MANAGEMENT OF CHRONIC RENAL FAILURE IN CHILDREN

It is no exaggeration to say that the composition of the blood is determined not by what the mouth takes in but by what the kidneys keep.

Homer W. Smith (1895-1962) From Fish to Philosopher

This monograph updates several major advances in the man- agement of chronic renal failure in children. We hope to help pediatricians recognize the signs and symptoms of renal fail- ure,lm21 particularly the many sion of renal failure.22-38

reversible causes of the progres- We discuss the classic features of so-

dium, potassium, and fluid electrolyte disorders in order to elucidate recent advances in our understanding of the conse- quences of “what the kidneys keep.” We focus on the increasing importance of nutritional management in retarding the progres- sive deterioration of renal function once chronic renal insuffi- ciency sets in, with particular attention to protein1°-15 and phosphate “-” dietary controls. The recent advances in the treatment of renal osteodystrophy,lg’ 2o together with practical comments on the use of antihypertensive agents, are concisely reviewed. Finally, a helpful approach to counseling parents con- cerning dialysis and transplantation concludes this volume.

OFFICE EVALUATION OF RENAL FUNCTION

The normally clear and yellow-colored urine may become dis- colored with hematuria, hemoglobinuria, myoglobinuria, and porphyria. A red or pink color in urine may also be due to food colorings, beets, blackberries, tives.3g

and phenolphthalein in laxa-

One of the earliest signs of interstitial nephritis, sickle cell nephritis, and chronic pyelonephritis is impairment of urinary concentrating ability. After an overnight thirst, even infants be- yond 2 months of age can concentrate urine to over 900 millios- mols (mOsm)/liter (specific gravity > 1.017).

Microscopic examination of O.&ml sediment of lo-ml centri- 244

fuged urine normally shows less than three erythrocytes and five leukocytes per high power field. Excessive crystals suggest a risk of renal stone formation or interstitial nephritis. The ma- jority of crystals (uric, cystine, oxalate, xanthine) precipitate in acid urine. Calcium phosphate and triple phosphate crystals pre- cipitate in alkaline urine. In addition, alkaline urine is sugges- tive of urinary infection with Proteus organisms, which split urea, thus contributing to ammonia formation.40

The urinary pH also provides diagnostic clues. Alkaline urine pH (> 6.5) is associated with renal tubular acidosis (type I, dis- tal), hypocitraturia, and increased risk of nephrocalcinosis and nephrolithiasis; acid urine (pH < 5.5) is associated with Type II (proximal) renal tubular acidosis and carries a lower risk of renal stones.

At one point or another, hematuria is present in almost every renal disease. The differential diagnosis of gross hematuria in- cludes acute glomerulonephritis, allergic hematuria, benign re- current hematuria including mesangial deposition of IgA (Berg- er’s disease), focal and segmental glomerulonephritis, hered- itary nephritis (associated with nerve deafness: Alport’s syn- drome), renal stones, trauma, tumors, and urologic disorders. Microscopic hematuria may be undetected and may persist be- tween episodes of gross hematuria in any of the conditions listed above, in addition to other glomerular nephropathies associated with systemic diseases, e.g., hemolytic uremic syndrome, lupus erythematosus, polyarteritis nodosa, renal vein thrombosis, sic- kle cell disease, and other hematological disorders, e.g., leuke- mia, lymphoma, and malignancies, e.g., Wilms’ tumor.

Proteinuria is commonly assessed with a dipstick impregnated with tetrabromphenol blue. Trace proteinuria is 10 mg/lOO ml, one plus is 30 mg/lOO ml, two plus is 100 mg/lOO ml, three plus is 300 mg/lOO ml, four plus is 1000 mg/lOO ml. Greater sensitiv- ity is provided by the sulfosalicylic acid method.

Transient, mild proteinuria is present in 5% of the normal population. The common causes of transient proteinuria are ex- ercise, fever, cold exposure, administration of epinephrine, blood transfusion, and extensive burns. Proteinuria in excess of 150 mg per day may occur in orthostatic proteinuria-present in the upright and absent in the prone position. Orthostatic protein- uria, usually less than 0.5 gm and rarely exceeding 1 gm per day, carries a benign prognosis.

Proteinuria in excess of 1 gm per day is indicative of more serious renal pathology, and a renal biopsy needs to be consid- ered. Massive proteinuria in excess of 2 gm per day is associated with a poor prognosis. If the child is over 10 years of age, a renal biopsy must be recommended in order to provide histologic di- agnosis.41

The selective proteinuria index quantitates the ratio between 245

the clearance of smaller protein molecules (e.g., transferrin) compared to large proteins (e.g., IgG, cY2-macroglobulin). Mini- mal change nephrosis is associated with highly selective pro- teinuria and implies a good prognosis.42 Nonselective protein- uria is associated with more serious renal pathology. Histologic diagnosis via a percutaneous renal biopsy has become so routine that indirect approximation by the protein-selectivity index is not commonly done in most medical centers in the United States.

The Addis count33 quantitates the cellular elements in urine. Normal children excrete less than l,OOO,OOO white blood cells, 600,000 red blood cells, and 10,000 casts in a 12-hour period. If the test is coupled with an overnight 12-hour thirst, the osmo- lality is normally greater than 850 mOsm/kg, and specific grav- ity usually exceeds 1.017 in children.

The blood urea nitrogen and serum creatinine are not elevated until after 50% impairment of glomerular filtration rate (GFR). Inulin clearance is the standard of reference for the GFR. Due to tubular secretion, creatinine clearance tends to overestimate the GFR. In view of the fact that urea clearance underestimates GFR to about the same degree, when the renal function is less than 20% of normal for age, the averaged value of creatinine and urea clearances closely approximates the true GFR. Normal GFR is achieved by 1 year of age and is approximated by the formula WV) + (P) where U = urinary concentration of inulin, V = urinary flow rate in ml per minute, and P = plasma con- centration.

Progressive rise in serum creatinine is a reliable indication of deteriorating renal function.43, 44 On the other hand, blood urea nitrogen rises in a variety of situations including dehydration, the catabolic state of infections and fever, excessive intake of protein, and administration of antianabolic agents such as cor- ticosteroids.

Serum concentrations of electrolytes are important in the evaluation of patients with renal disease. Interstitial nephritis is associated with sodium wasting, whereas sodium handling is normal until late stages of glomerulonephropathies. Hyperchlo- remit metabolic acidosis characterizes renal tubular acidosis which may be secondary to interstitial nephritis from analge- sics, anti-infectives (sulfonamides, penicillin, and derivatives), and heavy metals (cadmium, copper, lead, uranium). Advanced chronic renal insufficiency is characterized by hypocalcemia, hy- perphosphatemia, hyperparathyroidism, and anemia. Uric acid elevation is usually mild, and clinical gout is rarely encoun- tered. Lead nephropathy is the exception in that clinical gout occurs in over half of the patients.45

Anemia is usually not severe until end-stage renal failure in 246

the glomerulonephropathies. However, severe anemia out of pro- portion to the degree of renal failure is seen in various renal cystic diseases and interstitial nephropathies.46

Intravenous urography provides visualization of the renal structure and collecting system. Cystourethrography, radionu- elide imaging, renal angiography, renogram, ultrasound exami- nations, and computed axial tomography (CAT) scan are also useful diagnostic techniques. Ultrasound of the kidney, which does not expose the patient to radiation, is one of the most com- monly used techniques in the evaluation of hydronephrosis, pos- terior urethral valves, and cystic and solid lesions.

REVERSIBLE RENAL FAILURE

In chronic renal failure, progressive deterioration of renal function is slow and often asymptomatic until the end-stages. However, functional renal impairment occurs at an accelerated rate in alkalosis and hypokalemia, congestive heart failure, de- hydration and salt depletion, hypercalcemia, hypertension, hy- peruricemia, infection, obstruction, and following nephrotoxic agents. These reversible renal dysfunctions must be carefully watched for and treated in order to salvage whatever residual renal function remains.

ALKALOSIS AND HYPOKALEMIA

Chronic metabolic alkalosis, usually coupled with potassium depletion, causes a fall in glomerular filtration rate, and impair- ment of renal concentrating ability. Nitrogen retention and in- creased susceptibility to urinary tract infections have been dem- onstrated in rats subjected to potassium-depleted diets. The primary defect of potassium chloride reabsorption in Bartter’s syndrome47 abusers47

and secondary potassium deficiencies in diuretic or surreptitious vomiters47-4g are known to be associ-

ated with increasing risks of interstitial nephritis. Pyloric ste- nosis is a classic example of chronic loss of potassium and hydro- gen ions resulting in hypokalemic alkalosis.50-52 Prolonged vasogastric suction also results in significant depletion of these electrolytes. The ensuing hypokalemic alkalosis aggravates the condition because of “paradoxical aciduria,” and the normal renal compensation to correct the alkalosis cannot be brought into play until the chloride deficiency is corrected. When pa- tients with chronic renal failure receive diuretics as an adjunct to blood pressure control, the dual risks of hypokalemia and hy- peruricemia should be recognized and treatment instituted.

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CONGESTIVE HEART FAILURE

Children with chronic renal failure have a precarious margin of residual renal function, and congestive heart failure may push them into rapid.progressive uremia by further decreasing the renal blood flow and glomerular filtration rate. The signs of heart failure that accompany edema, such as dyspnea, rales, and increased venous and pulmonary pressure, may not be readily apparent; a therapeutic trial with digitalis is often needed. The advent of congestive heart failure is usually associated with worsening albuminuria, the presence of casts and hematuria as well as elevation of blood urea nitrogen. Because congestive heart failure may be secondary to overhydration or poorly con- trolled hypertension, renal function improves with correction of these disorders.

Uremic pericarditis, suggested by pericardial friction rub, may presage advanced end-stage renal disease. The signs of associ- ated complications of pericardial tamponade are pulsus para- doxus, jugular venous distention, Kussmaul’s sign with paradox- ical inspiratory accentuation, and a lowering of blood and pulse pressures. Confirmation is by ultrasonography or echocardio- gram. The treatment is pericardiocentesis.

DEHYDRATION AND SALT DEPLETION

One of the most common reversible causes of functional renal deterioration is dehydration, either from the nausea and vomit- ing of uremia or from diuretic-induced polyuria and too much salt restriction.53-55 The nausea and vomiting of renal failure is poorly understood, but the accumulation of nitrogen waste prod- ucts and the presence of metabolic acidosis are contributing fac- tors. Nausea on waking may be forestalled with the consump- tion of a carbohydrate drink immediately. Better control of metabolic acidosis with judicious amounts of sodium bicarbonate may alleviate these symptoms.

As mentioned earlier, sodium handling is usually normal in glomerulonephropathies until the late stages of renal failure. By contrast, children with chronic renal failure secondary to inter- stitial nephritis are often salt wasters. Replacement of the so- dium lost in their urine must be carefully monitored.

HYPERCALCEMIA

Deterioration of renal function follows hypercalcemia. The hy- percalcemia may be secondary to hyperparathyroidism, hyper- vitaminosis D, sarcoidosis, or excessive intake of calcium. Ne- phrocalcinosis may lead to interstitial nephritis, glomerular hyalinosis, or sclerosis. Nephrolithiasis may lead to obstruction

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and urinary tract infections. If hypercalcemia is prolonged, the impairment of renal function may be irreversible. Early recog- nition and treatment are vital to reverse such defects.

HYPERTENSION

The onset and degree of hypertension are highly variable, de- pending on the underlying primary renal disease. Uncorrected hypertension gives rise eventually to arteriolar nephrosclero- sis.56-58 The rate of deterioration of renal function may be slowed with effective blood pressure control.

HYPERURICEMIA

Moderate hyperuricemia (less than 10 mg/dl) has been ob- served in a large series of adult hospitalized patients, most of whom were receiving diuretics.5g Severe hyperuricemia (in ex- cess of 12 mg/dl) may occur at all ages secondary to cellular breakdown brought about by chemotherapy for certain hemato- logical disorders. Deposition of urate crystals in renal tubules may cause azotemia. Reversal of the hyperuricemia by alkalini- zation of urine or the use of allopurinol may lead to improve- ment in renal function.

INFECTION

In patients with marginal renal reserve, urinary tract infec- tions must be treated promptly with appropriate antibiotics. Other systemic infections, with the attendant accelerated catab- olism, place increasing demands on the kidneys to excrete nitro- genous wastes, which the compromised kidneys may be unable to meet. Control of infections give the kidneys a better chance to regain compensation.

OBSTRUCTION

Urinary tract obstruction depresses renal function, and also predisposes to urinary tract infections. Ultrasound of the uri- nary tract, to rule out anatomic or nephrolithiasis obstruction, must be included in the initial workup of any child with chronic renal insufficiency.

NEPHROTOXIC AGENTS

Interstitial nephritis may follow chronic ingestion of analge- sics (phenacetin, aspirin), anti-infectives (sulfonamide, penicil- lin), and other pharmaceutical agents (phenytoin, phenindione,

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thiazides, and furosemide).60 Nephropathies may accompany the use of nonsteroidal anti-inflammatory agents (prostaglandin in- hibitors).61 Although heavy metal ingestion (cadmium, copper, gold, lead, uranium) ~characteristically produces tubular disor- ders (amino aciduria, phosphaturia, glycosuria) and osteomala- cia, interstitial nephritis has also been known to frequently fol- low. History of intake of these agents should alert the pediatrician to watch for deterioration of renal function.

RECOGNITION AND PREVENTIONOFRENALFAILURE

The differential diagnosis of chronic renal failure in a child utilizes the classic approach: clinical history, physical findings, and laboratory confirmation. Obstructive uropathy accounts for over 50% of infant-onset chronic renal insufficiency. The history often includes failure to thrive, usually noticed by parents be- tween the sixth to the twelth month of life. The much heralded “difficulty in voiding” has not been a particularly frequent ob- servation. With older children, complaints of recurrent urinary tract infections, dysuria, and flank pain are classic. Congenital dysplastic kidneys are commonly associated with signs and symptoms of obstruction. Parents usually remember a history of nephrotic syndrome, hemolytic uremic syndrome, lupus erythe- matosis, or acute glomerulonephritis, but the history of anaphy- lactoid purpuric skin rash may be obscured. The history may also include encephalopathic and neuromuscular symptoms of urey$!aa4 The family history may reveal hereditary nephropa- thy, cystic dosis,68-70

diseases of the kidney,65-67 renal tubular aci- Fanconi syndrome,71-73

or sickle cell disease.75-7g broncho-otorenal dysplasia,74

Physical examination may detect edema, hypertension, the fa- cial rash of systemic lupus erythematosis, the corner calcifica- tion (medial and lateral margin, not the superior and inferior borders of arcus servilis) of hypercalcemia, the skin manifesta- tions of dehydration, the pale conjunctivae of anemia, the Chvostek’s and Trousseau’s signs of hypocalcemia, the hypotonia of hypokalemia, the tachypnea of acidosis, the pulmonary rales of congestive heart failure, or the friction rub of pericarditis. There may be evidence of chronic malnutrition and in end stages, a uremic odor.

Polyuria and nocturia are classic features of poor urinary con- centrating ability and, as discussed before, an early sign of in- terstitial nephritis and sickle cell nephropathy. Proteinuria of 1 to 2 gm per day with alpha 2 or beta globulin predominating is suggestive of interstitial nephritis. By contrast, proteinuria in excess of 2 gm per day is characteristic of glomerulopathies, in which albuminuria predominates. In addition, the urinary sedi- ments show numerous cells and casts.

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Currently, there is interest in the prevention of what has been the almost inevitable progression of kidney insufficiency to end- stage renal failure. Urological relief of obstructive uropathy early in infancy has been disappointing. Long held to improve the prognosis, it has unfortunately been shown not to affect the rate of progression of renal failure to dialysis/transplantation.*’ Intrauterine relief of obstruction, which is present in the fetus, may improve this prognosis.

The hope that early dietary protein restriction might prevent glomerular hyperperfusion derives from experimental data in animals which demonstrated a hepatic hormone (glomerulopres- sin) that reduces the tone of afferent glomerular arterioles and stimulates prostaglandin synthesis. However, hyperfiltration oc- curs in the absence of concomitant relaxation of the efferent ar- terioles. In one clinical report, Buddhist monks with chronic renal failure who ingested one low protein vegetarian meal a day had a slower rate of progression to end-stage renal failure than controls.sl But such studies have been faulted for the lack of renal histological evaluation of the study groups and other methodology difficulties.82

Dietary phosphate restriction,83-8g the use of tryptophan,“’ 88 and supplementation to reduce production of glomerulopressin are under investigation at this time as potentially useful pre- ventive measures.

SODIUM, POTASSIUM, ACIDOSIS, WATER, CALCIUM, PHOSPHATE HOMEOSTASIS

In contrast to other organs, the kidneys do not respond to pa- renchymal destruction by regeneration of new nephrons. In- stead, there is functional adaptation of the surviving intact nephrons to compensate for the loss of the other nephrons. In chronic renal failure, there is functional adaptation of a decreas- ing number of nephrons with a resulting increase in excretory function per surviving intact nephron.g0 Normally, each kidney contains one million functioning nephrons that regulate water, electrolyte, and acid-base homeostasis. However, as few as 5%- 10% of the total number of intact nephrons are able to maintain water and solute homeostasis.

PATTERNS OF ADAPTATION IN RENAL FAILURE

As the glomerular filtration rate (GFR) falls in chronic renal insufficiency, three patterns of adaptation emerge for solute ex- cretion (Fig l).gl’ ” For the solutes characterized by line A, no adaptation occurs; excretion of these solutes is almost totally de- pendent on the residual GFR. The upper limit of excretory ca- pacity for a solute that is filtered, not secreted, and partially

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I I I I I 100 75 50 25 0

GFR %

Patterns of adaptation for different solutes in chronic progressive renal disease. (From Bricker NS, et aLgo Used by permission.)

reabsorbed is less than or equal to the amount that is filtered. Creatinine and urea fall into this pattern of adaptation. For the solutes represented by line B, limited adaptation occurs and the serum concentration of the solute remains within normal until the GFR falls below 25% of normal. After that, any further de- crease in GFR results in an increase in the serum concentration. A solute falling into this pattern of adaptation is both filtered and secreted. Phosphate and hydrogen ions are examples of sub- stances that have limited adaptation in chronic renal insuffi- ciency. For line C solutes, complete adaptation occurs and the serum concentration of the solute remains normal until the end stages of chronic renal insufficiency. The rate of excretion per nephron increases inversely to the decrease in GFR. Sodium and potassium are two substances that fall into the complete adap- tation group.

Therefore, as the number of functioning nephrons decreases, each nephron’s contribution toward excretion increases and each solute’s excretory rate is regulated independently of the other solutes in the remaining intact nephrons.

SODIUM HOMEOSTASIS

The kidney is the principal organ of sodium homeostasis, al- though the intestinal tract and the skin provide minor contri- butions to sodium (Na) balance. In normal individuals, even though sodium intake varies widely from day to day, sodium

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homeostasis is maintained. This is achieved by altering the frac- tional excretion of sodium (FEN,% = Na excreted in the urine/ Na filtered by the glomerulus). It is also unusual for individuals with chronic renal insufficiency either to accumulate or to lose excess quantities of sodium and water.g3-g6 In fact, a normal salt intake can be tolerated with a GFR as low as 5-10 ml/min/1.73 sq m.g7 As the GFR declines in chronic renal insufficiency, the surviving nephrons respond with an increase in FENa.5’ 7-g Thus, for each 50% reduction in the GFR, the remaining nephrons compensate by doubling the FEN,%. However, the ability to in- crease the FEN,% is limited; the FEN,% cannot be greater than 30% of the filtered sodium either in individuals with a normal GFR or with chronic renal insufficiency.g3 Therefore, a positive sodium balance will occur if the GFR is so decreased or if the dietary sodium is so high that a FEN,% greater than 30% is needed to maintain sodium balance (sodium balance: dietary in- take minus urinary, gastrointestinal, and skin losses).

The increased FEN,% found in chronic renal insufficiency is due to a decrease in sodium reabsorption by the neph- ron. g4V g6, g8-100 Four factors may influence the kidney’s rate of sodium excretion: aldosterone, natriuretic hormone, changes in single-nephron GFR, and changes in intrarenal hemodynamics. Aldosterone secretion and activity at the distal tubule appear to be normal,“” lo2 and aldosterone plays an important antinatri- uretic role in chronic renal insufficiency.r” Changes in single- nephron GFR do not appear to be the etiolo FEN,% in chronic renal insufficiency.g4, g8,

g for an increased A humoral sub-

stance known as the natriuretic hormone has been found in the serum of patients with chronic renal insufficiency,“’ and this substance has been shown to increase the FEN,% by decreasing tubular sodium reabsorption.“’ ‘03-ro5

It is well known that the kidney’s ability to conserve sodium is lost in individuals with chronic renal insufficiency.” This is due to the inability of the distal tubule to lower the urinary sodium concentration below a relatively high fixed concentration (7-27 mEq of sodium/liter of urine, average 15 mEq/l).“’ If min- imum sodium intake is not maintained, hyponatremia and de- hydration will ensue. Therefore, it is unnecessary to use severe dietary sodium restriction or diuretics on a routine basis in pa- tients with chronic renal insufficiency.

POTASSIUM HOMEOSTASIS

The control of potassium homeostasis is mainly the responsi- bility of the kidney. More than 80% of dietary potassium is ex- creted as urinary potassium. Potassium is filtered at the glomer- ulus, and almost all of the filtered potassium is reabsorbed by the proximal tubule. For the most part, the potassium that ap-

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pears in the urine is due to secretion of potassium by the distal nephron. In patients with chronic renal insufficiency, potassium homeostasis is maintained in spite of diminishing GFR by the remaining ne@uo~;~~creasing the fractional excretion of potas- sium (FEx%). ’ ’ The remaining nephrons have the ability to increase the FEx% up to 300% of the filtered load.g3Y g7 While the enhanced FEN,% in chronic renal insufficiency is secondary to a decreased tubular reabsorption of the filtered sodium, the increased FEx% in chronic renal insufficiency is the result of enhanced secretion of potassium in the distal nephron.log

The major site of enhanced potassium secretion seen with re- duced nephron mass appears to be the collecting duct and not the distal tubule.“’ Experimental evidence in animals with renal insufficiency or receiving chronic potassium loading re- veals an increase in Na-K-activated adenosine triphosphatase (Na-K-ATPase) in the distal nephron/collectin duct located in the outer medulla and cortex of the kidney. 18 / ‘11, ‘12 This in- crease in Na-K-ATPase activity in the renal tubular cells of the collecting duct that occurs with increased potassium excretion appears to la an important role in potassium homeostasis and excretion. &,1&,112 However, increased aldosterone secretion does not appear to be the major determinant for the increased FEx% seen. 07, ‘11, ‘13, “* In fact, normal aldosterone and potas- sium levels were seen in some patients with chronic renal insuf- ficiency.l15 Some authors believe that aldosterone plays some

part i,“, lLl6 otassium homeostasis in chronic renal insuffi-

ciency. 3 Besides renal adaptation, gastrointestinal tract adaptation is

also seen with diminishing GFR.l17 Stool potassium excretion as a fraction of dietary potassium intake was shown to increase from 12% in the normal individual to 34% in chronic renal in- sufficiency.

ACID-BASE HOMEOSTASIS

As renal disease progresses, the kidney is able to maintain acid-base homeostasis until the GFR is reduced to less than 20- 30 ml/min/1.73 sq.m.ll’, il’ After that, the kidney is unable to handle the normal acid load, and metabolic acidosis results. In children, the daily production of hydrogen ions can be as high as 2 mEq/kg of body weight.12’ The hydrogen ions generate from the breakdown of amino acids, nuclear proteins, and oxidation of fats and carbohydrates. In chronic renal insufficiency, the metabolic acidosis is usually associated with an increased anion gap secondary to retained anions (i.e., sulfate and phosphate). However, in most individuals with chronic renal insufficiency, serum bicarbonate rarely falls below 12-15 mEq/L.“’

The acid-base homeostasis that is regulated by the kidney in- 254

volves three mechanisms: filtered bicarbonate reabsorption, am- monium excretion, and titratable acid excretion. Initially thought to have a problem with bicarbonate wastage, patients with chronic renal insufficiency appear to have an increased ability to reabsorb filtered bicarbonate in the proximal tubule as GFR falls.121’ 122 Titratable acid excretion is maintained in chronic renal insufficiency123 because the abilitz40f individual nephrons to excrete titratable acid is increased. Since titrat- able acid is mainly derived from phosphate, an increased frac- tional excretion of phosphate (FE,%), that maintains phosphate homeostasis, yields an increased excretion of titratable acid per nephron. Thus, the major factor responsible for the metabolic acidosis seen in chronic renal insufficiency is diminished excre- tion of ammonium by the kidney. As the GFR falls, there is in- creased excretion of ammonium per nephron.123, 125 However, at a critical level, total ammonium excretion falls because the re- maining nephrons (decreased kidney mass) are not capable of producing sufficient ammonium.1232 ’ 4

Extrarenal buffering occurs when the kidney is unable to off- set the positive acid balance seen in chronic renal insufficiency. The most important source of this extrarenal buffer capacity is the skeletal system. In chronic metabolic acidosis, deminerali- zation of the bone occurs in an attempt to alleviate the acidosis126 and those mechanisms that prevent bone reabsorp- tion are associated with decreased extrarenal buffering and a metabolic acidosis.127

WATER HOMEOSTASIS

As with sodium, potassium, and acid-base homeostasis, the kidney attempts to maintain water balance in chronic renal in- sufficiency by increasing the percent excretion of the filtered wa- ter. The fractional excretion of water (FEn,o%) is increased as the GFR declines because the diluting ability of the kidney (free water clearance) is maintained even in advanced chronic renal insufficiency.1282 12’ In fact, the FEn,o% can increase from less than 1% in normal individuals to greater than 50% in individ- uals with advanced chronic renal insufficiency. However, over- zealous fluid intake will overwhelm the ability of the remaining nephrons to excrete water, resulting in fluid overload. This does not occur as long as the thirst mechanism is intact, The concen- trating ability of the kidney is impaired early in renal failure and declines rapidly as GFR decreases.i3’ The defect in urine concentrating ability appears as the GFR falls below 60 ml/mini 1.73 sq.m.i3i The pathogenesis of the concentrating defect may be multifactorial, including pathologic changes in the renal me- dulla, resulting in disruption of the countercurrent system and loss of the interstitial solute concentration gradient or an im-

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paired ability of the ascending limb to transport chloride and sodium out.’ ‘a 133 There also appears to be an acquired defect in advanced chronic renal insufficiency resulting in nephro enic diabetes insipidus or ~vasopressin-resistant hyposthenuria.’ 8 4-136

The hallmark of those individuals with chronic renal insuffi- ciency is a relatively fixed urinary osmolality and inability to respond to sudden alterations in water intake. In an individual with normal renal function, the urinary osmolality will vary be- tween 60-1,200 mOsm per liter. However, the urinary osmolal- ity excreted by patients with advanced chronic renal insuffi- cienc liter 97

will vary in a narrow range between 266-350 mOsm per and tend to have a fixed specific gravity, around 1.010.

Even though there is an increased rate of urine flow per nephron as GFR decreases, there is also an increased solute load deliv- ered and excreted per remaining nephron. This results in a man- datory solute diuresis in order to excrete the daily dietary intake of solute. Therefore, the defect in concentrating ability and wa- ter conservation may cause a problem if free water is restricted, resulting in dehydration and hypernatremia.

CALCIUM AND PHOSPHATE HOMEOSTASIS

In individuals with normal renal function, calcium and phos- phate homeostasis consists of a balancing act between dietary calcium and phosphate absorption, calcium and phosphate entry and release from the skeletal system, and calcium and phos- phate loss via the urine. As the number of functioning nephrons decreases, this delicate balance of calcium and phosphate ho- meostasis becomes upset.137-‘3g Serum calcium and phosphate concentrations stay within the normal ranges until there is ad- vanced chronic renal insufficiency (GFR only 5% of normal), but serum alkaline phosphatase and parath

Y roid hormone begin to

rise as GFR falls below 50% of normal. 4o However, a negative calcium balance ensues because of decreased calcium absorption by the gastrointestinal tract. This decreased absorption is sec- ondary to decreased calcium intake due to anorexia and an im- paired absorption ability by the gastrointestinal tract due to di- minished levels of 1,25 dihydroxyvitamin-D3.141’ 142 in the kid- ney, 25 hydroxyvitamin-D3 is normally hydroxylated to 1,25 dihydroxyvitamin-D3.143 However, as the GFR declines, dimin- ished concentrations of 1,25 dihydroxyvitamin-D3 are noted sec- ondary to impaired formation by the kidney.144x 145

Next, increased parathyroid hormone (PTH) release is stimu- lated by the decreased serum calcium and negative calcium bal- ance, in an attempt to return the serum ionized calcium to nor- mal. PTH increases bone resorption, which decreases urinary calcium excretion and stimulates 1,25 dihydroxyvitamin-D3 pro- duction.146, 147 The net effect of increased plasma PTH on uri-

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nary calcium is to decrease the fractional excretion of calcium by the remaining nephrons by increasing the tubular reabsorp- tion of calcium. Finally, the hyperphosphatemia that is seen with chronic renal insufficiency is another mechanism that de- presses the serum ionized calcium which then stimulates PTH secretion.143’ I**

Phosphate homeostasis is maintained through the course of renal insufficiency until advanced renal failure is present.g73 ‘*’ Hyperphosphatemia develops only as the GFR markedly de- clines. The ability of the remaining nephrons to maintain phos- phate homeostasis is due to an increase’*’ in the fractional ex- cretion of phosphate (FEPo4 %). The elevation of circulating PTH and its effect on tubular reabsorption of phosphate is thought to be responsible for the increase in the FEpo4%.1502 15’ In addition to the phosphaturic effect of PTH on the renal tubules, there also appears to be a PTH-independent hosphaturic adaption in the renal tubule when GFR declines. 18,153 Eventually the kid- ney’s ability to adapt is overwhelmed and h occurs which can no longer be corrected1542 l5 5y perphosphatemia

by increasing the FEPo4%.

The major drawback of this adaptive increase in circulating PTH in an attempt to maintain serum calcium and reduce serum phosphate is the development of secondary hyperparathy- roidism and renal osteodystrophy.156-163 However, it has been shown that reduction in dietary phosphate will prevent eleva- tion in ;:-ug-$osphate and prevent secondary hyperparathy- roidism. ’

NUTRITIONAL MANAGEMENT

Unfortunately, growth retardation151 and malnutrition15* are often observed in children with chronic renal failure. Inadequate nutrient ingestion and utilization, bone impairment, excessive protein catabolism, hormonal disorders, and intercurrent infec- tions are characteristic complications of the uremic state and underlie these developmental disorders.15’

Periodic estimations of growth and nutritional status are im- portant in these children. Adequate assessment of statural growth rate should be based on sequential measurements of such parameters as length/height, head circumference in small infants, bone age, and sexual maturity.16’ Cautious interpreta- tion of these data is advised. Nutritional status may be assessed by anthropometric measurements including weight, midarm muscle circumference, and skin-fold thickness. Serum total pro- tein, albumin and transferrin determinations are useful in se- lected cases. It is advisable to relate these findings with dietary intake, estimated by a retrospective record of all items con- sumed during a three-day period.16’

257

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va

lues

of the

slo

pes

is sig

nifica

nt (p

< 0.0

1).

(From

Ma

schio

G,

et

al.6

Used

by

pe

rmiss

ion.)

Chronic renal insufficiency is a progressive disease. As the number of functioning nephrons decreases, the remaining neph- rons undergo an adaptive process that gives rise to increased glomerular perfusion and filtration.163 This hemodynamic situ- ation, possibly mediated by a hormonal mechanism, could be re- sponsible for both the initial compensatory glomerular hypertro- phy and the progressive renal damage that eventually leads to terminal glomerular sclerosis.164 Thus, renal damage tends to advance toward end-stage kidney disease regardless of the pri- mary nephropathg.

Recent studies’ 5 indicate that dietary protein restriction lim- its the hyperfiltration of the residual glomeruli. Studies167 also suggest that the progressive decline of renal function, as as- sessed by serial measurements of the reciprocals of serum cre- atinine, may be delayed in patients receiving a low-protein diet (Fig 2). The rate of deterioration of glomerular filtration depends on the primary disease (Fig 31, as well as on individual and probably dietetic factors (Fig 4).

Besides maintaining health, insofar as possible, nutritional management of children with chronic renal failure should be aimed at the avoidance of malnutrition and the prevention of growth retardation, as well as at slowing the rate of progression to end-stage kidney disease. In addition to these objectives, the physician and other health care professionals should try to keep the recommended therapeutic measures from creating more anx-

60 %

50

40

it , , , / , , ,

0 6 12 18 24 30 36 42 48 54 60 66 72

Time, months

FIG 3. Survival probability in three adult patient groups with early renal failure on a protein- restricted diet (renal death = serum creatine > 10 mgidl). The asterisk represents p < 0.01. Abbreviations: CP, chronic pyelonephritis; CG, chronic glomerulonephritis; PKD, polycystic kidney disease. (From Oldrizzi L, et al.7 Used by permission.)

259

GROU

P I

25 p

atie

nts,

ag

ed

6-17

year

s,

treat

ed

by

diet

ary

ther

apy

GROU

P II

diet

ary

ther

apy

not

emph

asize

d.

X W

ti (I

2~0.

8.

med

ullar

y cy

stic)

II

NP

(22

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ic glo

mer

ulo

neph

ritis)

l

VH

(16

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? , s

ickle

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ll) A

D~I

( I3

yo.

? , h

ered

itary

ne

phrit

is)

I I

1 1

I I

I I

-48

-36

-24

-12

0 12

24

36

48

M

ON

THS

FIG

4.

The

influe

nce

of die

tary

treatm

ent

on

prog

ress

ion

of ch

ronic

re

nal

failu

re

as

indica

ted

by

seru

m cre

atinin

e lev

els.

Zero

time

was

meas

ured

fro

m the

po

int

wher

e se

rum

creati

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reac

hed

5 mg

/dl.

(From

Ch

an

JCM,

Be

ale

MG.*

Used

by

pe

rmiss

ion.)

iety in these children who already have problems in social ad- aptation.

Although there is no general agreement on the time for start- ing different therapies, a suggested sequence is presented in Figure 5.

PROTEIN

Adequate protein intake must be provided to permit maxi- mum growth rate. However, excessive ingestion of proteins will increase the accumulation of nitrogenous waste products, exag- gerate uremic symptoms, and likely cause more rapid progres- sion to end-stage kidney disease.

Protein ingestion by individuals in developed countries ex- ceeds Recommended Dietary Allowances (RDA).” The protein intake of children with chronic renal failure should provide 8%- 10% of total calories.ll’ ~3’ With a caloric intake close to 100% of RDA, this diet meets RDA for proteins (Table 1).

Amino acid and protein metabolism is disturbed in chronic renal failure. Alterations in intracellular and plasma amino acid concentrations have been described.12, 16’ Partly due to the fact that uremia intensifies hypercatabolism,‘62 the rate of synthesis

CHRONIC RENAL FAILURE

CFR

--_-

75%

----

5 10%

o- 1%

FIG 5.

SYSTEMIC DISORDERS TREATMENT

Secondary hyperparathyroidism Calcitriol ( 1, 25-vitamin-D31 Phosphate-binders Calorie supplement Phosphate restriction

Rising BUN, creatinine Protein and salt restriction Multivitamins

Hypertension Diuretic, vasodilators

Nausea and vomiting Anti-emetic

DIALYSIS/TRANSPLANTATION

Sequence of chronic renal failure related disorders and suggested treatment in re- lation to glomerular filtration rate (GFR) at % of normal for age. (Modified from Chan JCM, et al.‘)

261

TABLE 1. Estimated Safe and Adequate Daily Dietary Intake for Calories, Protein, Sodium, Potassium, Calcium, and Phosphorus*

AGE ENERGY PROTEIN SODIUM POTASSIUM CALCIUM PHOSPHORUS

(yr) (kc&kg/day) @n/kg/day) (mg/day) (mg/day) (mg/day) (mgiday)

o-o.5 115 0.5-l 105

l-3 100 4-6 85 7-10 85

11-14 Male 60 Female 48 15-18 Male 42 Female 38

*From reference 2.

2.2 230 650 360 240 2.0 500 850 540 360 1.8 650 1,100 800 800 1.5 900 1,550 800 800 1.5 1,200 2,000 800 800

1.0 1,800 3,025 1,200 1,200 1.0 1.800 3.025 1,200 1,200

.85 1,800 3,025 1,200 1,200

.85 1,800 3,025 1,200 1,200

of proteins is also markedly deficient. To achieve maximum uti- lization of dietary proteins, it has been recommended that at least 50%-75% of these proteins should be of animal origin (high biologic value proteins).33 l1

Strict restriction of protein intake and increase of high bio- logic value proteins may give rise to patient noncompliance due to the monotonous and unpalatable diet. Long-term adherence to these diets is almost impossible to attain. Supplements of es- sential amino acids or their nitrogen-free analogues have been used in uremic patients on very low protein diets.13, l4 Such supplements improve the palatability of a low protein diet by decreasing the requirements for protein of high biologic value and may facilitate nitrogen utilization.15 Use of keto and hy- droxy analogues of essential amino acids is based on the theory that their endogenous transamination15 will result in positive ni- trogen balance at a lower total nitrogen intake.16 Experience with these therapeutic modalities in pediatric patients is very limited 17-lg

11: 160 and their use should be restricted to selected

cases. Urinary protein losses must be replaced. Each gram of pro-

teinuria requires provision of an additional 1.0-1.2 g of dietary protein.16 Likewise, transient increase of protein intake may be needed in hypercatabolic states such as in the presence of fever, infections, and surgical procedures.

FATS AND CARBOHYDRATES

Growth, high basal metabolism, and increased physical activ- ity account for the higher energy consumption per kg of body weight in children compared to adults.” Basal metabolic rate is higher during infancy because a greater proportion of body

262

weight is represented by organs with high metabolic activity (brain, liver, heart, and kidney).21

Energy intake is low in the majority of children with severe chronic renal failure because of the invariable presence of an- orexia.20 Deficient ingestion of calories may lead to malnutri- tion, negative nitrogen balance, and inadequate growth rate. Reduced growth velocity has been reported157 in uremic children with energy intake below 80% of RDA (Fig 6). Therefore, caloric ingestion of these children should be at least equivalent to the RDA (see Table 1) for healthy children of the same height age. 2, 16’ Approximately 40% of these calories should be provided as fats and 50% as carbohydrates.”

Caloric supplements must be given to uremic children who have evidence of malnutrition or deficient energy ingestion.162 These caloric supplements are supplied in the form of glucose polymers or foods with high energy content (soft beverages, honey, sugar, margarine4 etc.), provided they do not have exces- sive minerals or protein. Caloric supplementation may improve

0 20 * tp ap . Ener 3 Y intnkm -L . -e/ l

010 0

FIG 6. In children with renal disease, a significant correlation (r = 0.72, p < 0.001) exists between growth velocity, expressed as percentage of expected 50th percentile ve- locity, and energy intake expressed as percentage of that recommended for same age. (From Betts PR, Magrath G.15’ Used by permission.)

263

growth rate,22 although catch-up growth is usually not ob- served.23 Moreover, in some patients the extra calories lead to obesity without facilitating statural growth.24

Hypertriglyceridemia is commonly encountered in individuals undergoing chronic renal failure. Several lines of evidence sug- gest that this abnormality is related to increased hepatic pro- duction of triglycerides coupled with reduced lipolysis due to low activity of lipo sulinemia.16’ i6 l?

rotein lipase and/or hepatic lipase and hyperin- Peripheral tissues of patients with chronic renal

failure present partial insensibility to the hypoglycemic action of insulin,25’ 26 resulting in reduced glucose tolerance and hyper- insulinemia, which represent attempts to achieve normal blood glucose concentrations. Consequently, restriction of carbohy- drate intake and its substitution by fats may be advisable162 in uremic children with high plasma concentrations of triglycer- ides. Likewise, treatment of hyperparathyroidism27 and hemodi- alysis162 improve glucose metabolism disorders.

Hypercholesterolemia, unusual in uremic adult patients,16 is seen in a large number of children with chronic renal failure. This may be secondary to dietetic factors and may be treated by reducing ingestion of saturated fats and cholesterol.162

WATER AND ELECTROLYTES

As discussed earlier in this monograph, balances of sodium, potassium, and water are usually maintained until the terminal stages of chronic renal failure. However, due to the progres- sively reduced number of functioning nephrons, tolerance to large variations in intake of these nutrients declines, and with this comes increasing risk of water loading and electrolyte in- toxication or depletion. Thus, serum electrolyte concentrations and clinical signs of fluid retention (hypertension, weight gain, edema, cardiac insufficiency) or dehydration must be closely monitored. In a similar fashion, special attention has to be given to patients with salt-losing nephropathies such as polycystic kid- ney disease, interstitial nephritis, and nephronophthisis.

Unless the previously mentioned disorders are present, so- dium and water intakes generally do not need to be modified.2, l1 Habitual levels of water and sodium intakes of healthy children and suggested levels of sodium restriction are shown in Tables 2 and 3. In salt wasters, determination of 24-hour urinary so- dium excretion is a useful guide for deciding on the optimal so- dium supplementation.28

To maintain normal serum potassium concentrations, the in- take of this element must be restricted when the glomerular fil- tration rate falls below 15-25 mVmin1.73 sq.m.” ‘i Dietetic modifications needed to achieve a low potassium diet include suppression of high content potassium foods (Table 4) and soak-

264

TABLE 2.

Habitual Water Intake of Healthy Children*

CHILD AGE TOTAL WATERt (yrs) ml/kg/day

o-1 150 l-3 100 4-6 90 7-10 75

10-12 50-70 >12 50

*From reference 11. Used by permission. tTota1 water means drinking water plus wa-

ter included in solid food.

TABLE 3. Normal and Restricted Intake of Sodium and Potassium*

CHILD WEIGHT

(ka) VERY

ELEMENT HABITUAL RESTRICTED RESTRICTED

mEqikg/day

3-8 Na l-2 l-2 0.5-l K 1-4 1-3 <l

8-12 I Na 2-4 1-2 0.5-0.9 K 3-6 2-3 Cl

12-25 > Na -3 l-2 0.3-0.8 K 3-4 2-2.5 il

mEq/day >25 I Na 80-100 20-40 10-15 K 50-130 40-50 <20

*From reference 11. Used by permission

ing of vegetables and legumes before cooking. Patients whose serum potassium concentration consistently exceeds 6 mEq/L will require the administration of cation exchange resin. Kay- exelate at 1 @kg dose, given with sorbitol to prevent con- stipation’ is usually advised.g Constipation is particularly fre- quent in patients on chronic peritoneal dialysis, and this should be treated by dietary modifications before prescribingOpharma- cologic agents to decrease the excess body potassium.

VITAMINS AND TRACE ELEMENTS

Because persistent anorexia is associated with the uremic state, a daily multivitamin preparation providing RDA for water soluble vitamins (Table 5) is usually administered3 to children with chronic renal failure (see Fig 6). Vitamin A supplementa- tion should be avoided,16 since high plasma concentrations of this vitamin have been demonstrated3’ in individuals with renal insufficiency. Alterations in mineral metabolism related to vi-

265

TABLE 4. Foods in Which Potassium Content is Equal to or Greater Than 10 mEqilO0 gm of Weight*

FOOD mEq/lOO/gm

Sardines 12.9 Scallops 12.0 Peanuts 18.0 Peanut butter 16.7 Almonds 13.3 Pecans 16.0 Walnuts 10.0 Cooked beans 11.1 Potato chips 12.3 Baked white potato 13.0 Raw mushrooms 10.6 Baked winter squash 12.0 Pitted dates 16.7 Dried figs 16.7 Prunes 17.3 Raisins 19.3

*From reference 29. Used by permission.

TABLE 5. Recommended Dietary Allowance for the Main Water Soluble Vitamins*

VITAMIN VITAMIN VITAMIN AGE THIAMIN RIBOFLAVIN NIACIN FOLACIN B12 (yr) (mg) hlg) (mg N.E.) ( w PLg

o-.5 0.5-l

1-3 4-6 7-10

11-14 Male Female

15-18 Male Female

35 0.3 0.4 6 0.3 30 0.5 35 0.5 0.6 8 0.6 45 1.5 45 0.7 0.8 9 0.9 100 2.0 45 0.9 1.0 11 1.3 200 2.5 45 1.2 1.4 16 1.6 300 3.0

50 50

60 60

1.4 1.1

1.4 1.1

1.6 18 1.3 15

1.7 18 1.3 14

1.6 1.8

2.0 2.0

400 400

400 400

3.0 3.0

3.0 3.0

*From reference 10. Used by permission

tamin A accumulation have been suggested.31 In contrast, to avoid vitamin B6 deficiency, Kopple et a1.32 recommend daily pyridoxine supplement of 100 mg to uremic adult subjects.

With reference to vitamin D and calcium-phosphate metabo- lism, the reader is referred to the section on “Calcium and Phos- phate Homeostasis.”

When the glomerular filtration rate falls below one-third of normal,16’ anemia becomes a common complication in children

266

TABLE 6. Pathogenic Factors of the Anemia of Chronic Renal Failure*

Deceased erythropoiesis: Reduced availability of erythropoietin Inhibitor(s) of erythropoiesist Bone marrow fibrosist

Shortened red blood cell survival:t Hemolysis due to extracorpuscular factor(s)

Excessive blood losses Deficiency states:

Iron deficiency Folic acid deficiency

*Modified from reference 33. Used by permission. +These factors seem to be exacerbated by hyper-

parathyroidism.

with chronic renal failure. As summarized in Table 6, multiple factors are involved in the genesis of this anemia. Requirement for oral iron supplements is established by serum ferritin con- centrations.3S l6 In addition, to avoid anemia secondary to folate deficiency, 1 mglday of oral folic acid is required.16’

There is a definite risk of iron overload in uremic children receiving blood transfusions.

DIALYSIS

In general terms, the preceding recommendations are valid for children undergoing chronic dialysis. In relation to protein-ca- loric intake, individualized dietetic counseling34 and selective liberalization of dietary restrictions may alleviate the common anorexia and achieve a better growth and nutritional status.

Patients on chronic peritoneal dialysis absorb glucose contin- uously from the dialysate.35 In addition, they suffer a constant protein loss of 0.1 to 0.5 mgikg of body weight per day via the dialysis.36 Both factors must be taken into account in the dietary design for these subjects.

Energy and protein requirements of infants receiving chronic ambulator 1 peritoneal dialysis have been detailed by Alexander 7 and are summarized in Table 7.

Dialysis aggravates the loss of water soluble vitamins because these compounds are dialyzable. Thus, vitamin supplements should be prescribed and encouraged. In addition to giving the RDAs for the other water soluble vitamins, administration of folic acid-l mgiday, pyridoxine--5-10 mgiday, and ascorbic acid-75100 mg/day are currently recommended.16’

Low plasma zinc concentrations have been reported in pa- 267

TABL

E 7.

Su

gges

ted

Minim

um

Daily

Di

etary

Intak

es

for

Youn

g Inf

ants

Unde

rgoin

g Ch

ronic

Am

bulat

ory

Perit

onea

l Di

alysis

*

AVER

AGE

AVER

AGE

TOTA

L EN

ERG

Y N

ET

ENER

GY

DIA

LYSA

TE

DIE

TAR

Y H

EIG

HT

ENER

GY

FRO

M

REQ

UIR

EMEN

T PR

OTE

IN

PRO

TEIN

PR

OTE

IN

AGE

REQ

UIR

EMEN

T D

IALY

SATE

FR

OM

D

IET

REQ

UIR

EMEN

T LO

SSES

R

EQU

IREM

ENT

(mon

ths)

(kcal/

kg)

(kcal/

kg)

(kcal/

kg)

&n/1

00

kcal)

&m

/kg)

&m/kg

/day)

o-4

115

8 10

7 1.9

0.3

2.5

4-

6 11

5 8

107

1.7

0.3

2.3

6-12

10

5 8

97

1.7

0.3

2.1

*Am

ount

s ba

sed

on r

equir

emen

ts to

sus

tain

norm

al

grow

th

rate

s in

he

alth

y in

fant

s.

(Fro

m

refe

renc

e 37

. Us

ed

by

perm

ission

.)

tients on hemodialysis.38 The clinical symptoms of hypogeusia, ataxia, hair loss, and anorexia have been attributed to zinc de- ficiency.‘62 In such cases, supplements with lo-15 mg/day of zinc element are advisable.”

RECENT ADVANCES INTREATMENT OFBONE DISORDERS

The term renal osteodystrophy was proposed in 1943 by Liu and Chu171 to describe the bone disorders related to renal insuf- ficiency. Special attention to the prevention and management of this complication of chronic renal failure must be given by phy- sicians who care for uremic children because renal osteodystro- phy is particularly frequent in the pediatric age and results in consequential growth failure.172

Risk factors for developing renal osteodystrophy include fem- inine sex, tubulointerstitial nephropathies, the duration of ure- mia, and the early onset of renal failure.172-175 The principal features of the syndrome are summarized in Table 8.

Although there are still many unknowns about the mecha- nisms for the development of renal osteodystrophy, hyperpara- thyroidism secondary to phosphate retention and impairment of vitamin D metabolism seem to play important roles. Uremia,176

TABLE 8. Clinical Features of Renal Osteodystrophy in Childhood*

CLINICAL MANIFESTATIONS

Growth retardation Bone pain Myopathy Skeletal deformities Rickets signs in infants

BIOCHEMICAL DATA

Increased serum AP activity Elevated serum PTH concentrations Lower serum 1,25-(OH&D3

RADIOLOGIC ABNORMALITIES

Subperiosteal resorption Epiphyseal slipping Osteopenia Rickets signs

PATHOLOGIC FINDINGS

Osteomalacia Osteitis fibrosa

*Abbreviations: AP = alkaline phosphatase. PTH = parathyroid hormone. 1,25-(OH)2-D3 = 1,25-dihydroxyvitamin-D3.

269

acidosis, and bone resistance to parathyroid hormone action are also contributing factors (Fig 7).

Accordingly, control of hyperparathyroidism and vitamin D supplements are the two principal therapeutic means to foster the efficient management of renal osteodystrophy.

DIETARY PHOSPHORUS RESTRICTION

In 1972, Slatopolsky et a1.177 showed that progressive phos- phorus restriction proportional to the decrease in glomerular fil- tration rate precluded the development of hyperparathyroidism in dogs. Subsequent clinical studies178-180 have confirmed that the limitation of phosphorus intake retards the development of uremia-associated hyperparathyroidism. It has been suggested that the favorable effect of phosphorus restriction stems from slowing the progression of renal failure,17’, lB1 but evidence with respect to this assumption is still not conclusive.

Phosphorus intakes of 500-600 mg/day for children weighing less than 20 kg and 600-1,000 mg/day for larger children are currently recommended.lz7 Low phosphorus formulas with cal- cium to phosphorus ratios of 1.4: 1 to 2.0: 1 or human breast milk may be used in infants.126 In children, a low phosphorus diet is achieved by limiting the consumption of phosphate-rich foods, such as dairy products, meat, eggs-in general, foods with high contents of animal protein.le2

Owing to patient noncompliance with the impalatability of low phosphorus diets and/or the progressive diminution of glo-

r 1 CHRONIC R-k 1 I 1 l

I I

-I impaired formation of active metabolites of

vitamin 0

b Im aired

1 04 excretion

1

1 Raised serum

PO4

I

Hypocalcemia

I . Secondary hyperparathyroidism

FIG 7. Biochemical consequences of chronic renal failure. (From Chan JCM.‘89 Used by permission.)

270

merular filtration rate, additional measures to avoid phosphorus accumulation are usually necessary.

PHOSPHATE BINDERS, CALCIUM SUPPLEMENTS

Traditionally, aluminum salts, which react with the phospho- rus in the intestinal lumen and decrease its absorption, have been prescribed to individuals with chronic renal failure. How- ever, aluminum intoxication has been clearly demonstrated in patients receivin

44 chronic dialysisls3 as well as in nondialyzed

uremic children. Dialysate with high aluminum content and ingestion of aluminum-containing phosphate binders are the main sources of aluminum in these patients.ls5

Taking into account the serious consequences of aluminum toxicity, which include progressive encephalopathy183 and vita- min D-resistant osteomalacia,186 meticulous precautions must be taken to avoid aluminum accumulation in uremic individuals.

Thus, aluminum concentration of dialysate in patients with end-stage renal disease must be maintained below 20 kg/L, and the administration of oral aluminum salts must be restricted. Low phosphorus diets and alternative phosphates binders185 are preferred. Among these, calcium lactate or carbonate are cur- rently recommended.ls7 By providing these calcium salts, three beneficial effects may be obtained. First, improvement in cal- cium homeostasis occurs secondar

7 to improvement in the cal-

cium balances of uremic children. 2g Second, uremic acidosis is decreased with the use of sodium-free alkali therapy.“’ Even- tually, additional alkali therapy (Table 9) is needed, although excessive sodium intake represents a limitin

K factor in some hy-

pertensive children with chonic renal failure. 8g Third, reduction of phosphorus absorption is achieved by the binding of this ele- ment in the intestinal lumen.

The dosage of supplemental calcium must be individualized to maintain normal serum calcium and phosphate concentrations. Usually, calcium lactate (18% Caf ‘1 or carbonate (40% Caf ‘1 with provision of 1,000 mg/sq m/day of calcium element is rec- ommended.lgO

If adequate control of serum phosphorus is not achieved in

TABLE 9. Oral Prenarations for Alkali Theranv

DRUG PREPARATION Na CONTENT BASE CONTENT

Shohl’s solution Solution 1 ml = 1 mEq 1 ml = 1 mEq Sodium bicarbonate Solution 1M 1 ml = 1 mEq 1 ml = 1 mEq

Powder 1 gm = 12 mEq 1 gm = 12 mEq Calcium carbonate Tablets Free 1 gm = 19 mEq

271

TABLE 10. Aluminum-Containing Antacids That Can Be Used as Phosphate-Binders in the Treatment of Chronic Renal Failure

PHARMACOLOGIC! COMMERCIAL NAME NAME PREPARATION Al CONTENT

Aluminum hydroxide Amphojel Solution 5 ml = 111 mg Tablets 300 mg = 111 mg

600 mg = 222 mg Aluminum hydroxide Basaljel Suspension 5 ml = 138 mg

Capsules 1 capsule = 173 mg Tablets 1 tablet = 173 mg

spite of the low phosphorus intake and calcium salt supplemen- tation, aluminum-containing phosphate binders (Table 10) should be administered. In these cases, the dose of aluminum should not exceed 30 mgikglday. Careful monitoring of plasma aluminum concentration is required in children who need more than 30 mg/kg/day.lgl Signs of toxicity are usually detected when serum aluminum concentrations exceeded 100 pg/L.lg2

Magnesium hydroxide has been suggestedlg2 as a useful phos- phate binder in adult patients on maintenance hemodialysis. Risk of hypermagnesemia and magnesium toxicity contraindi- cates the prescription of magnesium compounds in uremic pa- tients undergoing conservative treatment.

In relation to the previously mentioned measures to control hyperparathyroidism, two additional points of interest are dis- cussed here. In the early stages of renal failure, secondary hy- perparathyroidism develops despite normal serum phosphorus concentration. Therefore, a low phosphorus diet and/or phos- phate binder administration must be initiated early, before hy- perphosphatemia becomes manifest.12’ On the other hand, se- vere osteomalacia secondary to hypophosphatemia has also been reportedlg3 in patients on hemodialysis. However, although the risk of phosphate depletion must be kept in mind, serious hypo- phosphatemia in patients with chronic renal failure is very un- usual.ls2

VITAMIN D SUPPLEMENTS

Vitamin D and its various derivatives have been used in the management of chronic renal failure. In general, it has been rec- ognized that similar effects may be achieved by using large enough doses of any one vitamin D analog, capable of overcom- ing the impaired formation of 1,25 dihydroxyvitamin-Ds associ- ated with chronic renal failure.ls7

The most potent metabolites are la hydroxyvitamin-D3 and 272

1,25 dihydroxyvitamin D3.1g4 Consequently, their administra- tion provides greater facility in obtaining therapeutic success but also incurs a higher incidence of hypercalcemic toxicity. Due to the relatively short half-lives of these drugs, their toxic effects are rapidly reversed on discontinuing their administration. By contrast, much more prolonged toxic manifestations must be waited out with the use of vitamin D or other less potent metab- olites.

Thus, the higher potency and shorter duration of potential toxicity provide the rational basis for recommending 1,25 dihy- droxyvitamin-D3 or lo hydroxyvitamin-D3 in the treatment of children with chronic renal failure.126, ia7 However, owing to the powerful hypercalcemic action and high cost of these drugs, the utilization of vitamin D or some of its less potent and less expen- sive metabolites as preventive therapy for renal osteodystrophy in the early stages of chronic renal failure would be justified also.lg5

In some countries, lack of availability of liquid preparations of lo hydroxyvitamin-Da and 1,25 dihydroxyvitamin D3 limits their use in infants and small children.

Dosages of 1,25 dihydroxyvitamin-D3 at l-2 kg/day (lo-50 ng/kg/day)1879 lg6 or of lo hydroxyvitamin-Da at l-3 kg/daylg5-ig7, given orally in one or two divided doses, are usually required. Minimum doses (0.25 pg) must be initially administered with progressive increases of this dose ever< two to four weeks until serum calcium reaches normal values.’ 8, lgg Doses of alternative vitamin D metabolites are detailed in Table 11. Administration of 24,25 dihydroxyvitamin-Da seems to improve bone minerali- zation and the concurrent use of 24, 25- and 1,25 dihydroxyvi- tamin-D seems to reduce the risk of hypercalcemia.200

Adequate therapy with vitamin D metabolites will produce in- creased intestinal absorption of calcium and decreased osseous resistance to parathyroid hormone.201-207 Improvement in cal- cium balance gives rise to progressive normalization of calcium

TABLE 11. Recommended Doses of Vitamin D and Its Active Metabolites in the Treatment of Children With Chronic Renal Failure

SUBSTANCE DOSE

Vitamin-D2 (ergocalciferol) 20,000-40,000 IU/day Vitamin-D3 (cholecalciferol) 20,000-40,000 IU/day 25(OH)-D, (calcifediol) l-2 mcg/kg/day l-w(OH)-D3 l-3 mcg/day Dihydrotachysterol 0,125-l mgiday 1,25-(OH&D3 (calcitriol) lo-50 ngikglday

273

80

70

0 c 80 0 5 ; 50 0

c 40

z 0 .- 30 z a

20

10

FIG 8.

s - .

.

? T

Pretherapy Posttherapy Normal

Favorable action of 1,25-dihydroxyvitamin-D, on hyperparathyroidism of chronic renal failure is shown. Ratio between serum concentrations of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin-D, (1,25-(OH),-D) decreases following treatment with oral 1,25-(OH),-D for at least 90 days at a dose of lo-15 nglkgiday. (From Chesney RW, et aLno Used by permission.)

homeostasis and reduction of hyperparathyroidism (Fig B), with subsequent decreases of both serum phos hate concentration and serum alkaline phosphatase activity 1~,208-210 (Fig 9). At this point, due to their ability to enhance phosphorus intestinal absorption, the administration of vitamin D metabolites can pro- duce an initial hyperphosphatemic effect. For this reason, it is advisablels2 to normalize serum phosphate concentration before initiating vitamin D therapy.

Simultaneous to the biochemical improvement, children with renal osteodystrophy receiving 1,25 dihydroxyvitamin-Da or la hydroxyvitamin-Da begin to show clinical alleviation of the signs of renal osteodystrozffghx:: the osseous lesionslg7, ‘08,

and radiologic amelioration of ’ (Figs 10 and 11). Just as impor-

tantly, the beneficial effect of these metabolites on growth (Fig 274

DAILY ORAL DOSE OF I,25-DIHYDROXYVITAMIN - D3

s 1.0 E df 0.5

SEWi! 5 105’ CALCIUM; r 10.5 r - - i 0 9.5 0 : I j 9.5

F SEWhi

if

“4 PHOSPHO,RUS 0 j - i ’ ; o i

-I

I ~2~3~4~5~6~7~6~9]10~llj12~13~14~15~16

DAYS

FIG 9. Improvement in calcium and phosphorus balances and reduction of serum parathy- roid hormone concentrations during 1,25-dihydroxyvitamin-D, treatment in a seven- year-old child with creatinine clearance of 25 mliminil.73 sq. m. and radiologic signs of uremic bone disease. (From Chan JCM, et al.*” Used by permission.)

12) of uremic children has been reported by Chan et al.sogz ‘11 and Chesney et a1.212 Accelerated growth velocity during 25 hy- drox vitamin-D treatment has also been shown by Langman et al 21J. m nine children with chronic renal failure.

Effects of vitamin D therapy on histologic abnormalities of uremic bone disease are not so uniformly satisfactory.214-216 In general, lesions of osteitis fibrosa respond favorably, as a conse- quence of better control of hyperparathyroidism. On the con- trary, osteomalacic lesions are relatively resistant.

The risk of vitamin D-related hypercalcemia is always pres- ent.173 One episode of hypercalcemia (serum calcium above 11.0

275

FIG

10

. Ra

diolog

ic fin

dings

en

coun

tered

in

the

right

index

fin

ger

of a

15-ye

ar-o

ld gir

l wi

th

end-

stage

re

nal

disea

se

seco

ndary

to

inter

stitia

l ne

phro

pathy

. Fa

vora

ble

evolu

tion

is ob

serve

d aft

er

1.5

to 5

month

s of

begin

ning

thera

py

with

1-

a-hy

drox

yvita

min-

D,.

Subs

eque

nt int

erru

ption

of

activ

e vit

amin

D su

pplem

ents

(thro

ugh

medic

al no

ncom

plian

ce)

brou

ght

abou

t se

vere

deter

iorati

on.

(From

Ch

an

JCM,

Hs

u AC

. “’

Used

by

pe

rmiss

ion.)

FIG 11. Remineralization of the distal end of the left clavicle subsequent to treatment with l- cu-hydroxyvitamin-D, in a 12-year-old girl undergoing chronic hemodialysis for end- stage renal failure secondary to focal segmental glomerulosclerosis. (From Chan JCM, et al.n’o Used by permission.)

mg/dl) every 13 months was documented in 29 uremic children receiving chronic administration of 1,25 dihydroxyvitamin D3 at 20-40 ng/kg/day.lg6 The risk of hypercalcemia increases as the serum alkaline phosphatase activity becomes norma1’82 (Fig 13). Therefore, when serum alkaline phosphatase returns to normal

277

= tJ 14- 0 = 12- >

- z IO

g 8- 5

6-

4-

2-

O-

\\ HEIGHT VELOCITY, BOYS

+2 SD

MEAN

\\ HEIGHT VELOCITY, GIRLS

+2 S.D

I I I I I I I I I I 1

0 2 4 6 8 IO I2 I4 I6 I8 20

AGE IN YEARS

FIG 12. Data on height velocity in 11 children with chronic renal failure before and after initiating 1,25-dihydroxyvitamin D3 supplementation at 10 to 35 ngikglday. The be- ginning of treatment is symbolized by arrows. Note how the growth improvement is not observed in two of three children older than 12 years. (From Chan JCM, et al.“’ Used by permission.)

278

ALKALINE

PnosPnAlAsE

(NJ/L)

SEmIa PnOSPmRUS

(mr/dl)

. 4 0 6 12 IS 24 30 36 42

FIG 13. Clinical data of an adult patient with chronic renal failure (serum creatine 7-9 mgi dl). Serum calcium increases as alkaline phosphatase decreases. A rapid reduction in alkaline phosphatase activity precedes the onset of hypercalcemia and increment of serum phosphorus concentrations. Hypercalcemia reverts after discontinuation of 1.25dihydroxyvitamin-D, (1,25-(OH),-D,) supplements. (From Salomon DR, Mitch WE.‘@ Used by permission.)

279

concentrations, particularly strict monitoring of serum calcium and even a preventive reduction in the 1,25 dihydroxyvitamin D3 dosage is advisable.“’

If, despite these measures, hypercalcemia is observed, vitamin D therapy has to be temporarily discontinued until serum cal- cium is normalized. This usually occurs after an interval of one to two weeks, provided the patient was receiving ~CK hydroxyvi- tamin D3 or 1,25 dihydroxyvitamin-D3.18g Reinstitution of these drugs at 50%-75% of the previous dose is recommended.18’ In a similar fashion, calcium supplements must be interrupted when serum calcium remains elevated.

With respect to other toxic effects, significant hypercalciuria is not habitually observed1873 211* 215 and risks of metastatic cal- cifications may be avoided by maintaining serum calcium phos- phorus product below 6O-7O.187X lg6 In children, a deleterious ef- fect of 1,25 dihydroxyvitamin-D3 on renal function has not been demonstrated (Fig 14).lg6, 211 However, episodes of hypercal- cemia are associated with accelerated renal function deteriora- tion.lg6 Consequently, good control of calcium homeostasis is im- perative.

Concerning the less well-known measures to control the hy- perparathyroidism of chronic renal failure, reduction of serum parathyroid hormone concentrations by over 50%-75% have been shown217 in hemodialysis patients treated with propanolol. Although a role of beta-2 receptors in parathxroid hormone and calcitonin secretions has been suggested,21 clinical trials21g have not yielded distinct benefits of propanolol therapy in pre- venting uremic bone disease. Similarly, appreciable decreases in serum parathyroid hormone concentrations have been detected220 in hemodialyzed adults receiving cimetidine.

At present, the role of these drugs in the treatment of renal osteodystrophy remains to be better elucidated.

PARATHYROIDECTOMY

As a rule, subtotal parathyroidectomy should be considered if severe h apy.l*% 1x8

erparathyroidism is’not controllable by medical ther- Specific indications for subtotal parathyroidectomy

are listed in Table 12. Currently, total parathyroidectomy and autotransplantation of a small part of excised

!? glands in the forearm musculature is recommended.2 arathyroid ’ With this

procedure, partial removal of the transplanted tissue may be easily performed if uncontrollable hyperparathyroidism recurs.

CHRONIC DIALYSIS

The influence of chronic dialysis on renal osteodystrophy is variable”‘, 222 and therapeutic implications have already been

280

1.25~DlHYDROXYVlTAMlN -D, BEFORE & AFTER

0.60 -

W z z 045

E l!i!

0.35

o 0.25

5 0.15 -.

iti

FIG 14. No deleterious effect of 1.25 dihydroxyvitamin-D, therapy on rate of renal function deterioration estimated by sequential determinations of reciprocal serum creatinine concentrations. (From Chan JCM, et al.*” Used by permission.)

-I 9 1.80- o E

1.60- 5 I40-

k 1.20 -

1.00 -

0.80 -

0.60 -

I 1 1 ‘, I ( (

-36-24 12 0 12 24 36 MONTHS

mentioned. Considering that a partly new metabolic situation arises in children entering into dialysis, adjustments in the medical treatment are frequently required. Dialysate with a cal- cium concentration of 7 mg/dl is currently recommended,‘87 be- cause long-term involution of secondary hyperparathyroidism by using hemodialysis with high calcium dialysate has not been ob- served.223

In addition, patients on chronic ambulatory peritoneal di- alysis, particularly if they are dialyzed with solutions enriched in glucose, will need greater calcium supplementation to com- pensate for the ~$&ieal losses of both calcium and 25-hy- droxyvitamin-D3. ’

281

TABLE 12. Suggested Indications for Parathyroidectomy After Failure of Adequate Conservative Treatment*

I. Marked secondary hyperparathyroidism (not responsive to medical management): A. Increased PTH B. Bony erosions C. Osteitis fibrosa cystica on bone

biopsy II. In association with:

A. Hypercalcemia B. Progressive extraskeletal

calcifications C. Intractable pruritus D. Severe bone pain, fractures through

known tumors for epiphyseal slipping in children

E. Calciphylaxis

‘From reference 187. Used by permission

RECENT ADVANCES IN TREATMENT OF HYPERTENSION

Renal reabsorption of sodium221 is diminished by diuretics such as thiazides. Diuresis ensues from the natriuresis, which brings about decreased plasma volume, reduced cardiac output, fall in peripheral resistance, and reversal of hypertension.

As a consequence, several complications can develop. Hypo- natremia may follow the natriuresis, cardiac output may be so reduced as to cause postural hypotension, plasma volume reduc- tion may cause a fall in renal blood flow and reduced glomerular filtration rate may bring about prerenal azotemia. In addition, hyperuricemia may result from the reduction in glomerular fil- tration rate, increased proximal reabsorption, and decrease in clearance of uric acid. Concomitantly, the elevated proximal cal- cium reabsorption secondary to diuretic therapy results in a fall in calcium clearance and subsequently hypercalcemia.223 Fur- thermore, the increased distal calcium reabsorption contributes to the hypercalcemia.

Finally, plasma renin and aldosterone secretion are stimu- lated by the contracted plasma volume, which promotes second- ary hyperkaliuria.224 The hypokalemia may be symptomatic, and patients may complain of muscle weakness, progressive polyuria, and reduced glucose tolerance.

The first stage of management of mild hypertension begins with diuretics (Table 13). In advanced chronic renal disease,

282

chlorothiazide and/or hydrochlorothiazide is avoided because it is not effective after the GFR is less than 50% of norma1.22” Furosemide or ethacrymic acid (see Table 13) is the preferred diuretic. In addition, propranolol and hydralazine are used (see Table 13).

With moderate hypertension, furosemide is initiated in con- junction with propranolol or hydrochlorothiazide. Subsequently, a combination of furosemide, propranolol, and another beta blocker such as atenolol and the vasodilator hydralazine.225-228 If this fails to control hypertension, individualized treatment with more potent antihy dil, clonidine and others, B

ertensives, such as captopril, minoxi- 25 is indicated.

For emergency treatment of acute hypertension,226, 228 intra- venous antihypertensives (Table 14) are ueeded. Diazoxide should be given by intravenous push and can be repeated once after 30 minutes. It should not be given more than twice. So- dium nitroprusside (see Table 14) must be given by a constant infusion pump. The dose of sodium nitroprusside should be ti- trated to the blood pressure response.

HOW TO EXPLAIN DIALYSIS AND TRANSPLANTATION TO THE PARENTS

At an early stage in the disease process of the child, a priority of the nephrologist is to explain to the parents about the details of the child’s renal disease and its prognosis.22g The initial step for parents with a child having a progressive renal disease is to reach a realistic acceptance of the situation and the need for treatment.22g* 230 As the patient’s renal function progresses to renal failure, education of the family about the different thera- peutic modalities (i.e., dialysis, transplantation) becomes a ma- jor concern. The parents should be educated over time about when dialysis will be needed and the different aspects of dialysis and renal transplantation. In addition, meetings with dialysis and transplantation personnel and visits to the dialysisitrans- plant units should be arranged to provide further information about these areas.

As with all chronic disease processes, the family of the child ill with renal disease will experience a series of emotional ups and downs concerning the future.231 The parental responses to a child with end-stage renal disease include the following coping responses: denial, anger, guilt, depression, marital stress, and rejection/overprotection of the sick child.22g The physician should plan to meet with both parents together on a frequent basis to minimize marital stress and convey information on their child. The time spent with the parents answering their ques- tions and assuaging their fears provides dividends in future co- operation by the parents. Initially renal transplantation for the

283

TABL

E 13

.

g Or

al An

tihyp

erten

sives

for

Ma

inten

ance

Tr

eatm

ent

P .

MEC

HAN

ISM

O

F AC

TIO

N

DR

UG

PR

EPAR

ATIO

N

INIT

IAL

DO

SE

ON

SET

DU

RAT

ION

C

OM

MEN

TS

Diur

etic

Hydr

ochlo

rothi

azide

25

- an

d 50

-mg

(Hyd

rodiu

ril)

tablet

s

Furo

semi

de

(Lasix

) 10

mgim

l

Vaso

dilato

r

Etha

crynic

ac

id (E

decri

n)

Hydr

alazin

e (A

pres

oline

)

25-

and

50-m

g tab

lets

50-m

g/50-

ml

vial

lo-,

25-,

and

50-m

g tab

lets

Comb

ined

6- rec

eptor

blo

ckad

e an

d inh

ibitio

n of

renin

re

lease

Prop

rano

lol

(Inde

ral)

Comb

ined

symp

atheti

c inh

ibito

r an

d pe

riphe

ral

nore

pinep

hrine

de

pletio

n

Methy

ldopa

(A

ldome

t)

0.5-l

mgikg

iday

2 hr

6-12

hr

2 mg

ikgido

se

0.5-l

mgikg

idose

1-2

mgikg

iday

30

min

1 mi

n (IM

) 30

mi

n 1

min

(IV)

3 hr

6-8

hr 4

hr

6-8

hr 4

hr

6 hr

lo-,

20-,

40-,

and

SO-m

g tab

lets

l-2

mglkg

lday

125-

an

d 25

0-mg

tab

lets

IO-60

mg

/kg/da

y

2 hr

3 hr

8 hr

8 hr

Hypo

kalem

ia,

hype

rglyc

emia,

hy

peru

ricem

ia Hy

poka

lemia,

hy

pona

tremi

a, dia

rrhea

Hy

poka

lemia,

hy

pona

tremi

a, dia

rrhea

Ta

chyc

ardia,

pa

lpita

tion,

he

adac

he,

nasa

l dry

ness

, lup

us-lik

e re

actio

n (ra

re in

child

ren)

Br

adyc

ardia

, br

onch

ospa

sm,

cong

estiv

e he

art

failu

re,

lighth

eade

dnes

s, hy

pertr

ichos

is Po

stura

l hy

poten

sion,

drow

sines

s, an

d ele

vated

Co

omb’s

tes

t an

d liv

er

enzy

me

P-re

cepto

r blo

ckad

e Me

topr

olol

50-

and

100-

mg

(Lopre

ssor)

ca

psule

s

P-re

cepto

r blo

ckad

e At

enolo

l 50

- an

d 10

0-mg

tT

enor

min)

tab

lets

Comb

ined

vaso

dilato

r an

d u-

block

ade

Praz

osin

(Mini

pres

s) l-,

Z-,

and

5-mg

Conv

ertin

g en

zyme

Ca

ptop

ril 25

an

d 10

0-mg

inh

ibito

r (C

apten

) tab

lets

Perip

hera

l (p

ostga

nglio

nic)

nore

pinep

hrine

de

pletio

n Va

sodil

ator

Guan

ethid

ine

(Isme

lin)

Mino

xidil

(Lon

iten)

lo-

and

25mg

tab

lets

2.5

and

lo-mg

tab

lets

Comb

ined

Rese

rpine

O.

l-, 0.2

5-,

06,

symp

atheti

c (S

andr

il, Se

rpas

il) l-m

g ta

blet

s

inhibi

tor

perip

hera

l no

repin

ephr

ine

deple

tion

h) g IV

mt

rave

nous

ly;

IM

= int

ramu

scula

rly.

l-5

mglkg

iday

l-l%

hr

0.5-l

mgikg

iday

1 hr

0.05

mgikg

iday

l-4

mgikg

lday

0.2-2

.5 mg

ikglda

y

1 mg

iday;

t 1

mg

every

2

days

0.02

mgikg

lday

2 hr

2 hr

2 da

ys

3 hr

3 da

ys

12 h

r

24 h

r

8 hr

8 hr

10 h

r

8 hr

14 d

ays

Fatig

ue,

head

ache

, diz

zines

s, ins

omnia

, br

onch

ospa

sm

Dizz

iness

, na

usea

, br

adyc

ardia

, br

onch

ospa

sm,

agra

nuloc

ytosis

Dr

owsin

ess,

dizzin

ess,

head

ache

, pa

lpita

tion,

po

sitive

AN

A Hy

perka

lemia,

fev

er,

rash,

tachy

card

ia,

“rebo

und

hype

rtens

ion”

Postu

ral

hypo

tensio

n, he

adac

he,

dizzin

ess,

brad

ycar

dia,

impo

tence

Ta

chyc

ardia,

flu

id re

tentio

n, hir

sutis

m,

peric

ardia

l eff

usion

Dr

owsin

ess,

tachy

card

ia,

nasa

l co

nges

tion,

ulcer

de

pres

sion

TABL

E 14

. Pa

rente

ral

Antih

yper

tensiv

es

for

Emer

genc

y Tr

eatm

ent

of Hy

perte

nsion

MEC

HAN

ISM

O

F AC

TIO

N

DR

UG

PR

EPAR

ATIO

N

INIT

IAL

DO

SE

ON

SET

DU

RAT

ION

C

OM

PLIC

ATIO

NS

Vaso

dilato

r

Vaso

dilato

r

Comb

ined

symp

atheti

c inh

ibito

r an

d pe

riphe

ral

nore

pinep

hrine

de

pletio

n Co

mbine

d sy

mpath

etic

inhibi

tor

and

perip

hera

l no

repin

ephr

ine

deple

tion

Vaso

dilato

r

o-blo

ckad

e

Diaz

oxide

(H

ypers

tat)

Hydr

alazin

e (A

pres

oline

) Me

thyldo

pa

(Aldo

met)

Rese

rpine

(S

erpa

sil)

Sodiu

m nit

ropr

ussid

e (N

ipride

)

Phen

tolam

ine

(Reg

itinel

300

mg

in 20

-ml

ampu

l

20

mg

in l-m

l am

pul

250

mg

in 5-

ml

ampu

l

5 mg

in

2-ml

am

pul

50

mg

in 5m

l via

l

5 mg

in

l-ml

2-5

mg/kg

IV

pu

sh

0.24

mgikg

ev

ery

6 hr

IV

5-10

mg

ikg

every

6

hr IV

0.02

mglkg

lever

y 4-

6 hr

IM

0.5-8

mc

glkglm

in

1 mc

gikgim

in inc

reas

e at

1 mc

glkgim

in ma

ximal

dose

7

mcgik

glmin

Imme

diate

10

min

2 hr

2 hr

Imme

diate

l-2

min

5 hr

l-6

hr

6 hr

12

hr

i/z-3

hr

Tach

ycard

ia,

weigh

t ga

in,

hype

rglyc

emia,

bu

rning

at

injec

tion

site

Tach

ycard

ia,

palpi

tatio

n,

head

ache

Po

stura

l hy

poten

sion,

drows

iness

an

d ele

vated

Co

omb’s

tes

t an

d liv

er

enzy

me

Drow

sines

s, tac

hyca

rdia,

na

sal

cong

estio

n, ulc

er

Light-

inacti

vatio

n, hy

pothy

roidi

sm,

cyan

ide

accu

mulat

ion

Tach

ycard

ia,

arrh

ythmi

as,

angin

a pe

ctoris

, diz

zines

s, ga

stroin

testin

al dis

turba

nces

Us

e no

repin

ephr

ine

to co

unter

act

hypo

tensio

n (d

o no

t us

e ep

ineph

rine)

child may be seen as an unrealistic goal by the parents. How- ever, this may change as the child’s health improves on di- alysis.231 In general, a great deal of time is needed to clarify medical information on dialysis/transplantation to the family and helping the parents cope with their feelings.

ACKNOWLEDGMENTS

The authors wish to thank Mrs. Betty Timozek and Ms. Rosa L. Bailey for secretarial assistance, and Mrs. B. I. Friedman and Martha D. Massie, R. D. for research assistance. Supported in part by NIH grant AM HD 31370.

287

APPENDIX

I NOMOGRAM ‘-1

HEIGHT cm. In

1

e.0 - -- 90

S!A. WiICHT

FIG A-l.

For Children of Normol HIqht

for Weight 90 00 TO

6

z

130 I.*0 LIO I.00

SO .eo

Surface area monogram. (From Boyd E, W esi t CD: The Harriet Lane Handbook, ed 10. Chicago, Year Book Medical Publishers, 1984. Used by permission.)

288

SA(m’l 90

60

65 55 60 50

75 - :5 -

70 - LO -

65 - 35 -

60 - 30 -

yj I5

- ,L

- 13

- 12

- I,

10

9

Cl

7

E 55 -

u 15 - -

x 50-

E

.o, _ ?O -

4 LS-

‘0 - I5 -

35 -

10 - -

30 -

- 25

- 2

- 15

-1

SA = W 5’mx H =x .02L265 FIG A-2. Surface area monogram in infants. To use the monogram, a ruler is used to align with the height and weight on the two lateral axes. The point at which the center line is intersected gives the corresponding value for surface area. (From Haycock GB, et al.: J Pediafr 1978; 33:62. Used by permission.)

289

REFERENCES

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2. Nelson P, Stover J: Principles of nutritional assessment and management of the child with E.S.R.D., in Fine RN, Gruskin AB (eds): End-Stage Renal Disease in Children. Philadelphia, WB Saunders Co, 1984, pp 209-226.

3. Blumenkrantz MJ, Kopple JD, Gutman RA, et al: Methods for assessing nutritional status of patients with renal failure. Am J Clin Nutr 1980; 33:1567.

4. Johannesen J, Lie M, Kiil F: Effect of glycine and glucagon on glomerular filtration and renal metabolic rates. Am J Physiol 1977; 223:F61.

5. Meyer TW, Lawrence WE, Brenner BM: Dietary protein and the progres- sion of renal disease. Kidney Znt 1983; 24:S243.

6. Maschio G, Oldrizzi L, Tessitore N, et al: Effects of dietary protein and phosphorus restriction on the progression of early renal failure. Kidney Znt 1982; 22:371.

7. Oldrizzi L, Rugiu C, Valvo E, et al: Progression of renal failure in patients with renal disease of diverse etiology on protein-restricted diet. Kidney Znt 1985; 27:553.

8. Chan JCM, Beale MG: The progression of end-stage kidney disease in chil- dren. Proc Child HOW Nat1 Med Ctr 1974; 30:202.

9. Chan JCM, Goplerud JM, Papadopoulou ZL, et al: Kidney failure in child- hood. Znt J Pediatr Nephrol 1981; 2:201.

10. Recommended Dietary Allowances. Food and Nutrition Board. Washington, DC, National Academy of Sciences-National Research Council, 1980.

11. Dartois AM, Broyer M: Dietetique et nephrologie pediatrique, in Royer P, Habib R, Mathieu H, et al (eds): Nephrologie Pediatrique. Paris, Flamma- rion Medecine-Sciences, 1983, pp 568-590.-

12. Counahan R. El-Bishti M. Cox BD. et al: Plasma amino acids in children and adolescents on hemodialysis. Kidney Znt 1976; 10:471.

13. Walser M, Coulter AW, Dighe S, et al: The effects of ketoanalogues of es- sential amino acids in severe chronic uremia. J Clin Invest 1973; 13:678.

14. Mitch WE, Walser M, Steinman TI, et al: The effect of a keto acid-amino acid supplement to a restricted diet on the progression of chronic renal fail- ure. N En& J Med 1984; 311:623.

15. Bergstrom J: Discovery ‘and rediscovery of low protein diet. Clin Nephrol 1984; 21:29.

16. Mitch WE: Nutritional therapy in renal failure, in Seldin DW, Giebisch G (eds): The Kidney: Physiology and Pathophysiology. New York, Raven Press, 1986, pp 2059-2082.

17. Jones RWA, Dalton W, Start K, et al: Oral essential amino acid supple- ments in children with advanced chronic renal failure. Am J Clin Nutr 1980; 33:1696.

18. Broyer M, Guillot M, Niaudet P, et al: Comparison of three low-nitrogen diets containing essential amino acids and their alpha analogues for se- verely uremic children. Kidney Znt 1983; 24:S290.

19. Sigstrom L, Attman PO, Jodal U, et al: Growth during treatment with low- protein diet in children with renal failure. Clin Nephrol 1984; 21:152.

20. Holliday MA: Calorie intake and growth in uremia. Kidney Znt 1975; S73. 21. Holliday MA: Metabolic rate and organ size during growth from infancy to

maturity and during late gestation and early infancy. Pediatrics 1971; 47:169.

22. Simmons JM, Wilson CJ, Potter DE, et al: Relation of calorie deficiency to growth failure in children on hemodialysis and the growth response to cal- orie supplementation. N Engl J Med 1971; 285:653.

23. Arnold WC, Danford D, Holliday MA: Effects of caloric supplementation on growth in children with uremia. Kidney Znt 1983; 24:205.

291

24.

25.

26.

27.

28.

29.

30.

31.

32

33

34

35

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47. 48.

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