ages 1 and 8. Kidney function, blood pressure, and C 3 complement levels are normal. Microscopic hematuria may be noted. Response to corticosteroids occurs within 3 weeks in the majority of children who then may con- tinue a relapsing/remitting course for 5–10 years, usu- ally followed by a permanent remission. Potentially serious complications include infections (peritonitis, pneumonia, bacteremia, and meningitis) as well as vas- cular thromboses. For children with frequent relapses (20–25% of cases) or the minority who do not respond to steroids, other medications that may be useful include cyclophosphamide, cyclosporine, tacrolimus, and mycophenolate mofetil. The cause of minimal change nephrotic syndrome is unknown. • Focal segmental glomerular sclerosis (FSGS) is the second most common glomerular disorder with nephrotic syndrome. Patients with FSGS rarely respond to steroids but may improve with cyclosporine, tacrolimus, cyclophosphamide, or mycophenolate mofetil. Untreated, most children progress from having normal kidney function to end-stage kidney disease and require transplantation. Unfortunately, the condition may recur after transplantation as well, but unlike the disease in native kidneys, it may remit after a course of intensive plasmapheresis. • Membranoproliferative glomerulonephritis (MPGN) and membranous glomerulonephropathy (MGN) often present with nephrotic-range proteinuria, often with overt nephrotic syndrome. MPGN may present with or without hematuria and is usually accompanied by profound hypocomplementemia. There are three subtypes of MPGN, each distinguished by kidney biopsy. Treatment with alternate day corticosteroids is often of benefit, particularly when started early in the course of the disease. MGN is uncommon in children and may accompany hepatitis B infection, systemic lupus erythematosus (SLE), or neonatal syphilis. As an idiopathic glomerular disorder, it is often treated with long-term, alternate-day steroids with benefit. Immunosuppressive agents also have been reported to be effective, although no prospective clinical trials have established the efficacy of either treatment in the pediatric age range. • Diffuse mesangial proliferative glomerulonephritis is often diagnosed on kidney biopsy after a nephrotic child remains with unremitting proteinuria after the initial 4–6 weeks of prednisone treatment. The course and prognosis vary, with approximately one-third of children achieving remission with either steroids or other immunosuppressive medications, one-third remaining persistently proteinuric while maintaining excellent glomerular function, and one-third progress- ing to kidney failure. • Nephrotic syndrome can accompany systemic child- hood diseases as well. Lupus nephritis and the nephritis of Henoch-Schonlein purpura are the two most common diseases in this category. When accompanied by heavy proteinuria, the kidney biopsy findings are usually abnormal, with extensive glomerular crescents. Treatment of the underlying ill- ness may improve the kidney disease but patients with the most damage on biopsy are the most likely to progress to end-stage kidney disease with the need for transplantation. • Diseases that less commonly present with nephrotic syndrome include human immunodeficiency virus (HIV) nephropathy, nephropathy of epithelial cello (solid-organ) malignancies, Hodgkin disease, and systemic vasculitis. • Congenital nephrotic syndrome (CNS) is a rare, autoso- mal recessive disorder that presents at birth with mas- sive proteinuria and anasarca. It occurs in many ethnic groups, but was first reported in Finland. The disorder results from mutations in the gene coding for nephrin (NPHS1), a transmembrane protein of the glomerular basement membrane. Most, but not all children, develop early kidney failure and require dialysis, bilateral nephrectomy, and kidney transplantation by age 5. Significant accompanying problems are poor nutrition, hypercoagulability, and hypothyroidism. Instead of a nephrin mutation, other children with a congenital form of nephrotic syndrome present with diffuse mesangial sclerosis. This condition is often associated with gonadal abnormalities when related to a mutation in the WT1 Wilms tumor gene. • Glomerular diseases that present without nephrotic syndrome are listed in Table 119-2. These conditions 442 SECTION 15 • DISEASES OF THE KIDNEY, URETERS, AND BLADDER TABLE 119-1 Glomerular Disorders That Usually Present with Nephrotic Syndrome Minimal change disease (lipoid nephrosis) Focal segmental glomerulosclerosis Mesangial IgM nephropathy Diffuse mesangial proliferation Congenital nephrotic syndrome Membranoproliferative glomerulonephritis Membranous nephropathy HIV nephropathy TABLE 119-2 Glomerular Disorders That Usually Present without Nephrotic Syndrome IgA nephropathy Henoch-Schonlein purpura nephritis Rapidly progressive glomerulonephritis Acute glomerulonephritis Alport syndrome Lupus nephritis CHAPTER 119 • GLOMERULAR DISEASE 443 can be separated into ones with an acute presentation and others that are chronic disorders. • Acute glomerulonephritis typically occurs after an acute, systemic viral or bacterial infection. Florid “textbook” cases present with the constellation of coca-cola colored urine, edema, hypertension, olig- uria, and hypertension, all following an antecedent infection 10–21 days earlier. While group A beta- hemolytic streptococcus is the most common etio- logic agent, other streptococci, Staphylococci, Pneumococcus, Mycoplasma, Leptospira, Menin- gococci, and viruses such as Varicella, Rubeola, CMV, Herpes simplex, and Epstein-Barr Virus have been reported to cause postinfectious glomeru- lonephritis. Blood levels of C 3 are very low at pres- entation in over 90% of cases and normalize within 6 weeks of diagnosis. Treatment is supportive and consists of sodium and water restriction, reduction of blood pressure, diuretics, and regulation of potas- sium, phosphorus, and acid-base homeostasis. The prognosis for full recovery is very high with almost all children experiencing resolution of proteinuria within 6 months and microscopic hematuria within 18–24 months of onset while maintaining normal kidney function. The few exceptions are children who experienced severe glomerular dysfunction at the onset with crescents on kidney biopsy and nephrotic-range proteinuria beyond 3 months. •A hypocomplementemic glomerulonephritis can accompany subacute bacterial endocarditis and ven- triculoatrial shunt infection. These nephropathies gen- erally resolve with successful treatment of the underlying infection. • Idiopathic crescentic glomerulonephritis is another acute glomerular disorder occasionally seen in chil- dren. Often an antineutrophil cytoplasmic antibody (ANCA) is found and may be useful in both diagnosis and assessing adequacy of treatment. Goodpasture syn- drome (antiglomerular basement membrane antibody- mediated nephritis with pulmonary hemorrhage) is extremely rare in children. • There are a number of chronic glomerular disor- ders. The most common of these is IgA nephropa- thy, which typically presents in a boy older than age 8 who develops recurrent episodes of gross hema- turia coincident with upper respiratory or other nonspecific infections, most often with normal kidney function, blood pressure, and C 3 levels. The diagnosis is established by the presence of IgA antibody within the mesangium of glomeruli on immunofluorescence microscopy. Patients with minimal proteinuria, normal blood pressure, and normal kidney function generally do not progress to more serious kidney disease in childhood. Definitive treatment of this condition has not been established though clinical trials in adults have sug- gested benefits from long-term use of omega-3 fish oils and ACE inhibitors. • Membranoproliferative glomerulonephritis and membranous glomerulonephropathy may present without nephrotic syndrome. They are described in the section on glomerular disorders associated with nephrosis. • Alport syndrome is a result of a mutation in the colla- gen gene responsible for the basement membrane of glomerulus, the cochlea, and the lens of the eye. Most often the mutation is in the alpha-5 chain of type IV collagen, coded on the X chromosome. These boys usually develop progressive glomerular dysfunction and a high-frequency, sensorineural hearing loss by late adolescence. They usually require kidney trans- plantation. •Patients with Henoch-Schonlein purpura develop hematuria, proteinuria, or kidney dysfunction in approximately 25% of cases. While microscopic hematuria alone carries a favorable prognosis, this may not be the case when heavy proteinuria, hypertension, or kidney dysfunction is present. Kidney biopsy find- ings may help define the prognosis and best course of treatment, which may consist of steroids and other immunosuppressives. • Clinical assessment: Children who present with a possible glomerular disorder should be differentiated with regard to whether they have hematuria and/or proteinuria. • Isolated proteinuria greater than 500 mg/m 2 /d, or pro- teinuria of 200 mg/m 2 /d when accompanied by hema- turia, suggest the presence of a significant glomerular lesion. • In assessing the history, the physician should, in par- ticular, determine whether the patient has had decreased urine output, headache (a potential sign of hypertension), an antecedent illness, or symptoms of inflammation such as rashes or arthritis. •A family history of deafness should be sought. •Physical examination should evaluate the patient for rashes or arthritis, edema, and most importantly for hypertension. • Initial laboratory evaluation, in addition to urinalysis for blood, protein, and casts, should examine blood urea nitrogen, serum creatinine, serum complement levels, and antinuclear antibody. • The finding of nephrotic symptoms, decreased renal function, abnormal serum electrolytes, or hyperten- sion should lend some urgency to this referral. • Referral to a pediatric nephrologist should be con- sidered for any patient with suspected glomerular disease. BIBLIOGRAPHY Bhimma R, Coovadia HM, Kramvis A, Adhikari M, Kew MC, Connolly CA. HBV and proteinuria in relatives and contacts of children with hepatitis B virus-associated membranous nephropathy. Kidney Int 1999;55:2440–2449. Braun MC, West CD, Strife CF. Differences between membra- noproliferative glomerulonephritis types I and III in long-term response to an alternate-day prednisone regimen. Am J Kidney Dis 1999;34:1022–1032. Niaudet P. Treatment of lupus nephritis in children. Pediatr Nephrol 2000;14:158–166. O’Donoghue DJ, Lawler W, Hunt LP, Acheson EJ, Mallick NP. IgM-associated primary diffuse mesangial proliferative glomerulonephritis: natural history and prognostic indicators. Q J Med 1991;79:333–350. Patrakka J, Kestila M, Wartiovaara J, Ruotsalainen V, Tissari P, Lenkkeri U, et al. Congenital nephrotic syndrome (NPHS1): features resulting from different mutations in Finnish patients. Kidney Int 2000;58:972–980. Ray PE, Rakusan T, Loechelt BJ, Selby DM, Liu XH, Chandra RS. Human immunodeficiency virus (HIV)-associated nephropathy in children from the Washington, DC area: 12 years’ experience. Semin Nephrol 1998;18–25. Robson WL, Leung AK. Henoch-Schonlein purpura. Adv Pediatr 1994;41:163–194. Schnaper HW. Focal segmental glomerulosclerosis. In: Neilson EG, Couser WG (eds.), Immunologic Renal Disease, 2nd ed. Philadelphia, PA: Lippincott Williams and Wilkins, 2001, pp. 1001–1027. Schnaper HW, Robson AM. Nephrotic syndrome: minimal change disease, focal glomerulosclerosis, and related disorders. In: Schrier RW, Gottschalk CW (eds.), Diseases of the Kidney and Urinary Tract, 7th ed. Philadelphia, PA: Lippincott Williams and Wilkins, 2001, pp. 1773–1831. 120 ACUTE INTERSTITIAL NEPHRITIS H. William Schnaper OVERVIEW • The term acute interstitial nephritis (AIN) refers to inflammation of nonglomerular and nonvascular ele- ments of the renal parenchyma; that is, the tubules and interstitium. It is also referred to as acute tubulointer- stitial nephritis. Normally tubules are closely packed with minimal intervening stromal elements. Mediators of inflammation (cytokines, chemoattractants) accom- pany cellular infiltration of the interstitium surround- ing tubules in both the cortex and medulla. It is also believed that nephrotoxic insults to tubular cells cause injured cells to release inflammatory mediators into the local interstitium, including chemoattractants that stimulate cellular infiltration. • Acute interstitial nephritis usually presents as the insidious but rapid onset of acute kidney failure. Although it is not commonly encountered in children, when it does occur it is usually as a consequence of a hypersensitivity reaction to a medication; however, in a technical sense, invasive bacterial infection of the renal parenchyma (acute pyelonephritis) is also a form of AIN. Acute transplant rejection is also a form of acute tubulointerstitial nephritis. ETIOLOGY • Most instances of AIN encountered in pediatrics are due to immune-mediated acute hypersensitivity reac- tions to medications. The Table 120-1 lists medica- tions implicated in hypersensitivity-induced AIN. • The precise mechanisms of immune mediation are under study but are believed to involve both B-cell and T-cell mediated mechanisms. It is possible that an unusual conformational configuration of a ligand- receptor complex functions as a neoantigen triggering an immune reaction. Although mononuclear cells are prominent in the interstitial infiltrate, eosinophils are sometimes seen when AIN is associated with a hyper- sensitivity reaction to a medication. CLINICAL PRESENTATION • The prodrome and onset of overt illness are accompa- nied by nonspecific symptoms and recognition of impaired kidney function may be delayed. Typical symptoms include malaise, fatigability, nausea, emesis, rash, and fever. DIAGNOSIS • The presence of azotemia may be the first evidence of kidney involvement. Acute kidney failure may be either oliguric or nonoliguric. If the inflammatory 444 SECTION 15 • DISEASES OF THE KIDNEY, URETERS, AND BLADDER TABLE 120-1 Medications That Cause Acute Interstitial Nephritis Penicillins Cephalosporins Sulfonamides Quinolones Thiazides Furosemide Allopurinol Phenytoin Rifampin CHAPTER 121 • PROXIMAL AND DISTAL TUBULAR DISEASE 445 process is especially active in the kidney medulla with disruption of the countercurrent multiplier mecha- nism, urine output may not be diminished and the urine concentration may be relatively dilute. • The urine may not have striking findings although microscopic hematuria, sterile pyuria, and low-grade proteinuria are common; however, since the dipstick is not sensitive to low-molecular mass proteins, the presence of tubular proteinuria may go unrecognized. Subnephrotic-range proteinuria for pediatric-age patients is a random urine protein-creatinine ratio less than 0.5–2.0. AIN associated with a hypersensitivity reaction to nonsteroidal anti-inflammatory drug (NSAID) administration may be accompanied by nephrotic-range proteinuria. Examination of the sedi- ment may reveal eosinophils if an appropriate cellular stain is used. A peripheral blood differential count may show eosinophilia. A definitive diagnosis is established by means of a kidney biopsy. TREATMENT • The usual management of acute kidney failure should be implemented, including dialysis if indicated. Prompt cessation of the offending medication will often be followed by rapid reversal of acute kidney failure. If resolution of impaired kidney function is delayed, a course of steroid treatment, for up to sev- eral weeks, is often used; however, there are no ran- domized controlled trials attesting to its efficacy. 121 PROXIMAL AND DISTAL TUBULAR DISEASE Craig B. Langman TUBULAR DISEASES PROXIMAL TUBULE • The proximal tubule of the kidney is responsible for bulk transport of fluid and all substances that enter after glomerular filtration. Failure of the proximal tubule may be restricted to the efficient movement of bicar- bonate out of the urinary filtrate, and is termed proxi- mal renal tubular acidosis (PRTA) (or type II). When the complete resorptive apparatus of the proximal tubule is inefficient, the term renal Fanconi syndrome is applied. The diseases of the proximal tubule may be genetic or acquired, and are listed in Table 121-1. Referral to a pediatric kidney diseases specialist is required for confirmation of most cases of proximal tubular dysfunction, as the testing is specialized. • The symptoms of chronic metabolic acidosis usually prevail, even in a Fanconi syndrome. Such symptoms may include anorexia, nausea, emesis, cachexia, muscle weakness, rickets, and linear growth failure. Signs include those associated with the symptoms listed above. The laboratory evaluation usually reveals a hypokalemic metabolic acidosis and any of the features that would be suggested by a systemic disease listed in the tables. TABLE 121-1 Causes of Proximal Renal Tubular Acidosis Primary Sporadic Transient childhood Persisting (adult onset) Genetically determined Primary PRTA Sporadic transient Genetic Autosomal dominant Autosomal recessive Isolated PRTA with mental retardation and occular and dental abnormalities Pyruvate carboxylase deficiency Mitochondrial myopathies Osteopetrosis with carbonic anhydrase deficiency Sporadic Genetic Drug-induced (acetazolamide, sulfanilamide, mafenide acetate) Secondary Hereditary multiple proximal tubular dysfunction, Fanconi syndrome Cystinosis Galactosemia Glycogen storage disease type 1 Hereditary fructose intolerance (with fructose exposure) Tyrosinemia Wilson disease Heavy metals Drugs and toxins Carbonic anhydrase (CA) inhibitors 6-Mercaptopurine Streptozotocin Iphosphamide Outdated tetracycline Sulfonamides Mafenide acetate Valproic acid Heavy metals (Cd, Pb, Hg) Miscellaneous • Amyloidosis • Cyanotic congenital heart disease •Fallot tetralogy • Hereditary nephritis • Hyperkalemia • Multiple myeloma • Nephrotic syndrome • Renal cystic disease • Renal transplant • Renal vascular accident • Sjögren syndrome It should be remembered that in proximal tubular acido- sis, once the serum bicarbonate is reduced to a level below a certain threshold, and almost always ≥14 mEq/L, the kidney stops losing bicarbonate at the level of the proximal tubule, a phenomenon termed “gradient-lim- ited.” Under such circumstances, the urinary pH may not reflect bicarbonate loss, and is below 6.0. • The treatment is aimed at both reversal of the extracel- lular acidosis as well as provision of optimal linear growth. This requires supplemental oral alkali, often in large amounts exceeding 10–15 mEq of base/kg/day. DISTAL TUBULE • Unlike the gradient-limited acidosis that occurs with dis- eases of the proximal tubule, the inability to sustain a hydrogen-ion gradient across the distal renal tubule results in an ongoing, relentlessly severe hypokalemic metabolic acidosis, where the serum bicarbonate level is generally ≤10 meq/L, in the untreated state. Table 121-2 lists the causes of distal renal tubular acidosis (RTA). Most are accompanied by hypokalemia, and are termed type I. A few are associated with an inability to excrete potassium, and are termed type IV. Kidney stones or nephrocalcinosis (interstitial deposition of calcium salts) are common in distal renal tubular acidosis, and occur more frequently than in type I disease. • The treatment is aimed at both restoration of the extra- cellular acidosis as well as provision of optimal linear growth. This requires supplemental oral alkali, often in large amounts exceeding 10–15 meq of base/kg/day. Thus, the treatments of the two general types of acido- sis often do not differ. 122 DISORDERS OF THE COLLECTING DUCT Ronald J. Kallen • The kidney collecting duct regulates the final move- ment of water into and out of the urine, in response to the hormone vasopressin (AVP, also known as antidi- uretic hormone, ADH). A disruption of this process produces the inability to adequately conserve water, and is termed nephrogenic diabetes insipidus when the defect is localized to the collecting duct. It is character- ized by the presence of elevated, circulating levels of AV P, in comparison to central diabetes insipidus, where there is a failure of pituitary production of the hormone. 446 SECTION 15 • DISEASES OF THE KIDNEY, URETERS, AND BLADDER TABLE 121-2 Causes of Distal Renal Tubular Acidosis Inability to secrete H+ (secretory defect) Primary distal RTA (persistent classic syndrome) In infancy, associated HCO 3 wasting In adolescence, secondary hyperparathyroidism Nerve deafness develops in adolescence Transient infantile form Genetic Sporadic Endemic Secondary distal RTA Disorders of calcium metabolism with nephrocalcinosis or hypercalciuria Primary hyperparathyroidism Hyperthyroidism Vitamin D intoxication Genetic Idiopathic hypercalciuria Hyperthyroidism (with nephrocalcinosis) MCD-FJN Hereditary fructose intolerance with fructose exposure Associated with genetically transmitted disease CA type 2 Erythrocyte CA B deficiency Ehlers-Danlos syndrome Hereditary elliptocytosis Marfan syndrome Sickle cell anemia Osteopetrosis (Type III RTA) With associated deafness Carnitine palmitoyl transferase deficiency type 1 Autoimmune disorders Hypergammaglobulinemia Sjögren syndrome Chronic active hepatitis Primary biliary cirrhosis Thyroiditis Fibrosing alveolitis Systemic lupus erythematosis Polyarteritis nodosa Rheumatoid arthritis Drug or toxin Amphotericin B Toluene Analgesic abuse Lithium Cyclamate Mercury Associated with other renal diseases Obstructive uropathy Pyelonephritis Renal transplant rejection Sickle cell disease Leprosy Associated with endocrine disease Hypothyroidism Salt-losing congenital adrenal hyperplasia Functional RTA (exchange defect) Marked volume depletion Hyponatremic states (hepatic cirrhosis/nephrotic syndrome) Sodium depletion Increased back-diffusion H+ (gradient defect) Amphotericin B CHAPTER 123 • RENOVASCULAR DISEASE 447 In central diabetes insipidus, provision of the hormone restores water balance, as the kidney apparatus remains intact. Searching for the presence of diabetes insipidus should be done carefully and generally by a specialist, as water deprivation, the mainstay of testing, may lead to profound volume depletion in the affected patient, with subsequent vascular collapse, shock, and death. • The symptoms of nephrogenic diabetes insipidus often start in the very young infant, with recurrent episodes of hypernatremic dehydration, fevers, poor growth, and often have a positive family history asso- ciated with the most common form of the disease that is X-linked dominant. The signs of severe volume depletion are evident. The laboratory manifestations include hypernatremia, and inappropriate low urine osmolality at the time of clinical volume depletion, to values often ≤100 mOsm/kg H 2 O. • Initial treatment consists of reduction of dietary salt intake to lessen overall urine volume and administra- tion of thiazide-class diuretics to increase proximal tubular water resorption, and/or administration of indome-thacin, to both reduce, mildly, overall glomeru- lar filtration rate, and hence, water filtration, and to sen- sitize the collecting duct, in some cases, to work a bit more at normalizing a response to the high levels of cir- culating AVP. Referral to a specialist is mandatory for treatment of this complex water disorder. 123 RENOVASCULAR DISEASE Jerome C. Lane EPIDEMIOLOGY • Kidney and renovascular diseases are the causes of hypertension in approximately 90% of young children with a definable cause of hypertension. Renovascular disease is the etiology of hypertension in 8–10% of children referred for evaluation of hypertension. The incidence of renovascular hypertension is much lower in the adult population (<1%). ETIOLOGY • Atherosclerosis comprises 60% of renovascular disease in adults, whereas in children 75–95% of renovascular disease is caused by various forms of arterial dyspla- sia, the most common of which is fibromuscular dysplasia. Table 123-1 lists the other causes of reno- vascular hypertension. • Fibromuscular dysplasia most often involves the media of kidney vessels. The main renal artery and/or segmental branches are involved. Stenotic lesions followed by post- stenotic dilatation can resemble a “string of beads” appearance on angiography. Involvement of the intima of vessels is occasionally seen, though adventitial involve- ment is rare. Medial lesions generally are characterized histologically by replacement of normal media with colla- gen and fibrous matrix, as well as degenerated elastic fibers and displaced smooth muscle cells. Other less common forms of arterial dysplasia include medial fibro- plasias, intimal fibroplasia, perimedial fibroplasia, and periarterial fibroplasia. Neurofibromatosis (NF-1) has been reported to comprise 10–25% of renovascular dis- ease in some reports. Neurofibromatosis typically involves the intima and often causes lesions close to the origin of the renal arteries from the aortic trunk. Fibromuscular dys- plasia, in contrast, typically involves more distal areas of the renal arteries. Renovascular disease most often (70%) occurs bilaterally in patients with neurofibromatosis. PATHOPHYSIOLOGY • The common physiologic pathway leading to hyperten- sion in renovascular disease involves activation of the renin-angiotensin-aldosterone axis. In unilateral reno- vascular disease, the affected kidney, sensing relative arterial hypoperfusion, generates and secretes renin. Renin results in the conversion of angiotensinogen to angiotensin I, which then is converted to angiotensin II by angiotensin converting enzyme (ACE). Angiotensin II is a direct vasoconstrictor, leading to a systemic rise in blood pressure. Angiotensin II also stimulates the release of aldosterone, which leads to tubular retention of sodium and water, also contributing to the rise in blood pressure from an expansion of blood volume. TABLE 123-1 Causes of Renovascular Hypertension Fibromuscular dysplasia Neurofibromatosis 1 Klippel-Trenaunay-Webber syndrome Feuerstein-Mimms syndrome Tuberous sclerosis Takayasu arteritis Moyamoya disease Sarcoidosis Kawasaki disease Thromboembolic disease Neonatal renal artery thrombosis Following angiography Following blunt abdominal trauma Extrinsic compression of the renal artery Tumors Congenital fibrous bands Posttraumatic hematomas Kidney transplant renal artery stenosis While the unaffected kidney generally compensates by excreting excess sodium and water, overall fluid and sodium balance remains positive in unilateral disease. • In bilateral renal artery disease, there also is an initial rise in renin, angiotensin II, and aldosterone, leading to vasoconstriction, tubular sodium and water retention, and expansion of plasma volume; however, since both kidneys are affected, there is no ability of the kidneys to compensate by excreting the excess salt and water. This leads to marked systemic volume expansion and subse- quent suppression of the renin response, such that renin levels eventually become normal in bilateral disease. CLINICAL FEATURES • The majority of children with renovascular hyperten- sion are asymptomatic. Typical symptoms, when pres- ent, are those of accelerated or malignant hypertension (see above). Features of systemic or genetic disease can be present. Features suggestive of renovascular disease include symptoms of genetic or systemic inflammatory disease, hypertension following trauma, severe and/or difficult to control hypertension, and hypertension associated with a change in kidney function. DIAGNOSIS •A thorough history and physical examination is the first step in evaluating a child for renovascular disease in the setting of hypertension. A complete neonatal history is essential, as umbilical artery catheterization is an important association with renovascular lesions. A history of symptoms associated with hypertension (see Clinical Features) should be sought. Prior history of renal disease, urologic malformation, or urinary tract infection should be elicited. Use of oral contra- ceptive agents or medications with vasopressor effects (stimulants, illicit drugs, corticosteroids, or anabolic steroids) must be reviewed. Endocrine symptoms also should be investigated, such as weight loss, sweating, flushing, and palpitations. A thorough family history is essential regarding genetic disorders, inflammatory diseases, malignancy, and essential hypertension. • Signs of hypertension should be sought (see above). It is essential to examine for signs of genetic syndromes, such as café au lait spots, lesions of tuberous sclerosis, or phenotypic characteristics of Williams syndrome. The presence of carotid bruits, midline abdominal bruits, or bruits over the renal fossae may suggest the presence of a systemic vascular disease, such as fibro- muscular dysplasia, Takayasu arteritis, or Moyamoya disease. Signs of endocrine diseases should be sought, such as hirsutisim, striae, buffalo hump, tremor, fine hair, sweating, or obesity. • Initial screening tests should include the following: uri- nalysis; urine culture; serum levels of urea nitrogen, creatinine, electrolytes, total carbon dioxide, and cal- cium; kidney ultrasound with Doppler of the kidney vessels; and echocardiography (to evaluate for end- organ damage, such as left ventricular hypertrophy, as well as cardiac disease). A peripheral plasma renin activity can be useful if hypertension is quite elevated, but a normal result does not rule out renovascular hypertension, since this test can be affected by medica- tions, hydration status, salt intake, and many other fac- tors. A captopril “challenge” test is not recommended. • Imaging studies of the kidney vessels remain an essen- tial, but controversial, part of investigating renovascular disease. The gold standard test for diagnosis of reno- vascular disease is the conventional renal arteriography with a radiocontrast agent; however, due to the expen- sive and invasive nature of this test, less invasive meth- ods have been investigated. Kidney ultrasound with Doppler study of the kidney vessels has been reported to have high sensitivity and specificity for renovascular disease is some studies, approaching 90% correlation with renal arteriography; however, this procedure is highly operator-dependent, and up to 20% of studies may be inadequate for diagnosis, even in experienced centers. Captopril renography also has been reported to have high sensitivity and specificity in adult studies. In this procedure, a radionuclide renal scan is performed after a dose of captopril. A reduction in renal function is seen in the kidney affected by renovascular disease; however, pediatric studies have demonstrated a low sensitivity (59%) and specificity (68%) in children, limiting the usefulness of this test. Additionally, since many causes of renovascular disease are bilateral in children, there is a remote risk of producing kidney fail- ure with the use of captopril. •Newer imaging modalities include magnetic resonance arteriography (MRA) and helical or spiral computed tomography angiography (CTA). MRA can detect lesions effectively in the proximal renal arteries; how- ever, MRA might not be sensitive enough to detect smaller lesions in the distal renal arteries, which are characteristic of fibromuscular dysplasia. CTA might provide better resolution for smaller lesions. The sensi- tivity and specificity of CTA has been reported to be 98 and 94% in adult studies. Neither MRA nor CTA have been studied in pediatric renovascular disease. •For those children with a high suspicion of renovascular disease as a cause of their hypertension, conventional renal arteriography remains the most reliable means of diagnosis. This procedure, though invasive, has the added advantage of providing a possible therapeutic intervention, through performance of percutaneous transluminal angioplasty (PTLA) at the time of diagnosis. Renal vein renin sampling can also be performed during 448 SECTION 15 • DISEASES OF THE KIDNEY, URETERS, AND BLADDER CHAPTER 124 • NEPHROLITHIASIS 449 conventional arteriography. Blood is selectively sam- pled from each renal vein; an elevated plasma renin activity ratio in the affected compared to the unaffected kidney (>1.5) confirms renovascular disease as the eti- ology of the hypertension. Such studies may be helpful in making therapeutic decisions for surgical cure of the hypertension by performance of a nephrectomy. TREATMENT • PTLA can often cure renovascular hypertension in selected patients. Patients who do well with this proce- dure are those with accessible unilateral main artery or main branch lesions. There is a lower success rate with bilateral and or distal renal arterial disease. Long stenotic lesions and lesions at the origin of the main renal artery also have a lower success rate. Overall suc- cess rates in children are reported in the range of 38–90%. About one-third of patients undergoing PTLA will experience a subsequent restenosis. The uses of intravascular stents or baffles have been reported in adults, but have not been studied in children. •Surgical vascular reconstruction, such as reconstruc- tion of the renal artery or a bypass graft from the aorta to the artery distal to the stenosis, may be performed in those patients in whom PTLA cannot be performed or is unsuccessful. Cure rates are reported in the range of 70–90%, with improvement in a further 19–26%. In patients with complex bilateral disease, the success rate is reported to be approximately 50%, with up to 18% requiring more than one procedure. Nephrectomy can be considered in the case of unilateral disease with a poorly functioning affected kidney (<10% of renal function as measured by radionuclide renography). • Pharmacotherapy is a critical component in the man- agement of patients with renovascular disease. ACE inhibitors should be used with caution, since they might precipitate renal failure in severe bilateral renovascular disease; however, once the renal lesions have been defined, ACE inhibitors can play a useful role in the treatment of renovascular hypertension, as they directly block the renin-mediated pathophysiologic pathway causing the hypertension. Other useful agents include calcium-channel blockers, beta-blockers, and diuretics. B IBLIOGRAPHY Bartosh SM. Childhood hypertension. An update on etiology, diagnosis, and treatment. Pediatr Clin North Am 1999; 46:235–252. Deal JE, Snell MF, Barratt TM, Dillon MJ. Renovascular disease in childhood. J Pediatr 1992;121:378–384. Ingelfinger JR. Renovascular disease in children. Kidney Int 1993;43:493–505. Leung DA, Hagspiel KD, Angle JF, Spinosa DJ, Matsumoto AH, Butty S. MR angiography of the renal arteries. Radiol Clin North Am 2002;40:847–865. McTaggart SJ, Gelati S, Walker RG, Powell HR, Jones CL. Evaluation and long-term outcome of pediatric renovascular hypertension. Pediatr Nephrol 2000;14:1022–1029. Swinford RD, Ingelfinger JR. Evaluation of hypertension in child- hood diseases. In: Barratt TM, Avner ED, Harmon WE (eds.), Pediatric Nephrology, 4th ed. Baltimore, MD: Lippincott Williams and Wilkins, 1999, pp. 1007–1030. 124 NEPHROLITHIASIS Craig B. Langman •A stone may occur in the urinary tract from the renal pelvis collecting system through the tip of the urethra, regardless of its etiology. It may occur as an isolated finding, or point toward a systemic disorder, regardless of a similar crystalline structure. A stone may be inno- cent, being seen only on an abdominal radiograph, ultra- sound, or computed tomography (CT) scan performed for other purposes, or may result abruptly in renal colic (see above). Stones tend to be recurrent problems, and over 90% of children with kidney stones have a defin- able, metabolic problem that is amenable to therapy. Therefore, the clinician is encouraged to evaluate every child with nephrolithiasis completely in order to ascer- tain the reason for the stone. •A simplified evaluation of nephrolithiasis involves col- lection of several complete, 24-hour urine samples for purposes of quantifying the overexcretion of lithogenic substances (calcium, oxalate, uric acid, phosphate), or the underexcretion of inhibitors of nephrolithiasis (citrate, magnesium). Such collections should be done with a gap from an acute stone event, perhaps several weeks, and when the patients are on their usual diet. Forced-fluid administration is not recommended during such collections, since the usual urinary volume is an important part of the overall evaluation. At the end of three to four collections over a short period of time (i.e., the same 7-day period), it is recommended that a blood comprehensive metabolic profile be obtained, including the measurement of serum uric acid. •Tables 124-1 through 124-5 list the common causes of each type of stone by primary etiology. The clinician is advised that simultaneous disturbances may coexist, and each deserving of treatment. Successful treatment of nephrolithiasis is judged by the absence of new 450 SECTION 15 • DISEASES OF THE KIDNEY, URETERS, AND BLADDER TABLE 124-1 Hypercalciuric Conditions Associated with Kidney Stone Formation ASSOCIATED WITH NORMAL SERUM ASSOCIATED WITH HYPERCALCEMIA TOTAL CALCIUM Primary hyperparathyroidism Idiopathic hypercalciuria Sarcoid; cat-scratch fever Mutations in kidney chloride gene CLCN5 Idiopathic infantile hypercalcemia Immobilization (common) Immobilization Associated with prematurity and furosemide therapy Neonatal Bartter syndrome Renal distal tubular acidosis, type I Seyberth syndrome Glycogen storage disease Thyrotoxicosis Hereditary hypophosphatemia with hypercalciuria Use of ketogenic diet Activating mutation of the extracellular calcium-sensor gene (hypocalcemia) Medullary sponge kidney Inflammatory diseases, such as juvenile arthritis Corticosteroid therapy TABLE 124-2 Causes of Hyperoxaluria Primary overproduction of oxalate Primary hyperoxaluria AGXT mutation: type I GRHPR mutation: type II Secondary overproduction of oxalate Ethylene glycol poisoning Vitamin C excess Pyridoxine deficiency Enteric overabsorption Increased serum bile acid levels Inflammatory bowel disease Dietary oxalate excess Dietary calcium deficiency Small bowed resection TABLE 124-3 Conditions Associated with Calcium-Phosphate Kidney Stones Distal renal tubular acidosis Urine infection Alkaline urine Hereditary hypophosphatemia with hypercalciuria Calcium-oxalate kidney stones Primary hyperparathyroidism Hypocitraturia TABLE 124-4 Causes of Hyperuricosuria INCREASED PRODUCTION INCREASED EXCRETION Hemolytic anemia Proximal tubular defect Hematologic malignancy Acidosis Irradiation or treatment with cytotoxic agents Gout Lesch-Nyhan syndrome TABLE 124-5 Normative Data for Excretion of Selected Lithogenic Substances SUBSTANCE REFERENCE RANGE Calcium ≤4 mg/kg/day for children ≥2 years of age Citrate ≥0.4 mg/m 2 BSA/day Oxalate ≤0.5 mmol/m 2 /day Uric acid Varies with age, up to a maximum of 750 mg/day in adolescence CHAPTER 125 • UROLOGIC ANOMALIES 451 stones, avoidance of urinary infection, and the absence of stone growth of existing stones. Referral to a spe- cialist in nephrolithiasis is recommended for all chil- dren who form a kidney stone. 125 UROLOGIC ANOMALIES Jerome C. Lane RENAL ECTOPIA • As the kidneys develop, they may fail to ascend nor- mally from the pelvis to their usual position in the renal fossae, resulting in renal ectopia. An ectopic kidney may be pelvic, iliac, thoracic, or contralateral. A contralateral ectopic kidney has a ureter that crosses the midline; such a kidney often fuses with the other kidney, a con- dition known as crossed-fused renal ectopia. Renal ectopia occurs in approximately 1 in 900 individuals. The adrenal gland usually remains in the normal posi- tion. Bilateral ectopia is less common (10% of cases). • Hydronephrosis is seen in 56% of ectopic kidneys, most commonly as a result of obstruction at the ureteropelvic or less commonly at the ureterovesical junctions. Hydronephrosis may also occur as a result of vesi- coureteral reflux or malrotation. Vesicoureteral reflux into the ectopic kidney is frequently observed in crossed-fused ectopia. There is a higher incidence of abnormalities in the nonectopic kidney. Approximately 25% of the nonectopic kidneys may exhibit hydronephrosis secondary to obstruction or vesi- coureteral reflux. There is also a higher incidence of renal agenesis on the side opposite to the ectopic kidney. •Patients with renal ectopia have a higher incidence of genital anomalies (15–45% of patients). Women may have one or more of the following anomalies in 20–66% of cases: bicornuate or unicornuate uterus with atresia of one horn, rudimentary or absent uterus and proximal and/or distal vagina, and duplication of the vagina. Approximately 10–20% of men may have anomalies, including undescended testes, duplication of the urethra or hypospadias. Other congenital anom- alies are seen in 21% of patients with renal ectopia, most commonly involving the heart or skeletal system. Renal ectopia can be isolated or associated with various syndromes. Some of the more common syndromes include Beckwith-Wiedemann, CHARGE association, infant of a diabetic mother, Denys-Drash, DiGeorge, Fanconi anemia, fetal alcohol, Goldenhar, Turner, VACTERL association, and Williams. • The majority of ectopic kidneys are asymptomatic and are found serendipitously during imaging of the abdomen or urinary tract for other reasons. The patient with renal ectopia may present with signs of urinary infection due to obstruction of the ectopic kidney, or reflux or obstruction of the contralateral kidney. An obstructing kidney stone leading to renal colic is a common reason for presentation. Ultrasonography, radionuclide renography, excretory urography, or abdominal/pelvic computed tomography (CT) scan all are adequate methods of diagnosing renal ectopia. •Total renal function generally is normal, although the ectopic kidney often is hypoplastic and may have reduced function. There is no increased risk of malig- nant transformation in renal ectopia. HORSESHOE KIDNEY •A horseshoe kidney arises when fusion of the lower poles of both kidneys occurs across the midline. The kidneys are connected by parenchymal or, less com- monly, fibrous tissue. Migration of the horseshoe kidney is usually incomplete and the kidney is situated lower in the abdomen than the usual kidney position. The incidence of horseshoe kidney is approximately 1 in 500 births. Patients with Turner syndrome have a 7% incidence of horseshoe kidney. Some of the syn- dromes associated with horseshoe kidney include Antley-Bixler; infant of diabetic mother; Fanconi anemia; Roberts; trisomies 13, 18, 21, and 22; Turner; and VACTERL association. • Congenital anomalies are frequently associated with horseshoe kidney, most commonly involving the skele- tal, cardiac, and central nervous systems. Three percent of children with neural tube defects have a horseshoe kidney. Anorectal anomalies are common. Approximately 20% of trisomy 18 patients have horse- shoe kidney. Genitourinary anomalies also are more fre- quent, including hypospadias (4% of male children), cryptorchidism (4%), bicornuate uterus (7% of female children), and septate vagina (7%). Ureteral duplication occurs with an incidence of 10%, occasionally associ- ated with an ectopic ureterocele. Vesicoureteral reflux can be demonstrated in approximately 50% of patients. One-third of patients may have ureteropelvic junction (UPJ) obstruction and hydronephrosis. • About 30% of patients are asymptomatic. Patients who present with symptoms usually have hydronephrosis, infection, or renal calculi. Horseshoe kidneys are occa- sionally detected after discovery of an abdominal mass (5–10% of cases). Ultrasonography, radionuclide renography, excretory urography, or abdominal/pelvic CT scan all are adequate methods of diagnosing horse- shoe kidney. [...]... posterior and flocculonodular lobe The cerebellar peduncles connect the cerebellum to the brain stem The superior cerebellar peduncle connects to the midbrain, the middle cerebellar peduncle connects to the pons, and the inferior cerebellar peduncle connects the medulla The cerebellar vermis lies between the two cerebellar hemispheres The cerebellum receives input from the frontal lobes (which essentially... despite their severe motor disabilities PERIPHERAL NERVE DISORDERS • The second anatomical site in the motor unit is the peripheral nerve There are two unique features present in nerve disorders that distinguish this anatomical category from the other three First, this is the only type of motor unit disorder in which sensation is effected Therefore, if the examination confirms sensory loss, the other... dysfunction in the cerebellum or from cerebellar afferents, thus the discussion of ataxia requires a basic understanding of the anatomy of the cerebellum and its connections • The cerebellum is divided into three lobes: the anterior lobe, the posterior lobe, and the flocculonodular lobe The primary fissure separates the anterior and posterior lobes The posterolateral fissure separates the posterior... provide either an audible or vibratory signal There is also an alarm that does both Most alarms have a “hard wired” connection between the moisture sensor in the underwear and the alarm which is attached to the pajama top so that it is close to the ear There are also wireless alarms which transmit a radiofrequency signal to the alarm-emitting unit • The alarm should not be prescribed until there is... of prognosis is the most eagerly sought information by the family and care providers for the infant with HIE The markers mentioned above for the diagnosis of HIE are also indicators of prognosis, to the extent that they indicate severity of injury CHAPTER 129 • NEURODEVELOPMENTAL DISABILITIES The longer the time to reach an Apgar greater than 7, the more likely will be CNS sequelae The longer to reach... The incidence of the syndrome is approximately 1 in 35,000 to 1 in 50,000 live births • Several theories have been proposed for the etiology of prune-belly syndrome, but the cause of the syndrome is unknown Obstruction of the fetal urethra may lead to severe dilation of the bladder and urinary tract, which then blocks descent of the abdominal testes and interferes with development of the abdominal wall... should be sent on the mother and possibly the newborn The condition is usually self-limited over a course of 2–3 days The newborn may require respiratory and feeding support, but once the ACHRA are cleared the symptoms resolve • The second form of MG that may affect children is congenital myasthenic syndromes (CMS) Presentation may be neonatal, infantile, or very early childhood The pathology is an... be necessary to present the stimulus within 5–10 cm of the eyes to elicit a response A face provides a particularly engaging target The optic fundus of the newborn may be difficult to see because of the small size of the pupil and difficulty opening the eye against resistance, but older infants often gaze in the direction of the ophthalmoscope Eye movements may be elicited by the oculocephalic reflex... all be present and symmetric Putting a finger on the tendon and striking the finger with the hammer works best for all except the Achilles, which can be activated by tapping the underside of the foot to flex the ankle Spread may be observed in the normal infant (crossed adductor in the legs, brachioradialis activation with biceps stretch in the arms) • The response to plantar stimulation (Babinski reflex)... implications For this reason the term neonatal encephalopathy is gaining favor unless hypoxia and ischemia are clearly the only causative factors • The pattern of parasaggital cerebral injury results from the acute interruption of perfusion of large regions of the brain, and as such is the pattern most typical of HIE in the full-term infant The most severely affected areas are in the borderzone or watershed . basement membrane of glomerulus, the cochlea, and the lens of the eye. Most often the mutation is in the alpha-5 chain of type IV collagen, coded on the X chromosome. These boys usually develop progressive. encountered in pediatrics are due to immune-mediated acute hypersensitivity reac- tions to medications. The Table 12 0-1 lists medica- tions implicated in hypersensitivity-induced AIN. • The precise. prune-belly syndrome, but the cause of the syn- drome is unknown. Obstruction of the fetal urethra may lead to severe dilation of the bladder and urinary tract, which then blocks descent of the