelated tostances. For example, perhaps when the filtered load of albumin hypoalbuminemia must be present if the extracellular space isis not very high, all reabsorbed protein is returned to the to expand and edema is to occur. circulation; it is possible that local catabolism only becomes DR. JEROME P. KASSIRER (Associate Physician-in-Chief, De- important in the presence of high rates of proteinuria. In that partment of Medicine, New England Medical Center): When Isituation, hypoalbuminemia would not occur until proteinuria last reviewed the mechanisms of hypoalbuminemia in nephroticwere substantial. Considerable evidence indicates that renal syndrome, I was struck by the concept of tubular reabsorptionalbumin catabolic rates increase as proteinuria increases [1, 3, 1196 NephrologyForum: Esirarenal complications of the nephro(ic syndrome

5, 14]. This finding raises the second point relating to theexists that cannot be treated in another way. The most obvious possible existence of a dual transport system for tubular albu-reason for trying to eliminate proteinuria is to control intracta- min uptake [18]. Perhaps the low-capacity system that isble edema that is resistant to treatment with diuretics and salt responsible for albumin reabsorption at low rates of filtrationrestriction; other possible reasons can include thromboembol- accounts for the return of absorbed protein to the body,ism, severe hyperhipidemia, severe protein malnutrition, and whereas the high-capacity, low-affinity system, which "turnslife-threatening infections. Two main therapeutic approaches on" when the filtered load increases, permits increased tubularexist: nonsteroidal antiinflammatory drugs and angiotensin- reabsorption and local catabolism. I realize these are not totallyconverting-enzyme inhibitors. Indomethacin and other nonste- satisfactory answers, but I don't believe we have any betterroidal antiinflammatory drugs decrease proteinuria by 60% to insight at present. 70%, especially if the patient is salt depleted and is taking DR. RONALD D. PERRONE (Division of Nephrology, Newdiuretics [27, 281. Glomerular filtration rate declines by a England Medical Center): Measurement of the blood volume issmaller percentage. Withdrawal of the drug I to 3 years after extremely sensitive to the marker used. The validity of a markeradministration is followed by a return of proteinuria to pretreat- for blood volume depends on its being confined to the intravas-ment levels in most cases [27]. This effect has been noted in cular space. Is the validity of this method established forexperimental studies as well [137]. The mechanism for the hypoalbuminernic nephrotic patients? resumed proteinuria might have to do with the drug's effect on DR. BERNARD: The transcapillary escape rate (TER) ofrenal prostaglandin production [28, 137]. Experimentally, the injected albumin has been studied in patients with nephroticfall in protein excretion is accompanied by a reduction in the syndrome and has been compared with that in normals [136].amount of filtrate formed through the "shunt" pathway of the The normal TER is 5% to 8% per hour, whereas in patients withglomerular capillary wall [1381. We should remember that nephrotic syndrome the TER is elevated to 9.5 2.5% [136]. although the decline in GFR induced by the nonsteroidal Using radiolabeled albumin, the overestimation of plasma vol-antiinflammatory drugs usually is reversible, that is not always ume that would result from this change would account for lessthe case [29]. So considerable caution and close monitoring are than 2% if a single post-injection sample only were used; theneeded when these agents are used. In the patient we are percentage would be lower if several timed blood samples werediscussing, because of his severe edema, a very low plasma taken [40, 1361. albumin concentration, significant abnormalities of serum lip- DR. PERRONE: In studies which show that attempts at in-ids, and a lack of response to steroids, we did elect to begin creasing blood volume in nephrotic patients were unsuccessfultreatment with indomethacin, 75 mg daily. When the patient in increasing interstitial volume, what method was used towas last seen, proteinuria and renal function were unchanged, increase the blood volume? If crystalloid was used, it wouldso the dose has been increased. have been expected to leave the circulation. More recently, angiotensin-converting-enzyme inhibition has DR. BERNARD: The studies I cited were those in which bloodbeen shown to reduce proteinuria in patients with a variety of volumes and extracellular fluid and interstitial volumes wereglomerular diseases and renal insufficiency [139]. I'm not aware compared among edematous patients with nephrotic syndromeof any studies that have examined this effect systematically in in relapse and two other groups of patients, normal healthypatients with nephrotic syndrome with normal renal function or subjects volume-expanded to an almost comparable degree byonly moderate renal insufficiency. It seems reasonable to me, markedly increased sodium intake [52] and patients withhowever, to try these agents in patients with severe nephrotic chronic renal failure who were spontaneously overhydrated bysyndrome and serious complications in whom elimination of a similar amount [42]. At comparable degrees of extracellular-proteinuria has not occurred with nonsteroidal antiinflamma- fluid volume expansion, blood volume, although normal ortory drugs. increased, was considerably lower in nephrotic subjects than in DR. VINCENT J. CANZANELLO (Division of Nephrology, New the other two groups. So, because of hypoalbuminemia, theEngland Medical Center): With respect to this particular pa- blood volume is not elevated in overhydrated nephrotic syn-tient, I notice renal venography was performed initially. Do you drome patients, whereas it is elevated in normoproteinemicbelieve that routine investigation of the renal veins is worth- patients comparably expanded. This finding is viewed by somewhile in all patients with membranous nephropathy? as an important homeostatic mechanism protecting against DR. BERNARD: Those studies had been done prior to the hypertension in nephrotic patients, and it might explain thepatient coming to our hospital. The answer to your question is discrepancy between the common presence of hypertension inno, I don't think routine radiologic investigation of the renal non-nephrotic azotemic patients and the much less commonveins is appropriate. Venography does seem indicated, how- incidence of hypertension in nephrotic patients [42]. ever, in patients with nephrotic syndrome who present with DR. MICHAEL P. MADAIO (Division of Nephrology, Newacute flank pain, macroscopic , unexplained rapid England Medical Center): Would you comment on treatment ofdeterioration in renal function, pleuritic chest pain, or other a patient, like the one presented in this Forum, whose protein-evidence of pulmonary . It has been suggested that uria has not responded to steroid therapy? Specifically, wouldbecause of the high incidence of renal-vein thrombosis in you attempt to reduce the protein excretion by alternativemembranous nephropathy, all patients with that glomerular pharmacologic measures? lesion should routinely undergo venography, but there's no DR. BERNARD: If a patient with nephrotic syndrome fails toconsensus on this point [122]. enter remission after having taken steroids and/or immunosup- DR. KASSIRER: You correctly described the prevalence of pressive agents, further attempts at eliminating proteinuriarenal vein thrombosis as reported in the literature as between probably are indicated only if a major metabolic complication2% and 60%. If it is 2%, then I do not worry about doing routine Nephrology Forum: Extrarenal complications of the nephrotic syndrome 1197 renal venography. But if it is truly 60%, then your recommen-proteinuria with nonsteroidal antiinflammatory agents or con- dation doesn't make sense. In fact, if it is 60%, then in principle,verting-enzyme inhibitors without treating the primary disease? we should be performing renal venography in everyone who DR. BERNARD:Ibelieve nobody has addressed that question. presents with nephrotic syndrome. What is your opinion of theIn the studies I referred to previously, in which nephrotic reports of a high frequency of renal-vein thrombosis in patientsproteinuria had been reduced or eliminated by the use of these with nephrotic syndrome? agents, no statement was made about the effects on sodium DR. BERNARD:Ido not know the answer, The problem, ofretention [27,28,137, 139]. In one of these studies, the authors course, is that renal-vein thrombosis is a very difficult diagnosisdid comment that as proteinuria was reduced with indometh- to make. There are no reliable noninvasive methods for diag-acm, plasma albumin concentration rose, but no data were nosing renal-vein thrombosis, although CT scanning might havepresented about sodium balance [27].Inone short-term study, some promise [140]. Even venography requires special skill incaptopril was administered to 8 patients with nephrotic syn- conducting the test and interpreting the results; small venulardrome in relapse, and sodium excretion was measured [145]. thrombi can be missed unless a venous-phase arteriogram isFour days later, the patients were still markedly sodium avid done at the same time; on the other hand, venograms can showand gaining weight; however, no information was given about apparent filling defects that are not thrombi. So perhaps tech-changes in urinary protein excretion. nical factors or misinterpretations of the findings account for DR.MARK SISKIND (RenalFellow, Boston University Medi- the differences in reported incidence. cal Center, Boston): What happens to the blood volume in DR. KASSIRER: My view is that the frequency of renal-veinpatients with nephrotic syndrome when they are standing? Is it thrombosis at any given moment in the life of the nephroticpossible that patients become hypovolemic in the upright posi- patient is not nearly as high as the highest figures. As yoution and that posture then becomes an important stimulus to the pointed out, many of these reports of renal-vein thrombosiskidney to retain sodium? have been misinterpreted because of the high blood flow in the DR.BERNARD: Thatquestion has been raised by some as a renal veins. potential flaw in the blood-volume studies reported to date. DR. CANZANELLO:Howaggressively do you search forWhereas most recent studies have shown blood and plasma in adults with newly discovered membranousvolumes to be normal in these patients, the measurements nephropathy? generally have been done while the patient was in the recum- DR.BERNARD: Untilrecently, it was believed that an under-bent position. In fact, when plasma volume is examined after lying malignant process, usually a carcinoma, is present in 6%the patient has been standing, patients with nephrotic syndrome to 10% of patients with membranous nephropathy: in one largedo have a greater-than-normal reduction [146]. After 20 minutes review, of all the instances of neoplasm in patients withof upright posture, plasma volume in normal persons falls by nephrotic syndrome, the renal lesion was membranous nephrop-about 7% to 10%, and in patients with nephrotic syndrome by athy in 34% of cases; if carcinomas only were considered, this15% to 18% [146, 1471. A recent study assessed whether this figure was 69% [1411. On the other hand, recent studies have"upright hypovolemia" was physiologically important in terms questioned the validity of these findings because, in most cases,of producing a renal sodium-retaining effect; heart rate, renin control figures for the incidence of malignancy in a comparableand norepinephrine levels, and postural changes in blood pres- general population without nephrotic syndrome had not beensure were compared in nephrotic patients and controls. Blood considered. These recent studies conclude that in fact novolume fell more in nephrotic patients, but no important differ- convincing proof exists of increased malignancy in patients withences in heart rate or blood pressure were apparent. On the nephrotic syndrome [120, 142]. 1 believe it is appropriate towhole, changes in plasma renin and norepinephrine also did not perform routine screening in all patients with nephroticdiffer between the two groups. A small subset of patients was syndrome. These tests, such as looking for blood in the stoolidentified who had an excessive increase in heart rate and and obtaining a chest x-ray, should be based on the patient'selevation of plasma renin on standing, although blood pressure age and medical history. Procedures beyond these are notchanges were the same as those for the entire group. Only one justified by the data now available. The need for a full workuppatient, who had amyloid disease, developed postural hypoten- for malignancy in all adult patients with membranous nephrop-sion. The authors concluded that, taken together, there was no athy probably was overstated. convincing evidence that the exaggerated hypovolemia in Da. MADrAS:Isuspect that the risk of an associated malig-standing nephrotics was exerting any significant circulatory nancy is higher in older patients with membranous nephropathyeffects in the majority of patients and thus could not be than in younger patients. Are there data on this issue? considered a signal for renal sodium retention. DR. BERNARD:Yes,there are, but again the data conflict. DR. MADAm:Whatis the pathogenesis of acute, reversible One study reported that the incidence of malignancy in olderrenal failure that occurs with nephrotic syndrome? What is your patients with membranous nephropathy was greater than 22%therapeutic approach to these patients? [143],but the lack of controls makes this information difficult to DR.BERNARD: lamnot aware of any new information on this interpret. Another study found I of 16 elderly patients withpoint. A large number of causes of acute renal failure exist in membranous nephropathy to have an underlying malignancy,idiopathic nephrotic syndrome, including tubular necrosis and and considered that incidence to be no greater than thatallergic interstitial [148]. The most interesting type of expected in the population at large [144]. reversible acute renal failure in these patients is that which DR. DAVIDSALANT (Chief,Renal Section, Boston Universityoccurs in association with unimpressive glomerular, tubular, or Medical Center, Boston): Is it known what happens to the renal interstitial changes on renal biopsy [25, 26, 1481. The causes of sodium-retentive defect in nephrotic syndrome if one reducesthis entity are unknown. A variety of suggestions have been put 1198 Nephrologv I—orion: Lx/,'a,'enalcomplicationsoftheneph,'ofic svnd,'one forward to explain it, including an increase in renal vascularalbumin production Ill. However, the explanation certainly is resistance, a decrease in glomerularcapillarypermeability, andnot as simple as that. Patients with nephrotic syndrome can renal interstitial edema [25, 26, 1481. Many patients withdevelop marked hyperlipidemia in the presence of nearly nor- minimal-change disease who present with acute renal failuremal plasma protein levels. Some studies have failed to show any have and massive proteinuria as well as [25,correlation between the increased lipids and the low plasma 261. Biopsies reveal no or mild evidence of tubular necrosis, butalbumin, and hyperlipoproleinemia is not a universal finding in interstitial edema can be marked. Edema is everywhere; whyncphrotic syndrome even when hypoalhuminemia is present not in the kidney as well? Interstitial edema might compress the[1]. In fact, several other ideas have been advanced. One is that renal tubules, produce intrarenal obstruction, and increasethe stimulus to the liver to increase lipoprotein production is hydrostatic pressure in proximal tubules and Rowman's space.related to a reduction in plasma oncotic pressure or tonicity; This distal obstruction could lead to a full in the net hydraulicinfusions of dextran into nephrotic patients or animals have a pressure, thus favoring filtration. In most of these patients, renallipid-lowering effect comparable to that of albumin infusion failure reverses with aggressive diuretic therapy, whether or not [ISO]. Furthermore, a reduction in apolipoprotein-B mRNA is remission of protcinuria subsequently occurs; this finding sug- noted in cultures of liver cells when albumin or dextran is added gests that diuretics can reduce renal interstitial edema as wellto the medium [1511. Another idea is that the liver's increased [251. An alternate mechanism has been suggested l'or increasingproduction of lipoprotein might he a response to decreased proximal tubule and Bowman's space hydraulic pressure,plasma viscosity. In one recent study of experimental nephrotic which would have the same effect, namely, tubule blockage bysyndrome, the injection of macromolecules to increase plasma inspissatcd protein casts [148, 1491. I think acute renal failure atviscosity delayed the development of hyperlipidemia and re- onset of nephrotic syndrome is more common than realized,duced the blood lipid levels [152]. The authors hypothesized particularly in older patients with anasarca. Many have ele-that the lipoproteins restore plasma viscosity in nephrotic vated serum crcatinine levels when first seen and, although thissyndrome, although this argument has been disputed by others finding was assumed to he due to hypovolemia, that possibility[661. Others have suggested that the liver responds to abnor- no longer seems tenable. The best treatment is steroids withmalities in mevalonate metabolism in nephrotic syndrome [153]. aggressive diuretic therapy. These workers have demonstrated that excretion and metabo- DR.ANDREWS. LEVEY (Division of Nephrologv, New En-lism of mevalonate by the nephrotic kidney is reduced, and that gland Medical Center): The sedimentation rate in this patientthis reduction results in increased delivery of this cholesterol was 80 mm/hr. Frequently, in our search for a systemic inflam-precursor to the liver. Finally, it has been proposed that there matory disease in patients with nephrotic syndrome, we mea-might he defective hepatic uptake of IDL in nephrotic syn- sure the sedimentation rate. How high should we expect it to hedrome because of abnormalities in the IDL molecule itself or in simply from the hypoalbuminemia and alterations in the plasmaits receptor [70]. The effect of this alteration would be to proteins'! eliminate the important negative feedback on hepatic lipid DR.BERNARD: Idonotknow. My hematology colleaguessynthesis normally exerted by the uptake and metabolism of assure me there is no definitive study to answer that question.IDL. Apparently a sedimentation rate over 100 mm/hr is unlikely to be due to nephrotic syndrome alone, and 50 mm/hr or less Reprinti'eqnests to Dr. I). Bernard.RenalUnit,Boston Lfnii'ersitv seems a more usual figure. I don't know what to say about thoseMedicalCenter, 88 East Neii'ton Street, Bo,c ton, Massachusetts between 50 and 100 mm/hr. (121/8-2393,USA DR. KASSIRER:Inmy experience, sedimentation rates as high as 100 mm/hr or even greater are common in nephrotic syn- References drome of all causes. I doubt that an elevated value of this 1. BERNARD DB: Metabolic abnormalities in nephrotic syndrome: magnitude favors an inliammatory cause. pathophysiology and complications, in Controversiesin Neplirol— DR. SAiANi: Would you comment on the stimulus for ogv,Vol 9, i/Ic NephroticSyndrome, editedby BRENNER BM, SrLiN JA. New York. Churchill Livingstone. 1982 liepatic lipoprotein synthesis in nephrotic syndrome? Is it a 2. ROTHSCHILD MA, ORArz M, Scl-IREIBER SS: Albumin synthesis. response related purely to hypoalbuminemia? N Eni,'l J Med 286:748—757, 1972 DR. BERNARD: This is another area where current knowledge 3. (iriirs 1), JANFWAY CA, FAISIS 1i2: Studies on the metabolism ol' is incomplete, Some have argued that the increased hepatic plasma pi-otcins in the nephrotic syndrome. t. Albumin, y-glohulin lipoprotein production is simply a result of increased liver and iron-binding globulin. J GUnInvest 35:44—Sb,1956 4. KAYSEN GA, GAMIIERTOGIIO J, JIMENEZ I, JONES H, HUTCHISON protein synthesis in response to hyalhuminemia. In support FN: Effects of dietary protein intake on albumin honieostasis in of this idea, a close inverse relationship exists between the nephrotic patients. KidneyJut29:572—577. 1986 elevated blood lipids and the lowered plasma albumin concen- 5. KATZ i, SELLvis AL., B0N0RRI5 G: Eflct of nephrectomy on tration: when a remission from nephrotie syndrome occurs, the plasma albumin catabolism in experimental . J Lab Cli,, serum cholesterol falls as the serum albumin rises, and an Med 63:680—686. 1964 6. KATZ J. BoNoRRis G, OKUYAMA S. SELLERS AL: Albumin infusion of albumin to nephrotic rats or humans acutely elevates synthesis in perfused liver of normal and nephrotic rats. Am J the plasma albumin concentration and reduces the serum lipo- Phy.siol 212:1255—1260, 1967 protein and lipid levels, by as much as 30% to 60% in some 7. MARSH JB, DRABK1N DL, BRALJN GA, PARKS iS: Factors in the cases [I. 62, 65. 66]. The notion has been put forward that stimulation of protein synthesis by suhcellular preparations from rat liver. J Iliol Chem241:4168l74, 1966 because VLDL and albumin follow the same synthetic and 8. 7.AHRINGF,R J, BALIGA BS, MUNRO HN: Increased levels of secretory routes in the liver, the lipoproteins are simply inno- microsomal albumin-mRNA in the liver of nephrotie rats. FEBS cent bystanders in the reaction whose prime aim is to increase Left 62:322—325, 1976 Nephrology Forum: Extrarenal complications of the nephrotic syndrome 1199

9. ROTHSCHILD MA, ORATZ M, EVANS CD, SCI-IREIBER SS: Role of 34. SCHIEPPATI A, DODESINI P, BENIGNI A, MASSAZZA M, MECCA G, hepatic interstitial albumin in regulating albumin synthesis. AmJ REMUZZI G, LIVI0 M, DEGAETANO G, RosSi EC: The metabolism Physiol210:57—62, 1966 of arachidonic acid by platelets in nephrotic syndrome. Kidney mt 10. YOUNG GA, BROWNJOI-IN AM, PARSONS FM: Protein losses in 25:671—676, 1984 patients receiving continuous ambulatory peritoneal . 35. BERNARD DB, ALEXANDER EA: Edema formation in the tie- Nephron 45:196—201, 1987 phrotic syndrome: Pathophysiologic mechanisms. Cardiovasc 11. KAYSENGA,SCHOENFELD PY: Albumin homeostasis in patients Med 4:605—625, 1979 undergoing continuous ambulatory peritoneal dialysis. Kidney In! 36. VAN LIEW JB, NOBLE B, BRENTJENS JR: Absence of sodium and 25:107—1 14, 1984 water in rats with severe proteinuria. Nephron 40:476—481, 1985 12. SHORT CD, DURRINGTON PN, MALLICK NP, HUNT LP, TETLOW 37. BENNHOLD H, KLAUS D, SCHEURLEN PG: Volume regulation and L, ISHOLA M: Serum and urinary high density lipoproteins in renal function in analbuminemia. Lancet2:1169—1170,1960 glomerular disease with proteinuria. Kidney lot 29:1224—1228, 38. BERNARD DB: Primary renal sodium retention in the nephrotic 1986 syndrome, in Nephrology, edited by ROBINSON RR, New York, 13. KAYSEN GA, KIRKPATRICK WG, COUSER WG: Albumin homeo- Springer-Verlag, 1984 stasis in the nephrotic rat. Nutrition considerations. Am J Physiol 39. DORHOUT MEES EJ, Roos JC, BOER P. OEI HY, SIMATUPANG 247:F192—202, 1984 TA: Observations on edema formation in the nephrotic syndrome 14. KATZ J, BON0RRIs G, SELLERS AL: Albumin metabolism in in adults with minimal lesions. AmJ Med67:378—384, 1979 aminonucleoside nephrotic rats. JLab Clin Med 62:910—934,1963 40. DORHOUT MEES EJ, GEERS AB, KOOMANS HA: Blood volume IS. EXAIRE E, POLLAK VE, PESCE AJ, Ooi BS: Albumin and y- and sodium retention in the nephrotic syndrome: A controversial globulinin the nephron of the normal rat and following the pathophysiological concept. Nephron 36:201—211, 1984 injection of aminonucleoside. Nephron 9:42—54, 1972 41. BROWN EA, MARKANDU N, SAGNELLA GA, JONES BE, MAC- 16. OLBRICI-IT Ci, CANNON JK, TISHER CC: Proteinuria stimulates GREGOR GA: Sodium retention in nephrotic syndrome is due to an cathepsin B and L activity in the rat proximal tubule (abstract). intrarenal defect: Evidence from steroid-induced remission. Kidney In!25:267,1984 Nephron 39:290—295, 1985 17. LANDWEHR DM, CARVALITOJS,OKEN DE: Micropuncture stud- 42. KOOMANS HA, BRAAM B, GEERS AB, Roos JC, DORHOUT MEES ies of the filtration and absorption of albumin by nephrotic rats. EJ: The importance of plasma protein for blood volume and blood Kidney liii 11:9—17, 1977 pressure homeostasis. KidneyIn! 30:730—735,1986 18. PARK CH, MAACK T: Albumin absorption and catabolism by 43. SHAPIRO MD, NICHOLLS KM, GROVES BM, SCHRIER RW: Role of isolated perfused proximal convoluted tubules of the rabbit. J Clin glomerular filtration rate in the impaired sodium and water excre- Invest73:767—778, 1984 tion of patients with the nephrotic syndrome. Am J Kidney Dis 19. GALASKE RG, BALDAMUS CA, STOLTE H: Plasma protein han- 8:81—87, 1986 dling in the rat kidney: micropuncture experiments in the acute 44. KOOMANS HA, GEERS AB, DORHOUS MEES El, KORTLANDT W: heterologous phase of anti-GBM-nephritis. PflugersArch 375: Lowered tissue-fluid oncotic pressure protects the blood volume 269—277,1978 in the nephrotic syndrome. Nephron 42:317—322, 1986 20. HARDWICKE J, SQUIRE JR: The relationship between plasma 45. FADNES HO, PAPE iF, SUNDSFJORD JA: A study on oedema albuniin concentration and protein excretion in patients with mechanism in nephrotic syndrome. Scand J C/in Lab Invest proteinuria. ClinSci 14:509—530, 1955 46:533—538, 1986 21.SCHULTZE G, AHUJA S, FABER U, MOLZAHN M: Gastrointestinal 46. DORHOUT MEES EJ, GEERS AB, KOOMANS HA, Roos JC: protein loss in the nephrotic syndrome studied with 51Cr-albumin. Changes in plasma volume and renin activity during correction of Nephron 25:227—230, 1980 edema in the nephrotic syndrome. Kidney tnt 25:163, 1984 22. JENSEN H, JARNUM 5, HART HANSEN JP: Gastrointestinal protein 47. MELTZER JL, KEIM Hi, LARAGH JH, SEALEY JE, JAN K-M, loss and intestinal function in the nephrotic syndrome. Nephron CHIEN 5: Nephrotic syndrome: Vasoconstriction and hypervol- 3:209--220, 1966 emic types indicated by renin-sodium profiling. Ann Intern Med 23. YAMAUCHI H, HOPPER J JR, MCCORMACK K: Blood volume and 91:688—696, 1979 fainting in nephrosis. C/in Res 8:195, 1960 48. KOOMANS HA, GEERS AB, VAN DER MEIRACKER AH, Roos JC, 24. CHAMBERLAIN Mi, PRINGLE A, WRONG OM: Oliguric renal BOER P. DORHOUT MEES EJ: Effects of plasma volume expansion failure in the nephrotic syndrome. QJMed 35:215—235, 1966 on renal salt handling in patients with the nephrotic syndrome. Am 25. LOWENSTEIN J, SCHACHT RG, BALDWIN DS: Renal failure in JNephro/ 4:227—234,1984 minimal change nephrotic syndrome. Am J Med 70:227—233, 1981 49. BROWN EA, MARKANDU ND, SAGNELLA GA, SQUIRES M, JONES 26. Case Records of the Massachusetts General Hospital: Clinical- BE, MACGREGOR GA: Evidence that some mechanism other than Pathologic Conference. NEngI J Med 306:221—231,1982 the renin system causes sodium retention in nephrotic syndrome. 27. DONKER AiM. BRENTJENS JRH, VAN DER HEM GK, ARISz L: Lancet 2:1237—1240, 1982 Treatment of the nephrotic syndrome with indomethacin. Neph- 50.KRISHNAGG, DANOVITCH GM: Effects of water immersion on ron 22:374—381, 1978 renal function in the nephrotic syndrome. Kidney In! 21:395—401, 28. VRIESENDORP R, DE ZEEUW D, DE JONG PE, DONKER AJM, 1982 PRATT ii, VAN DER HEM GK: Reduction of urinary protein and 51. BERLYNE GM, SUTTON J, BROWN C, FEINROTH MV, FEINROTH prostaglandin E2 excretion in the nephrotic syndrome by non- M, ADLER Al, FRIEDMAN EA: Renal salt and water handling in steroidal anti-inflammatory drugs. C/inNephrol 25:105—110,1986 water immersion in the nephrotic syndrome. C/in Sci 61:605—610, 29. KLEINKNECHT C, BROYER M, GUBLER M-C, PALCOUX JB: Irre- 1981 versible renal failure after indomethacin in steroid-resistant 52. GEERS AB, KOOMANS HA, Roos JC, DORHOUT MEES EJ: Pres- nephrosis (letter).N EngIJ Med302:691, 1980 ervation of blood volume during edema removal in nephrotic 30. BAUMELOU A, LEGRAIN M: Medical nephrectomy with anti- subjects. Kidney Int 28:652—657, 1985 inflammatory non-steroidal drugs. BrMed J 284:234—236,1982 53. ICHIKAWA I, RENNKE HG, HOYER JR. BADR KF, SCHOR N, TROY 31. GUGLER R, SHOEMAN DW, HUFFMAN DH, COHLMIA JB, JL, LECHENE CP, BRENNER BM: Role for intrarenal mechanisms AZARNOFF DL: Pharmacokinetics of drugs in patients with the in the impaired salt excretion of experimental nephrotic syn- nephrotic syndrome. JClin Invest 55:1182—1189,1975 drome. JC/in Invest 71:91—103,1983 32. BRIDGMAN iF, ROSEN SM, THORP JM: Complications during 54. CHANDRA M, HOYER JR, LEWY JE: Renal function in rats with clolibrate treatment of nephrotic syndrome hyperlipopro- unilateral proteinuria produced by renal perfusion with teinaemia. Lance!2:506—509, 1972 aminonucleoside. PediatrRes 15:340—344,1981 33. GANEVAL D, FISCHER AM, BARRE J, PERTUISET N, DAUTZEN- 55. VELHOTE VW, FUJIHARA C, MARCONDES M: Atrial natriuretic BERG MD, JUNGERS P, HOUIN G: Pharmacokinetics of warfarin in factor and generalized edema in rats. Braz J Med Bio/ Res the nephrotic syndrome and effect on vitamin K-dependent clot- 18:481—485, 1985 ting factors. C/inNephro/ 25:75—80, 1986 56. PERICO N, DELAINI F, LUPINI C, REMUZZI G: Renal response to 1200 Nephrology Forum: Extrarenal complications of the nephrotic syndrome

atrial peptides is reduced in experimental nephrotics. Am J with idiopathic nephrotic syndrome. J Pediatr 104:61—64, 1984 Physiol252:F654—F660,1987 80. SHORE VG, FORTE T, LICI-IT H, LEWIS SB: Serum and urinary 57. TULASSAY T, RASCHER W, LANG RE, SEYBERTH HW, SCHARER lipoproteins in the human nephrotic syndrome: Evidence for renal K: Atrial natriuretic peptide and other vasoactive hormones in catabolism of lipoproteins. Metabolism 31:258—268, 1982 nephrotic syndrome. Kidney mt 31:1391—1395, 1987 8!. MALLICK NP, SHORT CD: The nephrotic syndrome and ischaemic 58.FADNESHO, AUKLANDK:Protein concentration and colloid heart disease. Nephron 27:54—57, 1981 osmotic pressure of interstitial fluid collected by the wick tech- 82. GORDON T, CASTELLI WP, HJORTL.AND MC, KANNEL WB, nique—analysis and evaluation of the method. Micro,'asc Res DAWBER TR: High density lipoprotein as a protection factor 14:11—25, 1977 against coronary heart disease. A,n J Med 62:707—7 14, 1977 59. KOOMANSHA,KORTLANDTW,GEERS AB, DORI-louTMEESEJ: 83. WA5S V, CAMERON iS: Cardiovascular disease and the nephrotic Lowered protein content of tissue fluid in patients with the syndrome: the other side of the coin. Nephron 27:58—61, 1981 nephrotic syndrome: Observations during disease and recovery. 84. VALERI A, GELFAND J, BLUM C, APPEL GB: Treatment of the IVephron 40:391—395, 1985 hyperlipidemia of the nephrotic syndrome: A controlled trial. Am 60. NODDELAND H, RIISNES SM, FADNESS HO: Interstitial fluid JKidney Dis 8:388—396, 1986 colloicl osmotic and hydrostatic pressures in subcutaneous tissue 85. GOLPER TA, ILLINGWORTI-I OR, BENNETT WM: Effective and of patients with nephrotic syndrome. Scand J C/in Lab invest safe short term improvement in nephrotic 42:139—146,1982 with the HMG Co-A reductase inhibitor mevinolin (abstract). 61.FAUCHAI.DP, NODDELAND H, NORSETH J: An evaluationof Kidney mt 3 1:200, 1987 ultrafiltration as treatment of diuretic-resistant oedema in ne- 86. MOOREHEAD iF, CHAN MK, EL-NAHAS M, VARCHESE Z: Hy- phrotic syndrome. Acto Med Scand 217:127—131, 1985 pothesis-lipid nephrotoxicity in chronic progressive glomerular 62. BAXTER JH: Hyperlipoproteinemia in nephrosis. Arch Intern Med and tubulo-interstitial disease. Lancet 2:1309—1311, 1982 109:742—757,1962 87. OROND J, VAN GooR H, ERKELENS DW, ELEMA JO: Glomerular 63.THOMASEM,ROSENRLUMAH,LANDERHB,FISHER R: Relation- sclerotic lesions in the rat. Virchoa's Arch (Cell Pathol) 51: ship between blood lipid and blood protein levels in the nephrotic 521—534, 1986 syndrome, Am J Dis Child 81:207, 1951 88. KASISKE BL, O'DONNEL MP, DANIELS F, KEANE WF: The lipid 64. JENSEN H: Plasma protein and lipid pattern in the nephrotic lowering agent clofibric acid ameliorates renal injury in the '/ syndrome. Acta Med Scand 182:465—473, 1967 nephrectomy model of chronic renal -failure (abstract). C/in Rev 65. BAXTER JH, GOODMAN HC, HAVEL Ri: Serum lipid and lipopro- 33:488A, 1985 tein alterations in nephrosis. J C/in Invest 39:455—465, 1960 89. KASISKE BL, O'DoNNEI, MP, GARVIS Wi, KEANE WF: Choles- 66. APPELGB,BLUM CB, CHIEN S, KUNISCL, APPEL,AS:The terol synthesis inhibition reduces glomerular injury in the rat ¾ hyperlipidemiaof the nephrotic syndrome: Relation to plasma nephrectomy model of chronic renal failure (abstract). C/in Res albumin concentration, oncotic pressure, and viscosity. N Eng/ J 35:549A, 1987 Med 312:1544—1548,1985 90. MULLER EW, VAN T0I. A, DALLINGA-THIE GM, ELEMA JD, VAN 67.MULS E,ROSSENEUM,DANEELS R,SCHURGERSM,BOELAFRTJ: DER WOUDE Fi, VAN DER HEM GK: Serum lipids in rats with Lipoprotein distribution and composition in the human nephrotic different susceptibility to focal glomerulosclerosis. X hit Cong syndrome. Aiherosc/erosis 54:225—237, 1985 Nephro/.1987,p 509 68. 01-ITA T, MATSUDA1:Lipid and apolipoprotein levels in patients 91. HESLAN iM, LAUTIE JP, INTRATOR L. BLANC C, LAGRUE G, with nephrotic syndrome. C/in Chi,n AcIc, 117:133—143, 1981 SOBEL AT: Impaired lgG synthesis in patients with the nephrotic 69. TARUGI P, CALANDRA S, CHAN L: Changes in apolipoprotein A-I syndrome. C/in IVephrol 18:144-147, 1982 mRNA level in the liver of rats with experimental nephrotic 92. AR0 M, HARDWICKE I: Subclass composition of monomeric and syndrome. Biochi,nBiophysActc, 868:51—61, 1986 polymeric lgG in the serum of patients with nephrotic syndrome. 70. KAYSEN GA, MYERS BD, COUSER WG, RA1IKIN R, FELTS JM: C/in Nephro/ 22:244—252, 1984 Mechanisms and consequences of proteinuria. Lab invest 93. GARIN EH, SAUSVILLE PJ, RICHARD GA: Impaired primary 54:479—498, 1986 antibody response in experimental nephrotic syndrome. C/in Exp 71. CALANDRA S. GHERARDIE,FAINARUM,GUAITANIA, immuno/ 52:595—598, 1983 BARTOSEK 1: Secretion of lipoproleins, apolipoprotein A-I and 94. GIANGIACOMO i, CLEARY TO, COLE BR, H0FF5TEN P, ROBSON apolipoprotein E by isolated and perfused liver of rat with exper- AM: Serum immunoglobulins in the nephrotic syndrome. A pos- imental nephrotic syndrome. Biochim Biophys Ada 665:331—338, sible cause of minimal-change nephrotic syndrome. N Eng/ J Med 1981 293:8—12, 1975 72. MCKENZIE IFC, NESTEL PJ:Studieson the turnover of triglycer- 95. GROSI-IONG T, MENDEI.SON L, MENDOZA 5, BAZARAL M, 11AM- ide and esterified cholesterol in subjects with the nephrotic syn- BURGER R, TUNE B: Serum igE in patients with minimal-change drome. JC/inInvest 47:1685—1695, 1968 nephrotic syndrome. J Pediatr 83:767—771, 1973 73. KEKKI M, NIKKILA EA: Plasma triglyceride metabolism in the 96. FODOR P, SAITUA MT, RODRIGUEZ E, GONZALEZ B, SCHLES- adult nephrotic syndrome. EurJ C/in Invest 1:345—351, 1971 INGER L: T-cell dysfunction in minimal-change nephrotic syn- 74. GITLIN D, CORNWELL DO, NAKASATO 0, ONCLEY IL, HUGHES drome of childhood. Am JDis Chi/d 136:713—717, 1982 WL, JANEWAY CA: Studies on the metabolism of plasnia proteins 97. CHAPMAN S, TAUBE 0, BROWN Z, GWYN WILLIAMS D: Impaired in the nephrotic syndrome. 11. The lipoproteins. J C/in Invest lymphocyte transformation in minimal change nephropathy in 37:172—184, 1958 remission. C/in Nephro/ 18:34—38, 1982 75. NIKKILAEA,GRASRECK R: in lipoid nephrosis: observa- 98. McVICAR MI, CHANDRA M, MARGOULEFF D, ZANZI I: Splenic tions ofthe effectsonedema,proteinuria,serum proteins, lipids hypofunction in the nephrotic syndrome of childhood. Am J and lipoproteins. Acta Med Scand 150:39—46, 1954 Kidney Dis 7:395—401. 1986 76.CHANMK,VARGHESE Z, PERSAUDJM,MOORHEADiF: Post- 99. WARSHAW BL, CHECK Ii, HYMES LC, DIRUSSO SC: Decreased hepatic and lipoprotein lipase activities in nephrotic syndrome. serum transferrin concentration in children with nephrotic syn- Aust NZ J Med 14:841—847, 1984 drome: Effect on lymphocyte proliferation and correlation with 77. Coi-wr I., CRAMP DO, LEwIS AD, TICKNER TR: The mechanism serum immunoglobulin levels. C/in Irnmuno/ hnmunopatho/ 33: of hyperlipidaemia in nephrotic syndrome—Role of low albumin 210—219, 1984 and the LCAT reaction. C/in Chin, AcW 104:393—400, 1980 100. BENSMAN A, DARDENNE M. MURNAGHAN K. VASMANT D, BACH 78. LOPES-VIRELLA M, VIRELLA 0, DEBEUKELAER M, OWENS Ci, iF: Decreased biological activity of serum thymic COLWELL JA: Urinary high density lipoprotein in minimal change (thymulin) in children with nephrotic syndrome. mt J Pedinir glomerular disease and chronic glomerulopathies. C/in Chi,n Acta Nephro/ 5:201—204, 1984 94:73—81, 1979 101. DARDENNE M, PLEAU i-M, NABARRA B, LEFRANCIER P, DERRIEN 79. ZILLERUELO G, H5IASL,FREUNDLICH M, GORMAN HM, M, CHOAY I, BACH i-F: Contribution of zinc and other Inetals to STRAUSSI:Persistence of serum lipid abnormalities in children the biological activity of the serum thymic factor. Proc' Nat/Acad Nephrology Forum: Extrarenal complications of the nephrotic syndrome 1201

Sci USA 79:5370—5373, 1982 124. SULLIVANMi,HOUGHDR,AGODOA L: Peripheral arterial throm- 102. GARINEH,SAUSVILLEPJ,RICHARDGA:Plasma prostaglandin bosis due to the nephrotic syndrome: The clinical spectrum. South E2 concentration in nephrotic syndrome. J Pediatr 103:253—256, MedJ76:lOlI—1016, 1983 1983 125. LLACHF:Hypercoagulability, renal vein thrombosis, and other 103. GARINEH,BARRATMT:Effect of indomethacin on lymphocyte thrombotic complications of nephrotic syndrome. Kidney Jut mitogen response in puromycin aminonucleoside (PA) nephrosis 28:429—439, 1985 (abstract). Pediatr Res 15:693, 1981 126.CARVALHOACA, COLMAN RW, LEESRS:Platelet function in 104. LENARSKY C, JORDAN SC, LADISCH S: Plasma inhibition of hyperlipoproteinemia. NEngl J Med 290:434—438,1974 lymphocyte proliferation in nephrotic syndrome: Correlation with 127. BENNETT A,CAMERONIS:Platelethyperaggregability in the hyperlipidemia. J C/in Immunol 2:276—281, 1982 nephrotic syndrome which is not dependent on arachidonic acid 105. STRIFE CF, JACKSON EC, FORRISTALJ,WEST CD: Effect of the metabolism or on plasma albumin concentration. C/in Nephrol nephrotic syndrome on the concentration of serum complement 27:182—188, 1987 components. Am J Kidney Dis 8:37—42, 1986 128. ADLERAJ,LUNDIN AP, FEINROTH MV, FRIEDMAN EA, 106. MCLEAN RH, FORSGREN A, BJORKSTENB,KIM Y, QUIE PG, BERLYNE GM: /3-thromboglobulin levels in the nephrotic syn- MICHAEL AF: Decreased serum factor B concentration associated drome. Am J Med 69:55 1—554, 1980 with decreased opsonization of Escherichia co/i in the idiopathic 129.KAUFMANRH,VELTKAMPJJ,VAN TILBURO NH,VANESLA: nephrotic syndrome. Pediatr Res 11:910—916, 1977 Acquired antithrombin III deficiency and thrombosisinthe ne- 107. KRENSKY AM, INGELFINGER JR, GRUPE WE: Peritonitis in child- phroticsyndrome. AmJ Med 65:607—613, 1978 hood nephrotic syndrome. Am J Dis Child 136:732—736, 1982 130. DU XH, GLAS-GREENWALT P, KANTKS,ALLEN CM, HAYES S. 108. SPIKAJS,HALSEY NA, LE CT, FISH AJ, LUM GM,LAUERBA, POLLAK VE: Nephrotic syndrome with renal vein thrombosis: SCHIFFMAN G, GIEBINK GS: Decline of vaccine-induced pathogenetic importance of a plasmin inhibitor (alpha 2-antiplas- antipneumococcal antibody in children with nephrotic syndrome. mm).C/inNephrol24:186—191,1985 Am J Kidney Dis 7:466—470, 1986 131.CARTWR1GHTGE,GUBLERCJ,WINTROBEMM:Studies on cop- 109. GOLDSTEIN DA, HALDIMANNB,SHERMAN D, NORMAN AW, per metabolismXI.Copper and iron metabolismin the nephrotic MASSRY SG: Vitamin D metabolites and calcium metabolism in syndrome. J C/in Invest 33:685—698,1954 patients with nephrotic syndrome and normal renal function. J 132.ELLiS D: in the course of the nephrotic syndrome sec- Clin Endocrinol Metab 52:116—121,1981 ondary to transferrin depletion. J Pediatr 90:953—955, 1977 lb.MALLUCHEHH, GOLDSTEIN DA, MASSRY SG: Osteomalaciaand 133.BROWNEA,SAMPSON B, MULLER BR, CURTIS JR: Urinary iron hyperparathyroidbone disease in patients with nephrotic syn- loss in the nephrotic syndrome—An unusual cause of iron defi- drome. J C/in Invest 63:494—500, 1979 ciency with a note on urinary copper losses. Postgrad Med J Ill. GOLDSTEINDA,ODA Y, KUROKAWAK,MASSRY SG: Blood 160:125—128, 1984 levels of 25-hydroxy-vitamin D in nephrotic syndrome. Studies in 134. ADLKOFER F, HAIN H, MEINHOLD H, KRAFT D, RAMSDEN D, 26 patients. Ann Intern Med 87:664—667, 1977 HERRMANN J, HELLER W-D: Thyroid function in patients with 112. TESSITORE N, BONUCCI E, D'ANGELO A,LUNDB, CORGNATI A, proteinuria and normal or increased serum creatinine concentra- LUNDB,VALVO E, LUPOA,LOSCHIAVOC, FAERIS A,MA5CHI0 tion. Acta Endocrinol 102:367—376, 1983 G: Bone histology and calcium metabolism in patients with 135. SUSSMAN HC, FOWLER B, FINDLEY T: Observations on the renal nephrotic syndrome and normal or reduced renal function. Neph- metabolism of protein in experimental and clinical nephrotic ron37:153—159,1984 syndromes. Metabolism 17:336-344,1968 113. BARRAGRYJM,FRANCE MW, CARTER ND,AUTONJA, BEER M, 136.GEERS AB, K00MAN5 HA, BOER P, DORHOUT MEES EJ: Plasma BOUCHERBJ. COHEN RD: Vitamin D metabolism in nephrotic volume (PV) measurements in patients with nephrotic syndrome syndrome. Lancet 2:629—632, 1977 (NS): A methodological study on the labeled albumin method. 114. LAMBERTPW,DEOREO PB, Fu IY, KAETZEL DM, VON AHN K, KidneyJut 23:123,1983 HOLLIS BW. Roos BA: Urinary and plasma vitamin D3 metabo- 137. ZOJA C, BENIGNI A,VERROUSTP, RONCO P, BERTANI T, lites in the nephrotic syndrome. Metab Bone Dis Rd Res 4:7—IS, REMUZZI G: Indomethacin reduces proteinuria in passive Hey- 1982 mann nephritis in rats. Kidney Int 31:1335—1343, 1987 115.FREUNDLICHM,BOURGOIGNIE JJ, ZILLERUELOG,JACOBSAl, 138. SHEMESH 0, Ross IC, DEEN WM, GRANT GW, MYERS BD: CANTERBURY JM, STRAUSS J: Bone modulating factors in ne- Nature of the glomerular capillary injury in human membranous phrotic children with normal glomerular filtrate rate. Pediatrics . J C/in Invest 77:868—877, 1986 76:280—285, 1985 139. HEEG JE, DE JONG PE, VAN DER HEM GK, DE ZEEUW D: 116.KORKORA, SCHWARTZJ,BERGFELD M, TEITELBAUM5,Avoi..i Reduction of proteinuria by angiotensin converting enzyme inhi- L,KLAHR5,SLATOPOLSKYE:Absence of metabolic bone disease bition. Kidney Jut 32:78—83, 1987 inadult patients with the nephrotic syndrome and normal renal 140. GATEWOOD0MB,FISHMAN EK, BURROW CR, WALKERWG, function. J C/in Endocrinol Metab 56:496—500, 1983 GOLDMAN SM, SIEGELMAN SS: Renal vein thrombosis in patients 117. AUWFRX J, DE KEYSER L, BOUILLON R, DE MOORP:Decreased with nephrotic syndrome: CT diagnosis. Radiology 159:117—122, free I ,25-dihydroxy cholecalciferol index in patients with the 1986 nephrotic syndrome. Nephron42:231—235,1986 141. EAGEN JW, LEWIS EJ: Glomerulopathies of neoplasia.Kidneymt 118. ALON U, CHANJCM:Calcium and vitamin-I) metabolism in 11:297—306, 1977 nephrotic syndrome. mt i Pediatr Nephrol 4:115—118, 1983 142.ALPERSCE, COTRAN RS: Neoplasia and glomerular injury. Kid- ney Jut 30:465—473, 1986 119. STICKLER GB, HAYLES AB, POWER UI RICHIA:Renal MH, 143.ZECH POINTET tubular P. COLON5, PH, DETEIX P, LABEEUW M, dysfunction complicating the nephrotic syndrome. Pedi- LEITIENNEPH: atrics 26:75—85, 1960 The nephrotic syndrome in adults aged over 60: Etiology, evolution and treatment of 76 cases.C/in 120.ROSEN TORNROTH Nephrol 5, T,BERNARD DB: Membranous glomerulo- 18:232—236, 1982 Renal nephritis, in Pathology, edited by TISHE,R CC, BRENNER 144. LUSTIG S,ROSENFELDJB,BEN-BASSAT M, BONER G: Nephrotic BM,Philadelphia, Lippincott, inpress syndrome in the elderly. Isr J Med Sci 18:1010-1013, 1982 121. HALDIMANNB,TRECI-ISEL U: Vitamin D replacement therapy in145.BROWNEA,MARKANDUND,SAGNELLAGA, JONES BE, MAC- patients with the nephrotic syndrome. Miner Electrolyte Metab GREGOR GA: Lack of effect of on the sodium retention of 9:154—156, 1983 thenephrotic syndrome. Nephron37:43—48, 1984 122. CAMERONiS:Coagulation and thromboembolic complications in 146. EISENBERG 5:Posturalchanges in plasma volume in hypovolemia. thenephrotic syndrome.Adv Nephro/ 13:75—114, 1984 Arch Intern Med 112:544—549, 1963 123.HOYER,PF, GONDA S,BARTHELSM,KROHNHP,BRODEI-IL J: 147. GEERS AB, KOOMANS HA, DORI-IOUT MEES El: Effect of changes Thromboembolic complications in children with nephrotic syn- inposture oncirculatory homeostasis in patients with the ne- drome. Acta Paediazr Scand 75:804—810, 1986 phrotic syndrome. C/in Phy.s-iol 6:63—75, 1986 [202 Nephrology Forum: Extrurenol complications of the nephrotic syndrome

48. SALANT Di, ADLER 5, BERNARD DB, STILMANT MM: Acute renal of experimental nephrosis. J Clin loves! 40:499—508, 1961 failure associated with renal vascular disease, , glomer- 151. PULLINGER CR, DE BRrro AER, Rioici VA, MEDINA P, TENO B, ulonephritis and nephrotic syndrome, in Acute Renal Failure, SCOTT I: Effects of albumin on Apo-B mRNA levels on the edited by BRENNER BM, LAZARUS Mi, New York, Churchill secretion of triglyceride-rich lipoprotein by HepG2 cells. X mt Livingstone, 1988, pp 371—490 Cong Nephrol, 1987, p 514 49. KURODA5,AYNEDJIAN HS, BANK N: A micropuncture study of 152. YEDOAR 5, EILAM 0, SHAFRIR E: Regulation of plasma lipid renal sodium retention in nephrotic syndrome in rats: Evidence for levels by plasma viscosity in nephrotic rats. Am J Physiol increased resistance to tubular fluid flow. Kidney In! 16:561—571, 248:E10—E14, 1985 1979 153. GOLFER TA, FEING0LDKR,FULFORD MH, SIPER5TEIN MD: The 50. ALLEN JC, BAXTER .JH, GOODMAN HC: Effects of dextran, role of circulating inevalonate in nephrotic hypercholesterolemia polyvinylpyrrolidone and gamma globulin on the hyperlipidemia in the rat. JLipid Res 27:1044—1051, 1986