section epub:type=”chapter” id=”c0008″ role=”doc-chapter”> After studying this chapter, the student should be able to: Diseases of the kidney are often classified into four types based on the anatomic component initially affected: glomeruli, tubules, interstitium, or vasculature. Initially, renal disease may affect only one anatomic component; however, with disease progression, other components are involved because of their close structural and functional interdependence. Susceptibility to disease varies with each structural component. Glomerular diseases most often are immune-mediated, whereas tubular and interstitial diseases result from infectious or toxic substances. In contrast, vascular diseases cause a reduction in renal perfusion that subsequently induces both anatomic and functional changes in the kidney. Diseases that damage glomeruli are varied and include immunologic, metabolic, and hereditary disorders (Box 8.1). Systemic disorders are technically secondary glomerular diseases because they initially and principally involve other organs; the glomeruli become involved as a consequence as the systemic disease progresses. In contrast, primary glomerular diseases specifically affect the kidney, which is often the only organ involved. Primary glomerular disorders, collectively called glomerulonephritides, consist of several different types of glomerulonephritis. Four distinct morphologic changes of glomeruli are recognized: cellular proliferation, leukocytic infiltration, glomerular basement membrane thickening, and hyalinization with sclerosis. One or more of these changes accompany each type of glomerulonephritis and form the basis for characterizing glomerular diseases. In the glomerular tuft, cellular proliferation is characterized by increased numbers of endothelial cells (capillary endothelium), mesangial cells, and epithelial cells (podocytes). This proliferation may be segmental, involving only a part of each glomerulus. At the same time, proliferation can be focal, involving only a certain number of glomeruli, or diffuse, involving all glomeruli. Drawn by a local chemotactic response, leukocytes, particularly neutrophils and macrophages, can readily infiltrate glomeruli. Present in some types of acute glomerulonephritides, leukocyte infiltration may also be accompanied by cellular proliferation. Glomerular basement membrane thickening includes any process that results in enlargement of the basement membrane. Most commonly, thickening results from the deposition of precipitated proteins (e.g., immune complexes, fibrin) on either side of or within the basement membrane. However, in diabetic glomerulosclerosis, the basement membrane thickens without evidence of deposition of any material. Hyalinization of glomeruli is characterized by the accumulation of a homogeneous, eosinophilic extracellular material in the glomeruli. As this amorphous substance accumulates, glomeruli lose their structural detail and become sclerotic. Various glomerular diseases lead to these irreversible changes. The primary mode of glomerular injury results from immune-mediated processes. Circulating antigen–antibody complexes and complexes that result from antigen–antibody reactions that occur within the glomerulus (i.e., in situ) play a role in glomerular damage. Circulating immune complexes are created in response to endogenous (e.g., tumor antigens, thyroglobulin) or exogenous (e.g., viruses, parasites) antigens. These circulating immune complexes become trapped within the glomeruli. The antibodies associated with them have no specificity for the glomeruli; rather they are present in the glomeruli because of glomerular hemodynamic characteristics and physicochemical factors (e.g., molecular charge, shape, size). The result is that the immune complexes become entrapped in the glomeruli and bind complement, which subsequently causes glomerular injury. A second immune mechanism involves antibodies that react directly with glomerular tissue antigens (e.g., anti–glomerular basement membrane disease) or with nonglomerular antigens that currently reside in the glomeruli. These latter nonglomerular antigens can originate from a variety of sources, such as drugs and infectious agents (i.e., viral, bacterial, parasitic). Because immune complexes, immunoglobulins, and complement retain reactive sites even after their deposition, their presence in the glomeruli actually induces further immune complexation. Glomerular injury does not result from the immune complexes but rather from the chemical mediators and toxic substances that they induce. Complement, neutrophils, monocytes, platelets, and other factors at the site produce proteases, oxygen-derived free radicals, and arachidonic acid metabolites. These substances, along with others, stimulate a local inflammatory response that further induces glomerular tissue damage. The coagulation system also plays a role, with fibrin frequently present in these diseased glomeruli. Fibrinogen that has leaked into Bowman’s space also induces cellular proliferation. Glomerular damage produces characteristic clinical features or a syndrome—a group of symptoms or findings that occur together. These nephritic syndromes occur with primary glomerular diseases, as well as in patients with glomerular injury due to a systemic disease (see Box 8.1). It becomes the clinician’s task to differentiate among these conditions, identify the specific disease processes, and determine appropriate treatment. The features that characterize glomerular damage (i.e., nephritic syndrome) include hematuria, proteinuria, oliguria, azotemia, edema, and hypertension (Table 8.1). The severity of each feature and the combination present vary depending on the number of glomeruli involved, the mechanism of injury, and the rapidity of disease onset. A classic example of a condition characterized by all the features of a nephritic syndrome is acute poststreptococcal glomerulonephritis. In contrast, some forms of glomerulonephritis are asymptomatic and are detected only when routine screening reveals microscopic hematuria or subnephrotic proteinuria (e.g., membranoproliferative glomerulonephritis [MPGN], focal proliferative glomerulonephritis). Another syndrome that is a frequent manifestation of glomerular diseases is nephrotic syndrome (see next section). Glomerular diseases that manifest nephritic or nephrotic syndrome have the potential to ultimately develop into chronic kidney disease (CKD). When this occurs, only 15% to 20% of the functioning ability of the kidney remains. Table 8.2 presents selected glomerular diseases along with a summary of their typical urinalysis results. Table 8.1 Table 8.2 Nephrotic syndrome is a group of clinical features that occur simultaneously. Representing increased permeability of the glomeruli to the passage of plasma proteins, most notably albumin, nephrotic syndrome is characterized by heavy proteinuria (3.5 g/day or more). Additional features include hypoproteinemia, hyperlipidemia, lipiduria, and generalized edema. Plasma albumin levels are usually less than 3 g/dL because liver synthesis is unable to compensate for the large amounts of protein being excreted in the urine. Albumin is the predominant protein lost because of its high plasma concentration. However, proteins of equal or smaller size, such as immunoglobulins, low-molecular-weight complement components, and anticoagulant cofactors, are also excreted in increased amounts. As a result, patients with nephrotic syndrome are more susceptible to infections and thrombotic complications. Hyperlipidemia in nephrotic syndrome is caused by increased plasma levels of triglycerides, cholesterol, phospholipids, and very-low-density lipoproteins. Whereas the exact mechanisms causing hyperlipidemia are still unknown, it is caused at least in part by increased synthesis of these lipids by the liver and is compounded by a decrease in their catabolism. Because of increased glomerular permeability, these lipids are able to cross the glomerular filtration barrier and appear in the urine. They may be present as free-floating fat globules, found within renal epithelial cells or macrophages (i.e., oval fat bodies), or encased in casts. The generalized edema present with nephrotic syndrome is characteristically soft and pitting (i.e., when the flesh is depressed, an indentation remains). Development of edema is due primarily to decreased excretion of sodium.1 Whereas the exact mechanism is not clearly understood, it is due in part to increased reabsorption of sodium and water by the distal tubules. Loss of protein and its associated oncotic pressure from the blood plasma also results in the movement of fluid into interstitial tissues; however, its role is minor compared to that of sodium in the development of edema in these patients. Edema is usually apparent around the eyes (periorbital) and in the legs, but in severe cases, patients also develop pleural effusions and ascites. Along with heavy proteinuria and lipiduria in these patients, urine microscopic examination often shows a mild microscopic hematuria. In addition, pathologic casts such as fatty, waxy, and renal tubular casts are often present (see Table 8.2). Nephrotic syndrome occurs in patients with minimal change disease (MCD; lipoid nephrosis), membranous glomerulonephritis (MGN), focal segmental glomerulosclerosis, and MPGN. These glomerular diseases account for about 90% of all nephrotic syndrome cases in children and about 75% of those in adults. Systemic diseases that can present with nephrotic syndrome include diabetes mellitus, systemic lupus erythematosus (SLE), amyloidosis, malignant neoplasms, and infection, as well as renal responses to nephrotoxic agents (e.g., drugs, poisons). Each glomerulonephritis can be classified on the basis of its characteristic anatomic alterations to the glomeruli. These morphologic and immunologic changes are apparent in renal biopsy specimens by light microscopy or with the use of special stains (e.g., immunofluorescent stain) and other microscopy techniques (e.g., fluorescent microscopy, electron microscopy). The different types of glomerulonephritides are not disease specific. For example, a patient recovering from an infection can have glomerulonephritis of the crescentic type, typical acute glomerulonephritis (AGN), or MCD. In addition, although initial presentation may be of one type, the disease can progress into that of another. A classic example is the eventual development of chronic glomerulonephritis in 90% of patients with crescentic glomerulonephritis or RPGN. Table 8.3 summarizes the predominant forms of primary glomerulonephritides discussed in this section. Table 8.3 One cause of AGN is streptococcal infection, and it is specifically known as acute poststreptococcal glomerulonephritis. It is a common glomerular disease that occurs 1 to 2 weeks after a streptococcal infection of the throat or skin. Although the disease appears most often in children, AGN can affect individuals at any age. Only certain strains of group A β-hemolytic streptococci—those with M protein in their cell walls—induce this nephritis. The time delay between streptococcal infection and the clinical presentation of AGN actually correlates with the time required for antibody formation. Morphologically, all glomeruli show cellular proliferation of the mesangium and endothelium, as well as leukocytic infiltration. Swelling of the interstitium caused by edema and inflammation obstructs capillaries and tubules. As a result, fibrin forms in the capillary lumina and red blood cell casts form in the tubules. In addition, deposits of immune complexes, complement, and fibrin can be shown in the mesangium and along the basement membrane with the use of special staining and microscopy techniques. Typically, the onset of AGN is sudden and includes fever, malaise, nausea, oliguria, hematuria, and proteinuria. Edema may be present, often around the eyes (periorbital), knees, or ankles, and hypertension is usually mild to moderate. Because this disease is immune-mediated, any blood or urine cultures for infectious agents are negative. Blood tests reveal an elevated antistreptolysin O titer, a decrease in serum complement, and the presence of cryoglobulins. In addition, the creatinine clearance is decreased and the ratio of blood urea nitrogen to creatinine is increased. Serum albumin levels can be normal; however, if large amounts of protein are lost in the urine, these levels are decreased. More than 95% of children who develop acute poststreptococcal glomerulonephritis recover spontaneously or with minimal therapy. In contrast, only about 60% of adults recover rapidly; the remaining affected adults recover more slowly, with a subset ultimately developing chronic glomerulonephritis. Although rare, AGN caused by nonstreptococcal agents has been reported. It has been associated with other bacteria (e.g., pneumococci), viruses (e.g., mumps, hepatitis B), and parasitic infection (e.g., malaria). Note that the clinical features of AGN are the same, regardless of which agent is causing the immune complex formation that induces the disorder. Rapidly progressive glomerulonephritis (RPGN) is also termed crescentic glomerulonephritis. It is characterized by cellular proliferation in Bowman’s space to form crescents, from which its initial name was derived. These cellular crescents within the glomerular tuft cause pressure changes and can even occlude the entrance to the proximal tubule. Infiltration with leukocytes and fibrin deposition within these crescents are also characteristic of this type of glomerulonephritis. As a result of these degenerative glomerular changes, characteristic wrinkling and disruptions in the glomerular basement membrane are evident by electron microscopy. RPGN develops (1) after an infection; (2) as a result of a systemic disease, such as SLE or vasculitis; or (3) idiopathically (usually after a flulike episode). Hematuria is present, and the level of proteinuria varies. Edema or hypertension may or may not be present. Although an antibody to the basement membrane can be demonstrated in most patients, others may show few or no immune deposits in the glomeruli. This fact supports the theory of multiple pathways leading to severe glomerular damage. Regardless of therapy, 90% of patients with RPGN eventually develop chronic glomerulonephritis and require long-term renal dialysis or kidney transplantation. The deposition of immunoglobulins and complement along the epithelial (podocytes) side of the basement membrane characterizes membranous glomerulonephritis (MGN). With time, the basement membrane thickens, enclosing the embedded immune deposits and causing loss of the foot processes. Eventually, thickening of the basement membrane severely reduces the capillary lumen, causing glomerular hyalinization and sclerosis. No cellular proliferation or leukocytic infiltration is evident. MGN is the major cause of nephrotic syndrome in adults. Complement activation (specifically the action of C5b-9, the membrane attack complex of complement) is responsible for the glomerular damage that results in leakage of large amounts of protein into the renal tubules. In approximately 85% of patients, MGN is idiopathic. In the remaining patients, MGN is associated with immune-mediated disease. The antigens implicated can be exogenous (Treponema) or endogenous (thyroglobulin, DNA), and many antigens remain unknown. MGN frequently occurs secondary to other conditions, such as SLE, diabetes mellitus, or thyroiditis, or after exposure to metals (e.g., gold, mercury) or drugs (e.g., penicillamine). The typical clinical presentation of MGN is sudden onset of nephrotic syndrome. Hematuria and mild hypertension may be present. The clinical course varies, with no resolution of proteinuria in up to 90% of patients. Although this may take many years, eventually 50% of patients with MGN progress to chronic glomerulonephritis. Only 10% to 30% of patients with MGN show complete or partial recovery. Minimal change disease (MCD) is characterized by glomeruli that look normal by light microscopy; however, electron microscopy reveals the loss of podocyte foot processes. These foot processes are replaced by a simplified structure and their cytoplasm shows vacuolization. No leukocyte infiltration or cellular proliferation is present. Despite the absence of any immunoglobulin or complement deposits, MCD is believed to be immunologically based, involving a dysfunction of T-cell immunity. Various factors support this theory; the most notable factor is the onset of MCD after infection or immunization and its rapid response to corticosteroid therapy. T-cell dysfunction causes loss of the glomerular “shield of negativity” or polyanions (e.g., heparan sulfate proteoglycan). Remember, albumin can pass readily through the glomerular filtration barrier if the negative charge is removed; hence MCD is characterized by nephrotic syndrome (i.e., massive proteinuria). In children, MCD is responsible for most cases of nephrotic syndrome. Usually, no hypertension or hematuria is associated with it. Clinically, differentiation of MCD from MGN is based on the dramatic response of MCD to corticosteroid therapy. Although patients may become steroid dependent to keep the disease in check, the prognosis for recovery is excellent for children and adults. Focal segmental glomerulosclerosis (FSGS) is characterized by sclerosis of glomeruli. The process is both focal (occurring in some glomeruli) and segmental (affecting a specific area of the glomerulus). Morphologically, sclerotic glomeruli show hyaline and lipid deposition, collapsed basement membranes, and proliferation of the mesangium. FSGS is characterized most by diffuse damage to the glomerular epithelium (podocytes). Although not readily apparent by light microscopy, electron microscopy reveals the diffuse loss of foot processes in both sclerotic and nonsclerotic glomeruli. Glomerular hyalinization and sclerosis result from the mesangial response to the accumulation of plasma proteins and fibrin deposits. In addition, immunoglobulin (Ig)M and C3 are evident by immunofluorescence in these sclerotic areas. FSGS can occur (1) as a primary glomerular disease; (2) in association with another glomerular disease, such as IgA nephropathy; or (3) secondary to other disorders. Heroin abuse, acquired immunodeficiency syndrome (AIDS), reflux nephropathy, and analgesic abuse nephropathy are some conditions that can precede FSGS. Proteinuria is a predominant feature of FSGS. In 10% to 15% of patients, it initially presents as nephrotic syndrome. The remaining patients exhibit moderate to heavy proteinuria. Hematuria, reduced glomerular filtration rate (GFR), and hypertension can also be present. Patients with FSGS usually have little or no response to corticosteroid therapy, which helps differentiate this disorder from MCD. Many patients develop chronic glomerulonephritis at variable rates. An interesting note is that FSGS can recur after renal transplantation (25–50%), sometimes within days, suggesting a circulating systemic factor as the causative agent. Membranoproliferative glomerulonephritis (MPGN) is characterized by cellular proliferation, particularly of the mesangium, along with leukocyte infiltration and thickening of the glomerular basement membrane. As a result of the increased numbers of mesangial cells, the glomeruli take on a microscopically visible lobular appearance. Ultrastructural characteristics subdivide MPGN into two types, types I and II. Most cases of MPGN are immune-mediated, with the formation of immune complexes in the glomeruli or the deposition of complement in the glomeruli followed by its activation. MPGN is a slow, progressive disease, with 50% of patients eventually developing CKD. MPGN has a varied presentation pattern, with some patients showing only hematuria or subnephrotic proteinuria (less than 3–3.5 g/day), whereas it accounts for 5% to 10% of patients who present with nephrotic syndrome. MPGN is similar to FSGS in that it also has an unusually high incidence of recurrence after renal transplant. The deposition of IgA in the glomerular mesangium characterizes IgA nephropathy, one of the most prevalent types of glomerulonephritides worldwide. However, IgA deposits are detectable only with the use of special stains and microscopy techniques (e.g., immunofluorescence). Apparently, circulating IgA complexes or aggregates become trapped and engulfed by mesangial cells. Aggregated IgA is known to be capable of activating the alternative complement pathway, resulting in glomerular damage. Morphologically, the glomerular lesions are varied. Some may appear normal, whereas others may show evidence of focal or diffuse cellular proliferation. A common finding is recurrent hematuria in a range from gross to microscopic amounts. Proteinuria is usually present, varying in degree from mild to severe. IgA nephropathy often occurs 1 to 2 days after a mucosal infection of the respiratory, gastrointestinal (GI), or urinary tract from infectious agents (e.g., bacteria, viruses) that stimulate mucosal IgA synthesis. As a result, serum IgA levels are frequently elevated, and circulating IgA immune complexes are present in these patients. IgA nephropathy primarily affects children and young adults. The disease is slow and progressive, eventually causing CKD in 50% of patients. When disease onset occurs in old age or is associated with severe proteinuria and hypertension, renal failure develops more quickly. In time, numerous glomerular diseases result in the development of chronic glomerulonephritis. Morphologically, the glomeruli become hyalinized, appearing as acellular eosinophilic masses. In addition, the renal tubules are atrophied, fibrosis is evident in the renal interstitium, and lymphocytic infiltration may be present. About 80% of patients who develop chronic glomerulonephritis have previously had some form of glomerulonephritis (Table 8.4). The remaining 20% of cases represent forms of glomerulonephritis that were unrecognized or subclinical in their presentation. Table 8.4 The development of chronic glomerulonephritis is slow and silent, taking many years to progress. Some patients may present only with edema, which leads to the discovery of an underlying renal disease. Occasionally, hypertension and cerebral or cardiovascular conditions manifest first clinically. Other clinical findings associated with chronic glomerulonephritis include proteinuria, hypertension, and azotemia. Death resulting from uremia and pathologic changes in other organs (e.g., uremic pericarditis, uremic gastroenteritis) occurs if patients are not maintained on dialysis or do not undergo renal transplantation. Systemic lupus erythematosus (SLE), a systemic autoimmune disorder, presents with a constellation of lesions and clinical manifestations. Almost all patients with SLE show some type of kidney involvement. The pathogenesis of glomerular damage involves the deposition of immune complexes (specifically anti-DNA complexes) and complement activation. Five morphologic patterns of lupus nephritis are recognized; however, none of them is diagnostic or unique to SLE. In other words, patients with SLE may exhibit any of the clinical glomerular syndromes (see Table 8.1): recurrent hematuria, acute nephritic syndrome, or nephrotic syndrome. An important note is that CKD is a leading cause of death in these patients. Diabetes mellitus is another systemic disorder that frequently results in kidney disease. The most common renal conditions in diabetic patients present as a glomerular syndrome. However, other renal diseases occur and include vascular lesions of the renal arterioles, which are associated with hypertension, as well as enhanced susceptibility to pyelonephritis and papillary necrosis. Consequently, renal disease is a major cause of death in the diabetic population. Thickening of the glomerular basement membrane is evident by electron microscopy in all diabetic patients. Proteinuria eventually develops in up to 55% of diabetic patients and can range from subnephrotic to nephrotic levels. Within 10 to 20 years of disease onset, pronounced cellular proliferation of the glomerular mesangium eventually results in glomerulosclerosis (Fig. 8.1). CKD usually develops within 4 to 5 years after the onset of persistent proteinuria and requires long-term renal dialysis or transplantation. The development of diabetic glomerulosclerosis occurs more often with type 1 diabetes mellitus than with type 2. The Diabetes Control and Complications Trial demonstrated that blood glucose control significantly influences the development of microvascular complications in subjects with type 1 diabetes.2 A similar correlation was demonstrated in individuals with type 2 diabetes during the United Kingdom Prospective Diabetes Study.3 Therefore the same or similar underlying mechanisms of disease probably apply, and any improvement in blood glucose control can prevent the development and progression of diabetic nephropathy. Amyloidosis is a group of systemic diseases that involve many organs; it is characterized by the deposition of amyloid, a pathologic proteinaceous substance, among cells in numerous tissues and organs. Amyloid is made up of about 90% fibril protein and 10% glycoprotein. Microscopically in tissue, amyloid initially appears as an eosinophilic hyaline substance. It is differentiated from hyaline (e.g., collagen, fibrin) by Congo red staining, which imparts amyloid with a characteristic apple-green birefringence using polarizing microscopy. The deposition of amyloid within the glomeruli eventually destroys them. As a result, patients with amyloidosis present clinically with heavy proteinuria or nephrotic syndrome. With continual destruction of glomeruli over time, renal failure and uremia develop. Acute tubular necrosis (ATN) is characterized by the destruction of renal tubular epithelial cells, and the causes vary. It can be classified into two distinct types: ischemic ATN and toxic ATN. Ischemic ATN follows a hypotensive event (e.g., shock) that results in decreased perfusion of the kidneys followed by renal tissue ischemia. In contrast, toxic ATN results from exposure to nephrotoxic agents that have been ingested, injected, absorbed, or inhaled. The tubular damage that results from either type of ATN can be reversed once the initiating event or agent has been identified and addressed. An interesting note is that approximately 50% of all cases of ATN result from surgical procedures.4 The three principal causes of ischemic ATN are sepsis, shock, and trauma. However, any obstruction to renal blood flow or occlusion of renal arteries or arterioles can result in the hypoperfusion of renal tissue and ischemia. Examples of sepsis and shock include extensive bacterial infections and severe burns; examples of trauma include crush injuries and numerous surgical procedures. Toxic ATN is caused by a variety of agents that can be separated into two categories: endogenous and exogenous nephrotoxins. The tubular necrosis induced by these nephrotoxins can cause oliguria and Acute Kidney Injury (AKI). Endogenous nephrotoxins are normal solutes or substances that become toxic when their concentration in the bloodstream is excessive. They are primarily hemoglobin and myoglobin, and to a lesser degree uric acid and immunoglobulin light chains. Renal injury is due to a combination of factors including volume depletion, renal vasoconstriction (ischemia), direct heme-protein–mediated cytotoxicity, and cast formation.5,6 Myoglobin and hemoglobin are two heme-containing proteins that are known to be toxic to renal tubules. Myoglobinuria results from rhabdomyolysis—the breakdown or destruction of skeletal muscle cells. It can occur as the result of traumatic muscle injury (e.g., crush injuries, surgery) or after nontraumatic muscle damage that occurs with excessive immobilization (due to intoxication or seizure), ischemia, inflammatory myopathies, heat stroke, or drugs. In contrast, hemoglobinuria follows severe hemolytic events in which haptoglobin—the plasma protein that normally binds free hemoglobin to prevent its loss in the urine—has been depleted, and free hemoglobin readily passes the glomerular filtration barrier into the tubules. Exogenous nephrotoxins—substances ingested or absorbed—include numerous therapeutic agents (aminoglycosides, cephalosporins, amphotericin B, indinavir, acyclovir, foscarnet), anesthetics (enflurane, methoxyflurane), radiographic contrast media, chemotherapeutic drugs (cyclosporine), recreational drugs (heroin, cocaine), and industrial chemicals such as heavy metals (mercury, lead), organic solvents (carbon tetrachloride, ethylene glycol), and other poisons (mushrooms, pesticides). Morphologically, ischemic ATN affects short segments (i.e., focal) of the tubules in random areas throughout the nephron, from the medullary segments of the proximal tubules and ascending loops of Henle to the collecting tubules. The tubular basement membrane is often disrupted (i.e., tubulorrhexis) as a result of complete necrosis of the tubular cells; consequently, the renal interstitium is exposed to the tubular lumen. As a result, renal cell fragments are sloughed into the urine. These cell fragments consist of three or more tubular cells shed intact and usually originate in the collecting duct (see Figs. 7.5 and 7.33). In contrast, toxic ATN causes tubular necrosis primarily in the proximal tubules and usually does not involve their basement membranes. Convoluted renal tubular epithelial cells are found in the urine sediment; the presence of these distinctively large proximal tubular epithelial cells indicates toxic ATN (see Fig. 7.31). In addition to tubular cell death, nephrotoxins in high concentrations often cause renal vasoconstriction. Because of this, patients may have characteristics associated with ischemic ATN. Both types of ATN show cast formation within the distal convoluted and collecting tubules. Compared to toxic ATN, however, ischemic ATN shows an increased number and variety of casts in the urine sediment, including granular, renal tubular cell, waxy, and broad casts. The clinical presentation of ATN often is divided into three phases: onset, renal failure, and recovery. The onset of ATN may be abrupt after a hypotensive episode or deceptively subtle in a previously healthy individual after exposure to a toxin or administration of a nephrotoxic drug. This variable presentation develops into a renal failure phase with azotemia, hyperkalemia, and metabolic acidosis. At this time, approximately 50% of patients have a reduction in urine output to less than 400 mL/day (oliguria). The recovery phase is indicated by a steady increase in urine output; levels may reach 3 L/day. This diuretic state is exhibited by oliguric and nonoliguric patients and is explained best by the return to normal GFR before full recovery of the damaged tubular epithelium. This increased diuresis results in the loss of large amounts of water, sodium, and potassium until tubular function returns and the azotemia resolves. It takes about 6 months for full renal tubular function and concentrating ability to return. Renal tubular dysfunction may result from a primary renal disease or may be induced secondarily. The dysfunction may involve a single pathway with only one solute type affected or may involve multiple pathways, thereby affecting a variety of tubular functions. Tables 8.5 and 8.6 summarize proximal and distal tubular dysfunctions and associated disorders. Isolated areas of the nephrons (e.g., the proximal tubules) can be affected, while the other regions retain essentially normal function. Because renal tubular disorders do not affect glomerular function, the GFR is usually normal. This section discusses commonly encountered tubular dysfunctions, and Table 8.7 outlines the typical urinalysis findings associated with them. Table 8.5 Table 8.6 Table 8.7 ↑, Increased; ATN, acute tubular necrosis; RBCs, red blood cells; WBCs, white blood cells. aPatients with renal tubular acidosis can develop Fanconi’s syndrome. The term Fanconi’s syndrome is used to characterize any condition that presents with a generalized loss of proximal tubular function. As a consequence of this dysfunction, amino acids, glucose, water, phosphorus, potassium, and calcium are not reabsorbed from the ultrafiltrate and are excreted in the urine. A spectrum of disorders, including inherited diseases (e.g., cystinosis), toxin exposure (e.g., lead), metabolic bone diseases (e.g., rickets), and renal diseases (e.g., amyloidosis), can present with this syndrome. Both cystinosis and cystinuria are inherited autosomal recessive disorders that cause renal tubular dysfunction and urinary excretion of the amino acid cystine. These disorders are distinctively different in the gene involved, their clinical presentations, and the physiologic mechanisms responsible for cystine in the urine. For additional discussion, see subsection Amino Acid Disorders later in this chapter. Glucosuria can result from a lowered maximal tubular reabsorptive capacity (Tm) for glucose. Normally, the Tm for glucose is approximately 350 mg/min by the proximal tubules. Renal glucosuria is a benign inherited condition that results in excretion of glucose in the urine despite normal blood glucose levels. In these patients, glucosuria is caused by a reduction in the glucose Tm. As discussed in Chapter 6, glucosuria also occurs with prerenal conditions (e.g., diabetes mellitus) and intrinsic renal disease (i.e., defective tubular absorption) (see Table 6.17). Renal phosphaturia is an uncommon hereditary disorder characterized by an inability of the distal tubules to reabsorb inorganic phosphorus. The tubular defect appears to be twofold: a hypersensitivity of the distal tubules to the parathyroid hormone that causes increased phosphate excretion and a decreased proximal tubular response to lowered plasma phosphate levels. Because of low plasma phosphate levels, bone growth and mineralization are decreased. Patients with renal phosphaturia may be asymptomatic or can exhibit signs of severe deficiency such as osteomalacia or rickets and growth retardation. Inherited as a dominant sex-linked characteristic, this disorder is often termed familial hypophosphatemia or vitamin D–resistant rickets. Renal tubular acidosis (RTA) is characterized by the inability of the tubules to secrete adequate hydrogen ions despite a normal GFR. Consequently, despite being in acidosis, these patients are unable to produce an acid urine (i.e., urine pH <5.3). RTA can be inherited as an autosomal dominant trait, with partial or complete expression, or it can occur secondary to a variety of diseases. Several forms of RTA (types I, II, III, and IV) are identified based on their renal tubular defect(s). In type I RTA, the tubular dysfunction appears to be twofold: an inability to maintain the normal hydrogen ion gradient and an inability to increase tubular ammonia secretion to compensate. The defect in maintaining the hydrogen ion gradient results from a tubular secretory defect or from increased back-diffusion of hydrogen ions into the distal tubular cells. Regardless, patients with RTA become acidotic, and their bodies compensate by removing calcium carbonate from bone to buffer the retained acids. Consequently, these patients develop osteomalacia and hypercalcemia. The resultant hypercalciuria can cause the precipitation of calcium salts in the tubules and renal parenchyma (nephrocalcinosis). Type II RTA is characterized by decreased proximal tubular reabsorption of bicarbonate. As a result, an increased amount of bicarbonate remains for distal tubular reabsorption. To compensate, most of the hydrogen ions that the distal tubule secretes are used to retain bicarbonate and are not eliminated in the urine. Consequently, hydrogen ion excretion decreases and urine pH increases. This type of RTA rarely occurs without additional abnormalities of the proximal tubule (e.g., Fanconi’s syndrome). Patients with type III RTA express characteristics of type I and type II RTA. Type IV RTA is characterized by an impaired ability to exchange sodium for potassium and hydrogen in the distal tubule. Numerous conditions can give rise to acquired RTA. Approximately 30% of patients with acquired RTA type I have an autoimmune disorder that has an associated hypergammaglobulinemia such as biliary cirrhosis or thyroid disease. Drugs, nephrotoxins, and kidney transplant rejection can result in the development of RTA, as can inborn errors of metabolism such as Wilson’s disease or cystinosis. Individualized treatment for RTA consists of reducing acidemia by oral administration of alkaline salts (e.g., sodium bicarbonate) and potassium. This serves to raise the plasma pH toward normal and to replace lost potassium (primarily in RTA types I and II). Other clinical problems such as the development of renal calculi (stones) and upper urinary tract infection (UTI) may require additional treatment regimens. Because of their close structural and functional relationships, a disease process affecting the renal interstitium inevitably involves the tubules, leading to tubulointerstitial disease. Numerous conditions or factors are capable of causing a tubulointerstitial disease process, and the pathogenic mechanism for each can differ (Box 8.2). Tubulointerstitial disease and lower UTI can be intimately involved because the latter represents the principal mechanism leading to the development of acute pyelonephritis. Table 8.8 outlines typical routine urinalysis findings in selected UTIs and tubulointerstitial diseases. Table 8.8
Renal and Metabolic Disease
Key Terms1
Renal Diseases
Glomerular Disease
Morphologic Changes in the Glomerulus
Pathogenesis of Glomerular Damage
Clinical Features of Glomerular Diseases
Syndrome
Clinical Features
Asymptomatic hematuria or proteinuria
Variable hematuria, subnephrotic proteinuria
Acute nephritic syndrome
Hematuria, proteinuria, oliguria, azotemia, edema, hypertension
Nephrotic syndrome
Proteinuria (>3 g/day), lipiduria, hypoproteinemia, hyperlipidemia, edema
Disease
Physical and Chemical Examination
Microscopic Examination
Acute glomerulonephritis
Chronic glomerulonephritis
Nephrotic syndrome
Nephrotic Syndrome
Types of Glomerulonephritides
Disease
Typical Outlook Solution
Pathogenesis
Glomerular Changes
Acute glomerulonephritis (AGN), poststreptococcal
Acute nephritic syndrome
Antibody mediated
Cellular proliferation (diffuse); leukocytic infiltration; interstitial swelling
Rapidly progressive glomerulonephritis (RPGN)
Acute nephritic syndrome
Antibody mediated; often anti-GBM
Cellular proliferation to form characteristic “crescents”; leukocytic infiltration; fibrin deposition; GBM disruptions
Membranous glomerulonephritis (MGN)
Nephrotic syndrome
Antibody mediated
Basement membrane thickening because of immunoglobulin (Ig) and complement (C) deposits; loss of foot processes (diffuse)
Minimal change disease (MCD)
Nephrotic syndrome
T-cell immunity dysfunction; loss of glomerular polyanions
Loss of foot processes
Focal segmental glomerulosclerosis (FSGS)
Proteinuria variable; subnephrotic to nephrotic
Unknown; possibly a circulating systemic factor; can reoccur after kidney transplant
Sclerotic glomeruli with hyaline and lipid deposits (focal and segmental); diffuse loss of foot processes; focal IgM and C3 deposits
Membranoproliferative glomerulonephritis (MPGN)
Depends on type: nephrotic syndrome or hematuria or proteinuria
Immune complex or complement activation
Cellular proliferation (mesangium); leukocytic infiltration; IgG and complement deposits
IgA nephropathy
Recurrent hematuria and proteinuria
IgA mediated; complement activation
Deposition of IgA in mesangium; variable cellular proliferation
Chronic glomerulonephritis
Chronic renal failure
Variable
Hyalinized glomeruli
Acute glomerulonephritis
Rapidly progressive glomerulonephritis
Membranous glomerulonephritis
Minimal change disease
Focal segmental glomerulosclerosis
Membranoproliferative glomerulonephritis
IgA nephropathy
Chronic glomerulonephritis
Disease
Approximate Percentage
Rapidly progressive glomerulonephritis (RPGN)
90%
Focal segmental glomerulosclerosis (FSGS)
50–80%
Membranous glomerulonephritis (MGN)
50%
Membranoproliferative glomerulonephritis (MPGN)
50%
IgA nephropathy
30–50%
Poststreptococcal glomerulonephritis
1–2%
Systemic Diseases and Glomerular Damage
Tubular Disease
Acute Tubular Necrosis
Tubular Dysfunction
Dysfunction
Disease
Single Defect in Proximal Tubular Function
Impaired ability to reabsorb glucose
Renal glucosuria
Impaired ability to reabsorb specific amino acids
Cystinuria (cystine and dibasic amino acids)
Hartnup disease (monoamino-monocarboxylic amino acids)
Impaired ability to reabsorb sodium
Bartter’s syndrome
Impaired ability to reabsorb bicarbonate
Renal tubular acidosis type II
Impaired ability to reabsorb calcium
Idiopathic hypercalciuria
Excessive reabsorption of calcium
Hypocalciuric familial hypercalcemia
Excessive reabsorption of sodium
Gordon’s syndrome
Excessive reabsorption of phosphate
Pseudohypoparathyroidism
Multiple Defects in Proximal Tubular Function
Inherited diseases
Cystinosis
Tyrosinemia
Wilson’s disease
Galactosemia
Hereditary fructose intolerance
Glycogen storage disease
Metabolic diseases
Bone diseases, such as osteomalacia, primary hyperparathyroidism, vitamin D–dependent rickets
Renal diseases
Toxin Induced
Dysfunction
Disease
Impaired ability to reabsorb phosphate
Familial hypophosphatemia (vitamin D–resistant rickets)
Impaired ability to reabsorb calcium
Idiopathic hypercalciuria
Impaired ability to acidify urine
Renal tubular acidosis types I and IV
Impaired ability to retain sodium
Renal salt-losing disorders
Impaired ability to concentrate urine
Nephrogenic diabetes
Excessive reabsorption of sodium
Liddle’s syndrome
Disease
Physical and Chemical Examination
Microscopic Examination
Acute tubular necrosis
Cystinuria and cystinosis
Renal tubular acidosisa
pH >5.5
Unremarkable
Fanconi’s syndrome
Unremarkable
Fanconi’s syndrome
Cystinosis and cystinuria
Renal glucosuria
Renal phosphaturia
Renal tubular acidosis
Tubulointerstitial Disease and Urinary Tract Infections
Disease
Physical and Chemical Examination
Microscopic Examination
Lower Urinary Tract Infection
Cystitis
Tubulointerstitial Disease (Upper Urinary Tract Infection)
Acute pyelonephritis
Chronic pyelonephritis
Acute interstitial nephritis
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Renal and Metabolic Disease
Learning Objectives