16: Renal Disease

The Centers for Disease Control and Prevention estimates that in the United States, more than 10% of people 20 years and older (or 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 them 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 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 (eg, nephrolithiasis) in which there is involvement of the ureter or the renal capsule. In early stages of kidney disease, patients may only have abnormalities of urine volume (eg, oliguria) 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, and 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 balance 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 different manifestations of kidney disease.

Anatomy, Histology, & Cell Biology

The kidneys maintain homeostasis while functioning under a tremendous range of environmental water and salt availability. For example, the kidneys have the capacity to excrete free water in freshwater fish, 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 cortex to medulla and because the medulla has a relatively low 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.

The anatomic unit of kidney function is the nephron, a structure consisting 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.

A glomerulus consists of an afferent and an efferent arteriole and an intervening tuft of capillaries lined by endothelial cells and covered by 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 endothelial cells and the epithelial cells (Figure 16–2).

Closer examination of glomerular histology and cell biology reveals unique features not found in most peripheral capillaries (Figure 16–2). First, the glomerular capillary endothelium is fenestrated. 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 contains 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 both 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 accumulate under the endothelial cells. Likewise, because immune cells are not able 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 the urine is concentrated and additional electrolyte and water changes are made in response to hormonal control.

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, sometimes because of charge effects or because they are tightly bound to other proteins to give 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 of 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 that are 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 loops 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 regulation of urine volume and the site at which water, Na⁺, acid-base, and K⁺ balance are achieved. The crucial role of the collecting duct in regulation of 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 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 by virtue of its effect on Na⁺ and water balance, major determinants of blood pressure. First, the Na⁺ concentration in the proximal tubular fluid is sensed at the macula densa (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 to 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 triggering vasoconstriction directly 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 of these effects expand the extracellular fluid (ECF) and hence 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 for activation of 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, and cirrhosis) develop due to a pathophysiologic factor favoring fluid movement out of the intravascular space and into the interstitium or third spaces. In the case of heart failure, this is an elevated hydrostatic component related to cardiac congestion. In nephrotic syndrome, it is a fall in oncotic pressure due to 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 of 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 for activation of 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 of 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 due to 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, thereby increasing the number of water channels. This results in reabsorption of free water. Further discussions of water balance and the role of vasopressin are presented in Chapter 19.

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:

H⁺ + HCO₃⁻ ↔ H₂CO₃ ↔ H₂O + CO₂

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 acid-base imbalance is rapid (seconds to minutes), whereas the kidney’s response is delayed (hours to days). However, the lungs can only excrete volatile acids, and removal of nonvolatile (or “fixed”) acids relies on the kidneys.

During the ingestion of a normal daily diet, humans generate an obligate acid load from the metabolism of protein. To maintain homeostasis, this acid load is excreted in 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 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).

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 where the kidneys’ ability to generate ammonium is diminished. Conversely, metabolic acidosis can develop from 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 failure to reabsorb bicarbonate in the kidney (ie, proximal renal tubular acidosis) or from gastrointestinal (GI) loss of bicarbonate-rich fluids (eg, severe diarrhea, pancreatic fistula). Fourth, the administration of large amounts of bicarbonate-depleted solution 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, while 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 as a result of intracellular K⁺ shifting (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 due to unregulated Na⁺ reabsorption with 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. Further discussion of the role of the renin-angiotensin-aldosterone system in the regulation of potassium and intravascular volume is presented in Chapter 21.

Hyperkalemia can occur from extracellular shifting of potassium (eg, acidosis), cellular release of potassium (eg, hemolysis), increased ingestion of potassium, or decreased renal excretion of potassium (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 (or 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 of parathyroid hormone (PTH), resulting in Ca²⁺ retention and phosphate wasting in the urine. Further discussion of the role of the kidney in Ca²⁺ and phosphate homeostasis is presented in Chapter 17.

Renal Regulation of Erythropoiesis

The kidney is the main site of production of the hormone erythropoietin, which stimulates 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. The primary management of the anemia of chronic kidney disease is hormone replacement therapy with a recombinant analog of erythropoietin. Additional discussion of the role of erythropoietin in the regulation of red blood cell mass is presented in Chapter 6.

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 regulation of 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 cortex to 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, loss of nephrons 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. Alteration of 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.

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 that have led to kidney disease (eg, immunologic, metabolic, infiltrative, infectious, hemodynamic, or 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 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.

Nephritic disorders show immune complex deposits either in a subendothelial location or in the glomerular basement membrane or mesangium (Figure 16–4). The cellular immune system has ready access to all of 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 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 the 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).

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 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 unique set of symptoms, physical examination findings, and laboratory abnormalities (see Table 16–7), presumably caused by a buildup of one or more uncharacterized toxins. In the absence of adequate renal clearance, ingestion of 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.

Acute Kidney Injury

Clinical Presentation

Acute kidney injury is produced by a heterogeneous group of disorders that have in common the rapid deterioration of renal function, resulting in accumulation in the blood of nitrogenous wastes 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 16–3). 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.

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.

Etiology

The major causes of acute kidney injury are presented in Table 16–4.

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 relationship:

filtration = K_f [P_c – P_t] – σ[π_c – π_t]

K_f and σ are constants determined by the permeability of a given glomerulus and the effective contribution of osmotic pressure, respectively; P_c = intracapillary hydrostatic pressure, π_c = intracapillary oncotic pressure, P_t = intratubular hydrostatic pressure, and π_t = 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 resistance of the afferent and efferent arterioles across a wide range of systemic blood pressure. Most capillary beds only possess the former. 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 the “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 simply from ingestion of 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.

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 crush injury to muscle, precipitates in the renal tubules. The former may be mitigated by close monitoring of 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. As a complication of sepsis, acute kidney injury involves a combination of prerenal and intrarenal factors. The prerenal factor is renal hypoperfusion as a consequence of the hypotensive, low systemic vascular resistance septic state. The intrarenal component may be a consequence of the cytokine dysregulation that characterizes the sepsis syndrome (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.

Postrenal Causes

The postrenal causes of acute kidney injury are those that result 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 required to cause acute kidney injury unless the patient only has a solitary functioning kidney.

Pathology & Pathogenesis

Regardless of their origin, all forms of acute kidney injury, if untreated, result in acute tubular necrosis, with sloughing of epithelial cells that make up the renal tubule. Depending on the timing of intervention between onset of initial injury and eventual acute tubular necrosis, acute kidney injury may be irreversible or reversible, with either prevention of or recovery from acute tubular necrosis.

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, occlusion of the tubular lumen with cellular debris forms a cast that increases intratubular pressure sufficiently to offset perfusion pressure and decrease or abolish net filtration pressure. Vascular theories propose 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 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 (Figure 16–5). Another consequence may be dysregulation of elements that secure tubular cells together resulting in leak of filtrate out of the tubular lumen and 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 (Table 16–5). 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 activation of complement and neutrophils increase vasoconstriction in the already ischemic renal medulla and in that way exacerbate the degree of hypoxic injury that occurs in acute kidney injury.

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. Consequently, in recent years, significant research effort has been focused on identifying specific biomarkers of acute kidney injury earlier.

The initial symptoms are typically fatigue and malaise, probably early consequences of loss of the ability to excrete water, salt, and wastes via the kidneys. Later, more profound symptoms and signs of 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 pre-renal 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, or epithelial cells) takes on the cylindric, 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 FE_Na+ 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 progression of prerenal azotemia to acute kidney injury with acute tubular necrosis, this ability of the kidney to retain sodium avidly is generally lost. However, there are some conditions in which the FE_Na+ is less than 1% in patients with acute tubular necrosis (Table 16–6).

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 (Table 16–7). 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 (Chapter 18), followed by hypertension; GN is a distant third (Table 16–8). Polycystic kidney disease, obstruction, and infection are significant but less common causes of CKD.

Pathology & Pathogenesis

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 reestablishment of normal architecture, chronic injury results in 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.

The kidneys have 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 GFR is further reduced, leaving only about 20% of initial renal capacity, some degree of azotemia (elevation of 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 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, or nephrotoxic drugs) or with any catabolic state associated with increased turnover of nitrogen-containing products. Thus, patients with CKD are at significant risk for superimposed acute kidney injury.

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) 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 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

Na+ Balance and Volume Status

Patients with CKD typically have some degree of Na⁺ and water excess, 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 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 avoid excess salt intake 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, vomiting, diarrhea, and increased cutaneous losses such as with fever). Under these circumstances, they more easily develop ECF depletion, 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.

K+ Balance

Hyperkalemia is a serious problem in CKD, especially for patients whose GFR has fallen below 5 mL/min. Above that level, as GFR falls, aldosterone-mediated K⁺ transport in the distal tubule increases in a compensatory fashion. Thus, a patient whose GFR is between 50 mL/min and 5 mL/min is dependent on tubular transport to maintain K⁺ balance. Treatment with K⁺-sparing diuretics, ACE inhibitors, or β-blockers—drugs that may impair aldosterone-mediated K⁺ transport—can, therefore, precipitate dangerous hyperkalemia in a patient with CKD.

Patients with diabetes mellitus may develop a syndrome of hyporeninemic hypoaldosteronism (type 4 RTA). Decreased renin production by the kidney leads to decreased levels of angiotensin II and thus impairs aldosterone secretion. As a result, affected patients are unable to compensate for falling GFR by enhancing their aldosterone-mediated K⁺ transport and, therefore, have relative difficulty excreting K⁺. This difficulty is usually manifested as hyperkalemia even before GFR has fallen below 5 mL/min.

Patients with CKD are also at greater risk of hyperkalemia in the face of sudden loads of K⁺ from either endogenous sources (eg, hemolysis, infection, trauma) or exogenous sources (eg, K⁺-rich foods, blood transfusions, or K⁺-containing medications).

Metabolic Acidosis

The diminished capacity to excrete acid and generate base in CKD results in metabolic acidosis. In most cases when the GFR is above 20 mL/min, only moderate acidosis develops before reestablishment of a new steady state of buffer production and consumption. The fall in blood pH in these individuals can usually be corrected with 20–30 mmol (2–3 g) of sodium bicarbonate by mouth daily. However, these patients are highly susceptible to acidosis in the event of either a sudden acid load (eg, ketoacidosis, lactic acidosis, or toxic ingestions) or bicarbonate loss (eg, diarrhea).

Mineral and Bone

Several disorders of phosphate, Ca²⁺, and bone metabolism are observed in CKD as a result of a complex series of events (Figure 16–6). The key factors in the pathogenesis of these disorders include (1) diminished absorption of Ca²⁺ from the gut, (2) overproduction of PTH, (3) disordered vitamin D metabolism, (4) retention of phosphorus, and (5) chronic metabolic acidosis. All of these factors contribute to enhanced bone resorption. Hyperphosphatemia contributes to the development of hypocalcemia and thus serves as an additional trigger for secondary hyperparathyroidism, elevating blood PTH levels. The elevated blood PTH further depletes bone Ca²⁺ and contributes to osteomalacia of CKD (see later discussion). While hypophosphatemia can occur through overuse of phosphate binders, hyperphosphatemia is significantly more common in CKD. Hypermagnesemia can become a problem in the setting of magnesium-containing antacids and other medical uses of magnesium.

Cardiovascular and Pulmonary Abnormalities

Heart failure and pulmonary edema can develop in the context of volume and salt overload. Hypertension is a common finding in CKD and is often due to fluid and Na⁺ overload. However, hyperreninemia, where decreased renal perfusion triggers the failing kidney to overproduce renin, can also elevate systemic blood pressure.

Pericarditis can develop from irritation and inflammation of the pericardium by uremic toxins. In developed countries, this complication has become less common because of the availability of dialysis.

An increased incidence of cardiovascular disease is observed in patients with CKD and remains the leading cause of mortality in this population. Cardiovascular risk factors in CKD patients include hypertension, hyperlipidemia, glucose intolerance, chronic elevated cardiac output, valvular and myocardial calcification, as well as other, less well-characterized factors of the uremic milieu. As a result, an increased burden of myocardial infarction, stroke, and peripheral vascular disease is observed in CKD.

Hematologic Abnormalities

Patients with CKD have marked abnormalities in red blood cell count, white blood cell function, and clotting parameters. Normochromic, normocytic anemia, with symptoms of listlessness and easy fatigability and hematocrit levels typically in the range of 20–25%, is a consistent feature. The anemia is due chiefly to decreased production of erythropoietin and thus decreased erythropoiesis. Thus, patients with CKD, regardless of dialysis status, show a dramatic improvement in hematocrit when treated with erythropoietin analogs. Additional causes of anemia may include bone marrow suppressive effects of uremic toxins, bone marrow fibrosis due to elevated blood PTH, toxic effects of aluminum (historically, these effects occurred from aluminum-based phosphate-binding antacids and from contaminated dialysis solutions), and hemolysis and blood loss related to dialysis.

Patients with CKD display abnormal hemostasis manifested as increased bruising, decreased clotting, and an increased incidence of spontaneous GI and cerebrovascular hemorrhage (including both hemorrhagic strokes and subdural hematomas). Laboratory abnormalities include prolonged bleeding time, decreased platelet factor III, abnormal platelet aggregation and adhesiveness, and impaired prothrombin consumption, none of which are completely reversible even in well-dialyzed patients.

Uremia is associated with increased susceptibility to infections, likely due to leukocyte suppression by uremic toxins. Chemotaxis, the acute inflammatory response, and delayed hypersensitivity are all suppressed. Acidosis, hyperglycemia, malnutrition, and hyperosmolality also are believed to contribute to immunosuppression in chronic kidney disease. The invasiveness of dialysis and the use of immunosuppressive drugs in renal transplant patients further contribute to an increased incidence of infections.

Neuromuscular Abnormalities

Neurologic symptoms and signs of uremia range from mild sleep disorders and impairment of mental concentration, loss of memory, errors in judgment, and neuromuscular irritability (manifested as hiccups, cramps, fasciculations, and twitching) to asterixis, myoclonus, stupor, seizures, and coma in end-stage uremia. Asterixis is involuntary hand flapping when the arms are extended and wrists held back to “stop traffic.” It is due to altered nerve conduction in metabolic encephalopathy from a wide variety of causes, including renal failure.

Peripheral neuropathy, typified by the restless legs syndrome (poorly localized sense of discomfort and involuntary movements of the lower extremities), is a common finding in CKD.

GI Abnormalities

Nonspecific GI findings in uremic patients include anorexia, hiccups, nausea, vomiting, and diverticulosis. Although their precise pathogenesis is unclear, many of these findings improve with dialysis.

Endocrine and Metabolic Abnormalities

Women with uremia have low estrogen levels, which perhaps explains the high incidence of amenorrhea and the observation that they rarely are able to carry a pregnancy to term. Regular menses—but not a higher rate of successful pregnancies—typically return with frequent dialysis.

Similarly, low testosterone levels, impotence, oligospermia, and germinal cell dysplasia are common findings in men with chronic kidney disease.

In CKD, the kidney’s role in insulin degradation decreases, increasing the half-life of insulin. This often has a stabilizing effect on diabetic patients whose blood glucose was previously difficult to control and can lead to decreased need for insulin and other hypoglycemic medications.

Dermatologic Abnormalities

Skin changes are common and arise from many of the effects of CKD already discussed. Patients with CKD may display pallor because of anemia, skin color changes related to accumulated pigmented metabolites or a gray discoloration resulting from transfusion-mediated hemochromatosis, ecchymoses and hematomas as a result of clotting abnormalities, and pruritus and excoriations as a result of Ca²⁺ deposits from secondary hyperparathyroidism. Finally, when urea concentrations are extremely high, evaporation of sweat leaves a residue of urea termed “uremic frost.”

Glomerulonephritis & Nephrotic Syndrome

Clinical Presentation & Etiology

A number of disorders lead to glomerular injury that presents with some combination of hematuria, proteinuria, reduced GFR, and hypertension. This syndrome, regardless of its cause, is termed glomerulonephritis (GN). Acute GN is one of many intrarenal causes of acute kidney injury.

Glomerular disorders can originate in the kidney; they can also be manifestations of systemic diseases in which the kidney is prominently involved. GNs are currently characterized by both clinical and microscopic features. Renal biopsy is often the only way to correctly diagnose the cause of GN and hence determine the appropriate treatment.

Disorders resulting in glomerular disease typically fall into one of several categories of clinical presentation. However, there can be overlap between these categories:

1. Acute GN, in which there is an abrupt onset of hematuria and proteinuria with reduced GFR and renal salt and water retention, is sometimes followed by recovery of renal function. Acute GN often occurs in the setting of infectious diseases, classically pharyngeal or cutaneous infections with certain “nephritogenic” strains of group A β-hemolytic streptococci. However, other pathogens have also been implicated (Table 16–9). Rapidly progressive glomerulonephritis (RPGN) is a subset of acute GN in which there is a progressive and dramatic decline (weeks to months) in renal function, often leading to complete renal failure and oliguria. Early disease can be subtle but is marked by proteinuria and hematuria, followed by decreased GFR. This is often called “crescentic GN,” as the characteristic finding on biopsy is cellular crescents in the Bowman space. Cellular crescents, visible on light microscopy, form in response to severe damage to the glomerular capillaries. This appears to be a nonspecific final pathway in a variety of glomerular diseases. Recovery without specific treatment is rare. RPGN appears to be a heterogeneous group of disorders, all of which display pathologic features common to various categories of necrotizing vasculitis (Table 16–10; also see later discussion).

2. Chronic glomerulonephritis is characterized by persistent urinary abnormalities and slowly progressive (years) decline in renal function. Chronic GN does not typically resolve. Progressive renal deterioration in patients with chronic GN proceeds inexorably, resulting in CKD up to 20 years after initial discovery of an abnormal urinary sediment.

3. Nephrotic syndrome manifests as marked proteinuria, particularly albuminuria (defined as 24-hour urine protein excretion >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 (see Table 16–13). Each type of nephrotic syndrome may be primary (ie, idiopathic) or secondary to a specific cause (eg, medication-induced) or systemic syndrome (eg, systemic lupus erythematosus [SLE]). 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 are due to proteinuria.

4. Asymptomatic urinary abnormalities include hematuria and proteinuria (usually in amounts significantly below what seen in nephrotic syndrome) but 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. Other causes are listed in Table 16–11.

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 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 (Figure 16–4; Table 16–12). 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.

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. Binding of these pathologic anti-GBM antibodies to the glomerular basement membrane causes a cascade of inflammation. Light microscopy shows crescentic GN, and 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 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 Churg-Strauss syndrome. ANCA-negative pauci-immune necrotizing GN occurs less frequently but is also a well-described clinical entity.

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 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).

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 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 obliteration of epithelial foot processes and slit diaphragm disruption (Table 16–13).

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. 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 post-infectious 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 the 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 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 the nephrotic syndrome and is caused by renal losses of proteins C and S and antithrombin, as well as elevated serum fibrinogen and lipid levels.

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) 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).

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 preexisting renal disease), the presentation may be complicated by obstruction (Table 16–14) with decreased or absent urine production.

Etiology

Although a variety of disorders may result in the development of renal stones (Table 16–15), 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 up of magnesium, ammonium, and phosphate salts, are a result of chronic or recurrent urinary tract infection by urease-producing organisms (typically Proteus).

Pathology & Pathogenesis

Renal stones result from alterations in the solubility of various substances in urine, such that there is 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 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 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 subset of patients whose hypercalciuria is diet dependent. In others, decreased dietary calcium may actually increase oxalate absorption and predispose to stone formation.

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 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, combined with 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 is due to 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 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 obstruction of a ureter, with resulting backup of urine 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.

Yeong Kwok, MD

Case 78

Acute Kidney Injury: Acute Tubular Necrosis

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)?

The clinical summary and the elevated creatine kinase suggest rhabdomyolysis-induced acute tubular necrosis (ATN). Crush injuries release myoglobin into the bloodstream that precipitates in the renal tubules, causing intrarenal toxicity and subsequent failure. With this underlying defect, antibiotic therapy may exacerbate the situation or may induce a separate inflammatory interstitial nephritis. The absence of documented hypotension makes ischemia-mediated ATN less likely. Thus, she has an intrarenal cause of acute kidney injury.

B. Which two types are most likely in this patient? How might they be distinguished clinically?

Besides the likely intrarenal mechanism of disease, she may also have a prerenal cause as a result of dehydration from being trapped or from poor oral intake. To distinguish between these two possibilities, one can calculate the fractional excretion of sodium. The fractional excretion of sodium, FE_Na⁺, derived from measurement of the urine and plasma sodium and creatinine, reflects the ability of the kidney to generate a concentrated urine. This function is essentially lost in the setting of acute tubular necrosis, and the patient’s urine osmolarity is probably less than 350 mOsm/L. More commonly in the setting of myoglobinuria-induced ATN, her FE_Na⁺ would be greater than 2%; however the FE_Na⁺ has been noted to be less than 1% in some cases of rhabdomyolysis.

C. How should she be treated?

Mainstays of treatment involve maintenance of a vigorous alkaline diuresis to prevent myoglobin precipitation in the tubules and adjusting renally cleared antibiotics to prevent further nephrotoxicity.

Case 79

Chronic Kidney Disease

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 has 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 her increased likelihood of sustaining a fracture after a fall?

This patient probably suffers from osteoporosis, accelerated by her underlying renal failure. The pathogenesis of bone disease is multifactorial. Calcium is poorly absorbed from the gut because of decreased renally generated vitamin 1,25-(OH)₂D₃ levels. Hypocalcemia results and is further exacerbated by high serum phosphate levels from impaired phosphate excretion by the kidney. Low serum calcium and hyperphosphatemia trigger PTH secretion, which depletes bone calcium and contributes to osteomalacia and osteoporosis. Also implicated are the diminished responsiveness of bone to vitamin D₃ and chronic metabolic acidosis.

B. Why was erythropoietin therapy initiated?

Easy fatigability is often attributable to a worsening normochromic, normocytic anemia seen in chronic kidney disease. This occurs primarily because of impaired synthesis of erythropoietin by the kidney and thus decreased erythropoiesis. To improve symptoms, exogenous erythropoietin is started to raise the hematocrit of 25–28% typically seen in chronic kidney disease patients.

C. What is the significance of a pericardial friction rub in the setting of chronic kidney disease?

A pericardial friction rub suggests uremia-related pericarditis. This is thought to occur from uremic toxins that irritate and inflame the pericardium. The absence of this finding, lack of asterixis, and clear mentation suggest that despite underlying chronic kidney disease, the patient does not exhibit evidence of uremia at this time.

Case 80

Poststreptococcal Glomerulonephritis

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 new onset of global headaches and retention of fluid in her legs. Examination revealed a blood pressure of 158/92, 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 her skin infection and the subsequent development of glomerulonephritis?

Poststreptococcal glomerulonephritis results from a skin infection with a nephritogenic strain of group A (β-hemolytic) streptococci such as type 12. The abrupt onset of hematuria (“cola”-colored urine), edema, and variable degrees of hypertension most commonly occur 7–14 days after streptococcal pharyngitis or impetigo and can occur sporadically or in clusters. Significant glomerular damage can lead to rapid progression to oliguria and acute kidney injury.

B. Describe the pathogenesis of this disorder.

Bacterial infections can cause glomerular damage through the deposition of antibody-antigen complexes. Vasculitis does not occur, however, in the setting of all infections. Rather, subendothelial deposition of immune complexes is required to damage highly vascularized nephrons by fixing complement (this explains the serum levels measured) and by activating myelomonocytic cells. Deposition of these complexes can only occur in the presence of excess antigens to make the complexes soluble, permitting them access to the subendothelial space and enabling them to cause injury.

C. What is the natural history of this form of immune complex vasculitis?

This disorder is usually self-limited; 95% of individuals recover normal renal function within 2 months after onset. As antibody titers rise, immune complex formation decreases, and soluble complexes are eventually cleared provided that antigen administration is not sustained. Treatment of underlying infectious substrates may hasten resolution of the glomerulonephritis.

Case 81

Nephrotic Syndrome: Minimal Change Disease

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. 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 hours. 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?

Patients with the 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 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.

B. What are the characteristic morphologic features seen in minimal change disease? How does this differ from other forms of glomerulonephritis?

Minimal change disease, as the name suggests, is associated with few or no changes apparent on light microscopy, as opposed to other subtypes of glomerulonephritis associated with varying degrees of segmental sclerosis or basement membrane thickening. Immunofluorescence staining is generally unremarkable, whereas membranous glomerulonephritis is characterized by IgG and C3 deposited uniformly along capillary loops. However, the pathologic changes are most evident on electron microscopy, which reveals obliteration of epithelial foot processes and slit diaphragm disruption. Minimal change disease is typically seen in children, but when found in adults it can be idiopathic or can follow upper respiratory tract infection, be associated with tumors such as Hodgkin disease, or be related to hypersensitivity reactions.

C. How does nephrotic syndrome predispose this patient to thromboembolic disease?

Hypercoagulability is a clinically significant manifestation of the nephrotic syndrome and is caused by renal losses of proteins C and S and antithrombin, as well as elevated serum fibrinogen and lipid levels. Immobilization from a prolonged hospital stay puts this patient at additional risk for deep venous thrombosis.

Case 82

Renal Stone Disease

A 48-year-old white man presents to the emergency department with unremitting right flank pain. He denies dysuria or fever. He does report 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?

This patient is presenting with his first episode of renal stone disease. Most commonly, stones are calcium containing and reflect idiopathic hypocalciuria. Hyperparathyroidism and hyperuricosuria are other important causes of calcium stones. If the patient is able to collect a passed stone, analysis of its composition would be helpful in diagnosis of the subtype and in tailoring treatment.

B. Describe your discharge instructions to the patient, reflecting on the pathogenesis of stone disease.

After effective pain control is achieved, the patient may return home, and adequate hydration with 2 L/day should be reinforced. Hydration may dilute unknown substances that predispose to stone formation and minimize the likelihood of Ca²⁺ precipitation in the nephron. High-protein diets in known stone formers predispose to recurrent calcium nephrolithiasis. This results from a transient increase in calcium resorption from bone and increased filtration through the nephron in response to a protein load that stimulates the GFR. A high-sodium diet should be avoided because Na⁺ predisposes to Ca²⁺ excretion and increases the saturation of monosodium urate, which acts as a nidus for calcium oxalate stone formation. Finally, citrate supplementation may be considered because of its ability to chelate calcium in solution, forming soluble complexes as opposed to calcium oxalate or phosphate.

C. Why is this disorder painful?

Fragments of renal pelvis stones that break off and travel down the ureter produce the pain syndrome known as colic. Distention at the level of the renal pelvis, ureter, or renal capsule can produce pain that can become quite significant in the setting of acute obstruction.