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Clinical Presentation
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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.
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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.
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The major causes of acute kidney injury are presented in Table 16–4.
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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:
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filtration = Kf [Pc – Pt] – σ[πc – πt]
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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 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.
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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”).
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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.
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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).
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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.
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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.
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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.
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Pathology & Pathogenesis
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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.
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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.
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Clinical Manifestations
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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.
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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.
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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.
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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.
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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.
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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.
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Finally, the fractional excretion of Na+
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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 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 FENa+ is less than 1% in patients with acute tubular necrosis (Table 16–6).
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Checkpoint
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?
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Chronic Kidney Disease
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Clinical Presentation
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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.
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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.
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Pathology & Pathogenesis
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Development of Chronic Kidney Disease
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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.
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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.
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Pathogenesis of Uremia
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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).
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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.
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Clinical Manifestations
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Na+ Balance and Volume Status
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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.
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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.
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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.
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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.
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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).
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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).
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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.
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Cardiovascular and Pulmonary Abnormalities
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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.
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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.
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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.
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Hematologic Abnormalities
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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.
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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.
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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.
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Neuromuscular Abnormalities
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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.
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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.
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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.
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Endocrine and Metabolic Abnormalities
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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.
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Similarly, low testosterone levels, impotence, oligospermia, and germinal cell dysplasia are common findings in men with chronic kidney disease.
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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.
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Dermatologic Abnormalities
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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.”
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Checkpoint
13. What is uremia?
14. What are the most prominent symptoms and signs of uremia?
15. What is the mechanism by which altered sodium, potassium, and volume status develop in chronic kidney disease?
16. What are the most common causes of chronic kidney disease?
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Glomerulonephritis & Nephrotic Syndrome
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Clinical Presentation & Etiology
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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.
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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.
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Disorders resulting in glomerular disease typically fall into one of several categories of clinical presentation. However, there can be overlap between these categories:
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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).
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.
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.
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.
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Pathology & Pathogenesis
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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.
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Acute and Rapidly Progressive Glomerulonephritis
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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.
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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.
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.
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.
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Chronic Glomerulonephritis
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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).
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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).
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Clinical Manifestations
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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.
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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.
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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.
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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.
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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.
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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).
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Checkpoint
17. What are the categories of glomerulonephritis, and what are their common and distinctive features?
18. What are the pathophysiologic consequences of nephrotic syndrome?
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Clinical Presentation
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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.
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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).
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Pathology & Pathogenesis
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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Clinical Manifestations
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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.
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Checkpoint
19. How do patients with renal stones present?
20. Why do renal stones form?
21. What are the common categories of renal stones (by composition)?