Chapter 49. The Kidney: III. Tubulointerstitial Diseases; Vascular Diseases; Neoplasms

Tubulointerstitial diseases are a group of renal disorders characterized by primary abnormalities in the renal tubules or interstitium. There are four principal causes: infectious, toxic, metabolic, and immunologic.

The morphologic changes in tubulointerstitial disease include the following.

1. Acute tubular necrosis (Table 49-1), which if widespread causes acute renal failure. The changes in all causes of acute tubular necrosis are similar and are discussed under renal changes associated with shock.

2. Atrophy of tubules, with fibrosis of the interstitium, associated with nephron loss and chronic renal failure.

3. Interstitial inflammation, either acute, with numerous neutrophils in the tubules and interstitium (acute interstitial nephritis); or chronic, with lymphocytes, plasma cells, macrophages, and fibroblasts (chronic interstitial nephritis).

4. Tubular basement membrane thickening, as occurs in diabetes, amyloidosis, and transplant rejection.

5. Deposition of abnormal substances such as calcium, amyloid, urate, myeloma proteins, and oxalate in the tubules and interstitium.

Infectious Diseases

Acute Pyelonephritis

Incidence

Acute pyelonephritis is extremely common—1more so in females than in males (10:1). Acute pyelonephritis occurs at all ages, with highest frequency during early sexual activity and during pregnancy.

Etiology

Acute pyelonephritis is a bacterial infection, usually ascending from the lower urinary tract. Ascent of infection from the bladder is facilitated when vesicoureteral reflux is present. This is more important in children but occurs also in adults. Bacteria spread from the renal pelvis to the tubules by intrarenal reflux. Reflux from the pelvis into the tubules is common: Over 60% of normal kidneys have reflux into at least one papilla. Hematogenous infection of the kidney is uncommon. Factors important in etiology are as follows (Figure 49-1):

1. A short urethra, as in females.

2. Stasis of urine from any cause. The high incidence of urinary infections during pregnancy is believed to be the result of increased serum levels of progesterone, which decreases activity of the urinary tract smooth muscle, promoting stasis of urine.

3. Structural abnormalities in the urinary tract that promote stasis of urine or establish a communication between the urinary tract and an infected site, such as fistulous tracts between the urinary tract and intestine, skin, or vagina.

4. Vesicoureteral reflux of urine. Fifty percent of infants and young children with pyelonephritis show evidence of reflux, which is often familial and is due to an abnormality in the way the ureters enter the bladder.

5. Catheterization of the bladder. Strict aseptic precautions must be taken, and even then an indwelling urinary catheter is almost invariably associated with infection.

6. Diabetes mellitus.

Bacteriology

Seventy-five percent of cases of acute pyelo-nephritis are caused by Escherichia coli. When infections occur secondary to obstruction or catheterization, other organisms occur more often: Klebsiella, Proteus, Enterococcus faecalis, and Pseudomonas aeruginosa.

Postpubertal females have a significant incidence (5%) of asymptomatic bacteriuria (usually E coli), increasing to nearly 20% in pregnancy. The relationship of asymptomatic bacteriuria to acute pyelo-nephritis is not clearly established.

Pathology

Grossly, acute pyelonephritis may be unilateral or bilateral. The kidney is enlarged and shows areas of suppuration (abscesses) in the cortex with radial yellow streaks traversing the medulla (Figure 49-2). The renal pelvis is erythematous and frequently covered with exudate. Extension to the perinephric space with formation of a perinephric abscess is not uncommon.

Microscopically, there is an acute suppurative inflammation beginning in the renal tubules, which show infiltration by neutrophils and hyperemia (Figure 49-3). Liquefactive necrosis of the tubules (suppuration) follows. Involvement is characteristically patchy.

Clinical Features

Onset is with high fever, chills, rigors, and flank pain. Dysuria and increased frequency are present in most cases.

The urine shows mild proteinuria, with neutrophils, white cell casts, and bacteria in the sediment. The diagnosis is made by quantitative urine culture (colony count). A positive culture with over 100,000 organisms/mL is diagnostic.

Treatment & Prognosis

Treatment with antibiotics is effective. In an uncomplicated case, an antibiotic is selected that has activity against E coli (eg, ampicillin or trimethoprim-sulfamethoxazole). When culture and antibiotic sensitivity results are available, the antibiotic may be changed accordingly.

The prognosis is excellent. Most patients recover completely, and there are no long-term sequelae from a single episode. Recurrent attacks are associated with increasing fibrosis and may lead to chronic pyelonephritis.

Complications

Gram-Negative Sepsis with Shock

Blood culture is frequently positive in patients with acute pyelonephritis. In a few cases, bacteremia is severe and causes gram-negative shock. The mortality rate is then high.

Pyonephrosis

When infection supervenes in an obstructed, hydronephrotic kidney, the dilated pelvicaliceal system becomes filled with pus. This is called pyonephrosis.

Perinephric Abscess

Extension of infection through the renal capsule leads to abscess formation in the perinephric fat.

Renal Papillary Necrosis

Patients with diabetes mellitus who develop acute pyelonephritis tend to have more severe disease characterized by renal papillary necrosis (extreme inflammation of the papillae, which become necrotic and slough into the calices).

Emphysematous Pyelonephritis

This disorder, characterized by anaerobic bacterial fermentation of glucose with gas formation in the renal parenchyma, occurs rarely in diabetic patients. Radiologic visualization of gas in the renal parenchyma is the basis for clinical diagnosis. Emphysematous pyelonephritis is a severe infection, often complicated by gram-negative shock and death. It is an indication for emergency nephrectomy.

Chronic Pyelonephritis

Incidence & Etiology

Infectious chronic pyelonephritis accounts for 15–20% of cases of chronic renal failure. Several different etiologic factors are recognized (Figure 49-4).

Chronic Obstructive Pyelonephritis

Chronic obstructive pyelonephritis is common and occurs at all ages in both sexes. Obstruction may be mechanical (eg, calculi, prostatic hyperplasia, tumors, congenital anomalies, retroperitoneal fibrosis) or paralytic (neurogenic [neuropathic] bladder). About 50% of patients give a history of a previous episode of acute pyelonephritis.

Chronic Pyelonephritis Associated with Vesicoureteral Reflux

About 50% of children with vesicoureteral reflux develop chronic pyelonephritis; regurgitation of urine from the renal pelvis into the collecting tubules may be etiologically important. Early diagnosis of childhood vesicoureteral reflux (by voiding cystography) permits treatment to prevent chronic pyelonephritis.

Pathology

(Figure 49-4)

Kidneys involved by chronic pyelonephritis usually show asymmetric involvement, with irregular scarring and contraction. Deep cortical pits due to scarring over a deformed calix are typical. Deformity of the pelvicaliceal system is common. Hydronephrosis and suppuration may be present in cases due to obstruction (chronic suppurative pyelonephritis).

Chronic pyelonephritis may be distinguished grossly from chronic glomerulonephritis by the asymmetry of renal involvement and the larger size of the cortical scars (pitted scarred kidney) in the former.

Microscopically, there is marked patchy inflammation and fibrosis of the interstitium. The inflammatory cells are lymphocytes and plasma cells with scattered neutrophils. Periglomerular fibrosis later progresses to global sclerosis. Hypertrophy and dilation of surviving tubules may be present (called thyroidization because the numerous packed, dilated tubules superficially resemble thyroid follicles). Immunofluorescence and electron microscopy do not show immune complex deposition in the glomeruli.

Cases in which lipid-laden foamy histiocytes are conspicuous are sometimes classified as xanthogranulomatous pyelonephritis. Xanthogranulomatous inflammation is associated with enlargement of the kidney and the presence of caliceal staghorn calculi. The inflammatory process frequently extends into the perinephric tissues and may involve adjacent organs (eg, colon, skin of the back, diaphragm, and pleura). Rarely, fistulas form between the renal pelvis and these organs.

Clinical Features

Chronic pyelonephritis usually manifests as hypertension or chronic renal failure. Pyuria (neutrophils in urine), mild proteinuria, and bacteriuria are present. In end-stage pyelonephritis, bacteriuria may be absent, and differentiation from chronic glomerulonephritis then becomes difficult.

Renal Tuberculosis

Renal tuberculosis is uncommon in the United States and Western Europe but still occurs frequently in parts of the world where tuberculosis is endemic.

The kidneys are initially infected in the primary pulmonary stage by hematogenous dissemination (see Chapter 34: The Lung: I. Structure & Function; Infections). The bacilli remain dormant and become reactivated much later. Renal tuberculosis is most common in patients 20–50 years of age. Approximately half of the patients with renal tuberculosis have a normal chest x-ray because the original infection has long since healed.

The lesion usually begins in the corticomedullary region as a caseous granuloma (tuberculoma). Multiple granulomas are common. The kidney is grossly enlarged, and cut section shows several yellow crumbling foci. With progression, the granulomas open into the pelvicaliceal system, leading to discharge of the caseous material in the urine and cavitation of the lesion. Microscopically, there is central caseous necrosis surrounded by epithelioid cells, lymphocytes, and fibroblasts. Marked fibrosis is usually present. Acid-fast bacilli can be demonstrated in most cases.

Clinically, patients have a combination of chronic inflammatory and urinary symptoms: low-grade fever, weight loss, hematuria, frequency, and mild lumbar pain. The urine shows numerous neutrophils. Ordinary urine culture is sterile (leading to the misnomer “sterile pyuria”); however, culture for mycobacteria is positive and diagnostic.

Toxic Tubulointerstitial Disease

Radiation Nephritis

Radiation nephritis occurs when the kidneys are in the field of radiation during treatment of malignant neoplasms. The dose required to produce radiation nephritis is about 23 Gy—lower in children or when radiation is given in combination with cytotoxic drugs.

Pathologically, the main changes are in the small arteries, which show fibrinoid necrosis. Tubular atrophy and interstitial fibrosis follow.

Analgesic Nephropathy

Excessive use of analgesics is a relatively common cause of chronic renal disease in Australia and Europe but is rare in the United States. Analgesic nephropathy was first described following the use of analgesic powders containing phenacetin, aspirin, and caffeine. Phenacetin is believed to be the main offender.

Pathologically, analgesic nephropathy is characterized by necrosis of the apices of the renal papillae (renal papillary necrosis), which may be shed in the urine, causing ureteral colic. Interstitial medullary fibrosis and calcification may also occur. The mechanism of necrosis of renal papillae is unknown.

Clinically, there is hematuria, ureteral colic, hypertension, and progressive renal failure. The diagnosis may be suspected radiologically by the presence of calcification in the renal papillary region. In some cases, the shed necrotic renal papillary tissue may be identified in a sample of urine.

Drug-Induced Nephrotoxicity

Acute Interstitial Nephritis

Several drugs cause acute interstitial nephritis. Methicillin, other penicillin derivatives, sulfonamides, and various diuretics have been incriminated. Many cases show features of an immune hypersensitivity reaction. Immunofluorescence shows linear deposition of IgG, C3, and part of the methicillin molecule in the tubular basement membrane in methicillin-induced cases.

Pathologically, there is tubular degeneration and necrosis and marked inflammation of the interstitium with lymphocytes, plasma cells, and eosinophils.

Clinically, patients develop renal symptoms about 2 weeks after exposure to the drug. Fever, hematuria, proteinuria, skin rash, and eosinophilia are common. Acute renal failure develops in 50% of cases.

Recovery usually occurs when the drug is withdrawn.

Acute Renal Tubular Necrosis

Drug-induced acute renal tubular necrosis has been reported as a result of exposure to (1) aminoglycosides (gentamicin, kanamycin); (2) amphotericin B, an antifungal agent; (c) cephaloridine; and (4) methoxyflurane, an anesthetic agent.

Nephrotic Syndrome

Nephrotic syndrome may be caused by (1) mercurial compounds used as skin ointments and diuretics; (2) trimethadione, an antiepileptic drug; and (3) gold, used in the treatment of rheumatoid arthritis.

Metal Toxicity

Mercury and lead poisoning result in renal damage. Mercurial compounds cause proximal convoluted tubule damage. Lead poisoning damages the entire tubule. The presence of eosinophilic intranuclear inclusions is characteristic of lead poisoning. Both mercury and lead may cause acute or chronic renal failure.

Metabolic Tubulointerstitial Diseases

Urate Nephropathy (Gout)

Acute urate nephropathy occurs with very high serum uric acid levels; urate crystals deposited in the tubules cause obstruction. Chronic urate nephropathy occurs with protracted hyperuricemia, resulting in tubulointerstitial inflammation and fibrosis. Clinically, the manifestations are mild and progression slow.

Hypokalemia

Hypokalemia causes tubular epithelial cell injury, leading to inability to concentrate urine, polyuria, loss of sodium in urine, and failure to excrete acid (renal tubular acidosis). Histologically, there is vacuolization of tubular epithelial cells, most prominently in the proximal tubule.

Hypercalcemia

Acute hypercalcemia damages the distal convoluted tubular epithelium, resulting in failure to concentrate urine—manifested clinically as polyuria. With prolonged hypercalcemia, metastatic calcification occurs in the renal interstitium (nephrocalcinosis) and may lead to chronic renal failure.

Increased calcium excretion in the urine increases the risk of urinary calculi.

Immunologic Tubulointerstitial Disease

Immunologic mechanisms involving the renal tubules include transplant rejection (see Chapter 8: Immunologic Injury) and some cases of drug-induced acute interstitial nephritis. The latter is discussed under drug-induced nephrotoxicity (see above).

Hypertensive Renal Disease (Nephrosclerosis)

Benign Nephrosclerosis

Benign nephrosclerosis occurs in most patients with essential hypertension. Similar changes are seen at autopsy in nonhypertensive elderly patients, probably representing an aging change. There is bilateral symmetric reduction in the size of the kidneys. The renal surface has a fine, even granularity, and there is uniform thinning of the renal cortex (Table 49-2). Microscopically, there is hyaline thickening of the walls of small arteries and arterioles (luminal narrowing of these vessels causes chronic glomerular ischemia), global sclerosis of glomeruli, and atrophy of nephrons with interstitial fibrosis. Immunofluorescence and electron microscopy show no evidence of immune deposits.

The changes of benign nephrosclerosis are usually mild. Chronic renal failure occurs in less than 5% of cases.

Malignant Nephrosclerosis

Malignant nephrosclerosis occurs with malignant hypertension (see Chapter 20: The Blood Vessels). This complication occurs in about 5% of patients with hypertension.

The kidneys are normal in size or slightly enlarged and have a smooth surface with numerous small petechial hemorrhages (“fleabitten kidneys”). Microscopically, there is fibrinoid necrosis of arterioles and glomeruli (Figure 49-5). (Fibrinoid necrosis appears as pink granular material in which fibrin can be demonstrated by immunofluorescence.) Interlobar arteries show intimal cellular proliferation and laminated (onionskin) fibrosis. Luminal narrowing leads to ischemia.

Clinically, malignant nephrosclerosis is manifested by proteinuria and hematuria, rapidly followed by acute renal failure. Without treatment, 90% of patients die within 1 year. With modern antihypertensive therapy, over 60% of patients are alive 5 years after diagnosis.

Renal Artery Stenosis

Renal artery stenosis is uncommon but is an important disease in that it represents a potentially treatable form of hypertension. There are several causes.

1. Atherosclerosis is the most common cause, particularly in older patients.

2. Fibromuscular dysplasia of the renal artery is a rare condition of unknown cause, occurring in younger patients (20–40 years of age), particularly in women. It is characterized by unilateral or bilateral single or multiple constrictions of the renal arterial wall, caused by fibromuscular thickening of the media or, more rarely, the intima. Other arteries may be involved. Surgery is curative if the pathologic process is localized.

3. Posttransplantation stenosis occurs in 10–20% of patients after renal transplantation, most commonly as a manifestation of rejection. Intimal thickening follows immunoglobulin deposition in donor vessel walls. Less commonly, the stenosis occurs at the site of anastomosis.

Pathology & Clinical Features

When a significant degree (> 75%) of narrowing of the renal artery is present, diffuse ischemia of the kidney occurs. Glomerular filtration pressure is decreased (Figure 49-6), resulting in increased renin secretion by the juxtaglomerular apparatus and leading to hypertension via aldosterone secretion and sodium retention. Renal artery stenosis is responsible for only about 2–3% of cases of hypertension overall, but it is important because it is surgically curable. Plasma renin levels are elevated. Differential renal vein renin assays show a significant difference between the stenotic side (high) and the normal side (normal).

Decreased glomerular filtration is associated with a slow transit time of fluid in the tubules, leading to increased reabsorption of water in the tubules. Intravenous pyelography shows a delay in excretion of dye on the affected side, but later films show an increased dye concentration. The diagnosis is made by renal arteriography.

Treatment & Prognosis

Transluminal dilation of the stenotic segment with a balloon introduced via the arteriography catheter produces cure rates equivalent to those achieved by surgical resection of the stenosis. About 80–90% of patients so treated are cured. The prognosis depends on the duration of the disease. In long-standing stenoses, significant hypertensive changes in the opposite kidney prevent complete reversal of hypertension even when the stenosis is treated.

Renal Changes in Shock

The reduction in cardiac output in shock causes renal arteriolar constriction and a series of renal changes, as described below.

Prerenal Uremia (Functional Renal Insufficiency)

Intense vasoconstriction serves to retain fluid and maintain blood pressure and as such is the appropriate physiologic response to hypotension in shock (Figure 49-7). Renal vasoconstriction leads to decreased glomerular filtration pressure, diminished glomerular filtration volume, and increased tubular reabsorption of water. The vasoconstriction also leads to increased secretion of renin, which causes sodium and water retention via the aldosterone mechanism. Oliguria results and may be severe enough (< 400 mL/d) to fall within the definition of acute renal failure. The urine is highly concentrated, with high levels of urea and creatinine, reflecting the fact that the tubules are still functioning normally. Serum urea levels rise.

No morphologic changes are seen in the kidney. Reversal of the underlying shock leads to return of normal renal function.

Ischemic Acute Renal Tubular Necrosis (ATN)

Acute tubular necrosis may occur following exposure to nephrotoxins, as a manifestation of acute rejection in a transplanted kidney (Chapter 8: Immunologic Injury), and in ischemic states (Table 49-1). The most common cause of acute tubular necrosis is severe shock, in which reflex vasoconstriction in the kidney is prolonged and severe enough to lead to necrosis of the renal tubular epithelium. In general, any cause of shock may induce ischemic necrosis of the tubules. In massive trauma (crush syndrome) and transfusion reactions, precipitation of myoglobin or hemoglobin or fragmented red cell membranes in the tubules aggravates the condition.

Microscopically, the tubules typically show patchy necrosis affecting both proximal and distal convoluted tubules. Disappearance of the brush border of proximal convoluted tubular epithelial cells is an early microscopic feature of acute tubular necrosis. Disruption of the tubular basement membrane occurs and distinguishes ischemic necrosis from “toxic” tubular necrosis, in which the basement membrane is intact. Eosinophilic hyaline casts are present in the distal convoluted and collecting tubules. If the patient survives, evidence of tubular epithelial regeneration is seen in the second week.

Clinically, acute tubular necrosis is characterized by acute renal failure, with oliguria and azotemia. As tubular necrosis develops, urine volume remains low but osmolality approaches that of glomerular ultrafiltrate (specific gravity 1.010, ie, isosthenuria), indicating failure of tubular function. Failure of the tubules to concentrate urine and handle urea and electrolytes permits differentiation of tubular necrosis from the prerenal uremic state (Figure 49-7). The urine contains red cells and tubular epithelial casts.

The oliguric phase of tubular necrosis usually lasts 10–14 days. In patients who recover, this is followed by the diuretic phase, in which urine output increases—still without tubular reabsorption. In this diuretic phase, where there is unregulated loss of an increasing volume of isotonic urine, there is a risk of fluid and electrolyte imbalance. Tubular function is restored only 2–3 weeks after the occurrence of tubular necrosis, representing the time necessary for complete cell regeneration. Mild urinary abnormalities may persist for 2–3 months.

Renal Cortical Necrosis

Renal cortical necrosis is rare, being caused by severe, prolonged shock (hypotension). It is characterized by necrosis of the entire renal cortex, including the glomeruli. It is irreversible. In the acute phase the cortex is yellow and of normal thickness, but it shrinks rapidly and may undergo calcification.

Clinically, renal cortical necrosis presents in a similar manner to tubular necrosis except that the oliguric phase is profound and prolonged and the diuretic phase does not appear. The glomeruli do not regenerate, and function cannot be restored.

Renal cortical necrosis has a very high mortality rate unless hemodialysis or transplantation is undertaken. A few patients who have a sufficient number of viable glomeruli recover some renal function after a prolonged period of hemodialysis.

Renal Infarction

Renal infarction is an uncommon condition with several causes. Arterial occlusion by embolism is the most common cause. Emboli usually originate in the heart in infective endocarditis, myocardial infarction, mitral stenosis, or atrial fibrillation. Rarely, cholesterol emboli from aortic atherosclerotic plaques are responsible.

Arterial occlusion by thrombosis is usually secondary to atherosclerosis. More rarely, thrombosis of smaller intrarenal arteries in polyarteritis nodosa, progressive systemic sclerosis, or malignant hypertension may result in infarction.

Renal vein occlusion by thrombosis or neoplasms may rarely cause ischemia to the degree that hemorrhagic infarction occurs.

Pathologic & Clinical Features

Grossly, arterial infarcts are pale and wedge-shaped, with the occluded vessels at the apex of the wedge (see Chapter 9: Abnormalities of Blood Supply). Venous infarcts are hemorrhagic and often involve large areas, frequently the entire kidney. Microscopically, the infarcted area shows coagulative necrosis. A narrow zone of cortex supplied by capsular arteries is frequently spared. The infarct heals by progressive enzymatic liquefaction, macrophage phagocytosis of debris, and scar formation over a period of a few weeks. The ultimate result is a depressed cortical scar.

Clinically, infarction produces sudden-onset flank pain followed by hematuria. Unless infarction is bilateral and extensive, there is no impairment of renal function.

(Table 49-3)

Benign Neoplasms

Renal Cortical Adenoma

Renal cortical adenoma is a common incidental finding at autopsy, appearing as a well-circumscribed, round, yellowish nodule in the cortex, less than 3 cm in greatest diameter, and composed of cytologically benign cells arranged in a papillary or solid pattern.

When found during life—usually incidentally during radiologic examination of the abdomen—differentiation from early carcinoma is difficult or impossible. A diameter in excess of 3 cm, the presence of necrosis or hemorrhage, or cytologic features of cancer indicate renal carcinoma. When a small renal cortical tumor is found incidentally, either at surgery or during computerized tomography, it should be resected if possible.

Renal Oncocytoma

Renal oncocytoma is a special kind of cortical adenoma believed to be derived from proximal tubular cells. Unlike other adenomas, an oncocytoma may reach a large size but remain benign. Distinction from carcinoma is difficult.

The gross appearance is distinctive. Oncocytomas have a uniform mahogany brown color without necrosis or hemorrhage, although frequently there is a central scarred area. Histologically, oncocytomas are composed of a uniform population of large cells having small round nuclei and abundant pink, granular cytoplasm.

Angiomyolipoma

Renal angiomyolipoma is an uncommon but important renal tumor. It may be solitary or multiple and bilateral. In the latter event, it is often part of the syndrome of tuberous sclerosis (Chapter 62: The Central Nervous System: I. Structure & Function; Congenital Diseases).

Renal angiomyolipoma is best regarded as a renal hamartoma, but it may produce a large mass that clinically resembles carcinoma (Figure 49-8). Its content of fat gives it a characteristic appearance on computerized tomography, permitting accurate radiologic diagnosis preoperatively. Histologically, it is composed of a variable admixture of mature adipose tissue, proliferating smooth muscle cells, and abnormal blood vessels. The vessels have a typical appearance with irregularly proliferative medial smooth muscle and an eccentric lumen. The smooth muscle cells often show considerable cytologic pleomorphism, which may lead to a misdiagnosis of sarcoma.

Renal angiomyolipoma is a benign lesion. Rarely, similar hamartomas are present in the lymph nodes in the renal hilum; these do not constitute metastases.

Malignant Neoplasms

(Tables 49-4 and 49-5)

Renal Adenocarcinoma (Hypernephroma; Grawitz's Tumor)

Renal adenocarcinoma is the most common malignant neoplasm of the kidney and accounts for 1–2% of all cancers in adults. There are 18,000 new cases and 8000 deaths yearly in the United States. It occurs most frequently in the sixth decade but is not rare in younger patients. It is believed to be derived from proximal tubular epithelial cells. No strong etiologic factors have been identified; 60% of patients with von Hippel-Lindau syndrome and 10% with dialysis cystic disease of the kidney develop renal adenocarcinoma. Tumors are frequently multiple and bilateral in these cases. Many renal adenocarcinomas are associated with deletions in chromosome 3, suggesting that absence of a recessive gene that encodes a tumor suppressor substance may be involved in the pathogenesis. Familial forms of renal carcinoma are associated with 3;8 and 3;11 translocations.

Pathology

Grossly, renal adenocarcinoma varies in size from small to massive. Commonly solid (Figure 49-9), it may contain cystic areas or may be predominantly cystic (Figure 49-10). The cut surface is variegated, with yellow-orange areas mottled with hemorrhagic (red-black) and fibrous (gray) areas (Figure 49-9). Calcification is common. The yellow color of the neoplasm is caused by the high lipid content of the neoplastic cells.

Renal adenocarcinomas may infiltrate locally through the capsule of the kidney and rarely through the fascia around the perinephric fat to infiltrate surrounding organs (Figure 49-11). Invasion into renal vein is common; occasionally, tumor extends along the lumen of the inferior vena cava—rarely, all the way into the right atrium.

Microscopically, renal adenocarcinomas are composed of a mixture of clear cells and pink granular oncocytic cells. In well-differentiated neoplasms, the cells are arranged in glandular papillary and tubular formations separated by a highly vascular stroma. The cells in well-differentiated (grade I) carcinomas are large, with small nuclei and abundant clear cytoplasm rich in lipid and glycogen (clear cell carcinoma; Figure 49-12). There is little cytologic atypia. In less well differentiated neoplasms, the cells become more pleomorphic, with nuclear enlargement and atypia, the appearance of large nucleoli, and may be arranged in irregular sheets. Necrosis, cystic change, calcification, and hemorrhage are commonly present.

A histologic grading system ranging from grade I (well-differentiated) to grade IV (anaplastic) has been shown to correlate with prognosis. The nuclear size and appearance form the basis for histologic grading.

Clinical Features

The usual presentation is with hematuria (Table 49-5). A renal mass may be palpable when the tumor reaches a large size. Metastases occur early and may be the reason for clinical presentation when they occur with relatively small asymptomatic tumors. Common metastatic sites are lungs, bone, liver, brain, and skin.

Extension of the neoplasm into the renal vein on the left side may obstruct the testicular vein, which drains into it, causing a scrotal varicocele. Extension into the renal vein may also very rarely cause venous infarction of the kidney. Extension into the inferior vena cava may occlude it, leading to edema in the lower extremities.

A few renal adenocarcinomas secrete hormones, including (1) parathyroid hormone-like substances that cause hypercalcemia, low serum phosphate, and a clinical syndrome resembling primary hyperparathyroidism; (2) erythropoietin, causing polycythemia; and (3) other hormones such as prolactin (causing galactorrhea), renin (causing hypertension), prostaglandins, and gonadotropins.

The diagnosis is made by intravenous pyelography, computer tomography (CT) scan, or angiography, which show the presence of a renal mass. These radiologic studies are important in identifying the extent of invasion, such as involvement of a renal vein or inferior vena cava, which may require special handling at surgery.

Treatment & Prognosis

Treatment of renal adenocarcinoma is surgical removal, which is very successful in clinical stage I carcinomas. The prognosis correlates well with clinical stage (Table 49-6). Histologic grade is a relatively minor prognostic indicator.

Renal adenocarcinoma is unpredictable in its biologic behavior. It has been known in rare cases to regress spontaneously, and it is not uncommon for metastases to regress, at least temporarily, after removal of the primary neoplasm. Renal adenocarcinoma may also remain dormant for long periods, and cases have been recorded in which a metastatic lesion has occurred up to 30 years after treatment of the primary tumor.

Nephroblastoma (Wilms' Tumor)

Nephroblastoma constitutes about 25–30% of cancers in childhood, being second in frequency to leukemia and lymphoma as a cause of cancer in children. Most cases occur between 1 and 7 years of age. Adult nephroblastoma occurs rarely.

Nephroblastoma is believed to arise from primitive blastema cells that may persist in the outer part of the kidney in the first few months of life. A virus is known to cause nephroblastoma in birds. An antigen (W antigen) has been found in some human tumors and may be a clue to a viral origin of this neoplasm.

Genetic Features

All bilateral and approximately one-third of unilateral nephroblastomas are hereditary. Many patients have deletions in the short arm of chromosome 11, including loss of the cancer suppressor gene WT-1. Loss of both normal alleles is required for the development of Wilms' tumor. In the inherited form of the disease, one allele is inherited in a defective form so that only one acquired mutation is required. Hereditary Wilms' tumor is associated with aniridia.

Pathology

Grossly, nephroblastoma is commonly a large, firm tumor that is usually soft but may undergo cystic change (Figure 49-13). Bilateral nephroblastoma occurs in about 8% of cases. Microscopically, the most primitive nephroblastomas resembles renal blastema, which is the primitive mesodermal tissue of the embryonic renal anlage and is composed of small, somewhat spindle-shaped cells with hyperchromatic nuclei and scant cytoplasm. Undifferentiated neoplasms may display anaplasia, necrosis, and a high rate of mitotic figures. Differentiation may occur into epithelial tubular structures, primitive glomerular structures (Figure 49-14), and a variety of mesenchymal tissues such as cartilage, smooth muscle, striated muscle, and bone. Rarely, tumors of childhood resembling Wilms' tumor are composed of cells showing primitive skeletal muscle-like differentiation (rhabdoid sarcoma) or clear cells (clear cell sarcoma). These histologic subtypes have a more aggressive behavior than the usual Wilms' tumor and represent tumors that respond poorly to treatment and are associated with high mortality rates.

According to the degree of differentiation, three histologic grades are recognized. Grade I (differentiated) neoplasms have the best prognosis. Grade III (anaplastic) neoplasms have the worst prognosis.

Clinical Features & Treatment

Most patients with nephroblastoma present with a large abdominal mass that is usually felt by a parent. Nephroblastoma is staged clinically according to the size of tumor, the presence of tumor on either side of the midline, and distant spread. Treatment combines surgery, radiation, and chemotherapy. The prognosis has improved dramatically with introduction of more effective chemotherapeutic agents (eg, dactinomycin, vincristine). Currently, the 5-year survival rate exceeds 80% even when metastases are present. For tumors confined to the kidney and resected surgically, the 5-year survival rate exceeds 90%.

Urothelial Neoplasms of the Renal Pelvis

These may present as renal masses (Figure 49-15). The corresponding distal tumors (eg, bladder) are discussed in Chapter 50: The Ureters, Urinary Bladder, & Urethra.