Renal Disease PDF

CHAPTER 16 Renal Disease Rachel L. Perlman, MD, & Michael Heung, MD, MS Kidney disease contributes significantly to the global burden of disease, both in developing and developed countries. The Centers for Disease Contr...

CHAPTER 16 Renal Disease Rachel L. Perlman, MD, & Michael Heung, MD, MS Kidney disease contributes significantly to the global burden of disease, both in developing and developed countries. The Centers for Disease Control and Prevention estimate that in the United States, more than 10% of people 20 years of age and older (more than 20 million individuals) have chronic kidney disease. In addition, many more people suffer from acute kidney injury and other forms of kidney disease annually. Thus, clinicians of all specialties will encounter patients with renal disorders, and it behooves us to be aware of the various risk factors and causes of kidney disease. This is particularly important because with early detection and appropriate management, most forms of kidney disease can be treated to prevent or at least slow the rate of progression to kidney failure or other complications. The kidneys serve a crucial role in filtering blood, and a wide range of diseases of other organ systems and systemic diseases may be manifested in the kidney. For example, renal disease is a prominent presentation of long-standing diabetes mellitus and hypertension and of autoimmune disorders such as systemic lupus erythematosus. A particular challenge is that patients are typically asymptomatic until relatively advanced kidney failure is present. There are no pain receptors within the substance of the kidney, so pain is not a prominent presenting complaint, except in those renal diseases in which there is involvement of the ureter (eg, nephrolithiasis) or the renal capsule (eg, renal cell carcinoma). In early stages of kidney disease, patients may have only abnormalities of urine volume or composition (eg, presence of red blood cells and/or protein). Later, they may manifest systemic symptoms and signs of lost renal function (eg, edema, fluid overload, electrolyte abnormalities, anemia). Depending on the nature of the renal disease, they may progress to display a wide range of chronic complications resulting from inadequate renal function. The kidneys play multiple roles in the body, including blood filtration, metabolism and excretion of endogenous and exogenous compounds, and endocrine functions. Perhaps most significantly, the kidneys are the primary regulators of fluid, acid–base, and electrolyte balances in the body, and this remarkable pair of organs maintains homeostasis across a broad array of dietary and environmental changes. An understanding of each of these roles is required to illuminate the pathophysiologic basis behind the many manifestations of kidney disease. CHECKPOINT 1. What are some important causes of renal disease? 2. What are some consequences of renal failure? NORMAL STRUCTURE & FUNCTION OF THE KIDNEY ANATOMY, HISTOLOGY & CELL BIOLOGY A remarkable attribute of the kidneys is their ability to maintain homeostasis while functioning under a broad range of environmental water and salt availabilities. For example, the kidneys have the capacity to excrete free water in freshwater fish, widely varying amounts of water and solute in humans, and an extremely concentrated urine in the kangaroo rat, which can live its entire life without access to water. The kidneys are a pair of encapsulated organs located in the retroperitoneal area (Figure 16–1). A renal artery enters and a renal vein exits from each kidney at the hilum. Approximately 20% of cardiac output goes to the kidneys. Blood is filtered in the kidneys, removing wastes—in particular urea and nitrogen-containing compounds—and regulating extracellular electrolytes and intravascular volume. Because renal blood flow is from the cortex to the medulla, and because the medulla has a relatively low rate of blood flow for a high rate of metabolic activity, the normal oxygen tension in the medulla is lower than in other parts of the kidney. This makes the medulla particularly susceptible to ischemic injury. FIGURE 16–1 Vessels and organs of the retroperitoneum. (Redrawn, with permission, from Lindner HH. Clinical Anatomy. Originally published by Appleton & Lange. Copyright © 1989 by The McGraw-Hill Companies, Inc.) The nephron is the basic structural and functional unit of the kidney. Each nephron consists of a tuft of capillaries termed the glomerulus, the site at which blood is filtered, and a renal tubule from which water and salts in the filtrate are reclaimed (Figure 16–2). Each human kidney has approximately 1 million nephrons. FIGURE 16–2 Structures of the kidney. A: Landmarks of the normal kidney. B: Glomerulus and glomerular capillary. C: Detailed structure of the glomerulus and the glomerular filtration membrane composed of endothelial cell, basement membrane, and podocyte. Note that, for clarity, the distal tubule is separated from the glomerulus in A; however, its true anatomic relationship, which is essential for physiologic function, is illustrated in B. (Redrawn, with permission, from Chandrasoma P et al, eds. Concise Pathology, 3rd ed. Originally published by Appleton & Lange. Copyright © 1998 by The McGraw-Hill Companies, Inc.) A glomerulus consists of an afferent and an efferent arteriole and an intervening tuft of capillaries lined with endothelial cells and covered with epithelial cells that form a continuous layer with those of the Bowman capsule and the renal tubule. The space between capillaries in the glomerulus is called the mesangium. Material comprising a basement membrane is located between the capillary’s endothelial cells and the glomerular epithelial cells (on the other side of the basement membrane) (Figure 16–2C). A closer examination of glomerular histology and cell biology reveals unique features not found in most peripheral capillaries (see Figure 16–2). First, the glomerular capillary endothelium is fenestrated (see Figure 16–2C). However, because the endothelial cells have a coat of negatively charged glycoproteins and glycosaminoglycans, they normally exclude plasma proteins such as albumin. On the other side of the glomerular basement membrane are the epithelial cells. Termed podocytes because of their numerous extensions, or foot processes, these cells are connected to one another by modified desmosomes. The mesangium is an extension of the glomerular basement membrane but is less dense and consists of two distinct cell types: intrinsic glomerular cells and tissue macrophages. Both cell types contribute to the development of immune- mediated glomerular disease by their production of, and response to, cytokines such as transforming growth factor-β (TGF-β). Understanding the complex organization of the glomerulus is crucial for understanding normal renal function and also the characteristics of different glomerular diseases. Thus, in some conditions, immune complexes may accumulate under the epithelial cells, whereas in others, they may accumulate under the endothelial cells. Likewise, because immune cells are unable to cross the glomerular basement membrane, immune complex deposition under the epithelial cells is generally not accompanied by a cellular inflammatory reaction (see later discussion). The renal tubule itself has a number of different structural regions: the proximal convoluted tubule, from which most of the electrolytes and water are reclaimed; the loop of Henle; and a distal convoluted tubule and collecting duct (Figure 16–3), where urine is concentrated and additional electrolyte and water changes are made in response to hormonal control. FIGURE 16–3 The vascular supply of the cortical and juxtamedullary nephrons. (Redrawn, with permission, from Pitts RF. Physiology of the Kidney and Body Fluids, 3rd ed. Year Book, 1963. Copyright © Elsevier.) PHYSIOLOGY Glomerular Filtration & Tubular Resorption Approximately 100–120 mL/min of glomerular filtrate is generated in a normal adult with two fully functional kidneys. The approximate mass cutoff of substances for filtration is 70 kDa. However, substances smaller than this are often retained, either because of electric charge effects or because they are tightly bound to other proteins, giving them a larger effective size. After filtration at the glomerulus, there is extensive reabsorption of filtered substances along the renal tubular network. The degree of reabsorption varies by substance and anatomic location in the tubules, thus allowing for differential regulation of constituent components. Most (60–70%) of the filtered Na+—and, under normal conditions, almost all the K+ and glucose—is actively resorbed from the tubular fluid via co-transporter mechanisms in the proximal tubule. Water is resorbed passively and along osmotic gradients established by the reabsorption of Na+. In addition to absorption, a number of substances are secreted into the tubular fluid through the action of transporters along the renal tubule. Examples of substances secreted include organic anions and cations such as creatinine, histamine, and many drugs and toxins. Normally, about 30 mL/min of isotonic filtrate is delivered to the loop of Henle, where a countercurrent multiplier mechanism achieves concentration of the urine. The loop of Henle passes down into the medulla of the kidney, where secretion of Na+ from the cells in the thick ascending limb establishes a hypertonic concentration gradient to reabsorb water from the tubular fluid across the cells of the descending limb. Under normal circumstances, no more than 5–10 mL/min of glomerular filtrate is delivered to the collecting ducts. Water absorption in the collecting ducts occurs directly through water channels controlled by vasopressin (also known as antidiuretic hormone [ADH]). Under the control of aldosterone, Na+ resorption from tubular fluid and K+ and H+ transport into tubular fluid occur in different types of cells in the renal collecting ducts. Even though it deals with less than one-tenth of the total glomerular filtrate, the collecting duct is the site of urine volume regulation and the site at which water, Na+, acid–base, and K+ balance is achieved. The crucial role of the collecting duct in regulating kidney function depends on two features. First, the collecting duct is under hormonal control, in contrast to the proximal tubule, whose actions are generally a simple function of volume and the composition of tubular fluid and constitutively active transporters. Second, the collecting duct is the last region of the renal tubule traversed before the remaining 1–2 mL/min of the original glomerular filtrate exits into the ureters as urine. Renal Regulation of Blood Pressure & Blood Volume The kidney plays an important role in blood pressure regulation through their effect on Na+ and water balance, which are major determinants of blood pressure. First, the Na+ concentration in the proximal tubular fluid is sensed at the macula densa (see Figure 16–2), part of the juxtaglomerular apparatus. The juxtaglomerular apparatus also assesses the perfusion pressure of the blood, an important indicator of intravascular volume status under normal circumstances. Through the action of these two sensors, either low Na+ or low perfusion pressure acts as a stimulus for renin release. Renin, a protease made in the juxtaglomerular cells, cleaves angiotensinogen in the blood to generate angiotensin I, which is then cleaved to angiotensin II by angiotensin- converting enzyme (ACE). Angiotensin II raises blood pressure by directly triggering vasoconstriction and by stimulating aldosterone production and secretion in the adrenal cortex, resulting in Na+ and water retention by the collecting duct (see Chapter 21). All these effects expand the extracellular fluid (ECF) and thus renal perfusion pressure, completing a homeostatic negative feedback loop that alleviates the initial stimulus for renin release. However, these mechanisms can also be maladaptive and contribute to the pathophysiology of various disease states. Notably, the trigger activating the renin–angiotensin–aldosterone system is the physiologic signal of low effective circulating volume, which may not be synonymous with low total body volume. Edematous states (eg, heart failure, nephrotic syndrome, cirrhosis) develop owing to a pathophysiologic factor favoring fluid movement out of the intravascular space and into the interstitium or third spaces (eg, peritoneal cavity, pleural space). In the case of heart failure, this factor is an elevated hydrostatic component related to cardiac congestion. In nephrotic syndrome, it is a fall in oncotic pressure owing to a loss of protein in the urine. In cirrhosis, there can be a combination of lower oncotic pressures from decreased protein production and increased hydrostatic pressure from hepatic congestion, leading to third-spacing of fluid. In all these conditions, the resultant decreased effective circulating volume signals the kidneys to progressively retain Na+ and water until a new equilibrium is established between the vascular space and interstitial space. Another trigger activating the renin–angiotensin–aldosterone system is renovascular disease, an important cause of secondary hypertension. In renovascular disease, a fixed vascular abnormality in the renal arterial circulation (most commonly atherosclerosis) results in impaired blood flow, generating the signal for low effective circulating volume despite a normal circulating volume. The resultant activation of the renin–angiotensin–aldosterone system leads to hypertension because of the direct vascular effects of angiotensin and because of the increased circulating volume resulting from an aldosterone-mediated increase in Na+ reabsorption. Intravascular volume depletion also triggers vasopressin release. Receptors in the carotid body and elsewhere sense a fall in blood pressure and activate autonomic neural pathways, including fibers that go to the hypothalamus, where vasopressin release is controlled. Vasopressin is released and travels via the bloodstream throughout the body. At the collecting duct, vasopressin facilitates insertion of water channels into the cell membranes, allowing for the passive reabsorption of free water based on the medullary interstitial osmotic gradient. Chapter 19 provides further discussions of water balance and the role of vasopressin. Renal Regulation of Acid–Base Balance Along with the pulmonary system, the kidneys play a primary role in acid–base homeostasis. In normal conditions, the arterial blood pH is maintained within the range of 7.35–7.45 through a buffering system in which bicarbonate plays a key role: For example, a drop in pH (increase in H+ concentration) leads to an increase in CO2, which can be exhaled from the lungs. This immediate buffering effect depletes the body’s stores of bicarbonate. The kidneys subsequently excrete additional H+ and thus serve to replete bicarbonate stores. In this system, the pulmonary response to an acid–base imbalance is rapid (seconds to minutes), whereas the kidney’s response is delayed (hours to days). However, the lungs can excrete only volatile acids, and the removal of nonvolatile (“fixed”) acids relies on the kidneys. During the ingestion of a normal daily diet, humans generate an obligate acid load through protein metabolism. To maintain homeostasis, this acid load is excreted by the kidneys. The primary site of acid excretion is the distal collecting duct, where H+ is secreted into the tubular lumen, where it combines primarily with ammonia (NH3) to form ammonium (NH4+), which is subsequently excreted in the urine. In addition to acid excretion, the kidneys regulate acid–base balance through the reabsorption and regeneration of bicarbonate, primarily in the proximal tubule. Insight into the functional roles of the proximal and distal renal tubules in maintaining acid–base balance can be seen in the clinical features of the various forms of renal tubular acidosis (Table 16–1). TABLE 16–1 Characteristics of renal tubular acidosis.  Metabolic acidosis is a common and potentially severe condition that warrants careful evaluation in the clinical setting. Several mechanisms can lead to the development of metabolic acidosis. First, the excess production of endogenous acids can exceed the ability of the kidneys to excrete H+. This can occur in advanced kidney failure, as the kidneys’ ability to generate ammonium is diminished. Conversely, metabolic acidosis can develop from the excess production of endogenous acids even in the face of intact renal function (eg, in lactic acidosis from tissue ischemia or in diabetic ketoacidosis). Second, metabolic acidosis can result from the ingestion of exogenous acids (eg, in intoxication with methanol or ethylene glycol, which are metabolized to formic acid and oxalic acid, respectively). Third, metabolic acidosis can develop through the loss of bicarbonate, which can occur from a failure to reabsorb bicarbonate in the kidney (ie, proximal renal tubular acidosis) or from the gastrointestinal (GI) loss of bicarbonate-rich fluids (eg, severe diarrhea, pancreatic fistula). Fourth, the administration of large amounts of bicarbonate- depleted solution (such as 0.9% normal saline) to patients can lead to a dilutional acidosis. Renal Regulation of Potassium Balance Potassium balance is primarily regulated in the distal collecting duct, where it is secreted into the lumen in response to aldosterone-mediated Na+ reabsorption. Therefore, aldosterone is the primary hormonal regulator of K+. Indeed, in addition to the angiotensin-mediated stimulus discussed above, hyperkalemia is a signal for aldosterone release, whereas hypokalemia provides negative feedback for such release (see Chapter 21). The kidneys’ ability to regulate K+ balance is such that K+ excretion can be upregulated to exceed even the amount filtered in the glomerulus. Hypokalemia can develop from three main mechanisms: shifting of K+ from the extracellular to intracellular compartments (eg, alkalosis, use of β-agonist therapy), extrarenal losses (eg, diarrhea), or renal losses. In general, increased delivery of Na+ to the distal tubules/collecting duct will result in increased K+ secretion, with the most common causes of renal K+ wasting being diuretic use and osmotic kaliuresis. Hyperaldosteronism, either primary aldosteronism from an adrenal tumor (ie, Conn syndrome) or secondary (eg, hyperreninemic) hyperaldosteronism, frequently presents with hypokalemia owing to unchecked Na+ reabsorption with the resultant secretion of both K+ and H+. Therefore, the clinical presentation of hypokalemia with hypertension and metabolic alkalosis should prompt an evaluation for a state of aldosterone excess. Chapter 21 provides a further discussion of the role of the renin–angiotensin–aldosterone system in regulating potassium and intravascular volume. Hyperkalemia can occur from extracellular potassium shifting (eg, acidosis), cellular potassium release (eg, hemolysis), increased potassium ingestion, or decreased renal potassium excretion (eg, renal insufficiency or kidney failure). Numerous drugs can also interfere with renal K+ excretion. Renal Regulation of Ca2+ Metabolism The kidney plays a number of important roles in Ca2+ and phosphate homeostasis. First, the kidney is the site of 1α-hydroxylation or 24- hydroxylation of 25-hydroxycholecalciferol, the hepatic metabolite of vitamin D3. This produces calcitriol (1,25-dihydroxy vitamin D), the biologically active form of vitamin D that increases Ca2+ absorption from the gut. Second, the kidney is a site of action for parathyroid hormone (PTH), resulting in Ca2+ retention and phosphate wasting in the urine. Chapter 17 provides a further discussion of the role of the kidney in Ca2+ and phosphate homeostasis. Renal Regulation of Erythropoiesis The kidney is the main site of production of the hormone erythropoietin, which stimulates the bone marrow production and maturation of red blood cells. The signal for erythropoietin production is thought to be the level of blood oxygenation, which is monitored in the kidney. With progressive renal insufficiency, the capacity to produce erythropoietin becomes impaired and anemia can develop. Anemia typically begins to occur when the glomerular filtration rate (GFR) has fallen to 30–45 mL/min or less, and it is nearly universally observed in patients with end-stage renal disease. Although common, anemia of chronic kidney disease is a diagnosis of exclusion. Iron deficiency and other underlying abnormalities should be investigated and corrected if possible. The primary management of severe anemia of chronic kidney disease is hormone replacement therapy with a recombinant analog of erythropoietin. Chapter 6 provides additional discussion of the role of erythropoietin in the regulation of red blood cell mass. Regulation of Renal Function There are a variety of physical, hormonal, and neural mechanisms by which the functions of the kidney are controlled. Vasopressin, together with the physics of the countercurrent multiplier in the loop of Henle and the hypertonic medullary interstitium, makes it possible to concentrate the urine under normal circumstances. This confers on the healthy kidney the ability to maintain fluid homeostasis under widely diverse conditions (by generating either a concentrated or dilute urine, depending on whether the body needs to conserve or excrete salt and water). Tubuloglomerular feedback refers to the ability of the kidney to regulate the GFR in response to the solute concentration in the distal renal tubule. When an excessive concentration of Na+ in the tubular fluid is sensed by the macula densa, afferent arteriolar vasoconstriction is triggered. This diminishes the GFR so that the renal tubule has a smaller solute load per unit time, allowing Na+ to be more efficiently reclaimed from tubular fluid. A variety of vasoactive substances, including adenosine, prostaglandins, nitric oxide, and peptides such as endothelin and bradykinin, contribute to the humoral control of tubuloglomerular feedback. Another important challenge for the kidney is regulating renal cortical versus medullary blood flow. Renal cortical blood flow needs to be sufficient to maintain a GFR high enough to clear renally excreted wastes efficiently without exceeding the capacity of the renal tubules for solute reabsorption. Likewise, medullary blood flow must be closely regulated. Excessive medullary blood flow can disrupt the osmolar gradient achieved by the countercurrent exchange mechanism. Insufficient medullary blood flow can result in anoxic injury to the renal tubule. From the perspective of individual nephrons, redistribution of blood flow from the cortex to the medulla involves preferentially supplying blood (and therefore oxygen) to those nephrons with long loops of Henle that dip down into the inner medulla. Adaptations of the kidney to injury can also be thought of as a form of regulation. Thus, nephron loss results in compensatory glomerular hyperfiltration (increased GFR per nephron) and renal hypertrophy. Although hyperfiltration may be adaptive in the short term, allowing maintenance of the total renal GFR, it has been implicated as a common inciting event in further nephron destruction from a variety of causes. There are other clinically important adaptations to injury. Poor renal perfusion from any cause results in responses that improve perfusion through afferent arteriolar vasodilation and efferent arteriolar vasoconstriction in response to hormonal and neural cues. These regulatory effects are reinforced by inputs sensing Na+ balance. Altering the Na+ balance is another way to influence blood pressure and hence renal perfusion pressure. Sympathetic innervation by the renal nerves influences renin release. Renal prostaglandins play an important role in vasodilation, especially in patients with chronically poor renal perfusion. CHECKPOINT 3. What are the parts of the nephron, and what role does each play in renal function? 4. How is renal function regulated? 5. What are the nonexcretory functions of the kidney? 6. What are the relationships, if any, between each nonex-cretory function named previously and the kidney’s role in fluid, electrolyte, and blood pressure regulation? OVERVIEW OF RENAL DISEASE ALTERATIONS OF KIDNEY STRUCTURE & FUNCTION IN DISEASE Renal disease can be categorized either by the site of the lesion (eg, glomerulopathy vs. tubulointerstitial disease) or by the nature of the factors leading to kidney disease (eg, immunologic, metabolic, infiltrative, infectious, hemodynamic, toxic). Glomerular disease can be further categorized according to clinical presentation. Thus, some disorders present with profound proteinuria but no evidence of a cellular inflammatory reaction (nephrotic disorders), whereas others have variable degrees of proteinuria associated with red and white blood cells in the urine (nephritic disorders). Nephrotic disorders typically show immune complex deposition at or under the epithelial cells, often with morphologic changes in the foot processes (Figure 16–4). This probably reflects damage to the selective nature of the glomerular filter (eg, by immune complex formation) or the deposition of preformed complexes, in some cases with complement activation but without concomitant activation of a cellular immune response. Although the lack of a cellular immune response may limit the damage done, it also slows the resolution of the disorder, with proteinuria taking months or years to resolve even when the underlying disease has been brought under control. FIGURE 16–4 The anatomy of a normal glomerular capillary is shown on the left. Note the fenestrated endothelium (EN), glomerular basement membrane (GBM), and the epithelium with its foot processes (EP). The mesangium is composed of mesangial cells (MC) surrounded by extracellular matrix (MM) in direct contact with the endothelium. Ultrafiltration occurs across the glomerular wall and through channels in the mesangial matrix into the urinary space (US). The typical localization of immune deposits and other pathologic changes is depicted on the right. (1) Uniform subepithelial deposits as in membranous nephropathy. (2) Large, irregular subepithelial deposits or “humps” seen in acute postinfectious glomerulonephritis. (3) Subendothelial deposits as in diffuse proliferative lupus glomerulonephritis. (4) Mesangial deposits characteristic of immunoglobulin A nephropathy. (5) Antibody binding to the glomerular basement membrane (as in Goodpasture syndrome) does not produce visible deposits, but a smooth linear pattern is seen on immunofluorescence. (6) Effacement of the epithelial foot processes is common in all forms of glomerular injury with proteinuria. Nephritic disorders show immune complex deposits either in a subendothelial location or in the glomerular basement membrane or mesangium (see Figure 16– 4). The cellular immune system has ready access to all these locations, and the resulting inflammatory reaction can be a “double-edged sword.” Thus, when the underlying process can be controlled, phagocytosis of the subendothelial deposits speeds recovery. On the other hand, an uncontrolled or prolonged inflammatory response can result in a greater degree of destruction of the glomerular architecture, in part because of the local production and action of cytokines. Specific regions of the kidney are particularly susceptible to certain kinds of injury: (1) Hemodynamic factors regulating blood flow have profound effects on the kidney, both because the GFR, a primary determinant of renal function, depends on renal blood flow and because the kidney is susceptible to hypoxic injury; (2) the renal medulla is a low-oxygen-tension environment, which makes it very susceptible to ischemic injury; and (3) the glomerulus is the initial filter of blood entering the kidney and thus is a prominent site of injury related to immune complex deposition and complement fixation. One useful organizing scheme that combines a consideration of both the site and cause of renal disease in approaching patients with new renal failure is to first categorize the cause of the patient’s renal failure as prerenal, intrarenal, or postrenal and then to subdivide each of these categories according to specific causes and anatomic locations (Table 16–2). TABLE 16–2 Kidney diseases by site of injury. MANIFESTATIONS OF ALTERED KIDNEY FUNCTION Decreased kidney function leads to an accumulation of urea and an inability to maintain electrolyte, water, and acid–base balance. The failure to adequately excrete urea, manifested as a progressive elevation of blood urea nitrogen (BUN), serum creatinine, and other poorly defined toxins, results in uremia (see Chronic Kidney Disease, below). Uremia is a syndrome characterized by a constellation of symptoms, physical examination findings, and laboratory abnormalities (Table 16–3), presumably caused by a buildup of one or more uncharacterized toxins. In the absence of adequate renal clearance, ingesting excess amounts of Na+, K+, water, or acids results in electrolyte, volume, and acid–base abnormalities that can be life threatening. Furthermore, excess Na+ ingestion in a patient with renal insufficiency results in intravascular volume expansion, which in turn can lead to hypertension and heart failure. TABLE 16-3 Clinical abnormalities in uremia.1  CHECKPOINT 7. What characteristics of various parts of the nephron make it particularly susceptible to certain types of injury? 8. What is uremia, and what are its most prominent symp-toms and signs? PATHOPHYSIOLOGY OF SELECTED RENAL DISEASES ACUTE KIDNEY INJURY Clinical Presentation Acute kidney injury is a syndrome characterized by a rapid deterioration of renal function (typically within days to a week), resulting in the accumulation of nitrogenous wastes in the blood that would normally be excreted in the urine. The patient presents with a rapidly rising BUN (ie, azotemia) and serum creatinine. Depending on the cause and when the patient comes to medical attention, there may be other presenting features as well (Table 16–4). Thus, diminished urine volume (oliguria) is commonly but not always seen. Urine volume may be normal early or indeed at any time in milder forms of acute kidney injury. Patients presenting relatively late may display any of the clinical manifestations described later. TABLE 16–4 Initial clinical and laboratory data base for defining major syndromes in nephrology. The most widely accepted definition of acute kidney injury is a rise in serum creatinine of 0.3 mg/dL or more within a 48-hour period or a fall in urine output to less than 0.5 mL/kg/h for at least 6 hours. However, in patients who develop acute kidney injury outside the hospital setting, the time course of serum creatinine rise may be difficult to ascertain, and an empiric diagnosis may be required. Etiology Table 16–5 presents the major causes of acute kidney injury. TABLE 16–5 Major causes of acute kidney injury. A. Prerenal Causes As demonstrated by the Starling equation, filtration across a glomerulus is determined by the hydrostatic and oncotic pressures in both the glomerular capillary and its surrounding tubular lumen as described by the following relationship: Kf and σ are constants determined by the permeability of a given glomerulus and the effective contribution of osmotic pressure, respectively; Pc = intracapillary hydrostatic pressure; πc = intracapillary oncotic pressure; Pt = intratubular hydrostatic pressure; and πt = intratubular oncotic pressure. Perturbations in any of the above factors may alter renal filtration. Of particular importance is the intracapillary hydrostatic pressure, which is determined by relative blood flow into and out of the glomerular capillary. A normal kidney has the unique ability to autoregulate blood flow both in and out of the glomerular capillary through alterations in the resistance of the afferent and efferent arterioles across a wide range of systemic blood pressures. (Most capillary beds possess only the ability to regulate blood flow in to the bed.) Lower relative flows into the glomerulus with decreased renal blood flow or afferent artery constriction may lower intracapillary hydrostatic pressure and diminish filtration. Likewise, higher relative flows out of the glomerulus with efferent artery dilation may also lower intracapillary hydrostatic pressure. Despite the ability of the kidney to autoregulate and maintain the GFR, more advanced volume depletion can result in the development of azotemia. This can result from excessive volume losses (renal, GI, or cutaneous in origin), low fluid intake, or low effective circulating volume. An example of the latter is decompensated heart failure with poor cardiac output and diminished renal perfusion (termed cardiorenal syndrome). Drugs are another important cause of prerenal acute kidney injury. Some patients who are dependent on prostaglandin-mediated vasodilation to maintain renal perfusion can develop renal failure from ingesting nonsteroidal anti- inflammatory drugs (NSAIDs). Similarly, patients with renal hypoperfusion (eg, renovascular disease) who are dependent on angiotensin II–mediated vasoconstriction of the efferent renal arterioles to maintain renal perfusion pressure may develop acute kidney injury on ingesting ACE inhibitors. B. Intrarenal Causes The intrarenal causes of acute kidney injury can be further divided into specific inflammatory diseases (eg, vasculitis, glomerulonephritis [GN], drug-induced injury) and acute tubular necrosis resulting from many causes (including ischemia and endogenous or exogenous toxic injury). Notable among intrarenal causes are the toxic effects of aminoglycoside antibiotics and rhabdomyolysis, in which myoglobin, released into the bloodstream after a crush injury to muscle, precipitates in the renal tubules. Drug toxicity may be mitigated by closely monitoring renal function during antibiotic therapy, especially in elderly patients and those with some degree of underlying renal compromise. Rhabdomyolysis may be detected by obtaining a serum creatine kinase level in patients admitted to the hospital with trauma or altered mental status and may be mitigated by maintaining a vigorous alkaline diuresis to prevent myoglobin precipitation in the tubules. Sepsis is one of the most common causes of acute kidney injury, and the injury results from a combination of prerenal and intrarenal factors. The prerenal factor is renal hypoperfusion owing to the hypotensive, low systemic vascular resistance of the septic state. The intrarenal component may be a consequence of the cytokine dysregulation that characterizes sepsis syndrome (see Chapter 4), including elevated blood levels of tumor necrosis factor, interleukin-1, and interleukin-6, which contribute to intrarenal inflammation, sclerosis, and obstruction. Patients with sepsis are often also exposed to nephrotoxic drugs such as aminoglycoside antibiotics or iodinated intravenous contrast for computed tomography imaging. C. Postrenal Causes The postrenal causes of acute kidney injury are those resulting in urinary tract obstruction, which may occur at any level of the urinary tract. Obstruction can be either intrinsic (eg, nephrolithiasis causing ureteral obstruction) or extrinsic (eg, retroperitoneal mass compressing a ureter). For obstruction occurring above the level of the bladder, bilateral obstruction is typically required to cause acute kidney injury unless the patient has only one functioning kidney. Pathology & Pathogenesis Regardless of their origin, all forms of acute kidney injury, if untreated, result in acute tubular necrosis, with sloughing of the epithelial cells that make up the renal tubule.  The precise molecular mechanisms responsible for the development of acute tubular necrosis remain unknown. Theories favoring either a tubular or vascular basis have been proposed (Figure 16–5). According to the tubular theory, cellular debris occludes the tubular lumen, forming a cast that increases intratubular pressure sufficiently to offset perfusion pressure and decrease or abolish net filtration pressure. The vascular theory proposes that decreased renal perfusion pressure from the combination of afferent arteriolar vasoconstriction and efferent arteriolar vasodilation reduces glomerular perfusion pressure and, therefore, glomerular filtration. It may be that both mechanisms act to produce acute kidney injury, varying in relative importance in different individuals depending on the cause and time of presentation. Studies suggest that one consequence of hypoxia is the disordered adhesion of renal tubular epithelial cells, resulting both in their exfoliation and subsequent adhesion to other cells of the tubule, thereby contributing to tubular obstruction (see Figure 16–5). Another consequence may be a dysregulation of elements that secure tubular cells together, resulting in a leak of filtrate out of the tubular lumen and an abnormal sorting of cellular transmembrane channels required for the normal function of the nephron. Renal damage, whether caused by tubular occlusion or vascular hypoperfusion, is potentiated by the hypoxic state of the renal medulla, which increases the risk of ischemia. Research has implicated cytokines and endogenous peptides, such as endothelins, and the regulation of their production as possible explanations for why, subjected to the same toxic insult, some patients develop acute kidney injury and others do not, and why some with acute kidney injury recover and others do not. It appears that these products, together with the activation of complement and neutrophils, increases vasoconstriction in the already ischemic renal medulla and, in that way, exacerbate the degree of hypoxic injury occurring in acute kidney injury. FIGURE 16–5 Pathophysiology of ischemia-induced acute kidney injury. Mild or uncomplicated medullary hypoxia results in tubuloglomerular reflex adjustments that restore medullary oxygen sufficiency at the price of diminished renal function. However, in the event of extreme renal medullary hypoxia or when associated with complicating factors such as those indicated in the figure, full-blown acute kidney injury develops. Whether acute kidney injury is reversible or irreversible depends on a balance of reparative and complicating factors. (IGF-1, insulin-like growth factor 1; NSAID, nonsteroidal anti-inflammatory drug.) Clinical Manifestations Acute kidney injury can contribute to significant morbidity and is an independent predictor of mortality. Patients hospitalized in an intensive care setting who develop acute kidney injury requiring dialysis therapy have a 50– 60% hospital mortality rate. Thus, in recent years, significant research effort has been focused on identifying specific biomarkers of acute kidney injury earlier in the hospital course, before the serum creatinine is elevated or urine output is decreased. The initial symptoms of kidney injury are typically fatigue and malaise, probably early consequences of the loss of the ability to excrete water, salt, and wastes via the kidneys. Later, more profound symptoms and signs of the loss of renal water and salt excretory capacity develop: dyspnea, orthopnea, rales, a prominent third heart sound (S3), and peripheral edema. Altered mental status reflects the toxic effect of uremia on the brain, with elevated blood levels of nitrogenous wastes and fixed acids. The clinical manifestations of acute kidney injury depend not only on the cause but also on the stage in the natural history of the disease at which the patient comes to medical attention. Patients with renal hypoperfusion (prerenal causes of acute kidney injury) first develop prerenal azotemia (elevated BUN without tubular necrosis), a direct physiologic consequence of a decreased GFR. With appropriate treatment, renal perfusion can typically be improved, prerenal azotemia can be readily reversed, and the development of acute tubular necrosis can be prevented. Without treatment, prerenal azotemia may progress to acute tubular necrosis. Recovery from acute tubular necrosis, if it occurs, will then follow a more protracted course, potentially requiring supportive dialysis before adequate renal function is regained. A variety of clinical tests can help determine whether a patient with signs of acute kidney injury is in the early phase of prerenal azotemia or has progressed to full-blown acute tubular necrosis. However, the overlap in clinical presentation along the continuum between prerenal azotemia and acute tubular necrosis is such that the results of any one of these tests must be interpreted in the context of other findings and the clinical history. Perhaps the earliest manifestation of prerenal azotemia is an elevated ratio of BUN to serum creatinine. Normally 10–15:1, this ratio may rise to 20–30:1 in prerenal azotemia, with a normal or near-normal serum creatinine. If the patient proceeds to acute tubular necrosis, this ratio may return to normal but with a progressively elevated serum creatinine. Urinalysis is a simple and inexpensive test that serves as an important tool in the initial evaluation of the patient with acute kidney injury. The presence of hematuria and proteinuria should prompt an evaluation for GN. There are no typical abnormal findings in simple prerenal azotemia, whereas granular casts, tubular epithelial cells, and epithelial cell casts suggest acute tubular necrosis. Casts are formed when debris in the renal tubules (protein, red cells, epithelial cells) takes on the cylindrical, smooth-bordered shape of the tubule. Likewise, because hypovolemia is a stimulus to vasopressin release (see Chapter 19), the urine is maximally concentrated (up to 1200 mOsm/L) in prerenal azotemia. However, with progression to acute tubular necrosis, the ability to generate a concentrated urine is largely lost. Thus, a urine osmolality of less than 350 mOsm/L is a typical finding in acute tubular necrosis. Finally, the fractional excretion of Na+ is an important indicator in oliguric acute kidney injury to determine whether a patient has progressed from simple prerenal azotemia to frank acute tubular necrosis. In simple prerenal azotemia, more than 99% of filtered Na+ is reabsorbed, and the FENa+ will be less than 1% (except when the patient is on a diuretic). This value allows accurate identification of Na+ retention states (such as prerenal azotemia) even when there is water retention as a result of vasopressin release. With the progression of prerenal azotemia to acute kidney injury with acute tubular necrosis, this ability of the kidney to avidly retain sodium is generally lost. However, there are some conditions in which the FENa+ is less than 1% in patients with acute tubular necrosis (Table 16–6). TABLE 16–6 Causes of acute kidney injury in which FENa+ may be below 1%. CHECKPOINT 9. What are the features that distinguish prerenal, intrare-nal, and postrenal causes of renal failure? 10. What are the current theories for the development of acute tubular necrosis? 11. What clues are helpful in determining whether newly diagnosed renal failure is acute or chronic? 12. What is the natural history of acute kidney injury? CHRONIC KIDNEY DISEASE Clinical Presentation Patients with chronic kidney disease (CKD) and uremia show a constellation of symptoms, signs, and laboratory abnormalities in addition to those observed in acute kidney injury. This reflects the long-standing and progressive nature of their renal disease and its systemic effects. A clinical pearl is to always assume that renal failure is acute—this gives clinicians the opportunity to identify and treat acute kidney injury in a timely fashion while it still has the potential to respond to treatment. However, osteodystrophy, neuropathy, bilateral small kidneys on imaging, and anemia are typical initial findings that suggest a chronic course for a patient newly diagnosed with renal failure on the basis of elevated BUN and serum creatinine. Etiology In developed nations, the most common cause of CKD is diabetes mellitus (see Chapter 18), followed by hypertension; GN is a distant third cause (Table 16–7). Polycystic kidney disease, obstruction, and infection are significant but less common causes of CKD. In addition, episodes of acute kidney injury are associated with an increased risk for later development of CKD and end-stage renal disease. TABLE 16–7 Prevalence by etiology for U.S. Medicare–treated end-stage renal disease for 2014. Pathology & Pathogenesis A. Development of Chronic Kidney Disease The pathogenesis of acute renal disease is very different from that of CKD. Whereas acute injury to the kidney leads to death and sloughing of tubular epithelial cells, often followed by their regeneration with the re-establishment of normal architecture, chronic injury results in the irreversible loss of nephrons. As a result, a greater functional burden is borne by fewer nephrons, leading to an increase in glomerular filtration pressure and hyperfiltration. For reasons not well understood, this compensatory hyperfiltration, which can be thought of as a form of “hypertension” at the level of the individual nephron, predisposes to fibrosis and scarring (glomerular sclerosis). As a result, the rate of nephron destruction and loss increases, thus speeding the progression to uremia, the complex of symptoms and signs that occurs when residual renal function is inadequate (see Table 16–3). The kidneys have a tremendous functional reserve—up to 50% of nephrons can be lost without any short-term evidence of functional impairment. This is why individuals with two healthy kidneys are able to donate one for transplantation. When the GFR is further reduced, leaving only about 20% of initial renal capacity, some degree of azotemia (elevated blood levels of products normally excreted by the kidneys) is observed. Nevertheless, patients may be largely asymptomatic because a new steady state is achieved in which the blood levels of these products are not high enough to cause overt toxicity. However, even at this apparently stable level of renal function, hyperfiltration-accelerated evolution to end-stage chronic kidney disease is in progress. Furthermore, because patients with this level of GFR have little functional reserve, they can easily become uremic with any added stress (eg, infection, obstruction, dehydration, use of nephrotoxic drugs) or with any catabolic state associated with an increased turnover of nitrogen-containing products. Thus, patients with CKD are at significant risk for superimposed acute kidney injury. B. Pathogenesis of Uremia The pathogenesis of uremia derives in part from a combination of the toxic effects of (1) retained products normally excreted by the kidneys (eg, nitrogen- containing products of protein metabolism); (2) normal products such as hormones now present in increased amounts; and (3) the loss of normal products of the kidney (eg, loss of erythropoietin). Excretory failure also leads to fluid shifts, with increased intracellular Na+ and water and decreased intracellular K+. These alterations may contribute to subtle alterations in the function of a host of enzymes, transport systems, and so on. Regardless of the etiology, CKD tends to have an impact on many other organ systems and thus is truly a systemic disease. Clinical Manifestations A. Na+ Balance and Volume Status Patients with CKD typically have some degree of excess Na+ and water, reflecting loss of the renal route of salt and water excretion. A moderate degree of Na+ and water retention may occur without objective signs of extracellular fluid excess. However, continued excessive Na+ ingestion (as found in a typical Western diet) leads to further fluid retention and contributes to heart failure, hypertension, peripheral edema, and weight gain. On the other hand, excessive water ingestion contributes to hyponatremia. A common recommendation for the patient with chronic kidney disease is to limit sodium to 2 g/d or less and to restrict fluid intake so that it equals urine output plus 500 mL (to compensate for insensible losses). Further adjustments in volume status can be made either through the use of diuretics (in a patient who still makes urine) or at dialysis. Because these patients also have impaired renal salt and water conservation mechanisms, they are more sensitive than normal to sudden extrarenal Na+ and water losses (eg, via vomiting, diarrhea, or increased cutaneous losses such as with fever). Under these circumstances, they more easily develop ECF depletion, a further deterioration of renal function (which may not be reversible), and even vascular collapse and shock. Dry mucous membranes, tachycardia, hypotension, and dizziness all suggest volume depletion. B. K+ Balance Hyperkalemia is a potentially life-threatening complication of CKD, especially with advanced renal impairment (eg, GFR 3.5 g), hypoalbuminemia, hyperlipidemia, and edema. Nephrotic syndrome may be either isolated (eg, minimal-change disease) or part of some other glomerular syndrome (eg, with hematuria and casts). The underlying causes of the nephrotic syndromes are very often unclear, and these syndromes are distinguished instead by their histologic features (discussed below). Each type of nephrotic syndrome may be primary (ie, idiopathic), or it may be secondary to a specific cause (eg, medication induced) or systemic syndrome (eg, systemic lupus erythematosus, malignancy). Some cases of nephrotic syndrome are variants of acute GN, RPGN, or chronic GN in which massive proteinuria is a presenting feature. Other cases of nephrotic syndrome fall into the category of minimal-change disease, in which many of the pathologic consequences result from proteinuria. 4. Asymptomatic urinary abnormalities include hematuria and proteinuria (usually in amounts significantly below that seen in nephrotic syndrome) but with no functional abnormalities associated with reduced GFR, edema, or hypertension. Many patients with these findings will slowly develop progressive renal dysfunction over decades. The most common causes of asymptomatic urinary abnormalities are immunoglobulin A (IgA) nephropathy, an immune complex disease characterized by diffuse mesangial IgA deposition, and thin basement membrane nephropathy, a familial disorder characterized by a defect in collagen synthesis. Table 16– 9 lists other causes. TABLE 16–9 Glomerular causes of asymptomatic urinary abnormalities. Pathology & Pathogenesis The different forms of GN and nephrotic syndrome probably represent differences in the nature, extent, and specific cause of immune-mediated renal damage. Genetic predisposition and poorly understood environmental triggers are likely involved and lead to the activation of an immune response. Leukocyte activation, complement deposition, and cytokines—in particular transforming growth factor-1 (TGF-1) and platelet-derived growth factor (PDGF)— synthesized by mesangial cells, incite an inflammatory reaction and subsequent glomerular injury in many forms of glomerular disease. Histologic patterns can be nonspecific; however, classic associations between the natural history and defining immunofluorescence and electron microscopic observations have been made (see Figure 16–4; Table 16–10). However, because it is not yet known exactly how the various forms of immune-mediated renal damage occur, each category is described separately with its associated findings. TABLE 16–10 Location of electron-dense deposits in glomerular disease. A. Acute and Rapidly Progressive Glomerulonephritis There are several ways to classify acute GN. Light microscopy is essential for establishing areas of injury. Circulating autoantibodies and measures of complement deposition combined with immunofluorescence studies and electron microscopy allow GN to be categorized into subgroups correlating with other features of the disease. Three patterns emerge: 1. Antiglomerular basement membrane (anti-GBM) antibody disease (eg, Goodpasture syndrome): This disease results from the development of circulating antibodies to an antigen intrinsic to the glomerular basement membrane. The binding of these pathologic anti-GBM antibodies to the glomerular basement membrane causes a cascade of inflammation. Light microscopy shows crescentic GN, and a characteristic linear immunoglobulin deposition in the glomerular capillaries is seen on immunofluorescence. 2. Immune complex glomerulonephritis: Immune complex deposition can be seen in a variety of diseases. On renal biopsy, granular immunoglobulin deposits are suggestive of immune complexes from the underlying systemic disease. A classic example is postinfectious GN in which there is cross-reactivity between an antigen of the infecting organism and a host antigen, resulting in the deposition of immune complexes and complement in the glomerular capillaries and the mesangium. Resolution of glomerular disease typically occurs weeks after treatment of the original infection. Other examples are IgA nephropathy, lupus nephritis, and membranoproliferative GN. 3. Anti-neutrophil cytoplasmic antibody (ANCA) disease or pauci- immune GN: Characterized by a necrotizing GN but few or no immune deposits (hence, pauci-immune) seen on immunofluorescence or electron microscopy, this pattern is typical of granulomatosis with angiitis, microscopic polyangiitis, or eosinophilic granulomatosis with polyangiitis. ANCA-negative pauci-immune necrotizing GN occurs less frequently but is also a well-described clinical entity. B. Chronic Glomerulonephritis Some patients with acute GN develop CKD slowly over a period of 5–20 years. Cellular proliferation, in either the mesangium or the capillary, is a pathologic structural hallmark in some of these cases, whereas others are notable for the obliteration of glomeruli (sclerosing chronic GN, which includes both focal and diffuse subsets), and yet others display irregular subepithelial proteinaceous deposits with uniform involvement of individual glomeruli (membranous GN). C. Nephrotic Syndrome In patients with nephrotic syndrome, the podocyte is the usual target of injury. On light microscopy, the glomerulus may appear intact or only subtly altered, without a cellular infiltrate as a manifestation of inflammation. Immunofluorescence with antibodies to IgG often demonstrates the deposition of antigen–antibody complexes in the glomerular basement membrane. In the subset of patients with minimal-change disease, in which proteinuria is the sole urinary sediment abnormality and in which (often) no changes can be seen by light microscopy, electron microscopy reveals the obliteration of epithelial foot processes and slit diaphragm disruption (Table 16–11). TABLE 16–11 Clinical and histologic features of idiopathic nephrotic syndrome. Clinical Manifestations In glomerulonephritic diseases, damage to the glomerular capillary wall results in the leakage of red blood cells and proteins, which are normally too large to cross the glomerular capillary, into the renal tubular lumen, giving rise to hematuria and proteinuria. The GFR falls either because glomerular capillaries are infiltrated with inflammatory cells or because contractile cells (eg, mesangial cells) respond to vasoactive substances by restricting blood flow to many glomerular capillaries. The decreased GFR leads to fluid and salt retention that clinically manifests as edema and hypertension. A fall in serum complement is observed as a result of immune complex and complement deposition in the glomerulus, as can be seen with lupus nephritis, membranoproliferative GN, and postinfectious GN. An elevated titer of antibody to streptococcal antigens is observed in cases associated with group A β-hemolytic streptococcal infections. Another characteristic of the clinical course in poststreptococcal acute GN is a lag between clinical signs of infection and the development of clinical signs of nephritis. Patients with nephrotic syndrome have hypoalbuminemia and profoundly decreased plasma oncotic pressures because of the loss of serum proteins in the urine. This leads to intravascular volume depletion and the activation of the renin–angiotensin–aldosterone system and the sympathetic nervous system. Vasopressin secretion is also increased. Such patients also have altered renal responses to atrial natriuretic peptide. Despite signs of volume overload such as edema or anasarca, patients may develop signs of intravascular volume depletion, including syncope, shock, and acute kidney injury. Hyperlipidemia associated with nephrotic syndrome appears to be a result of decreased plasma oncotic pressure, which stimulates hepatic very-low-density lipoprotein synthesis and secretion. Hypercoagulability is a clinically significant manifestation of nephrotic syndrome and is caused by renal losses of proteins C and S and antithrombin, as well as elevated serum fibrinogen and lipid levels. The loss of other plasma proteins besides albumin in nephrotic syndrome may present as any of the following: (1) a defect in bacterial opsonization and thus increased susceptibility to infections (eg, as a result of loss of IgG); (2) a vitamin D deficiency state and secondary hyperparathyroidism (eg, resulting from loss of vitamin D–binding proteins); and (3) altered thyroid function tests without any true thyroid abnormality (resulting from reduced levels of thyroxine-binding globulin).  CHECKPOINT 15. What are the categories of glomerulonephritis, and what are their common and distinctive features? 16. What are the pathophysiologic consequences of nephrotic syndrome? RENAL STONES Clinical Presentation Patients with renal stones present with flank pain that may radiate to the groin region and hematuria that may be macroscopic or microscopic. Depending on the level of the stone and the patient’s underlying anatomy (eg, if there is only a single functioning kidney or significant pre-existing renal disease), the presentation may be complicated by obstruction (Table 16–12), with decreased or absent urine production. TABLE 16–12 Common mechanical causes of urinary tract obstruction. Etiology Although a variety of disorders may result in the development of renal stones (Table 16–13), at least 75% of renal stones contain calcium. Most cases of calcium stones are due to idiopathic hypercalciuria, with hyperuricosuria and hyperparathyroidism as other major causes. Uric acid stones are typically caused by hyperuricosuria, especially in patients with a history of gout or excessive purine intake (eg, a diet high in organ meat). Defective amino acid transport, as occurs in cystinuria, can result in stone formation. Finally, struvite stones, made of magnesium, ammonium, and phosphate salts, are a result of chronic or recurrent urinary tract infection by urease-producing organisms (typically Proteus). TABLE 16–13 Major causes of renal stones. Pathology & Pathogenesis Renal stones result from alterations in the solubility of various substances in urine, which lead to the nucleation and precipitation of salts. A number of factors can tip the balance in favor of stone formation. Dehydration favors stone formation, and a high fluid intake to maintain a daily urine volume of 2 L or more appears to be protective. The precise mechanism of this protection is unknown. Hypotheses include the dilution of unknown substances that predispose to stone formation and decreased transit time of Ca2+ through the nephron, minimizing the likelihood of precipitation. A high-protein diet predisposes to stone formation in susceptible individuals. A dietary protein load causes transient metabolic acidosis and an increased GFR. Although serum Ca2+ is not detectably elevated, there is probably a transient increase in calcium resorption from bone, an increase in glomerular calcium filtration, and an inhibition of distal tubular calcium resorption. This effect appears to be greater in known stone formers than in healthy controls. A high-Na+ diet predisposes to Ca2+ excretion and calcium oxalate stone formation, whereas a low dietary Na+ intake has the opposite effect. Furthermore, urinary Na+ excretion increases the saturation of monosodium urate, which can act as a nidus for Ca2+ crystallization. Despite the fact that most stones are calcium oxalate stones, oxalate concentration in the diet is generally too low to support a recommendation to avoid oxalate to prevent stone formation. Similarly, calcium restriction, formerly a major dietary recommendation to calcium stone formers, is beneficial only to the small subset of patients whose hypercalciuria is diet dependent. In others, decreased dietary calcium may actually increase oxalate absorption in the GI tract and thus predispose to stone formation. Therefore, calcium restriction is not recommended for stone prevention. A number of factors are protective against stone formation. In order of decreasing importance, fluids, citrate, magnesium, and dietary fiber appear to have a protective effect. Citrate decreases the likelihood of stone formation by chelating calcium in solution and forming highly soluble complexes compared with calcium oxalate and calcium phosphate. Although pharmacologic supplementation of the diet with potassium citrate has been shown to increase urinary citrate and pH and to decrease the incidence of recurrent stone formation, the benefits of a naturally high-citrate diet are less clear. However, some studies suggest that vegetarians have a lower incidence of stone formation. Presumably, they avoid the stone-forming effect of high protein and Na+ in the diet and benefit from the protective effects of fiber and other factors. Stone formation per se within the renal pelvis is painless until a fragment breaks off and travels down the ureter, precipitating ureteral colic. Hematuria and renal damage can occur in the absence of pain. Clinical Manifestations The pain associated with renal stones results from distention of the ureter, renal pelvis, or renal capsule. The severity of pain is related to the degree of distention that occurs and thus is extremely severe in acute obstruction. Anuria and azotemia are suggestive of bilateral obstruction or the unilateral obstruction of a single functioning kidney. The pain, hematuria, and even ureteral obstruction caused by a renal stone are typically self-limited. For smaller stones, passage usually requires only fluids, bed rest, and analgesia. The major complications are (1) hydronephrosis and potentially permanent renal damage as a result of complete ureter obstruction, with its resulting urine backup and pressure buildup; (2) infection or abscess formation behind a partially or completely obstructing stone; (3) renal damage subsequent to repeated kidney stones; and (4) hypertension resulting from increased renin production by the obstructed kidney. CHECKPOINT 17. How do patients with renal stones present? 18. Why do renal stones form? 19. What are the common categories of renal stones (by composition)? CASE STUDIES Yeong Kwok, MD (See Chapter 25, p. 775–76 for answers) CASE 84 A healthy 26-year-old woman sustained a significant crush injury to her right upper extremity while on the job at a local construction site. She was brought to the emergency department and subsequently underwent pinning and reconstructive surgery and received perioperative broad-spectrum antibiotics. Her blood pressure remained normal throughout her hospital course. On the second hospital day, a medical consultant noted a marked increase in her creatinine, from 0.8 to 1.9 mg/dL. Her urine output dropped to 20 mL/h. Serum creatine kinase was ordered and reported as 3400 units/L. Questions A. What are the primary causes of this patient’s acute kidney injury? How should her kidney injury be categorized (as prerenal, intrarenal, or postrenal)? B. Which two types are most likely in this patient? How might they be distinguished clinically? C. How should the patient be treated? CASE 85 A 58-year-old obese woman with hypertension, type 2 diabetes, and chronic kidney disease is admitted to hospital after a right femoral neck fracture sustained in a fall. Recently, she had been complaining of fatigue and was started on epoetin alfa subcutaneous injections. Her other medications include an angiotensin-converting enzyme inhibitor, a β-blocker, a diuretic, calcium supplementation, and insulin. On review of systems, she reports mild tingling in her lower extremities. On examination, her blood pressure is 148/60 mm Hg. She is oriented and able to answer questions appropriately. There is no evidence of jugular venous distention or pericardial friction rub. Her lungs are clear, and her right lower extremity is in Buck traction in preparation for surgery. Asterixis is absent. Questions A. Describe the pathogenesis of bone disease in chronic kidney disease. How could this explain the patient’s increased likelihood of sustaining  a fracture after a fall? B. Why was erythropoietin therapy initiated? C. What is the significance of a pericardial friction rub in the setting of chronic kidney disease? CASE 86 A 28-year-old nursery school teacher developed a marked change in the color of her urine (“cola-colored”) 1 week after she contracted impetigo from one of her students. She also complained of a new onset of global headaches and fluid retention in her legs. Examination revealed a blood pressure of 158/92 mm Hg, resolving honey-crusted pustules over her right face and neck, 1+ pitting edema of her ankles, and no cardiac murmur. Urinalysis revealed 2+ protein and numerous red cells and red cell casts. Her serum creatinine was elevated at 1.9 mg/dL. Serum complement levels (CH50, C3, and C4) were low. She was diagnosed with poststreptococcal glomerulonephritis. Questions A. What is the relationship between the patient’s skin infection and the subsequent development of glomerulonephritis? B. Describe the pathogenesis of this disorder. C. What is the natural history of this form of immune complex vasculitis? CASE 87 A 40-year-old man with Hodgkin lymphoma is admitted to the hospital because of anasarca. He has no known history of renal, liver, or cardiac disease. His serum creatinine level is slightly elevated at 1.4 mg/dL. His serum albumin level is 2.8 g/dL. Liver function test results are normal. Urinalysis demonstrates no red or white blood cell casts, but 3+ protein is noted and a 24-hour urine collection shows a protein excretion of 4 g/24 h. He is diagnosed with nephrotic syndrome, and renal biopsy suggests minimal-change disease. Steroids and diuretics are instituted, with gradual improvement of edema. The hospital course is complicated by deep venous thrombosis of the left calf and thigh that requires anticoagulation. Questions A. This patient suffers from generalized body edema (anasarca). By what mechanism does the edema form? B. What are the characteristic morphologic features seen in minimal- change disease? How does this differ from other forms of glomerulonephritis? C. How does nephrotic syndrome predispose this patient to thromboembolic disease? CASE 88 A 48-year-old white man presents to the emergency department with unremitting right flank pain. He denies dysuria and fever. He reports significant nausea without vomiting. He has never experienced anything like this before. On examination, he is afebrile, and his blood pressure is 160/80 mm Hg with a pulse rate of 110/min. He is writhing on the gurney, unable to find a comfortable position. His right flank is mildly tender to palpation, and abdominal examination is benign. Urinalysis is significant for 1+ blood, and microscopy reveals 10–20 red blood cells per high-power field. Nephrolithiasis is suspected, and the patient is intravenously hydrated and given pain medication with temporary relief. Questions A. What is the most likely cause of this patient’s renal stone disease? B. Describe your discharge instructions to the patient, reflecting on the pathogenesis of stone disease. C. Why is this disorder painful?