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Renal diseases
Introduction
Clinical Manifestations of Renal Diseases
Glomerular Diseases
Acute tubular necrosis
Tubulointerstitial nephritis. Pyelonephritis and urinary tract infection
Renal tumors
Introduction
Renal diseases are responsible for a great deal of morbidity but, fortunately, are not equally major causes of mortality. To place the problem in some perspective. Millions of people are affected annually by nonfatal kidney diseases, most notably infections of the kidney or lower urinary tract, kidney stones, and urinary obstruction. Twenty per cent of all women suffer from infection of the urinary tract or kidney at some time in their lives, and as many as 5% of the U.S. population develops renal stones. Similarly, dialysis and transplantation keep many patients alive who would formerly have died of renal failure, adding to the pool of renal morbidity.
Severe glomerular damage impairs the flow through the peritubular vascular system and also delivers potentially toxic products to tubules; conversely, tubular destruction, by increasing intraglomerular pressure, may induce glomerular atrophy. Thus, whatever the origin, there is a tendency for all forms of chronic renal disease ultimately to destroy all four components of the kidney, culminating in chronic renal failure and what has been called end-stage kidneys. The functional reserve of the kidney is large, and much damage may occur before there is evident functional impairment. For these reasons, the early signs and symptoms are particularly important clinically.
OBJECTIVES:
1. Know the common causes and mechanisms producing acute renal failure.
2. Describe the uremic syndrome and the possible mechanisms causing its clinical manifestations.
3. Understand the pathogenesis of glomerulonephritis and know the clinical and morphological features of the important diseases classified as glomerulonephritis.
4. Define the nephrotic syndrome and know the clinical and morphological features of the important diseases causing nephrotic syndrome.
5. Understand the natural history and pathologic characteristics of the common renal neoplasms.
6. Know the clinical and morphological features of acute and chronic pyelonephritis. List eight major clinical syndromes with which a patient with renal disease may present. Know the five major glomerular syndromes. (PBD, Table 20-4, p. 967)
Key words: kidney, renal failure, uremic syndrome, glomerulonephritis, nephrotic syndrome, nephritic syndrome, renal neoplasms, pyelonephritis.
Laboratory OBJECTIVES:
1. Describe the characteristic light microscopic (LM), immunofluorescence (IF), and electron microscopic (EM) findings of MCD.
2. Describe the suggested mechanism for proteinuria in MCD. Know what happens to the negative charge of the
3. Describe the characteristic light microscopic and EM findings of FSGS.
4. Define membranous GN, and distinguish between primary and secondary forms.
5. Describe the morphologic glomerular changes of MGN by LM, IF, and EM.
6. Describe the major histologic glomerular findings in RPGN.
7. Name a systemic disease in which you may see MPGN-type renal disease.
8. Define and be able to use correctly the terms urinary tract infection (UTI) and acute and chronic pyelonephritis (PN).
9. Describe the gross and microscopic changes in acute PN, including necrotizing papillitis. Know what diseases predispose to necrotizing papillitis.
10. How does scarring in chronic PN differ from that seen in chronic glomerulonephritis or longstanding benign hypertension?
11. Describe the difference, grossly, between adenoma and renal cell carcinoma.
Clinical Manifestations of Renal Diseases
The clinical manifestations of renal disease can be grouped into reasonably well-defined syndromes. Some are peculiar to glomerular diseases, and others are present in diseases that affect any one of the components. Before we list the syndromes, a few terms must be clarified.
Azotemia is a biochemical abnormality that refers to an elevation of the blood urea nitrogen (BUN) and creatinine levels and is related largely to a decreased glomerular filtration rate (GFR). Azotemia is produced by many renal disorders, but it also arises from extrarenal disorders. Prerenal azotemia is encountered when there is hypoperfusion of the kidneys (e.g., in hemorrhage, shock, volume depletion, and congestive heart failure) that impairs renal function in the absence of parenchymal damage. Similarly, postrenal azotemia is seen whenever urine flow is obstructed below the level of the kidney. Relief of the obstruction is followed by correction of the azotemia.
When azotemia becomes associated with a constellation of clinical signs and symptoms and biochemical abnormalities, it is termed uremia. Uremia is characterized not only by failure of renal excretory function, but also by a host of metabolic and endocrine alterations resulting from renal damage. There is, in addition, secondary involvement of the gastrointestinal system (e.g., uremic gastroenteritis), peripheral nerves (e.g., peripheral neuropathy), and heart (e.g., uremic fibrinous pericarditis), which is usually necessary for the diagnosis of uremia.
We can now turn to a brief description of the clinical presentations of renal disease:
• Acute nephritic syndrome is a glomerular syndrome dominated by the acute onset of usually grossly visible hematuria (red blood cells in urine), mild to moderate proteinuria, and hypertension; it is the classic presentation of acute poststreptococcal glomerulonephritis.
• The nephrotic syndrome is characterized by heavy proteinuria (more than 3.5 gm/day), hypoalbuminemia, severe edema, hyperlipidemia, and lipiduria (lipid in the urine).
• Asymptomatic hematuria or proteinuria, or a combination of these two, is usually a manifestation of subtle or mild glomerular abnormalities.
• Acute renal failure is dominated by oliguria or anuria (reduced or no urine flow), with recent onset of azotemia. It can result from glomerular, interstitial, or vascular injury or acute tubular necrosis.
• Chronic renal failure, characterized by prolonged symptoms and signs of uremia, is the end result of all chronic renal parenchymal diseases.
• Renal tubular defects are dominated by polyuria (excessive urine formation), nocturia, and electrolyte disorders (e.g., metabolic acidosis). They are the result of either diseases that directly affect tubular structure (e.g., medullary cystic disease) or defects in specific tubular functions. The latter can be inherited (e.g., familial nephrogenic diabetes, cystinuria, renal tubular acidosis) or acquired (e.g., lead nephropathy).
• Urinary tract infection is characterized by bacteriuria and pyuria (bacteria and leukocytes in the urine). The infection may be symptomatic or asymptomatic, and it may affect the kidney (pyelonephritis) or the bladder (cystitis) only.
• Nephrolithiasis (renal stone) is manifested by renal colic, hematuria, and recurrent stone formation.
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• Urinary tract obstruction and renal tumors represent specific anatomic lesions with often varied clinical manifestations.
Acute renal failure implies a rapid and frequently reversible deterioration of renal function. It is discussed in the section on acute tubular necrosis because it frequently occurs in this disorder. Here, the discussion is limited to chronic renal failure, which is the end result of a variety of renal diseases and is the major cause of death from renal disease.
Although exceptions abound, the evolution from normal renal function to symptomatic chronic renal failure progresses through four stages that merge into one another.
1. In diminished renal reserve, the GFR is about 50% of normal. Serum BUN and creatinine values are normal, and the patients are asymptomatic. However, they are more susceptible to developing azotemia with an additional renal insult.
2. In renal insufficiency, the GFR is 20% to 50% of normal. Azotemia appears, usually associated with anemia and hypertension. Polyuria and nocturia can occur as a result of decreased concentrating ability. Sudden stress (e.g., with nephrotoxins) may precipitate uremia.
3. In renal failure, the GFR is less than 20% to 25% of normal. The kidneys cannot regulate volume and solute composition, and patients develop edema, metabolic acidosis, and hypocalcemia. Overt uremia may ensue, with neurologic, gastrointestinal, and cardiovascular complications.
4. In end-stage renal disease, the GFR is less than 5% of normal; this is the terminal stage of uremia.
Principal Systemic Manifestations of Chronic Renal Failure and Uremia
Fluid and Electrolytes
Dehydration
Edema
Hyperkalemia
Metabolic acidosis
Calcium Phosphate and Bone
Hyperphosphatemia
Hypocalcemia
Secondary hyperparathyroidism
Renal osteodystrophy
Hematologic
Anemia
Bleeding diathesis
Cardiopulmonary
Hypertension
Congestive heart failure
Pulmonary edema
Uremic pericarditis
Gastrointestinal
Nausea and vomiting
Bleeding
Esophagitis, gastritis, colitis
Neuromuscular
Myopathy
Peripheral neuropathy
Encephalopathy
Dermatologic
Sallow color
Pruritus
Dermatit
Glomerular Diseases
Glomerular diseases constitute some of the major problems in nephrology; indeed, chronic glomerulonephritis is one of the most common causes of chronic renal failure in humans. Glomeruli may be injured by a variety of factors and in the course of a number of systemic diseases. Systemic immunologic diseases such as systemic lupus erythematosus (SLE), vascular disorders such as hypertension and polyarteritis nodosa, metabolic diseases such as diabetes mellitus, and some purely hereditary conditions such as Fabry disease often affect the glomerulus. These are termed secondary glomerular diseases to differentiate them from disorders in which the kidney is the only or predominant organ involved. The latter constitute the various types of primary glomerulonephritis or, because some do not have a cellular inflammatory component, glomerulopathy. However, both the clinical manifestations and glomerular histologic changes in primary and secondary forms can be similar.
Histologic alteration
Various types of glomerulonephritis are characterized by one or more of four basic tissue reactions.
1. Hypercellularity. Some inflammatory diseases of the glomerulus are characterized by an increase in the number of cells in the glomerular tufts. This hypercellularity is characterized by one or more combinations of the following:
• Cellular proliferation of mesangial or endothelial cells
• Leukocytic infiltration, consisting of neutrophils, monocytes, and, in some diseases, lymphocytes
Acute glomerulonephritis
A fairly high power view showing the cellular glomeruli. PMNs can be seen.
• Formation of crescents. These are accumulations of cells composed of proliferating parietal epithelial cells and infiltrating leukocytes. The epithelial cell proliferation that characterizes crescent formation occurs following an immune/inflammatory injury. Fibrin, which leaks into the urinary space, often through ruptured basement membranes, has been long thought to be the molecule that elicits the crescentic response. In support of this, fibrin can be demonstrated immunohistochemically in the glomerular tufts and urinary spaces of glomeruli that contain crescents.
Rapidly Progressive Glomerulonephritis
Note crescent formation. (
• Other molecules that have been implicated in crescent formation and recruitment of leukocytes into crescents include precoagulants such as tissue factor and cytokines such as interleukin-1, tumor necrosis factor, and interferon-γ.
Glomerular Diseases classification
Primary Glomerulopathies
Acute diffuse proliferative glomerulonephritis
-Poststreptococcal
-Non-poststreptococcal
Rapidly progressive (crescentic) glomerulonephritis
Membranous glomerulopathy
Minimal change disease
Focal segmental glomerulosclerosis
Membranoproliferative glomerulonephritis
IgA nephropathy
Chronic glomerulonephritis
Systemic Diseases with Glomerular Involvement
SLE
Diabetes mellit
Amyloidosis
Goodpasture syndrome
Microscopic polyarteritis/polyangiitis
Wegener granulomatosis
Henoch-Schönlein purpura
Bacterial endocarditis
Hereditary Disorders
Alport syndrome
Thin basement membrane disease
Fabry disease
The Glomerular Syndromes
Acute nephriticSyndrome
• Hematuria, azotemia, variableproteinuria, oliguria, edema, andhypertension
Rapidly progressiveglomerulonephritis
• Acute nephritis, proteinuria, andacute renal failure
Nephrotic syndrome
• >3.5 gm proteinuria, hypoalbuminemia,hyperlipidemia, lipiduria
Chronic renal failure
• Azotemia → uremia progressing foryears
Asymptomatichematuria orproteinuria
• Glomerular hematuria; subnephroticproteinuria
2. Basement Membrane Thickening. By light microscopy, this change appears as thickening of the capillary walls, best seen in sections stained with periodic acid-Schiff (PAS). By electron microscopy, such thickening can be resolved as one of two alterations:
Glomerulus, membranoproliferative glomerulonephritis
(1) deposition of amorphous electron-dense material, most often immune complexes, on the endothelial or epithelial side of the basement membrane or within the GBM itself. Fibrin, amyloid, cryoglobulins, and abnormal fibrillary proteins may also deposit in the GBM; or (2) thickening of the basement membrane proper, as occurs in diabetic
3. Hyalinization and Sclerosis. Hyalinization, or hyalinosis, as applied to the glomerulus, denotes the accumulation of material that is homogeneous and eosinophilic by light microscopy.
Chronic glomerulonephritis
Hyalinized arterioles and sclerotic glomeruli.
By electron microscopy, the hyalin is extracellular and consists of amorphous substance, made up of plasma proteins that have exuded from circulating plasma into glomerular structures. This change contributes to obliteration of capillary lumina of the glomerular tuft (a feature of sclerosis). Hyalinosis is usually a consequence of endothelial or capillary wall injury and typically is the end result of various forms of glomerular damage. Additional alterations include intraglomerular thrombosis or accumulation of lipid or
other metabolic materials. glomerulosclerosis.
Because many of the primary glomerulonephritides are of unknown cause, they are often classified by their histology, as can be seen in table-2. The histologic changes can be further subdivided into diffuse, involving all glomeruli; global, involving the entire glomerulus; focal, involving only a proportion of the glomeruli; segmental, affecting a part of each glomerulus; and mesangial, affecting predominantly the mesangial region. These terms are sometimes appended to the histologic classifications.
Pathogenesis of glomerular injury
Although we know little of etiologic agents and triggering events, it is clear that immune mechanisms underlie most forms of primary glomerulonephritis and many of the secondary glomerular disorders. Glomerulonephritis can be readily induced experimentally by antigen-antibody reactions. Furthermore, glomerular deposits of immunoglobulins, often with various components of complement, are found in the majority of patients with glomerulonephritis. Cell-mediated immune reactions also clearly play a role, usually in concert with antibody-mediated events.
Two forms of antibody-associated injury have been established: (1) injury by antibodies reacting in situ within the glomerulus, either with insoluble fixed (intrinsic) glomerular antigens or with molecules planted within the glomerulus, and (2) injury resulting from deposition of circulating antigen- antibody complexes in the glomerulus. In addition, there is experimental evidence that cytotoxic antibodies directed against glomerular cell components may cause glomerular injury. These pathways are not mutually exclusive, and in humans, all may contribute to injury.
I. ACUTE GLOMERULONEPHRITIS
This group of glomerular diseases is characterized anatomically by inflammatory alterations in the glomeruli and clinically by the syndrome of acute nephritis. The nephritic patient usually presents with hematuria, red cell casts in the urine, azotemia, oliguria, and mild to moderate hypertension. The patient also commonly has proteinuria and edema, but these are not as severe as those encountered in the nephrotic syndrome, discussed later. The acute nephritic syndrome may occur in such multisystem diseases as SLE and microscopic polyarteritis. Typically, however, it is characteristic of acute proliferative glomerulonephritis and is an important component of crescentic glomerulonephritis, which is described later.
1. Acute Proliferative (Poststreptococcal, Postinfectious) Glomerulonephritis
As the name implies, this cluster of diseases is characterized histologically by diffuse proliferation of glomerular cells, associated with influx of leukocytes. These lesions are typically caused by immune complexes. The inciting antigen may be exogenous or endogenous. The most common infections are streptococcal, but the disorder has also been associated with other infections
Poststreptococcal Glomerulonephritis.
It usually appears 1 to 4 weeks after a streptococcal infection of the pharynx or skin (impetigo). Skin infections are commonly associated with overcrowding and poor hygiene. Poststreptococcal glomerulonephritis occurs most frequently in children 6 to 10 years of age, but adults of any age can be affected.
Etiology and Pathogenesis. Only certain strains of group A β-hemolytic streptococci are nephritogenic, more than 90% of cases being traced to types 12, 4, and 1, which can be identified by typing of M protein of the cell wall.
Poststreptococcal glomerulonephritis is an immunologically mediated disease. The latent period between infection and onset of nephritis is compatible with the time required for the production of antibodies and the formation of immune complexes. Morphology. The classic diagnostic picture is one of enlarged, hypercellular glomeruli. The hypercellularity is caused by (1) infiltration by leukocytes, both neutrophils and monocytes; (2) proliferation of endothelial and mesangial cells; and (3) in severe cases by crescent formation.
Acute Glomerulonephritis
Note numerous neutrophils
The proliferation and leukocyte infiltration are diffuse, that is, involving all lobules of all glomeruli. There is also swelling of endothelial cells, and the combination of proliferation, swelling, and leukocyte infiltration obliterates the capillary lumens. There may be interstitial edema and inflammation, and the tubules often contain red cell casts.
The characteristic electron microscopic findings are discrete, amorphous, electron-dense deposits on the epithelial side of the membrane, often having the appearance of "humps", presumably representing the antigen- antibody complexes at the epithelial cell surface. Subendothelial and intramembranous deposits are also commonly seen, and mesangial deposits may be present. There is often swelling of endothelial and mesangial cells.
Clinical Course. In the classic case, a young child abruptly develops malaise, fever, nausea, oliguria, and hematuria (smoky or cocoa-colored urine) 1 to 2 weeks after recovery from a sore throat. The patients exhibit red cell casts in the urine, mild proteinuria (usually less than 1 gm/day), periorbital edema, and mild to moderate hypertension. In adults, the onset is more likely to be atypical, with the sudden appearance of hypertension or edema.
2.Nonstreptococcal Acute Glomerulonephritis (Postinfectious Glomerulonephritis
A similar form of glomerulonephritis occurs sporadically in association with other bacterial infections (e.g., staphylococcal endocarditis, pneumococcal pneumonia, and meningococcemia), viral disease (e.g., hepatitis B, hepatitis C, mumps, human immunodeficiency virus [HIV] infection, varicella, and infectious mononucleosis), and parasitic infections (malaria, toxoplasmosis). In this setting, granular immunofluorescent deposits and subepithelial humps characteristic of immune complex nephritis are present.
II. RAPIDLY PROGRESSIVE (CRESCENTIC) GLOMERULONEPHRITIS
Rapidly progressive glomerulonephritis (RPGN) is a syndrome associated with severe glomerular injury and does not denote a specific etiologic form of glomerulonephritis. It is characterized clinically by rapid and progressive loss of renal function associated with severe oliguria and (if untreated) death from renal failure within weeks to months. Regardless of the cause, the classic histologic picture is characterized by the presence of crescents in most of the glomeruli (crescentic glomerulonephritis). As discussed earlier, these are produced in part by proliferation of the parietal epithelial cells lining Bowman capsule and in part by infiltration of monocytes and macrophage
Morphology. The kidneys are enlarged and pale, often with petechial hemorrhages on the cortical surfaces. Depending on the underlying cause, the glomeruli may show focal necrosis, diffuse or focal endothelial proliferation, and mesangial proliferation. The histologic picture, however, is dominated by the formation of distinctive crescents.
The glomerulus on the left shows a crescent.
Crescents are formed by proliferation of parietal cells and by migration of monocytes and macrophages into the urinary space. Neutrophils and lymphocytes may be present. The crescents eventually obliterate Bowman space and compress the glomerular tuft. Fibrin strands are prominent between the cellular layers in the crescents; indeed, as discussed earlier, the escape of fibrin into Bowman space is an important contributor to crescent formation.
There is, however, a ruptured GBM, indicating marked glomerular damage
Electron microscopy may, as expected, disclose subepithelial deposits in some cases, but in many cases, it shows distinct ruptures in the GBM, the severe injury that allows leukocytes, proteins, and inflammatory mediators into the urinary space, where they trigger the crescent formation. In time, most crescents undergo sclerosis, but restoration of normal glomerular architecture marks a successful clinical outcome in some patients, particularly those with an infection-associated immune complex etiology
By immunofluorescence microscopy, postinfec-tious cases exhibit granular immune deposits; Goodpasture syndrome cases show linear fluorescence for immunoglobulin and complement, and pauci-immune cases have little or no deposition of immune reactants
Clinical Course. The renal manifestations of all forms include hematuria with red cell casts in the urine, moderate proteinuria occasionally reaching the nephrotic range, and variable hypertension and edema. In Goodpasture syndrome, the course may be dominated by recurrent hemoptysis or even life-threatening pulmonary hemorrhage. Serum analyses for anti-GBM antibodies, antinuclear antibodies, and ANCA are helpful in the diagnosis of specific subtypes. Although milder forms of glomerular injury may subside, the renal involvement is usually progressive over a matter of weeks and culminates in severe oliguria. Recovery of renal function may follow early intensive plasmapheresis (plasma exchange) combined with steroids and cytotoxic agents in Goodpasture syndrome. This therapy appears to reverse both pulmonary hemorrhage and renal failure. Other forms of RPGN also respond well to steroids and cytotoxic agents. Despite therapy, patients may eventually require chronic dialysis or transplantation.
Nephrotic syndrome
Certain glomerular diseases virtually always produce the nephrotic syndrome. In addition, many other forms of primary and secondary glomerulonephritis discussed in this chapter may underlie the syndrome. Before the major diseases associated with nephrotic syndrome are presented, the pathophysiology of this clinical complex is briefly discussed, and the causes are listed
The manifestations of the nephrotic syndrome include:
1. Massive proteinuria, with the daily loss of 3.5 gm or more of protein
2. Hypoalbuminemia, with plasma albumin levels less than 3 gm/dL
3. Generalized edema
4. Hyperlipidemia and lipiduria
The various components of nephrotic syndrome bear a logical relationship to one another. The initial event is a derangement in glomerular capillary walls resulting in increased permeability to plasma proteins. It will be remembered that the glomerular capillary wall, with its endothelium, GBM, and visceral epithelial cells, acts as a size and charge barrier through which the glomerular filtrate must pass. Increased permeability resulting from either structural or physicochemical alterations allows protein to escape from the plasma into the glomerular filtrate. Massive proteinuria results.
The heavy proteinuria leads to depletion of serum albumin levels below the compensatory synthetic abilities of the liver, with consequent hypoalbuminemia and a reversed albumin-globulin ratio. Increased renal catabolism of filtered albumin also contributes to the hypoalbuminemia. The generalized edema is, in turn, the consequence of the loss of colloid osmotic pressure of the blood with subsequent accumulation of fluid in the interstitial tissues. There is also sodium and water retention, which aggravates the edema. This appears to be due to several factors, including compensatory secretion of aldosterone, mediated by the hypovolemia-enhanced antidiuretic hormone secretion; stimulation of the sympathetic system; and a reduction in the secretion of natriuretic factors such as atrial peptides. Edema is characteristically soft and pitting, most marked in the periorbital regions and dependent portions of the body. It may be massive, with pleural effusions and ascites.
The largest proportion of protein lost in the urine is albumin, but globulins are also excreted in some diseases. The ratio of low- to high-molecular-weight proteins in the urine in various cases of nephrotic syndrome is a manifestation of the selectivity of proteinuria. A highly selective proteinuria consists mostly of low-molecular-weight proteins (albumin: 70 kDa; transferrin: 76 kDa molecular weight), whereas a poorly selective proteinuria consists of higher-molecular-weight globulins in addition to albumin
The genesis of the hyperlipidemia is complex. Most patients have increased blood levels of cholesterol, triglyceride, very-low-density lipoprotein, low-density lipoprotein, Lp(a) lipoprotein, and apoprotein, and there is a decrease in high-density lipoprotein concentration in some patients. These defects seem to be due in part to increased synthesis of lipoproteins in the liver, abnormal transport of circulating lipid particles, and decreased catabolism. Lipiduria follows the hyperlipidemia because not only albumin molecules but also lipoproteins leak across the glomerular capillary wall. The lipid appears in the urine either as free fat or as oval fat bodies, representing lipoprotein resorbed by tubular epithelial cells and then shed along with the degenerated cells.
These patients are particularly vulnerable to infection, especially with staphylococci and pneumococci. This vulnerability could be related to loss of immunoglobulins or low-molecular-weight complement components in the urine. Thrombotic and thromboembolic complications are also common in nephrotic syndrome, owing in part to loss of anticoagulant factors (e.g., antithrombin III) and antiplasmin activity through the leaky glomerulus. Renal vein thrombosis, once thought to be a cause of nephrotic syndrome, is most often a consequence of this hypercoagulable state.
Causes. The relative frequencies of the several causes of the nephrotic syndrome vary according to age and geography. In children younger than 17 years for example, the nephrotic syndrome is almost always caused by a lesion primary to the kidney; whereas among adults, it may often be associated with a systemic disease.
The most important of the primary glomerular lesions are minimal change disease, membranous glomerulopathy, and focal segmental glomerulosclerosis. Other primary causes, the various proliferative glomerulonephritides, frequently present as a mixed syndrome with nephrotic and nephritic features.
III. MEMBRANOUS GLOMERULOPATHY (MEMBRANOUS NEPHROPATHY)
Membranous glomerulopathy is the most common cause of the nephrotic syndrome in adults. It is characterized by diffuse thickening of the glomerular capillary wall and the accumulation of electron-dense, immunoglobulin-containing deposits along the subepithelial side of the basement membrane.
Membranous glomerulopathy occurring in association with other systemic diseases and a variety of identifiable etiologic agents is referred to as secondary membranous glomerulopathy. The most notable such associations are as follows:
• Drugs (penicillamine[pic], captopril[pic], gold, nonsteroidal anti-inflammatory drugs NSAIDs.
• Underlying malignant tumors, particularly carcinoma of the lung and colon and melanoma.
• SLE. About 15% of glomerulonephritis in SLE is of the membranous type.
• Infections (chronic hepatitis B, hepatitis C, syphilis, schistosomiasis, malaria)
• Other autoimmune disorders, such as thyroiditis
Etiology and Pathogenesis. Membranous glomerulopathy is a form of chronic immune complex-mediated disease. In secondary membranous glomerulopathy, particular antigens can sometimes be identified in the immune complexes. For example, membranous glomerulopathy in SLE is associated with deposition of autoantigen-antibody complexes. Exogenous (hepatitis B, Treponema antigens) or endogenous (thyroglobulin) antigens have been identified within deposits in some patients.
Morphology. By light microscopy, the glomeruli either appear normal in the early stages of the dis-ease or exhibit uniform, diffuse thickening of the glomerular capillary wall. By electron microscopy, the thickening is seen to be caused by irregular dense deposits between the basement membrane and the overlying epithelial cells, the latter having effaced foot processes.
Basement membrane material is laid down between these deposits, appearing as irregular spikes protruding from the GBM. These spikes are best seen by silver stains, which color the basement membrane black. In time, these spikes thicken to produce domelike protrusions and eventually close over the immune deposits, burying them within a markedly thickened, irregular membrane. Immunofluorescence microscopy demonstrates that the granular deposits contain both immunoglobulins and various amounts of complement. As the disease advances, the membrane thickening progressively encroaches on the capillary lumens, and sclerosis of the mesangium may occur; in the course of time, glomeruli may become totally sclerosed. The epithelial cells of the proximal tubules contain protein reabsorption droplets, and there may be considerable mononuclear cell interstitial inflammation.
Clinical Course. In a previously healthy individual, this disorder usually begins with the insidious onset of the nephrotic syndrome or, in 15% of patients, with non-nephrotic proteinuria. Hematuria and mild hypertension are present in 15% to 35% of cases. Progression is associated with increasing sclerosis of glomeruli, rising BUN reflecting renal insufficiency, and development of hypertension. Although proteinuria persists in more than 60% of patients, only about 10% die or progress to renal failure within 10 years, and no more than 40% eventually develop renal insufficiency. Concurrent sclerosis of glomeruli in the renal biopsy at the time of diagnosis is a predictor of worse prognosis. Spontaneous remissions and a relatively benign outcome occur more commonly in women and in those with proteinuria in the non-nephrotic range. Because of the variable course of the disease, it has been difficult to evaluate the overall effectiveness of corticosteroids or other immunosuppressive therapy in controlling the proteinuria or progression
IV.MINIMAL CHANGE DISEASE (LIPOID NEPHROSIS)
This relatively benign disorder is the most frequent cause of nephrotic syndrome in children, but it is less common in adults. It is characterized by diffuse effacement of foot processes of epithelial cells in glomeruli that appear virtually normal by light microscopy. The peak incidence is between 2 and 6 years of age. The disease sometimes follows a respiratory infection or routine prophylactic immunization. Its most characteristic feature is its usually dramatic response to corticosteroid therapy
Etiology and Pathogenesis. Although the absence of immune deposits in the glomerulus excludes classic immune complex mechanisms, several features of the disease point to an immunologic basis, including (1) the clinical association with respiratory infections and prophylactic immunization; (2) the response to corticosteroids and/or other immunosuppressive therapy; (3) the association with other atopic disorders (e.g., eczema, rhinitis); (4) the increased prevalence of certain HLA haplotypes in patients with minimal change disease associated with atopy (suggesting a genetic predisposition); (5) the increased incidence of minimal change disease in patients with Hodgkin disease, in whom defects in T cell-mediated immunity are well recognized; and (6) reports of proteinuria-inducing factors in the plasma or lymphocyte supernatants of patients with minimal change disease and focal glomerulosclerosis.
Morphology. The glomeruli are normal by light microscopy. By electron microscopy, the basement membrane appears normal, and no electron-dense material is deposited. The principal lesion is in the visceral epithelial cells, which show a uniform and diffuse effacement of foot processes, these being replaced by a rim of cytoplasm often showing vacuolization, swelling, and hyperplasia of villi. This change, often incorrectly termed "fusion" of foot processes, actually represents simplification of the epithelial cell architecture with flattening, retraction, and swelling of foot processes.
The glomerulus has normal mesangial cellularity with normal open tufts. The basement membrane is of uniform thickness. No inflammation is seen. The tubules are of normal shape and size. The interstitium is also unremarkable.
Foot process effacement is also present in other proteinuric states (e.g., membranous glomerulopathy, diabetes); it is only when effacement is associated with normal glomeruli by light microscopy that the diagnosis of minimal change disease can be made. The visceral epithelial changes are completely reversible after corticosteroid therapy, concomitant with remission of the proteinuria. The cells of the proximal tubules are often laden with lipid and protein, reflecting tubular reabsorption of lipoproteins passing through diseased glomeruli (thus, the historical term lipoid nephrosis).
Clinical Course. Despite massive proteinuria, renal function remains good, and there is commonly no hypertension or hematuria. The proteinuria usually is highly selective, most of the protein consisting of albumin. Nevertheless, the long-term prognosis for patients is excellent, and even steroid-dependent disease resolves when children reach puberty. Although adults are slower to respond, the long-term prognosis is also excellent
As has been noted, minimal change disease in adults can be associated with Hodgkin disease and, less frequently, other lymphomas and leukemias. In addition, secondary minimal change disease may follow NSAID therapy, usually in association with acute interstitial nephritis, to be described later in this chapter.
V. FOCAL SEGMENTAL GLOMERULOSCLEROSIS
As the name implies, this lesion is characterized by sclerosis of some, but not all, glomeruli (thus, it is focal); and in the affected glomeruli, only a portion of the capillary tuft is involved (thus, it is segmental). Focal segmental glomerulosclerosis is frequently accompanied clinically by the nephrotic syndrome or heavy proteinuria.
Classification and Types. Focal segmental glomerulosclerosis (FSGS) occurs in the following settings.
• In association with other known conditions, such as HIV infection (HIV nephropathy), heroin addiction (heroin nephropathy), sickle cell disease, and massive obesity
• As a secondary event, reflecting glomerular scarring, in cases of focal glomerulonephritis (e.g., IgA nephropathy)
• As a component of the adaptive response to loss of renal tissue (renal ablation, described earlier) in advanced stages of other renal disorders, such as reflux nephropathy, hypertensive nephropathy, or with unilateral renal agenesis
• In certain inherited forms of nephrotic syndrome where the disease, in some pedigrees, has been linked to mutations in genes encoding nephrin, podocin, or α-actinin 4
• As a primary disease (idiopathic focal segmental glomerulosclerosis)
- HIV-Associated Nephropathy
HIV infection can result directly or indirectly in a number of renal complications, including acute renal failure and/or acute interstitial nephritis induced by drugs or infection, thrombotic microangiopathies, postinfectious glomerulonephritis, and, most commonly, a severe form of the collapsing variant of focal segmental glomerulosclerosis.64 The last occurs in 5% to 10% of HIV-infected patients in some series, more frequently in blacks than in whites. In rare cases, the nephrotic syndrome may precede the development of acquired immunodeficiency syndrome. The morphologic features are characterized by:
• A high frequency of the collapsing variant of focal segmental glomerulosclerosis, with global involvement of the tuft
• A striking focal cystic dilation of tubule segments, which are filled with proteinaceous material, and inflammation and fibrosis
• The presence of large numbers of tubuloreticular inclusions in endothelial cells, detected by electron microscopy. Such inclusions, also present in SLE, have been shown to be induced by circulating interferon-α. They are not present in idiopathic focal segmental glomerulosclerosis and therefore may have diagnostic value in a biopsy specimen.
Morphology. By light microscopy, the segmental lesions may involve only a minority of the glomeruli and may be missed if the biopsy specimen contains an insufficient number of glomeruli. The lesions initially tend to involve the juxtamedullary glomeruli, although they subsequently become more generalized. In the sclerotic segments, there is collapse of basement membranes, increase in matrix, and segmental insudation of plasma proteins along the capillary wall (hyalinosis), which may extend to aggregates within glomerular capillaries that occlude the lumina. Lipid droplets and foam cells are often present. Glomeruli that do not exhibit segmental lesions either appear normal on light microscopy or may show increased mesangial matrix and mesangial proliferation.
In a later stage of FSGS, dense glomerular sclerosis and more interstitial fibrosis, tubular atrophy, and chronic inflammation are seen, trichrome stain
On electron microscopy, both sclerotic and nonsclerotic areas show the diffuse effacement of foot processes characteristic of minimal change disease, but in addition, there may be focal detachment of the epithelial cells with denudation of the underlying GBM. By immunofluorescence microscopy, IgM and C3 may be present in the sclerotic areas and/or in the mesangium. In addition to the focal sclerosis, there may be pronounced hyalinosis and thickening of afferent arterioles. With the progression of the disease, increased numbers of glomeruli become involved, sclerosis spreads within each glomerulus, and there is an increase in mesangial matrix. In time, this leads to total sclerosis of glomeruli, with pronounced tubular atrophy and interstitial fibrosis.
A morphologic variant of focal segmental glomerulosclerosis, called collapsing glomerulopathy, is characterized by collapse and sclerosis of the entire glomerular tuft in addition to the usual focal segmental glomerulosclerosis lesions.
Notice the collapse of capillary loops in a portion of a single glomerulus (segmental capillary collapse), accompanied by intracapillary foam cells and extracapillary epithelial cell proliferation.
A characteristic feature is proliferation and hypertrophy of glomerular visceral epithelial cells. This lesion may be seen in situations in which it is idiopathic, but it is the most characteristic lesion of HIV-associated nephropathy. In both cases, there is associated prominent tubular injury with formation of microcysts. It has a particularly poor prognosis
Pathogenesis. Whether idiopathic focal segmental glomerulosclerosis represents a distinct disease or is simply a phase in the evolution of a subset of patients with minimal change disease remains unresolved. The characteristic degeneration and focal disruption of visceral epithelial cells are thought to represent an accentuation of the diffuse epithelial cell change typical of minimal change disease. It is this epithelial damage that is the hallmark of focal segmental glomerulosclerosis. The hyalinosis and sclerosis represent entrapment of plasma proteins in extremely hyperpermeable foci with increased ECM deposition. The recurrence of proteinuria, sometimes within 24 hours after transplantation, suggests that a circulating factor, perhaps a cytokine, may be the cause of the epithelial damage. An approximately 50-kDa nonimmunoglobulin factor causing proteinuria has been isolated from sera of such patients
Clinical Course. There is little tendency for spontaneous remission in idiopathic focal segmental glomerulosclerosis, and responses to corticosteroid therapy are variable. In general, children have a better prognosis than adults do. Progression of renal failure occurs at variable rates. About 20% of patients follow an unusually rapid course, with intractable massive proteinuria ending in renal failure within 2 years. Recurrences are seen in 25% to 50% of patients receiving allografts.
VI. MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS
Membranoproliferative glomerulonephritis (MPGN) is characterized histologically by alterations in the basement membrane, proliferation of glomerular cells, and leukocyte infiltration. Because the proliferation is predominantly in the mesangium, a frequently used synonym is mesangiocapillary glomerulonephritis. MPGN accounts for 10% to 20% of cases of nephrotic syndrome in children and young adults. Some patients present only with hematuria or proteinuria in the non-nephrotic range, and others have a combined nephrotic-nephritic picture. Like many other glomerulonephritides, MPGN either can be associated with other systemic disorders and known etiologic agents (secondary MPGN) or may be idiopathic (primary MPGN).
Primary MPGN is divided into two major types on the basis of distinct ultrastructural, immunofluorescent, and pathologic findings: type I and type II MPGN (dense-deposit disease).
Morphology. By light microscopy, both types are similar. The glomeruli are large and hypercellular. The hypercellularity is produced both by proliferation of cells in the mesangium and so-called endocapillary cell proliferation involving capillary endothelium and infiltrating leukocytes. Parietal epithelial crescents are present in many cases. The glomeruli have a "lobular" appearance accentuated by the proliferating mesangial cells and increased mesangial matrix.
Notice the lobular pattern, the hypercellularity, and the collapse of the capillaries.
The GBM is clearly thickened, often focally; this is most evident in the peripheral capillary loops. The glomerular capillary wall often shows a "double-contour" or "tram-track" appearance, especially evident in silver or PAS stains. This is caused by "duplication" of the basement membrane, usually as the result of new basement membrane synthesis. Within the besement membrane there is inclusion or interposition of cellular elements, which can be of mesangial, endothelial, or leukocytic origin. Such interposition gives rise to the appearance of "split" basement membranesType I MPGN (the great majority of cases) is characterized by the presence of subendothelial electron-dense deposits. Mesangial and occasional subepithelial deposits may also be present. By immunofluorescence, C3 is deposited in a granular pattern, and IgG and early complement components (C1q and C4) are often also present, suggesting an immune complex pathogenesis In dense-deposit disease (type II MPGN), a relatively rare entity, the lamina densa of the GBM is transformed into an irregular, ribbon-like, extremely electron-dense structure because of the deposition of dense material of unknown composition in the GBM proper, giving rise to the term dense-deposit disease.
Pathogenesis. In most cases of type I MPGN there is evidence of immune complexes in the glomerulus and activation of both classical and alternative complement pathways. The antigens involved in idiopathic MPGN are unknown. In many cases, they are believed to be proteins derived from infectious agents such as hepatitis C and B viruses, which presumably behave either as "planted" antigens after first binding to or becoming trapped within glomerular structures or are contained in preformed immune complexes deposited from the circulation.
Most patients with dense-deposit disease (type II MPGN) have abnormalities that suggest activation of the alternative complement pathway. These patients have a consistently decreased serum C3 but normal C1 and C4, the immune complex-activated early components of complement.
Clinical Course. The principal mode of presentation is the nephrotic syndrome occurring in older children or young adults (idiopathic MPGN type I and cases of type II), but usually with a nephritic component manifested by hematuria or, more insidiously, as mild proteinuria. Few remissions occur spontaneously in either type, and the disease follows a slowly progressive but unremitting course. Some patients develop numerous crescents and a clinical picture of RPGN. About 50% develop chronic renal failure within 10 years. Treatments with steroids, immunosuppressive agents, and antiplatelet drugs have not been proved to be materially effective. There is a high incidence of recurrence in transplant recipients, particularly in dense-deposit disease; dense deposits may recur in 90% of such patients, although renal failure in the allograft is much less common.
Secondary MPGN (invariably type I) is more common in adults and arises in the following settings:
• Chronic immune complex disorders, such as SLE; hepatitis B infection; hepatitis C infection, usually with cryoglobulinemia; endocarditis; infected ventriculoatrial shunts; chronic visceral abscesses; HIV infection; and schistosomiasis
• α1-Antitrypsin deficiency
• Malignant diseases (chronic lymphocytic leukemia and lymphoma)
• Hereditary deficiencies of complement regulatory proteins
The mechanisms underlying the process of immune complex deposition in the last three categories above remain unknown
VII. IGA NEPHROPATHY (BERGER DISEASE)
This form of glomerulonephritis is characterized by the presence of prominent IgA deposits in the mesangial regions, detected by immunofluorescence microscopy. The disease can be suspected by light microscopic examination, but diagnosis is made only by immunocytochemical techniques. IgA nephropathy is a frequent cause of recurrent gross or microscopic hematuria and is probably the most common type of glomerulonephritis worldwide. Mild proteinuria is usually present, and the nephrotic syndrome may occasionally develop. Rarely, patients may present with rapidly progressive crescentic glomerulonephritis
Morphology. On histologic examination, the lesions vary considerably. The glomeruli may be normal or may show mesangial widening and proliferation (mesangioproliferative glomerulonephritis), segmental proliferation confined to some glomeruli (focal proliferative glomerulonephritis), or rarely, overt crescentic glomerulonephritis. The presence of leukocytes within glomerular capillaries is a variable feature. The mesangial widening may be the result of cell proliferation, accumulation of matrix, or both. Healing of the focal proliferative lesion may lead to focal segmental sclerosis. The characteristic immunofluorescent picture is of mesangial deposition of IgA, often with C3 and properdin and lesser amounts of IgG or IgM.
Clinical Course. The disease affects people of any age, but older children and young adults are most commonly affected. Many patients present with gross hematuria after an infection of the respiratory or, less commonly, gastrointestinal or urinary tract; 30% to 40% have only microscopic hematuria, with or without proteinuria; and 5% to 10% develop a typical acute nephritic syndrome. The hematuria typically lasts for several days and then subsides, only to return every few months. The subsequent course is highly variable. Many patients maintain normal renal function for decades. Slow progression to chronic renal failure occurs in 15% to 40% of cases over a period of 20 years.
VIII. CHRONIC GLOMERULONEPHRITIS
Chronic glomerulonephritis is best considered a pool of end-stage glomerular disease fed by a number of streams of specific types of glomerulonephritis. Most of these diseases were described earlier in this chapter. Poststreptococcal glomerulonephritis is a rare antecedent of chronic glomerulonephritis, except in adults. Patients with RPGN, if they survive the acute episode, usually progress to chronic glomerulonephritis. Membranous glomerulonephritis, MPGN, IgA nephropathy, and focal segmental glomerulosclerosis all may progress to chronic renal failure. Nevertheless, in any series of patients with chronic glomerulonephritis, a variable percentage of cases arise mysteriously with no antecedent history of any of the well-recognized forms of acute glomerulonephritis. These cases must represent the end result of relatively asymptomatic forms of glomerulonephritis, either known or still unrecognized, that progress to uremia. Clearly, the proportion of such unexplained cases depends on the availability of renal biopsy material from patients early in their disease
Morphology. The kidneys are symmetrically contracted and have diffusely granular, cortical surfaces. On section, the cortex is thinned, and there is an increase in peripelvic fat. The glomerular histology depends on the stage of the disease.
Chronic glomerulonephritis
Demonstrates some sclerotic glomeruli and renal vascular changes.
In early cases, the glomeruli may still show evidence of the primary disease (e.g., membranous glomerulopathy or MPGN). However, there eventually ensues hyaline obliteration of glomeruli, transforming them into acellular eosinophilic masses. The hyalin represents a combination of trapped plasma proteins, increased mesangial matrix, basement membrane-like material, and collagen. Because hypertension is an accompaniment of chronic glomerulonephritis, arterial and arteriolar sclerosis may be conspicuous. Marked atrophy of associated tubules, irregular interstitial fibrosis, and mononuclear leukocytic infiltration of the interstitium also occur.
Chronic glomerulonephritis
Advanced tubular atrophy with "thyroidization".
Dialysis Changes. Kidneys from patients with end-stage disease on long-term dialysis exhibit a variety of changes that are unrelated to the primary disease. These include arterial intimal thickening caused by accumulation of smooth muscle-like cells and a loose, proteoglycan-rich stroma; focal calcification, usually within residual tubular segments; extensive deposition of calcium oxalate crystals in tubules and interstitium; acquired cystic disease, discussed earlier; and increased numbers of renal adenomas and adenocarcinomas
Uremic Complications. Patients dying with chronic glomerulonephritis also exhibit pathologic changes outside the kidney that are related to the uremic state and are also present in other forms of chronic renal failure. Often clinically important, these include uremic pericarditis, uremic gastroenteritis, secondary hyperparathyroidism with nephrocalcinosis and renal osteodystrophy, left ventricular hypertrophy due to hypertension, and pulmonary changes of diffuse alveolar damage often ascribed to uremia (uremic pneumonitis).
Clinical Course. In most patients, chronic glomerulonephritis develops insidiously and slowly progresses to renal insufficiency or death from uremia during a span of years or possibly decades (see the discussion of chronic renal failure). Not infrequently, patients present with such nonspecific complaints as loss of appetite, anemia, vomiting, or weakness. In some, the renal disease is suspected with the discovery of proteinuria, hypertension, or azotemia on routine medical examination. In others, the underlying renal disorder is discovered in the course of investigation of edema. Most patients are hypertensive, and sometimes the dominant clinical manifestations are cerebral or cardiovascular. In all, the disease is relentlessly progressive, although at widely varying rates. In nephrotic patients, as glomeruli become obliterated, the protein loss in the urine diminishes. If patients with chronic glomerulonephritis are not maintained with continued dialysis or if they do not receive a renal transplant, the outcome is invariably death.
Diseases Affecting Tubules and Interstitium
Most forms of tubular injury involve the interstitium as well; therefore, diseases affecting these two components are discussed together. Under this heading, we consider two major groups of processes: (1) ischemic or toxic tubular injury, leading to acute tubular necrosis (ATN) and acute renal failure, and (2) inflammatory reactions of the tubules and interstitium (tubulointerstitial nephritis).
Acute tubular necrosis
ATN is a clinicopathologic entity characterized morphologically by destruction of tubular epithelial cells and clinically by acute diminution or loss of renal function. It is the most common cause of acute renal failure, which signifies rapid reduction of renal function and urine flow, falling within 24 hours to less than 400 mL per day. It can be caused by a variety of conditions, including:
• Ischemia, due to decreased or interrupted blood flow, examples of which include diffuse involvement of the intrarenal blood vessels such as in polyarteritis nodosa, malignant hypertension, or the hemolytic-uremic syndrome, or decreased effective circulating blood volume
• Direct toxic injury to the tubules (e.g., by drugs, radiocontrast dyes, myoglobin, hemoglobin, radiation)
• Acute tubulointerstitial nephritis, most commonly occurring as a hypersensitivity reaction to drugs
• Disseminated intravascular coagulation
• Urinary obstruction by tumors, prostatic hypertrophy, or blood clots (so-called postrenal acute renal failure)
Pathogenesis. The critical events in both ischemic and nephrotoxic ATN are believed to be (1) tubular injury and (2) persistent and severe disturbances in blood flow.
• Tubule cell injury: Tubular epithelial cells are particularly sensitive to ischemia and are also vulnerable to toxins. Several factors predispose the tubules to toxic injury, including a vast charged surface for tubular reabsorption, active transport systems for ions and organic acids, a high metabolic rate and oxygen consumption requirement in order to perform these transport and reabsorption functions, and the capability for effective concentration.
• Ischemia causes numerous structural and functional alterations in epithelial cells, as discussed earlier. The structural changes include those of reversible injury (such as cellular swelling, loss of brush border, blebbing, loss of polarity, and cell detachment) and those associated with lethal injury (necrosis and apoptosis). Biochemically, there is depletion of adenosine triphosphate; accumulation of intracellular calcium; activation of proteases (e.g., calpain), which cause cytoskeletal disruption, and phospholipases, which damage membranes; generation of reactive oxygen species; and activation of caspases, which induce apoptotic cell death. One early reversible result of ischemia is loss of cell polarity due to redistribution of membrane proteins (e.g., the enzyme Na+K+-ATPase) from the basolateral to the luminal surface of the tubular cells, resulting in abnormal ion transport across the cells, and increased sodium delivery to distal tubules. The latter incites vasoconstriction via tubuloglomerular feedback, which will be discussed below. In addition, ischemic tubular cells express cytokines and adhesion molecules (such as ICAM-1), thus recruiting leukocytes that appear to participate in the subsequent injury. In time, injured cells detach from the basement membranes and cause luminal tubule obstruction, increased intratubular pressure, and decreased GFR. In addition, fluid from the damaged tubules can leak into the interstitium, resulting in interstitial edema, increased interstitial pressure, and further damage to the tubule.
• Disturbances in blood flow: Ischemic renal injury is also characterized by hemodynamic alterations that cause reduced GFR. The major one is intrarenal vasoconstriction, which results in both reduced glomerular plasma flow and reduced oxygen delivery to the functionally important tubules in the outer medulla (thick ascending limb and straight segment of the proximal tubule). A number of vasoconstrictor pathways have been implicated, including the renin-angiotensin mechanism, stimulated by increased distal sodium delivery (via tubuloglomerular feedback), and sublethal endothelial injury, leading to increased release of the vasoconstrictor endothelin and decreased production of the vasodilators nitric oxide and PGI2. Finally, there is also some evidence of a direct effect of ischemia or toxins on the glomerulus, causing a reduced glomerular ultrafiltration coefficient, possibly due to mesangial contraction.
The patchiness of tubular necrosis and maintenance of the integrity of the basement membrane along many segments allow ready repair of the necrotic foci and recovery of function if the precipitating cause is removed. This repair is dependent on the capacity of reversibly injured epithelial cells to proliferate and differentiate.
Morphology. Ischemic ATN is characterized by focal tubular epithelial necrosis at multiple points along the nephron, with large skip areas in between, often accompanied by rupture of basement membranes (tubulorrhexis) and occlusion of tubular lumens by casts. The straight portion of the proximal tubule and the ascending thick limb in the renal medulla are especially vulnerable, but focal lesions may also occur in the distal tubule, often in conjunction with casts. Paradoxically, the clinical syndrome of ATN is not manifest by overt tubular cell necrosis, but often lesser degrees of tubular injury. This includes attenuation or loss of proximal tubule brush borders, simplification of cell structure, cell swelling and vacuolization, and sloughing of non-necrotic tubular cells into the tubular lumina. The severity of the morphologic findings often does not correlate well with the severity of the clinical findings.
The glomeruli are normal. Note the Bowman space and the nuclei of the glomerular cells. Several of the proximal tubules show necrosis of the epithelium.
Toxic ATN is manifested by acute tubular injury, most obvious in the proximal convoluted tubules. On histologic examination, the tubular necrosis may be entirely nonspecific, but it is somewhat distinctive in poisoning with certain agents. With mercuric chloride, for example, severely injured cells that are not yet dead might contain large acidophilic inclusions. Later, these cells become totally necrotic, are desquamated into the lumen, and may undergo calcification. Carbon tetrachloride poisoning, in contrast, is characterized by the accumulation of neutral lipids in injured cells, but again, such fatty change is followed by necrosis. Ethylene glycol produces marked ballooning and hydropic or vacuolar degeneration of proximal convoluted tubules. Calcium oxalate crystals are often found in the tubular lumens in such poisoning.
Clinical Course. The clinical course of ATN is highly variable, but the classic case may be divided into initiation, maintenance, and recovery stages. The initiation phase, lasting for about 36 hours, is dominated by the inciting medical, surgical, or obstetric event in the ischemic form of ATN. The only indication of renal involvement is a slight decline in urine output with a rise in BUN. At this point, oliguria could be explained on the basis of a transient decrease in blood flow to the kidneys.
The maintenance phase is characterized by sustained decreases in urine output to between 40 and 400 mL/day (oliguria), with salt and water overload, rising BUN concentrations, hyperkalemia, metabolic acidosis, and other manifestations of uremia dominating this phase. With appropriate attention to the balance of water and blood electrolytes, including dialysis, the patient can be carried over this oliguric crisis.
The recovery phase is ushered in by a steady increase in urine volume that may reach up to 3 L/day. The tubules are still damaged, so large amounts of water, sodium, and potassium are lost in the urinary flood. Hypokalemia, rather than hyperkalemia, becomes a clinical problem. There is a peculiar increased vulnerability to infection at this stage. Eventually, renal tubular function is restored, with improvement in concentrating ability. At the same time, BUN and creatinine levels begin to return to normal. Subtle tubular functional impairment may persist for months, but most patients who reach this phase eventually recover completely.
The prognosis of ATN depends on the clinical setting surrounding its development. Recovery is expected with nephrotoxic ATN when the toxin has not caused serious damage to other organs, such as the liver or heart. With modern methods of care, 95% of those who do not succumb to the precipitating cause have a chance of recovery. Conversely, in shock related to sepsis, extensive burns, or other causes of multiorgan failure, the mortality rate can rise to more than 50%.
TUBULOINTERSTITIAL NEPHRITIS
This group of renal diseases is characterized by histologic and functional alterations that involve predominantly the tubules and interstitium. We have previously seen that chronic tubulointerstitial injury may occur in diseases that primarily affect the glomerulus and indeed that such injury may be an important cause of progression in these diseases. This secondary tubulointerstitial nephritis is also present in a variety of vascular, cystic (polycystic kidney disease), metabolic (diabetes), and renal disorders, in which it may also contribute to progressive damage. Here we discuss disorders in which tubulointerstitial injury appears to be a primary event. These disorders have diverse causes and different pathogenetic mechanisms. Thus, the disorders are identified by cause or by associated disease (e.g., analgesic nephropathy, radiation nephropathy). Glomerular and vascular abnormalities may also be present but either are mild or occur only in advanced stages of these diseases.
Tubulointerstitial nephritis can be acute or chronic. Acute tubulointerstitial nephritis has a rapid clinical onset and is characterized histologically by interstitial edema, often accompanied by leukocytic infiltration of the interstitium and tubules, and focal tubular necrosis. In chronic interstitial nephritis, there is infiltration with predominantly mononuclear leukocytes, prominent interstitial fibrosis, and widespread tubular atrophy. Morphologic features that are helpful in separating acute from chronic tubulointerstitial nephritis include edema and, when present, eosinophils and neutrophils in the acute form, contrasted with fibrosis and tubular atrophy in the chronic form.
A cellular infiltrate of predominantly lymphocytes with numerous examples of lymphocytes percolating through the renal tubular walls.
These conditions are distinguished clinically from the glomerular diseases by the absence, in early stages, of such hallmarks of glomerular injury as nephritic or nephrotic syndromes and by the presence of defects in tubular function. The latter may be subtle and include impaired ability to concentrate urine, evidenced clinically by polyuria or nocturia; salt wasting; diminished ability to excrete acids (metabolic acidosis); and isolated defects in tubular reabsorption or secretion. The advanced forms, however, may be difficult to distinguish clinically from other causes of renal insufficiency
Pyelonephritis
Pyelonephritis is a renal disorder affecting the tubules, interstitium, and renal pelvis and is one of the most common diseases of the kidney. It occurs in two forms. Acute pyelonephritis is caused by bacterial infection and is the renal lesion associated with urinary tract infection. Chronic pyelonephritis is a more complex disorder: bacterial infection plays a dominant role, but other factors (vesicoureteral reflux, obstruction) are involved in its pathogenesis. Pyelonephritis is a serious complication of an extremely common clinical spectrum of urinary tract infections that affect the urinary bladder (cystitis), the kidneys and their collecting systems (pyelonephritis), or both. Bacterial infection of the lower urinary tract may be completely asymptomatic (asymptomatic bacteriuria) and most often remains localized to the bladder without the development of renal infection. However, lower urinary tract infection always carries the potential of spread to the kidney
Etiology and Pathogenesis. The dominant etiologic agents, accounting for more than 85% of cases of urinary tract infection, are the Gram-negative bacilli that are normal inhabitants of the intestinal tract. By far the most common is Escherichia coli, followed by Proteus, Klebsiella, and Enterobacter. Streptococcus faecalis, also of enteric origin, staphylococci, and virtually every other bacterial and fungal agent can also cause lower urinary tract and renal infection. In immunocompromised patients, particularly those with transplanted organs, viruses such as polyoma virus, cytomegalovirus, and adenovirus can also be a cause of renal infection.
In most patients with urinary tract infection, the infecting organisms are derived from the patient's own fecal flora. This is thus a form of endogenous infection. There are two routes by which bacteria can reach the kidneys: (1) through the bloodstream (hematogenous infection) and (2) from the lower urinary tract (ascending infection). Although the hematogenous route is the less common of the two, acute pyelonephritis does result from seeding of the kidneys by bacteria from distant foci in the course of septicemia or infective endocarditis. Hematogenous infection is more likely to occur in the presence of ureteral obstruction, in debilitated patients, in patients receiving immunosuppressive therapy, and with nonenteric organisms, such as staphylococci and certain fungi and viruses
Ascending infection is the most common cause of clinical pyelonephritis. Normal human bladder and bladder urine are sterile; therefore, a number of steps must occur for renal infection to occur:
• The first step in the pathogenesis of ascending infection appears to be the colonization of the distal urethra and introitus (in the female) by coliform bacteria. This colonization is influenced by the ability of bacteria to adhere to urethral mucosal cells.
• From the urethra to the bladder, organisms gain entrance during urethral catheterization or other instrumentation. Long-term catheterization, in particular, carries a risk of infection. In the absence of instrumentation, urinary infections are much more common in females, and this has been variously ascribed to the shorter urethra in females, the absence of antibacterial properties such as are found in prostatic fluid, hormonal changes affecting adherence of bacteria to the mucosa, and urethral trauma during sexual intercourse or a combination of these factors.
• Multiplication in the bladder. Ordinarily, organisms introduced into the bladder are cleared by the continual flushing of voiding and by antibacterial mechanisms. However, outflow obstruction or bladder dysfunction results in incomplete emptying and increased residual volume of urine. In the presence of stasis, bacteria introduced into the bladder can multiply unhindered without being flushed out or destroyed in the bladder wall. Accordingly, urinary tract infection is particularly frequent among patients with lower urinary tract obstruction, such as may occur with benign prostatic hypertrophy, tumors, or calculi or with neurogenic bladder dysfunction caused by diabetes or spinal cord injury.
• Vesicoureteral reflux. Although obstruction is an important predisposing factor in the pathogenesis of ascending infection, it is incompetence of the vesicoureteral valve that allows bacteria to ascend the ureter into the renal pelvis. The normal ureteral insertion into the bladder is a competent one-way valve that prevents retrograde flow of urine, especially during micturition, when the intravesical pressure rises. An incompetent vesicoureteral orifice allows the reflux of bladder urine into the ureters (vesicoureteral reflux). Reflux is most often due to a congenital absence or shortening of the intravesical portion of the ureter, such that the ureter is not compressed during micturition. In addition, bladder infection itself, probably as a result of the action of bacterial or inflammatory products on ureteral contractility, can cause or accentuate vesicoureteral reflux, particularly in children. Acquired vesicoureteral reflux in adults can result from persistent bladder atony caused by spinal cord injury. The effect of vesicoureteral reflux is similar to that of an obstruction in that after voiding, there is residual urine in the urinary tract, which favors bacterial growth.
• Intrarenal reflux. Vesicoureteral reflux also affords a ready mechanism by which the infected bladder urine can be propelled up to the renal pelvis and deep into the renal parenchyma through open ducts at the tips of the papillae (intrarenal reflux). Intrarenal reflux is most common in the upper and lower poles of the kidney, where papillae tend to have flattened or concave tips rather than the convex pointed type present in the midzones of the kidney (and depicted in most textbooks). Reflux can be demonstrated radiographically by a voiding cystourethrogram: The bladder is filled with a radio-opaque dye, and films are taken during micturition.
In the absence of vesicoureteral reflux, infection usually remains localized in the bladder. Thus, the majority of patients with repeated or persistent bacterial colonization of the urinary tract suffer from cystitis and urethritis (lower urinary tract infection) rather than pyelonephritis
Acute Pyelonephritis
Acute pyelonephritis is an acute suppurative inflammation of the kidney caused by bacterial and sometimes viral (e.g., polyoma virus) infection, whether hematogenous and induced by septicemic spread or ascending and associated with vesicoureteral reflux
Morphology. The hallmarks of acute pyelonephritis are patchy interstitial suppurative inflammation, intratubular aggregates of neutrophils, and tubular necrosis. The suppuration may occur as discrete focal abscesses involving one or both kidneys, which can extend to large wedge-shaped areas of suppuration. The distribution of these lesions is unpredictable and haphazard, but in pyelonephritis associated with reflux, damage occurs most commonly in the lower and upper poles
In the early stages, the neutrophilic infiltration is limited to the interstitial tissue. Soon, however, the reaction involves tubules and produces a characteristic abscess with the destruction of the engulfed tubules. Since the tubular lumens present a ready pathway for the extension of the infection, large masses of intraluminal neutrophils frequently extend along the involved nephron into the collecting tubules. Characteristically, the glomeruli appear to be resistant to the infection. Large areas of severe necrosis, however, eventually destroy the glomeruli, and fungal pyelonephritis (e.g., Candida) often affects glomeruli.
Three complications of acute pyelonephritis are encountered in special circumstances.
• Papillary necrosis is seen mainly in diabetics and in those with urinary tract obstruction. Papillary necrosis is usually bilateral but may be unilateral. One or all of the pyramids of the affected kidney may be involved. On cut section, the tips or distal two-thirds of the pyramids have areas of gray-white to yellow necrosis. On microscopic examination, the necrotic tissue shows characteristic coagulative necrosis, with preservation of outlines of tubules. The leukocytic response is limited to the junctions between preserved and destroyed tissue.
Note the area of coagulative necrosis in the papilla, and a surrounding neutrophilic infiltrate.
• Pyonephrosis is seen when there is total or almost complete obstruction, particularly when it is high in the urinary tract. The suppurative exudate is unable to drain and thus fills the renal pelvis, calyces, and ureter, producing pyonephrosis.
• Perinephric abscess implies extension of suppurative inflammation through the renal capsule into the perinephric tissue.
After the acute phase of pyelonephritis, healing occurs. The neutrophilic infiltrate is replaced by one that is predominantly mononuclear, with macrophages, plasma cells, and (later) lymphocytes. The inflammatory foci are eventually replaced by scars that can be seen on the cortical surface as fibrous depressions. Such scars are characterized microscopically by atrophy of tubules, interstitial fibrosis, and lymphocyte infiltrate and may resemble scars produced by ischemic or other types of injury to the kidney. However, the pyelonephritic scar is almost always associated with inflammation, fibrosis, and deformation of the underlying calyx and pelvis, reflecting the role of ascending infection and vesicoureteral reflux in the pathogenesis of the disease.
Clinical Course. Acute pyelonephritis is often associated with predisposing conditions, some of which were mentioned in the discussion of pathogenetic mechanisms. These include the following:
• Urinary tract obstruction, either congenital or acquired
• Instrumentation of the urinary tract, most commonly catheterization
• Vesicoureteral reflux
• Pregnancy. Four percent to 6% of pregnant women develop bacteriuria sometime during pregnancy, and 20% to 40% of these eventually develop symptomatic urinary infection if not treated.
• Patient's sex and age. After the first year of life (when congenital anomalies in males commonly become evident) and up to around age 40 years, infections are much more frequent in females. With increasing age, the incidence in males rises owing to the development of prostatic hypertrophy and frequent instrumentation.
• Preexisting renal lesions, causing intrarenal scarring and obstruction
• Diabetes mellitus, in which acute pyelonephritis is caused by more frequent instrumentation, the general susceptibility to infection, and the neurogenic bladder dysfunction exhibited by patients
• Immunosuppression and immunodeficiency
When acute pyelonephritis is clinically apparent, the onset is usually sudden, with pain at the costovertebral angle and systemic evidence of infection, such as fever and malaise. There are usually indications of bladder and urethral irritation, such as dysuria, frequency, and urgency. The urine contains many leukocytes (pyuria) derived from the inflammatory infiltrate, but pyuria does not differentiate upper from lower urinary tract infection. The finding of leukocyte casts, typically filled with neutrophils (pus casts), indicates renal involvement, because casts are formed only in tubules. The diagnosis of infection is established by quantitative urine culture.
Uncomplicated acute pyelonephritis usually follows a benign course, and the symptoms disappear within a few days after the institution of appropriate antibiotic therapy. Bacteria, however, may persist in the urine, or there may be recurrence of infection with new serologic types of E. coli or other organisms. Such bacteriuria then either disappears or may persist, sometimes for years. In the presence of unrelieved urinary obstruction, diabetes mellitus, or immunodeficiency, acute pyelonephritis may be more serious, leading to repeated septicemic episodes. The superimposition of papillary necrosis may lead to acute renal failure.
An emerging viral pathogen causing pyelonephritis in kidney allografts is polyoma virus. Latent infection with polyoma virus is widespread in the general population, but immunosuppression of the allograft recipient can lead to reactivation of latent infection and the development of a nephropathy resulting in allograft failure in up to 1% to 5% of kidney transplant recipients This form of pyelonephritis is characterized by viral infection of tubular epithelial cell nuclei, leading to nuclear enlargement and intranuclear inclusions visible by light microscopy (viral cytopathic effect). The inclusions are composed of viral structures arrayed in distinctive crystalline-like lattices when visualized by electron microscopy. An interstitial inflammatory response is invariably present. Treatment is reduction in immunosuppression
Chronic Pyelonephritis and Reflux Nephropathy
Chronic pyelonephritis is a chronic tubulointerstitial renal disorder in which chronic tubulointerstitial inflammation and renal scarring are associated with pathologic involvement of the calyces and pelvis. Chronic pyelonephritis is an important cause of end-stage kidney disease; at one time, it accounted for up to 10% to 20% of patients in renal transplant or dialysis units, until predisposing conditions such as reflux became better recognized and diligently evaluated. This condition remains an important cause of kidney destruction in children with severe lower urinary tract abnormalities
Chronic pyelonephritis can be divided into two forms: chronic reflux-associated and chronic obstructive
Reflux Nephropathy. This is by far the more common form of chronic pyelonephritic scarring. Renal involvement in reflux nephropathy occurs early in childhood as a result of superimposition of a urinary infection on congenital vesicoureteral reflux and intrarenal reflux, the latter conditioned by the number of potentially refluxing papillae. Reflux may be unilateral or bilateral; thus, the resultant renal damage either may cause scarring and atrophy of one kidney or may involve both and lead to chronic renal insufficiency. Vesicoureteral reflux occasionally causes renal damage in the absence of infection (sterile reflux) but only in the presence of severe obstruction
Chronic Obstructive Pyelonephritis. We have seen that obstruction predisposes the kidney to infection. Recurrent infections superimposed on diffuse or localized obstructive lesions lead to recurrent bouts of renal inflammation and scarring, resulting in a picture of chronic pyelonephritis. In this condition, the effects of obstruction contribute to the parenchymal atrophy; indeed, it is sometimes difficult to differentiate the effects of bacterial infection from those of obstruction alone. The disease can be bilateral, as with obstructive anomalies of the urinary tract (e.g., posterior urethral valves), resulting in renal insufficiency unless the anomaly is corrected, or unilateral, such as occurs with calculi and unilateral obstructive anomalies of the ureter
Morphology. The characteristic changes of chronic pyelonephritis are seen on gross examination. The kidneys usually are irregularly scarred; if bilateral, the involvement is asymmetric. This contrasts with chronic glomerulonephritis, in which the kidneys are diffusely and symmetrically scarred. The hallmark of chronic pyelonephritis is the coarse, discrete, corticomedullary scar overlying a dilated, blunted, or deformed calyx. The scars can vary from one to several in number and may affect one or both kidneys. Most are in the upper and lower poles, consistent with the frequency of reflux in these sites.
The surface of the kidney is irregularly, or geographically, depressed in the scarred areas with pseudobulging of the remaining intact parenchyma above the damaged foci.
The microscopic changes involve predominantly tubules and interstitium. The tubules show atrophy in some areas and hypertrophy or dilation in others. Dilated tubules with flattened epithelium may be filled with colloid casts (thyroidization).
There are varying degrees of chronic interstitial inflammation and fibrosis in the cortex and medulla. In the presence of active infection, there may be neutrophils in the interstitium and pus casts in the tubules. Arcuate and interlobular vessels demonstrate obliterative intimal sclerosis in the scarred areas; and in the presence of hypertension, hyaline arteriosclerosis is seen in the entire kidney.
Many dilated "colloid"-filled tubules are present. This phenomenon is known, appropriately enough, as thyroidization of the kidney. Notice also the markedly thickened arterial wall in the lower right of the image.
There is often fibrosis around the calyceal epithelium as well as a marked chronic inflammatory infiltrate. Glomeruli may appear normal except for periglomerular fibrosis, but a variety of glomerular changes may be present, including ischemic fibrous obliteration as well as secondary changes related to hypertension. Patients with chronic pyelonephritis and reflux nephropathy who develop proteinuria in advanced stages exhibit secondary focal segmental glomerulosclerosis, as described later.
Xanthogranulomatous pyelonephritis is an unusual and relatively rare form of chronic pyelonephritis characterized by accumulation of foamy macrophages intermingled with plasma cells, lymphocytes, polymorphonuclear leukocytes, and occasional giant cells. Often associated with Proteus infections and obstruction, the lesions sometimes produce large, yellowish orange nodules that may be confused with renal cell carcinoma.
Clinical Course. Chronic obstructive pyelonephritis may be insidious in onset or may present with clinical manifestations of acute recurrent pyelonephritis with back pain, fever, frequent pyuria, and bacteriuria. Chronic pyelonephritis associated with reflux may have a silent onset. These patients come to medical attention relatively late in the course of their disease because of the gradual onset of renal insufficiency and hypertension or because of the discovery of pyuria or bacteriuria on routine examination. Reflux nephropathy is often discovered when the etiology of hypertension in children is investigated. Loss of tubular function-in particular of concentrating ability-gives rise to polyuria and nocturia. Radiographic studies show asymmetrically contracted kidneys with characteristic coarse scars and blunting and deformity of the calyceal system. Significant bacteriuria may be present, but it is often absent in the late stages.
Although proteinuria is usually mild, some patients with pyelonephritic scars develop focal segmental glomerulosclerosis with significant proteinuria, even in the nephrotic range, usually several years after the scarring has occurred and often in the absence of continued infection or persistent vesicoureteral reflux. The appearance of proteinuria and focal segmental glomerulosclerosis is a poor prognostic sign, and patients with these findings may proceed to chronic or end-stage renal failure. The glomerulosclerosis, as we have discussed, may be attributable to the adaptive glomerular alterations secondary to loss of renal mass caused by pyelonephritic scarring (renal ablation nephropathy)
Tubulointerstitial Nephritis Induced by Drugs and Toxins
Toxins and drugs can produce renal injury in at least three ways: (1) They may trigger an interstitial immunologic reaction, exemplified by the acute hypersensitivity nephritis induced by such drugs as methicillin; (2) they may cause acute renal failure, as described earlier; and (3) they may cause subtle but cumulative injury to tubules that takes years to become manifest, resulting in chronic renal insufficiency.89 The last type of damage is especially treacherous because it may be clinically unrecognized until significant renal damage has occurred. Such is the case with analgesic abuse nephropathy, which is usually detected only after the onset of chronic renal insufficiency
Morphology. On histologic examination, the abnormalities are in the interstitium, which shows variable but frequently pronounced edema and infiltration by mononuclear cells, principally lymphocytes and macrophages. Eosinophils and neutrophils may be present, often in large numbers, and plasma cells and basophils are sometimes found in small numbers. With some drugs (e.g., methicillin, thiazides), interstitial granulomas with giant cells may be seen. "Tubulitis," the infiltration of tubules by lymphocytes, is common. Variable degrees of tubular necrosis and regeneration are present. The glomeruli are normal except in some cases caused by NSAIDs, when minimal change disease and the nephrotic syndrome develop concurrently
Pathogenesis. Many features of the disease suggest an immune mechanism. The basis for the immune response is idiosyncratic and not dose related. Clinical evidence of hypersensitivity includes the latent period, the eosinophilia and rash, the fact that the onset of nephropathy is not dose related, and the recurrence of hypersensitivity after re-exposure to the same or a cross-reactive drug. Serum IgE levels are increased in some patients, and IgE-containing plasma cells and basophils are sometimes present in the lesions, suggesting that the late-phase reaction of an IgE-mediated (type I) hypersensitivity may be involved in the pathogenesis. The mononuclear or granulomatous infiltrate, together with positive results of skin tests to drug haptens, suggests a delayed hypersensitivity type reaction (type IV).
Clinical Features. It is important to recognize drug-induced renal failure because withdrawal of the offending drug is followed by recovery, although it may take several months for renal function to return to normal, and irreversible damage may occur occasionally in older subjects. It is also important to remember that while drugs are the leading identifiable cause of acute interstitial nephritis, in many affected patients (approximately 30% to 40%) an offending drug or mechanism for nephritis cannot be identified.
END STAGE RENAL DISEASE
1. Skin manifestations - pruritus, uremic "frost", skin
2. Cardiac manifestations - uremic pericarditis
3. Neurological manifestations - peripheral neuropathy
4. Pulmonary complications - pneumonitis and hemorrhage
5. Hematopoietic manifestations - anemia, bleeding diathesis
6. Skeletal abnormalities - renal osteodystrophy (secondary hyperparathyroidism)
7. Other - metabolic imbalances
Tumors of the Kidney
Both benign and malignant tumors occur in the kidney. With the exception of oncocytoma, the benign tumors rarely cause clinical problems. Malignant tumors, on the other hand, are of great importance clinically and deserve considerable emphasis. By far the most common of these malignant tumors is renal cell carcinoma, followed by Wilms tumor, which is found in, and finally urothelial tumors of the calyces and pelves
Benign tumors
Renal Papillary Adenoma
Small, discrete adenomas arising from the renal tubular epithelium are found commonly (7% to 22%) at autopsy. They are most frequently papillary and are therefore called papillary adenomas in the most recent international classifications.
Morphology. These are small tumors, usually less than 5 mm in diameter. They are present invariably within the cortex and appear grossly as pale yellow-gray, discrete, well-circumscribed nodules. On microscopic examination, they are composed of complex, branching, papillomatous structures with numerous complex fronds. Cells may also grow as tubules, glands, cords, and sheets of cells. The cells are cuboidal to polygonal in shape and have regular, small central nuclei, scanty cytoplasm, and no atypia
By histologic criteria, these tumors do not differ from low-grade papillary renal cell adenocarcinoma and indeed share some immunohistochemical and cytogenetic features (trisomies 7 and 17) with papillary cancers, to be discussed later, although less extensively. The size of the tumor was once used as a prognostic feature, with a cutoff of 3 cm separating those that metastasize from those that rarely do. However, because tumors of relatively small size, 1 to 3 cm in diameter, are increasingly being detected during X-ray procedures performed for nonrenal symptoms and because of occasional reports of small tumors that have metastasized, the current view is to consider and treat all adenomas, regardless of size, as early cancers until an unequivocal marker of benignity is discovered
Malignant tumors
Renal Cell Carcinoma
Renal cell carcinomas represent about 1% to 3% of all visceral cancers and account for 85% of renal cancers in adults. The tumors occur most often in older individuals, usually in the sixth and seventh decades of life, showing a male preponderance in the ratio of 2 to 3 : 1. Because of their gross yellow color and the resemblance of the tumor cells to clear cells of the adrenal cortex, they were at one time called hypernephroma. It is now clear that all these tumors arise from tubular epithelium and are therefore renal adenocarcinomas.
Most renal cancer is sporadic, but unusual forms of autosomal-dominant familial cancers occur, usually in younger individuals. Although they account for only 4% of renal cancers, familial variants have been enormously instructive in studying renal carcinogenesis.
• Von Hippel-Lindau (VHL) syndrome: Half to two-thirds of patients with VHL characterized by hemangioblastomas of the cerebellum and retina, develop renal cysts and bilateral, often multiple, renal cell carcinomas (nearly all, if they live long enough). As we shall see, current studies implicate the VHL gene in the development of both familial and sporadic clear cell tumors.
• Hereditary (familial) clear cell carcinoma, confined to the kidney, without the other manifestations of VHL but with abnormalities involving the same or a related gene.
• Hereditary papillary carcinoma. This autosomal-dominant form is manifested by multiple bilateral tumors with papillary histology. These tumors exhibit a series of cytogenetic abnormalities and, as will be described, mutations in the MET protooncogene.
Morphology. Renal cell carcinomas have a characteristic macroscopic appearance. The tumor may arise in any portion of the kidney, but more commonly, it affects the poles, particularly the upper one. They are spherical masses, which can vary in size, composed of bright yellow-gray-white tissue that distorts the renal outline. The yellow color is a consequence of the prominent lipid accumulations in tumor cells. There are commonly large areas of ischemic, opaque, gray-white necrosis, foci of hemorrhagic discoloration, and areas of softening. The margins are usually sharply defined and confined within the renal capsule.
In clear cell carcinoma, the growth pattern varies from solid to trabecular (cordlike) or tubular (resembling tubules). The tumor cells have a rounded or polygonal shape and abundant clear or granular cytoplasm; the latter on special stains contains glycogen and lipids. The tumors have delicate branching vasculature and may exhibit cystic as well as solid areas. Most tumors are well differentiated, but some show marked nuclear atypia with formation of bizarre nuclei and giant cells.
The malignant cells contain abundant clear cytoplasm and are arranged in gland-like or tubule-like formations.
Papillary carcinoma is composed of cuboidal or low columnar cells arranged in papillary formations. Interstitial foam cells are common in the papillary cores. Psammoma bodies may be present. The stroma is usually scanty but highly vascularized. Chromophobe renal carcinoma is made up of pale eosinophilic cells, often with a perinuclear halo, arranged in solid sheets with a concentration of the largest cells around blood vessels. Collecting duct carcinoma is a rare variant showing irregular channels lined by highly atypical epithelium with a hobnail pattern. Sarcomatoid changes arise infrequently in all types of renal cell carcinoma and are a decidedly ominous feature of these tumors.
Clinical Course. The three classic diagnostic features of renal cell carcinoma are costovertebral pain, palpable mass, and hematuria, but these are seen in only 10% of cases. The most reliable of the three is hematuria, but it is usually intermittent and may be microscopic; thus, the tumor may remain silent until it attains a large size. At this time, it gives rise to generalized constitutional symptoms, such as fever, malaise, weakness, and weight loss. This pattern of asymptomatic growth occurs in many patients, so the tumor may have reached a diameter of more than 10 cm when it is discovered. In current times, however, many of these tumors are being discovered in the asymptomatic state by incidental radiologic studies (e.g., computed tomographic scan or magnetic resonance imaging) usually performed for nonrenal indications.
Renal cell carcinoma is classified as one of the great mimics in medicine because it tends to produce a diversity of systemic symptoms not related to the kidney. In addition to the fever and constitutional symptoms mentioned earlier, renal cell carcinomas produce a number of paraneoplastic syndromes, ascribed to abnormal hormone production, including polycythemia, hypercalcemia, hypertension, hepatic dysfunction, feminization or masculinization, Cushing syndrome, eosinophilia, leukemoid reactions, and amyloidosis.
One of the common characteristics of this tumor is its tendency to metastasize widely before giving rise to any local symptoms or signs. In 25% of new patients with renal cell carcinoma, there is radiologic evidence of metastases at the time of presentation. The most common locations of metastasis are the lungs (more than 50%) and bones (33%), followed in order by the regional lymph nodes, liver and adrenals, and brain.
The average 5-year survival rate of patients with renal cell carcinoma is about 45% and up to 70% in the absence of distant metastases. With renal vein invasion or extension into the perinephric fat, the figure is reduced to approximately 15% to 20%. Nephrectomy has been the treatment of choice, but partial nephrectomy to preserve renal function is being done with increasing frequency and similar outcome.
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