Less Commonly Recognized Features of Childhood Nephrotic Syndrome

Pediatric Nephrology

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Less Commonly Recognized Features of Childhood Nephrotic Syndrome Jose Strauss, MD, * Gaston Zilleruelo, MD, t Michael Freundlich, MD,t and Carolyn Abitol, MD§

The nephrotic syndrome (NS) in children can be defined as a derangement characterized by fluid-electrolyte and hormonal imbalances, proteinuria, hypoproteinemia, hyperlipidemia, oliguria, and edema. This article will review general and specific aspects of NS that can be present or frequently are present but do not constitute the usual characteristics of the syndrome's definition.

CLINICAL PRESENTATION Here we review aspects in the clinical presentation of NS that are not usually present or that are regarded by some as unusual or incompatible with the diagnosis. Hematuria Microscopic hematuria (defined as > 1,200,000 RBCs per 12 hr and probably equivalent to > 3 to 5 RBCs per HPF or Dipstix with ;::: trace blood) has been reported to be present at time of diagnosis iIi 22.7 per cent of patients with minimal change nephrotic syndrome (MCNS) or in 25 per cent of those with the three most common histologic changes. These patients were part of a new and large population of children with idiopathic *Professor of Pediatrics; Director, Division of Pediatric Nephrology, University of Miami School of Medicine, Miami, Florida tAssociate Professor, Division of Pediatric Nephrology, University of Miami School of Medicine, Miami, Florida *Pediatric Nephrologist; formerly, Assistant Professor, Division of Pediatric Nephrology, University of Miami School of Medicine, Miami, Florida §Assistant Professor, Division of Pediatric Nephrology, University of Miami School of Medicine, Miami, Florida This project is funded in part under an agreement with the State of Florida, Department of Health and Rehabilitative Services, Children's Medical Services.

Pediatric Clinics of North America-Vol. 34, No.3, June 1987

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NS recruited from multiple centers in various countries. 34 It may be asymptomatic or accompany a urinary tract infection (UTI), in which case the hematuria would be associated with the clinical presentation of a UTI in the non-NS population. 53 It also may be associated with the conditions listed below. Macroscopic hematuria in the presentation of NS should be expected only in cases associated with UTI, acute postinfectious glomerulonephritis (AGN), sickle cell hemoglobinopathies, renal vein thrombosis (usually with a membranous nephropathy), membranoproliferative glomerulonephritis (MPGN), systemic diseases (systemic lupus erythematosus [SLE], lues, vasculitides, etc), and congenital or inherited renal diseases (Alport's syndrome, Finnish type of congenital NS). Hypertension High blood pressure is not frequently described among primary nephrotic patients as part of the clinical presentation. Still, 20.7 per cent and 13.5 per cent of MCNS patients had systolic and diastolic BPs, respectively, that were in the 98th percentile for age and sex prior to initiation of corticosteroid therapy. In children with the three most common histologic types, 25.7 per cent and 16.3 per cent presented with systolic and diastolic hypertension, respectively.34 The hypertension of these patients may be related causally to changes in their blood volume, and associated hormonal production. History The search for the common causes of NS must focus on the patient's and the family's medical histories. In some patients, seizures treated with dilantin derivatives, untreated syphilis or parasitic infestations, hepatitis, some GU and cardiac anomalies, AIDS, hypersensitivities, allergies, hemoglobinopathies, or general manifestations of systemic disorders like SLE or vasculitides may be involved. In the family, history of renal or systemic disorders may be elicited. Laboratory Findings Not Commonly Emphasized An elevation of the erythrocyte sedimentation rate (ESR) during the initial episode or during relapses is often overlooked; this will be present in primary as well as in secondary NS, and in minimal change (MeNS) as well as in non-MCNS forms of the disorder. Likewise, serum IgG levels are decreased at those times; the reported concomitant increase in serum IgM28 seems to be less consistently present. Serum IgE levels are elevated in some patients with hypersensitivity reactions to foods or inhalants 78 ; in those patients, eosinophiluria may be present. 2 There is an increased urine protein to urine creatinine ratio (Upr/Ucr) in NS patients in relapse; a ratio greater than 0.13 in a random specimen is more solid proof of increased proteinuria than is an elevated reading by the Albustix in a urine specimen, which may be concentrated and have only borderline proteinuria. Quantitation of proteinuria has been made much easier by the confirmation of the applicability of the UprlUcr ratio to children\ it should be used more frequently than in current practice.

FEATURES OF CHILDHOOD NEPHROTIC SYNDROME

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Bacteriuria may be documented more frequently in this population than in a comparable group of children. 53 Other laboratory findings are those well known to be present in idiopathic and in secondary NS; in the latter, those of the primary disease should be sought. Histology Even though MCNS is the most common form in childhood, it is recognized more and more that this histologic picture may progress to focal and segmental glomerulosclerosis (FSS).73, 79 In NS associated with hemoglobin S, MPGN has been identified most frequently; other initial histologic findings in this group include FSS and membranous glomerulopathy.77 In patients with AIDS and proteinuria, at most, only an increase in the mesangial matrix of the glomeruli has been identified76 ; when a full-blown NS is present, the histology resembles that of the adult, in which FSS is by far the predominant finding. 61 The presence of IgM in the mesangium constitutes a poor prognostication for some,80 but we have found no difference in the outcome of patients with and without this glomerular finding in biopsy material. 62 Management The use of PO prednisone and IV albumin and furosemide are standard treatments and therefore are only mentioned here. Furosemide may have a vasodilator effece1; if confirmed, this finding would lead us to conclude that its prolonged use may not necessarily lead to vascular complications. In addition, furosemide together with metolazone (Zaroxolyn) forms a potent diuretic combination which although helpful may also lead to severe dehydration and associated complications. Newer volume expanders and concepts of edema formation will likely be of practical help in the future. 91 The question of allergies, hypersensitivity reactions, or chemical effects of inhalants and foods is still unanswered. Up to 50 per cent of patients who were prednisone nonresponders or dependent, went into remission when the presumed offending food was withdrawn. 78 Because this is an unproven form of therapy, it should be undertaken only under closely monitored conditions and when other measures have failed in patients with a suggestive history. SPECIFIC ASPECTS Lipid Alterations Hyperlipidemia is considered to be one of the cardinal features in the definition of nephrotic syndrome. It usually reflects an increase in total cholesterol, triglyceride, and various lipoprotein component levels, including very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL) and apo-protein B.8 Although the true prevalence in which hyperlipidemia is found in NS is difficult to assess, it is generally believed that it is almost always present in minimal change NS (MCNS) (95 per cent of children

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JOSE STRAUSS ET AL.

with MCNS had serum cholesterol >250 mg per dl)34 but it also can be found less frequently in other forms of nephrotic syndrome (only 68 per cent of patients with membranoproliferative glomerulonephritis had cholesterol >250 mg per dl).34 Despite this high prevalence, hyperlipidemia in NS has several unusual features. In addition, neither its pathogenesis nor the best approach to its management is clearly established. Type of Hyperlipoproteinemia. Although there have been many reviews addressing the problem of hyperlipidemia in NS,8, 57, 59, 60 attention has been only recently focused on the importance of defining the pattern of hyperlipoproteinemia, its severity, and its eventual complications. 5, 89 Plasma lipoproteins are complexes of lipids and proteins that function to transport lipids in a stable, soluble form. Lipid and lipoprotein fractions may be affected in NS in a pattern quite variable from one patient to another. Neutral fat, fatty acids, and phospholipids are increased markedly, as is cholesterol. It has been suggested that after onset of the disease, fatty acids start to increase sooner than cholesterol does. 25 Fat droplet deposition in renal tubules is believed to result from tubular absorption and catabolism of lipoproteins. 31 Refractile lipid bodies in the urinary sediment of nephrotic urine probably represent the excessive amount of lipoprotein excreted in the urine. 31 Serum cholesterol and phospholipid levels are elevated more consistently than are those of serum triglyceride. Increased levels of VLDL, IDL, and LDL are observed early in the course of NS. As the disease worsens, triglyceride-VLDL levels rise at a greater rate than LDL. 9 On the other hand, HDL levels have been reported to be low, normal, or elevated in nephrotic patients. 27, 82, 89 It appears that elevated HDL is seen only in MCNS during relapse, but patients with non-MCNS and persistent proteinuria tend to have a significant decrease in HDL. 89 Serum total cholesterol and triglyceride levels were found to be greater than the 95th percentile for age and sex in all patients with MCNS in relapse and those with non-MCNS and persistent proteinuria. 89 The degree of hyperlipidemia is also quite variable from one patient to another. Factors influencing the concentration of lipoproteins include the severity of the proteinuria, age, diet, obesity, use of corticosteroids, diuretics, and beta blockers, nutritional state, and degree of residual renal function. 90 High proportions of patients, even with MCNS, have significant elevations (> 500 mg per dl) in total cholesterol and in triglycerides. In a group of children with NS during relapse, mean serum total cholesterol was 354 mg per dl for patients with MCNS in relapse and 557 mg per dl for those with non-MCNS persistent protenuria. Corresponding mean values for triglycerides were 249 mg per dl and 620 mg per dl, respectively. In this group of patients no clear correlation between hyperlipidemia and urinary protein excretion was observed, however. 89 Duration of hyperlipidemia is also quite variable. Although in many patients it is transient and correlates well with activity of the disease, in others it may persist for prolonged periods. In these patients, we have observed elevated cholesterol and LDH levels even after months or years in remission. 89 Severity and persistence of lipid changes correlate well with

595

FEATURES OF CHILDHOOD NEPHROTIC SYNDROME

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Figure 1. Mean values and standard deviations for serum cholesterol in different subgroups of children with nephrosis according to activity of disease and frequency of relapses. Results are compared to normal controls. *p < 0.01. (From: Zilleruelo G, Hsia S, Freundlich M, et al: Persistence of serum lipid abnormalities in children with minimal change nephrotic syndrome. J Pediatr 104:61-64, 1984; with permission.)

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duration of the disease and frequency of relapse. Patients with a history of frequent relapses of corticosteroid dependency had significantly elevated total cholesterol levels during relapse and remission as compared with normal controls (Fig. 1). Other features of the abnormal lipid metabolism in patients with NS include an abnormal distribution of omega-6 fatty acids. We have found a significantly increased proportion of arachidonic acid in plasma phospholipids and elevated proportion of linoleic acid in triglycerides of subcutaneous adipose tissue, in comparison with an age-matched group of healthy children. 58, 88 Since no difference in the composition of dietary fat between NS and normal children was observed, we postulated that the alteration in structural composition of lipoproteins (in response to their increased synthesis or impaired degradation) could lead to a selective retention of some long-chain polyunsaturated fatty acids, particularly those of the omega-6 series (omega-6 20:4 arachidonic acid and omega-6 18:2 linoleic acid). Since arachidonic acid plays a major role in prostaglandin metabolism as the only natural precursor of various prostanoids, its retention may be related to the elevated plasma levels of certain prostaglandins described in nephrotic children. In effect, both increased plasma levels of PGE 2 and increased excretion of 6-keto PGF1a have been described in children with idiopathic NS.26.35 A recent study has proposed that alteration in the synthesis of the glomerular thromboxane (Tx) A2 may be secondary to the increase in arachidonic acid availability; in turn, (Tx) A2 could be the cause of proteinuria in experimental nephrosis in rats. 65 Mechanisms of Hyperlipidemia. The exact mechanism(s) responsible for the hyperlipidemia of NS remains largely unknown. Most evidence suggests increased hepatic synthesis of lipoproteins as the principal cause. It appears that both decreased plasma oncotic pressure and lower albumin concentration,1g,36 or decreased plasma viscosity,86 are stimuli for enhanced hepatocyte synthesis of lipoproteins and lipids. 19. 36 Studies in adults have raised doubts about this explanation, however.5 In addition, an excessive production of abnormal lipoproteins may be linked to an impaired

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catabolism85 due to a decrease in lipoprotein lipase (with slower removal of VLDL) or a decrease in lecithin cholesterol acyltransferase, with reduced HDL production. Still, the essential question of how hypoalbuminemia leads to an increase in VLDL synthesis remains unanswered. Conceivably, in the severe nephrotic state with plasma serum albumin under 2 gm per dl, HDL lipoproteinuria produces a relative deficiency ofLPL activators which limits triglyceride clearance, aggravating the accumulation of VLDL. This would explain the rapid rise ofVLDL and triglyceride whenever the plasma serum albumin is under 2 gm per dl. 13 In the mild form of NS, elevation of VLDL in the serum due to overproduction is followed by a simultaneous increase in IDL (VLDL remnants) and LDL since the VLDL removal mechanism is not saturated. 27 As the nephrotic syndrome worsens with serum albumins under 2 gm per dl, the conversion of IDL to LDL is impaired and leads to progressive accumulation of IDL. Eventually in the more severe forms, with serum albumin under 1 gm per dl or in the presence of uremia, the catabolism of VLDL is also impaired because of the defect of lipoprotein lipase activity. As a consequence, triglyceride-rich VLDL and chylomicrons would accumulate in the serum whereas the concentration of IDL and LDL eventually may fall. 27 In NS, VLDL and LDL are inversely related to HDL. It appears that the interconversion of VLDL to LDL is affected. In addition, there are marked changes in the composition of all lipoprotein fractions: they contain more phospholipids and less protein than normal. Elevation of VLDL and LDL is paralleled by a fall in HDL2 , and in more severe cases, in HDL3 • Since HDL is involved in the catabolism of VLDL, it is possible that the defect in HDL will contribute to the defective catabolism of VLDL and, therefore, the accumulation of these lipoproteins. Clinical Relevance and Management of Hyperlipidemia in Nephrotic Children. Many epidemiologic studies emphasize the importance of assessing lipoprotein distribution of cholesterol as well as total plasma cholesterol concentration in predicting the risk of atherosclerotic coronary heart disease (ACHD). The risk of ACHD in patients with NS has not been clearly defined. Previous reports of postmortem examinations in children and adults with INS have documented evidence of early atheroma formation. 18. 38 Based on current knowledge of the epidemiology of ACHD, the lipoprotein profile of NS patients (particularly those with prednisone non-responsiveness and persistent proteinuria) and significantly decreased ratios of HDL to LDL, places these patients at an increased risk for ACHD. 90 In addition, hyperlipidemia has been proposed as a factor that may influence progression of nephrotic syndrome to a sclerotic form of the disease. The mechanism would involve abnormally filtered lipoproteins, which in turn would induce a nephrotoxic effect on the mesangial cells. 55 Finally, hyperlipidemia and hypercholesterolemia are both associated with an increased platelet aggregation and decreased responsiveness to prostacyclin. 12• 72. 74 This could induce or contribute to the hypercoagulable state described in NS. The best approach for the management of the nephrotic child with hyperlipidemia is not clearly established. However,

597

FEATURES OF CHILDHOOD NEPHROTIC SYNDROME Hypercoagulability and thrombotic complications of nephrotic syndrome Increased glomerular permeability

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1 Urinary loss of clotting inhibitors, zymogens. plasminogen, etc. .

Increased hepatic synthesis of fibrinogen, co-factors, lipoproteins, etc. . .

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Hypercoagulability

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Steroid therapy

Egress of fluid from vascular space

Hypoalbuminemia - - - - - - -

Diuretics

Platelet aggregation

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Immunological injury (membranous nephropathy)

Figure 2. Schematic representation of pathogenetic factors leading to hypercogulability in the nephrotic syndrome. (From: Llach F: Hypercoagulability, renal vein thrombosis, and other thrombotic complications of nephrotic syndrome. Kidney Intern 28:429-439, 1985; with permission.)

patients with NS should have serum lipid profile evaluations performed at regular intervals even during remission of proteinuria. Patients who develop severe and persistent hyperlipidemia should be encouraged to achieve and maintain an adequate weight for height and regular aerobic physical exercise. Diet should contain less than 30 per cent of fat and less than 250 mg per day of total cholesterol with a ratio of polyunsaturated to saturated fatty acids of 1:1. Various drugs that may adversely affect lipoprotein metabolism should be discontinued if possible. Finally, in selected groups of patients, the use of hypolipidemic drugs (cholestiramine) or fish oil supplemented diet (rich in eicosapentaenoic acid) could be attempted to discourage potentially dangerous serum lipid concentrations. 90 Coagulation Abnormalities in Nephrotic Syndrome. The NS has been considered a hypercoagulable state since it may be complicated by thrombotic episodes of the venous or arterial circulation. 49 This hypercoagulable state has a multifactorial etiology; it is influenced by an increase in platelet aggregability and the loss of low molecular weight regulator proteins in the urine. This hyperaggregability state may be made worse by an increase in viscosity resulting from the use of diuretics. A general schematic representation of the pathogenetic factors leading to the hypercoagulable state of NS is shown in Figure 2. A variety of coagulation abnormalities have been described in NS. Thromboembolic episodes have involved pulmonary vessels, inferior vena cava, renal vein, mesenteric artery with small bowel necrosis, femoral artery, subclavian artery, retinal artery, and coronary artery.83 The real incidence of thromboembolic episodes in children is not known and it is possible that subclinical involvement of different vessels may be much more common, however. The NS is commonly associated with a Factor XII deficiency which presents with prolonged PIT. Despite the laboratory abnormality, patients with isolated Factor XII deficiency are hemostatically competent and can undergo surgery without complications (including a

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renal biopsy). Factor IX also may be deficient; Factor VIII and Factor V are markedly elevated which may induce a shortened P1T. Fibrinogen is increased in a manner parallel with serum cholesterol and reflecting increase in liver synthesis. Antithrombin III (an alpha globulin and the main inhibitor of thrombin) has been reported to be deficient in NS patients with serum albumin under 2 gm per dl. 39 Thrombocytosis is found in 60 per cent of these patients, usually associated with abnormal platelet aggregation in response to ADP and collagen. 83 The incidence of renal vein thrombosis is 5 to 62 per cent with an overall incidence up to 35 per cent. 49 Overall incidence of thromboembolic complications, other than renal vein thrombosis, is 20 per cent. Pulmonary embolism is the most frequent and serious complication, accounting for 8 per cent of the known renal vein thromboembolic complications. 49 Beta-thromboglobulin is a specific protein released by platelets on aggregation; it is elevated significantly in patients with NS during relapse and returns to normal with remission. 43 However, the role of other coagulation inhibitors such as proteins C or S is still unknown in NS. The high incidence of thromboembolic complications has raised the question of possible use of prophylactic anticoagulant therapy in patients with NS. In patients with previous thromboembolic complications who are at high risk because of fractures, immobilizations, etc., continuous anticoagulation therapy or the use of antiplatelet agents, Le., aspirin, should be considered. Calcium and Vitamin D Metabolism While disturbances of divalent ion and vitamin D metabolism are frequently sought after and identified in patients with diminished glomerular filtration rate (GFR),51 its occurrence in patients with NS and normal GFR is less well appreciated. Although hypocalcemia has long been recognized in nephrotic patients, it was simply ascribed to a reduction in protein-bound calcium caused by hypoalbuminemia. 47, 67 More recent studies, however, have demonstrated that serum ionized calcium is also reduced in these patients. 48 The availability of techniques for determination of immunoreactive parathyroid hormone (iPTH) and circulating vitamin D metabolites has paved the way to a series of investigations attempting to understand mineral metabolism in the NS. 7, 16, 29 Total serum calcium concentration tends to overestimate the ionized fraction even after correction for the decrease in serum protein concentration. 48 In fact, several studies have confirmed true hypocalcemia (low ionized calcium) during active nephrotic syndrome 4, 23, 29; this may be the cause of some ill-defined muscle cramps and occasional tetany observed in children during the active and edematous stage of the nephrotic syndrome. 33 Intestinal calcium malabsorption with excessive calcium elimination in the stools,33, 47 low circulating levels of vitamin D metabolites,29, 30 and diminished bone sensitivity to the calcemic action of YfH29 have been implicated in the genesis of hypocalcemia. The data on intestinal calcium absorption are still controversial, however: while noted to be low in metabolic balance studies,47 it was generally normal when measured with radiocalcium. 29,56

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FEATURES OF CHILDHOOD NEPHROTIC SYNDROME

Table 1. Laboratory Data During Relapse and Remission in 20 Children with Nephrotic Syndrome

Relapse Remission

CALCIUM

PHOSPHORUS

PARATHORMONE

CALCIDIOL

CALCITRIOL

(mg/dl)

(mg/dl)

(ILlEq/ml)

(ng/ml)

(pg/ml)

8.2±0.17 9.7±0.08*

S.1±0.18 4.8±0.12

123± 14 94±10

9.0±6.7 26± 14 *

44±S.0 Sl±S.O

Values represent ± SEM of 43 episodes of relapse and 47 remissions. *p <0.0001. Data from J Pediatr 108:383-387, 1986.

Alterations in the circulating levels of vitamin D metabolites have been described by several investigators. 29, 30, 49, 50, 69, 81 While universal agreement exists about the low blood levels of 25-hydroxyvitamin D (calcidiol) during the a~tive stage of the nephrotic syndrome, data on circulating levels of 1,25-dihydroxyvitamin D (calcitriol) remain controversial. The strikingly decreased plasma levels of calcidiol during active nephrotic syndrome 23, 29, 30 are probably a result of urinary losses. 7, 45 This explanation is supported by the inverse correlation between proteinuria and plasma calcidiol and the direct correlation between serum albumin and calcidiol values. 24 Furthermore, on disappearance of the proteinuria during remission of the' active nephrotic stage, plasma levels of calcidiol return to the normal range.24 Although some investigators have reported low plasma calcitriol concentrations,29, 45 in most patients23 . 24, 42 and nephrotic rats, 14 plasma calcitriol levels were normal during periods of active nephrotic syndrome (Table 1). Discrepancies in published results on plasma calcitriol could be the reflection of several factors: differences in methodology, patient's age, duration of illness, degree of proteinuria and serum albumin concentration, and dose and duration of corticosteroid therapy. Finally, plasma calcitriol levels should be interpreted as they relate to factors regulating renal production l7 , 66: whereas hypocalcemia and elevated PTH stimulate calcitriol synthesis, its production is limited by hyperphosphatemia, decreased GFR, and low substrate (calcidiol) availability. Our observations, following short-term « 3 months) conventional lowdose prednisone therapy, support the concept that plasma calcitriol concentrations are not affected by such a regimen. 23, 24 Glucocorticoid administration for more extended periods has been associated with diminished circulating levels of calcitriol. 15 Secondary hyperparathyroidism has seldom been recognized in nephrotic children. 8. 15 Of interest, however, is the lack of consistent elevation in iPTH, despite hypocalcemia during relapses of nephrotic syndrome. 23. 29 Hitherto uncovered alterations in calcium-PTH feedback regulation or peripheral hormonal metabolism during the nephrotic stage may explain those inconsistencies, Still, some nephrotic patients do exhibit elevated circulating iPTH. As expected, the above derangements can have biologic consequences on bone integrity, However, here again controversy exists as to the prevalence of bone histomorphometric changes in these patients, Some

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Table 2. Alterations of Calcium Metabolism in Patients with Nephrotic Syndrome and Normal Glomerular Filtration Rate Hypocalcemia (total and ionized) Hyperparathyroidism (iPTH) Low circulating vitamin D metabolites (mostly calcidiol, rarely calcitriol) Bone undermineralization (densitometry) Osteomalacia and hyperparathyroidism (bone histology)

found evidence of defective mineralization (osteomalacia) and parathyroid overactivity,50 while others observed normal bone histology. 42, 47 Data from a larger series of adult patients with nephrotic syndrome and normal renal function 81 showed that although most patients had normal bone histology, some displayed either isolated osteomalacia or changes of mixed mineralization defect and bone resorption. Data in children demonstrating bone undermineralization by photon absorptiometry,23 would go along with the latter studies. 81 Since bone densitometry cannot differentiate osteomalacia from hyperparathyroidism, it is impossible to know which lesion is the cause for the observed bone undermineralization. With all of the above considerations, it appears that patients with nephrotic syndrome constitute a heterogeneous group in which derangements of mineral metabolism are not uniformly identified (Table 2). Factors such as age, frequency of relapses, duration of disease and of corticosteroid therapy, degree of proteinuria, and serum albumin concentration may influence the ability to identifY some of these changes. It would seem logical to assume that children with relapsing or protracted nephrotic syndrome are at risk of developing metabolic bone disease, even without impairment of glomerular filtration rate. Nutritional Aspects

Nephrotic syndrome may be nutritionally equated to clinical kwashiorkor, that is, relative protein-calorie malnutrition. Patients with unrelenting nephrosis not only present with hypoproteinemia associated with peripheral edema and ascites, but also frequently manifest anemia, malaise, anorexia with food intolerance, diarrhea, and abdominal pain. Management of these manifestations of the illness is usually focused on the relief of edema through vigorous diuresis. Unfortunately, improvement is often marginal and short-lived. Appropriate nutritional intervention may provide a longterm influence, particularly in the pediatric patient with steroid nonresponsive or frequently relapsing nephrosis. Growth in children with nephrotic syndrome is variable and appears to be primarily dependent on steroid sensitivity. Despite periods of highdose corticosteroid treatment, catch-up growth and attainment of normal adult height seem possible from reports in a number of centers. 6, 22, 44 Severe stunting occurs most frequently in patients who are steroid nonresponsive and develop severe persistent malnutrition. Total energy intake is often limited by anorexia and dyspepsia during episodes of the NS. These symptoms have been attributed to bowel edema, which may also cause malabsorption of some nutrients. 37 Lactose intolerance

FEATURES OF CHILDHOOD NEPHROTIC SYNDROME

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may occur temporarily, contributing to the onset of diarrhea and abdominal cramping during periods of severe edema. 37 En:ergy requirements vary with age, the level of physical activity, and the metabolic and nutritional state of the patient. Recommended dietary allowances (RDA) for each age group for energy have been derived and designated from the mean of that reference population. 21 The patient on high-dose corticosteroids should receive no more than the RDA for energy and may even require restriction if obesity seems imminent and intake is excessive. However, the patient with chronic nephrosis may very well require calorie supplementation to provide for increased needs imposed by negative nitrogen balance and catch-up growth. 32 The components of energy distribution are the macronutrients: carbohydrate, fat, and protein. Carbohydrates are the major component of a normal diet, providing 40 to 60 per cent· of the energy allotment. Oral supplementation is frequently provided in the form of glucose polymers. Although these are usually well tolerated due to their low intestinal osmolar load, there are two distinct disadvantages apparent in the nephrotic patient. On the short term, carbohydrate loading is associated with increased salt and water retention, probably on the basis of increased aldosterone stimulation. 3 Noncomplexed simple sugars are also well known to aggravate the hyperlipidemia of nephrosis. 68 High-fat meals are seldom tolerated in the nephrotic patient, although whipping cream and corn oil supplements have been used. The poor tolerance may be related to slowed gastric emptying with stimulation of the pyloric sphincter by the high fat meal. (Other aspects of lipid metabolism are covered in the section on lipid abnormalities.) Particular discussion is warranted for recommendations relative to protein intake in nephrotic patients. Therapeutic rationale has long focused on replacement of urinary protein losses by dietary supplementation in an effort to replenish negative stores. 10 It is becoming increasingly apparent that protein losses in the NS are not solely from the glomerular membrane46 ; losses occur from other body surfaces, including the intestine. 70 Moreover, in nephrosis, the kidney becomes an important site of albumin catabolism at a rate that appears to vary with the severity of the proteinuria. 87, 91 High-protein diets for nephrotic patients have generally been recommended since Blainey10 reported improved plasma proteins in nephrotic children treated with high protein intakes. This study, however, was performed in only three patients who were undergoing a vigorous diuresis and receiving sequentially increasing dietary protein. Although their serum albumin concentrations increased, this could have been related to contraction in plasma volume during the period of observation. Recent studies in laboratory animals 40 and nephrotic patients 41 have compared urinary albumin excretion, albumin synthesis rates, and changes in plasma albumin mass during treatment with low and high protein diets. When dietary protein was restricted, a decrease in urinary albumin excretion was demonstrated despite maintenance of normal creatinine clearances. Moreover, during the low protein diet, total albumin mass was preserved and plasma albumin mass actually increased while albumin synthesis rates were maintained. In those nephrotic patients receiving a high protein diet, rates of

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albumin synthesis increased but so did the rate of albuminuria and the fractional albumin catabolic rate. Hence, the strategy of attempting to increase serum albumin concentrations in nephrotic patients by protein loading may have an opposite effect with perpetuation of urinary protein losses and increased renal albumin catabolism. The potential noxious effect of dietary protein on the progression of glomerular renal disease must also be considered. Progressive glomerulosclerosis has been ascribed to glomerular hyperfiltration and hyperperfusion associated with unrestricted protein intake that is abated by dietary protein restrictions. 54 Since this same lesion of focal glomerulosclerosis is described as a morphologic transition from minimal change nephrotic syndrome, 73, 79 we are forced to consider the influence of dietary protein manipulation in all children with the nephrotic syndrome. Morever, the practice of inducing diuresis by infusions of albumin or plasmanate to reexpand intravascular volume and improve response to diuretic therapy may impose a similar stress on the nephrotic glomerulus. Recent evidence suggests that worsening of glomerular histopathology is associated with this type of treatment. 84 After review of the potentially adverse effects of each of the macronutrients in the diet of the nephrotic patient, it is difficult to recommend a specific dietary prescription. In fact, food manipulation by elimination of major components of the diet in our experience has induced remission in half of the nephrotic children studied. 78 References for dietary prescription are usually derived from the published RDA for any described population. 21 RDA for energy is set at the mean requirements whereas protein and other nutrients are recommended at two standard deviations above the mean to ensure an adequate intake. As previously noted, a total energy intake for the nephrotic patient should be at 100 per cent RDA, although the anorectic patient or the malnourished patient may require supplementation to or above the RDA for energy. When making recommendations for absolute quantities of protein intake in patients, it is important to recognize that 100 per cent RDA for protein is actually an overestimate of need for the population by approximately 25 per cent. Hence, if restriction is advisable, this allows some flexibility in prescription to 75 per cent of the RDA. It should also be emphasized that intake of protein above 100 per cent RDA is most certainly excessive and warrants careful scrutiny. We therefore recommend that chronically nephrotic patients receive 75 to 100 per cent RDA for protein. If negative nitrogen balance is apparent with this allowance, the protein-energy ratio should be examined. Protein-energy ratios are extremely important and should be maintained at relatively high levels to promote anabolism. A ratio of 2 gm of protein per 100 calories has been recommended for patients with renal insufficiency.32 However, a ratio of 3 to 4 gm protein per 100 calories should be provided in the nephrotic patient. This does not exceed protein-energy ratios known to promote catabolism but does maintain an optimal relationship for maximum utilization of nitrogen intake. With minimal restriction of dietary protein to 15 per cent of calorie allowance and absolute restriction of total dietary fat to 30 per cent of the

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FEATURES OF CHILDHOOD NEPHROTIC SYNDROME

Table 3. Nutritional Management of Persistent Nephrotic Syndrome COMPONENT

ALLOWANCE

Protein

100 per cent RDA for age 100 kcal/kg/day < 1 yr 75-100 per cent RDA

Carbohydrate

5-15 gm/kg/day

Fat

2-4 gm/kg/day

Energy

SOURCE

Carbohydrates 50---60 per cent Fats 25-30 per cent Protein 15-20 per cent High biological value whey or human milk (Similac PM 60/40) fish, fowl, beef, egg 50 per cent complex carbohydrate and fiber Whole grain cereals and breads, pasta, rice Vegetable starches (potato, beets, carrots) Vegetable sources 50 per cent unsaturated fats Eicosapentaenoic acid Fish skin oils Mackerel Salmon

POSSIBLE SUPPLEMENTAL NEEDS ABOVE RDA

Vitamin D* Calcium*

1-2 fLg/kg/day 0.025-0.05 fLg/kg/day 10---20 mg/kg/day

Potassium*

1-3 mEq/kg/day

Iron* Zinc*

2-6 mg/kg/day 5-20 mg/day

Calcidiol Calcitriol Neocalglucon CaC03 (Turns, Titralac) Adolph's Salt Substitute 63 mEq/5 gm Morton's Salt Substitute 70 mEq/5 gm Lawry's Seasoned Salt Free 30 mEq/5 gm Rarely responsive Rarely responsive

*Supplementation must be monitored.

dietary allowance, carbohydrate remains the major component of the dietary prescription. Although this seems to be somewhat excessive, carbohydrates offer tremendous flexibility in terms of patient tolerance and therapeutic impact. The differentiation between simple and complex carbohydrates is a very important one. Complex carbohydrates include high-fiber foods, which have actually been associated with improvement in hyperlipidemic syndromes. 2o They cause less increase in insulin stimulation and are absorbed more slowly. 20 Although no absolute data are available in nephrotic patients, it would seem feasible to provide at least half of the carbohydrate allowance in the form of complex carbohydrates. Water and mineral requirements in nephrotic patients can vary widely. Hypovolemia in nephrotic patients is certainly not as prevalent as previously assumed, with patients frequently presenting with normal or increased plasma volumes. 75 In addition to the renin-angiotensin-aldosterone system, possible intrarenal mechanisms ll as well as elevated antidiuretic hormone 63 have been postulated to account for antinatriuresis and low free water clearances in the nephrotic sydrome. Clearly, careful attention must be paid to maintenance of blood volume and appropriate allowance for dietary water and salt. Potassium also requires frequent supplementation due to diuretic induced losses as well as contraction alkalosis with increased kaliuresis. Zinc deficiency may occur in chronic nephrosis with persistent proteinuria due to excessive urinary losses of zinc complexed with protein. 64 Symptoms such as hypogeusia and delayed sexual development may be

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related to the hypozincemia and warrants supplementation in a very few patients. Appropriate dietary prescription in the nephrotic patient is certainly most important when the syndrome is unrelenting and results in the clinical setting of protein-calorie malnutrition (Table 3). Dietary supplements must be used with extreme caution in cognizance of the -potential toxicity of dietary manipulation on the already aberrant metabolism of the chronic nephrotic. In the steroid-sensitive, relapsing nephrotic patient, the wiser course would be to offer few restrictions other than some minimal salt limitation during the periods of relapse. Protein and calorie loading could be extremely problematic and might have long-term implications in the steroid nonresponsive patient.

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