Flashcards in Fifteen Deck (26):
1
List 8 steps in the right order that should be taken in evaluating kidney disease. Why is this order taken ?
• Obtain a detailed medical history, current and past, that may provide a clue to the diagnosis (eg, family history of polycystic kidney disease).
• Perform a thorough clinical examination, with special focus on the flank and abdominal areas (eg, audible abdominal bruit suggests renal artery stenosis).
• Assess the glomerular filtration rate to determine the extent and severity of kidney disease.
• Quantitate 24-hour urine protein xcretion (>3.5gm/day is tantamount to glomerular disease). Screen the urine for the presence of blood (hematuria is a very common feature of kidney and urinary tract disease).
• Examine the urine sediment for specific features consistent with kidney disease (eg, red blood cell casts are pathognomonic for acute glomerulonephritis).
• Obtain imaging studies to detect anatomical features consistent with renal disease (eg, ultrasonograhy can easily detect the cystic changes of polycystic kidney disease)
• Obtain serologic studies to detect or refine the underlying disease process (eg, serum complement titers are reduced in lupus nephritis)
• Obtain a kidney biopsy to definitively establish the diagnosis of a suspected glomerular, tubular, or interstitial kidney disease.
2
Why is a careful history important in kidney disease? What aspects of it are especially helpful?
A careful history can provide important clues to ascertain the etiology of kidney disease. Eliciting the duration of the illness is helpful in establishing the chronicity of the disease. The presence of comorbid conditions such as diabetes, cancer, lupus, or viral hepatitis may provide a vital clue to the underlying kidney disease. For example, membranous glomerulonephritis has been described in various malignant disorders, particularly solid tumors of the gastrointestinal tract. Finally, obtaining a detailed family history is an essential step in the evaluation of hereditary kidney disorders.
3
What findings of the physical exam are helpful in diagnosing kidney diseases? What are some non specific findings found in many different kidney diseases?
The physical examination may also provide important information in the evaluation of the patient with kidney disease. Hypertension, edema, and generalized fatigue are nonspecific findings observed in a variety of kidney diseases. All patients should be carefully examined for the presence of skin rashes, arthritic changes, lymphadenopathy, and peripheral neuropathy. The presence of a malar rash in a patient with proteinuria and hematuria suggests renal involvement secondary to lupus. In contrast, peripheral neuropathy in an elderly patient with proteinuria and an elevated serum globulin should prompt an investigation for amyloidosis. The presence of livedo reticularis in a patient recently undergoing cardiac catheterization should raise the possibility of cholesterol embolization. Abdominal pain and a purpuric rash in an adolescent with renal failure would support the diagnosis of Henoch-Schönlein purpura.
4
Why is the GFR important in evaluating renal disease? How is it determined? What might make these methods inaccurate?
A hallmark of renal disease is a reduction in glomerular filtration rate (GFR). At steady state the serum creatinine measurement inversely correlates with GFR. Thus, a doubling of the serum creatinine indicates a 50% reduction in the GFR. Since the rate of creatinine production largely depends on muscle mass, the serum creatinine will vary depending on body size and composition. Therefore, a random serum creatinine det-ermination only provides an estimate of the absolute GFR.
The clearance of endogenous creatinine is the most widely used method of determining GFR (Eq. 5.5). The endogenous creatinine clearance tends to overestimate GFR since approximately 10% of urine creatinine is derived from tubular secretion. The endogenous creatinine clearance may grossly overestimate the GFR when renal function is reduced by more than 50%. Under these conditions the percentage of creatinine undergoing tubular secretion may exceed 60%.
Alternate methods of measuring GFR using plasma disappearance curves of markers of filtration (iohexol or iothalamate) are simple and accurate; however, these methods are not yet routinely available.
5
How much protein is in excreted in normal subjects each day? Where does it come from? What is THP? Where does it come from? What are its functions? What is low grade proteinuria and how is it detected? What is transient proteinuria? What is it like? In which patients is it common? What is a possible mechanism for it? What are the clinical consequences? What is postural, or orthostatic, proteinuria? What is it like? In which patients is it common? What are some qualifications for diagnosing benign orthostatic proteinuria?
Normal subjects excrete between 40 and 150 mg of protein per day. Some urine protein is derived from the daily filtered load (1000-1500 mg/d), although most is reabsorbed in the proximal tubule via endocytosis (see Fig. 6.9).
Tamm-Horsfall protein (THP, also known as uromodulin) is a 68 kDa GPI-anchored glycoprotein produced by the medullary thick ascending limb. THP accounts for 30-50 mg of urine protein per day. THP comprises the matrix for urinary casts (see Evaluation of the Urine Sediment). THP also inhibits crystallization in the urine and kidney stone formation. Excretion of THP in urine may provide defense against urinary tract infections caused by uropathogenic bacteria.
Low-grade proteinuria (150-500 mg/d), as seen in early kidney disease, may go undetected via routine dipstick. Therefore, a 24-hour urine collection for protein is required to establish the presence of low-grade proteinuria. Isolated or transient proteinuria must be distinguished from abnormalities secondary to kidney disease (Fig. 15.2).
Transient proteinuria may occur in up to 10% of otherwise healthy individuals. The magnitude of proteinuria is typically mild but can rarely be severe. Transient proteinuria is particularly common in patients with congestive heart failure, infection, and other stress-related illnesses. The mechanism responsible for transient proteinuria in these settings is poorly understood but may involve changes in the circulating levels of stress hormones (angiotensin II, epinephrine). These hormones alter glomerular permeability for protein and modulate intrarenal blood flow and glomerular pressure. Importantly, transient episodes of proteinuria are not associated with the presence of significant kidney disease and are, thus, considered benign.
Postural, or orthostatic, proteinuria is noted only during upright posture and not during recumbency. The magnitude of proteinuria is generally mild (
6
How is nephrotic syndrome characterized? What is it synonymous with? What six clinical entities account for most cases of it?
The nephrotic syndrome is characterized by a 24-hour urine protein excretion that exceeds 3.5 g. This syndrome is synonymous with a glomerular disease. Six clinical entities account for most cases of the nephrotic syndrome:
(1) diabetic nephropathy,
(2) membranous glomerulonephritis (MGN),
(3) focal segmental glomerulosclerosis (FSGS),
(4) amyloidosis,
(5) minimal change disease (MCD), and
(6) membranoproliferative glomerulonephritis (MPGN).
MPGN frequently exhibits significant hematuria and is, therefore, also included in the nephritic category of glomerular disease (see Fig. 15.3).
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Describe the two methods for obtaining or estimating urine protein. What are the pros and cons for each ?
The 24-hour urine protein is the reference standard for measuring protein excretion, if reliably performed. Nonetheless, it is inconvenient, requires detailed instructions for urine collection, and is subject to various laboratory errors (incorrect reporting of urine volume and protein concentration). Recently, the random protein to creatinine ratio has supplanted the 24-hour collection in the routine measurement of urine protein excretion. This technique is convenient, only requiring a random morning urine specimen. Several studies have confirmed that the random protein to creatinine ratio correlates well with the 24-hour urine collection. However, it is less accurate in patients with variable lean muscle mass (since muscle influences creatinine production). The 24-hour protein excretion (in g per 1.73-m2 body surface area) is estimated as follows:
Random urine protein / random urine creatinine
Thus, if the random urine protein is equal to 430 mg/dL and the random urine creatinine equals 50 mg/dL, the daily urine protein excretion is approximately 8.6 g per 1.73-m2 body surface area.
8
What is considered a significant finding of hematuria? Where do the RBCs usually originate? What are some common etiologies? How do the RBCs differ depending on where they originate?
The presence of >5 red blood cells (RBCs) per high power field (HPF) on two or more urine specimens in a male or nonmenstruating female constitutes a significant finding in the urine. RBCs can originate from anywhere within the urinary tract (eg., kidney, pelvis, ureter, bladder, or urethra). Isolated hematuria is usually related to pathology within the urinary collecting system, rather than the kidney parenchyma. Hematuria may occur in as many as 40% of all adults but <10% will originate from the kidney. Most instances are due to pathologic crystalluria (stones), urinary tract infections, and tumors. Phase-contrast microscopy of the urine may provide a clue to the source of the hematuria; RBCs originating from the glomerulus are typically misshapen (dysmorphic) because of passage through the hypertonic interstitium and exposure to the acidic pH of the urine. RBCs originating from the urinary pelvis, ureter, bladder, or urethra are usually round and uniform in shape. An evaluation scheme useful in the approach to the diverse causes of hematuria is depicted in Fig. 15.3.
9
What are the two steps in urinalysis?
The urinalysis is an essential step in the evaluation of suspected renal disease. The urinalysis typically comprises two steps: (1) dipstick analysis and (2) microscopic examination of the urine sediment. In particular, evaluation of the urine sediment for cells, casts, and crystals is a vital and often underappreciated step in the evaluation of a patient with suspected kidney disease.
10
What are 10 urine tests included in a dipstick analysis?
The urine dipstick or test strip is comprised of ten chemical pads embedded with a reagent that reacts to components of the urine to produce a color change. The test can be performed quickly at the bedside (usually requiring <90 seconds) and furnishes the cornerstone for the initial evaluation of virtually all kidney diseases (Fig. 15.4). The ten urine tests include:
Urine pH
Glucose
Ketones
Nitrite
Leukocyte esterase
Heme
Protein
Urine specific gravity
Bilirubin
Urobilinogen
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What can urine pH tell you? What causes a pH >7.0? What causes a low pH (<5.5)?
Urine pH (detection limit = 4.5-8.0). Depends on dietary composition. pH >7.0 is observed with urinary tract infection (ammonia producing organisms), metabolic alkalosis, and a strict vegetarian diet. A low pH (<5.5) is observed with a high-protein intake and metabolic acidosis. The urine pH can be used to refine the diagnosis of a renal tubular acidosis, but is unreliable as an index of net renal acidification.
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What can cause glucosuria? Which ketones are detected? What causes ketones to be in the urine? When might the test underestimate the degree of ketoacidosis? Why? What does a positive nitrite test tell you? What does a positive leukocyte esterase test tell you?
• Glucose (detection limit = 40 mg/dL). Glycosuria occurs when the transport maximum for glucose in the proximal tubule is exceeded (eg, hyperglycemia secondary to diabetes mellitus). Renal glucosuria may also arise from a primary defect in proximal tubule reabsorption of glucose (eg, Fanconi syndrome).
• Ketones. This test determines the presence of acetoacetic acid (>5 mg/dL) and acetone (>40 mg/dL), not b-hydroxybutyric acid. These compounds accumulate in starvation, uncontrolled diabetes, and alcohol intoxication. The urine ketone test may underestimate the severity of ketoacidosis when tissue perfusion is compromised (since oxygen deprivation favors the conversion of acetoacetic acid to b-hydroxybutyric acid)
.• Nitrite. Dietary nitrates are normally excreted in the urine, however, in the presence of gram-negative bacteria, nitrates are converted to nitrites. A positive nitrite test is a surrogate marker of bacteruria.
• Leukocyte esterase (detection limit 10-25 WBC/μL). Detects the presence of whole or lysed white blood cells (WBCs) in the urine. A positive test correlates well with urinary tract infection (false-negative tests occur in 20% of cases)
13
What does the heme test detect? What does a positive test tell you? What does the protein test detect? What does it not detect? When might it be falsely positive or falsely negative? What does the urine specific gravity tell you? When is bilirubin increased in the urine? When is urobilinogen increased in the urine?
• Heme. Positive test occurs with nonhemolyzed (>5 RBCs) or hemolyzed blood (0.03 mg/dL of hemoglobin) in the urine. Also detects the presence of myoglobin. Therefore, this test is positive with hematuria, hemoglobinuria, or myoglobinuria.
• Protein (detection limit = 10 mg/dL). Detects albumin not gamma globulins. Can be falsely positive in highly concentrated or extremely alkaline urine. A negative test may occur in dilute or extremely acidic urine. The test does not detect immunoglobulin proteins (eg, monoclonal light chains as seen in multiple myeloma).
• Urine specific gravity (detection limit = 1.000-1.040). Equivalent to the weight of urine divided by the weight of an equivalent volume of distilled water. Depends on both the number of particles and the weight of particles in solution. Low values (1.030) are consistent with concentrated urine.
• Bilirubin (detection limit = 0.5 mg/dL). Increased in hepatobiliary disease.
• Urobilinogen (detection limit = 0.4 mg/dL). Bilirubin is converted to urobilinogen by intestinal bacteria. Most urobilinogen is excreted in the feces. Urine excretion is increased in hepatobiliary disease with the notable exception of biliary obstruction (since bilirubin does not enter the duodenum).
14
How is microscopic examination of the urine sediment performed? What is looked for?
Microscopic examination of the urine sediment is the classic noninvasive test performed to evaluate kidney and urinary tract disease. The urine must be freshly voided and examined within 30-60 minutes. Red cells and casts tend to disintegrate upon standing and in alkaline urine. The urine sediment (prepared from 10 mL of urine) should be examined under high power magnification (400×). The sediment is examined for cells (RBCs and WBCs), casts, crystals, and bacteria. This information is invaluable in the diagnosis of kidney and urinary tract disease.
15
What are urinary casts? What are 7 major types of casts that are of clinical interest? What is the significance of dysmorphic RBCs in the urine? Eosinophils?
Urinary casts coalesce in the collecting duct because the urine is maximally concentrated and acidic at this site. Casts are comprised of a matrix (THP) with or without cellular elements. There are seven major types of casts that are of clinical interest, including: (1) hyaline casts, (2) granular casts, (3) WBC casts, (4) RBC casts, (5) epithelial cell casts, (6) waxy casts, and (7) fatty casts. The nature of these casts and their pathologic significance is summarized in Fig. 15.5. In addition, two cell types are of clinical significance: (1) leukocytes, and (2) erythrocytes (Fig. 15.6). Dysmorphic erythrocytes are misshapen cells that arise as they pass through the tubular lumen and are subjected to the hypertonic medullary environment. They are consistent with a glomerular source of hematuria. Eosinophils are occasionally seen in the urine. Their presence suggests an allergic reaction (eg, allergic interstitial nephritis).
16
Which crystals are found in normal urine? When might they herald a clinical condition? What significance do drug-induced crystals have? What crystals are always pathologic? What do they signify ? What other disease are crystals seen in?
Crystals are commonly found in the routine examination of the urine sediment. While often normal, pathologic crystals may be found in the urine and must be recognized (Fig. 15.7). Crystals encountered in the urine are classified as, (1) normal, (2) drug-induced, and (3) pathologic. Uric acid, calcium oxalate, and calcium phosphate crystals are seen in up to 10% of normal urine. They are usually of no pathologic significance, but when persistent or abundant they may herald a clinical condition (eg, ethylene glycol intoxication is associated with calcium oxalate crystals). Drug-induced crystals are usually of no pathologic significance (although it is advisable to discontinue the drug if crystals are seen). They typically appear as needle-like or have a “shocks of wheat” appearance. The most common drugs associated with crystalluria are sulfadiazine, amoxicillin, ciprofloxacin, and acyclovir. Cystine crystals are always pathologic. They are pathognomonic for hereditary cystinuria. Crystals are commonly seen in renal stone disease (eg, uric acid crystals with uric acid stones).
17
How are plain films of the abdomen used? What diseases is an ultrasound important for diagnosing? What is color doppler US used to detect?
Plain Films of the Abdomen
Plain films of the abdomen are rarely used to evaluate kidney and urinary tract disease. If obtained, the plain films may reveal radioopaque kidney stones (usually calcium-containing stones). This imaging technique may also provide information about kidney size and shape.
Renal Ultrasonography
This imaging tool is invaluable as a screening test for urinary tract dilatation (hydronephrosis). Dilation of the urinary tract is a hallmark of urinary tract obstruction. However, it may also be observed in polyuria and normal pregnancy (uterine enlargement causes partial urinary tract obstruction). Urinary tract dilation may persist even after relief of urinary tract obstruction.
The ultrasound remains the procedure of choice for evaluation of acquired or hereditary polycystic kidney disease (Fig. 15.8). Renal masses are also readily identified with ultrasonography. Advanced kidney disease is usually accompanied by scarring and thinning of the renal cortex with small kidneys (<9 cm in longitudinal length). These features are readily identified with renal ultrasonography. Although renal ultrasonography was routinely used to identify kidney stones, non-contrast helical computed tomography has supplanted the ultrasound for the diagnosis of nephrolithiasis.
Color Doppler ultrasonography measures flow or velocity of blood in the main renal artery. It is primarily used to detect renal artery stenosis. Color Doppler flow studies in the renal artery are highly operator dependent.
18
What is intravenous pyelography useful for evaluating at this point? When is CT useful? What are its pros and cons compared to US? When is the MRI useful?
Intravenous pyelography (IVP) was the imaging technique of choice to define the anatomy of the renal and urinary tract. However, other modalities have largely supplanted its use. The IVP remains useful in the evaluation of medullary sponge kidney and papillary necrosis.
Computed Tomography
Computed tomography (CT) provides similar information as the renal ultrasound but with additional detail. Non-contrast helical CT is the procedure of choice for evaluation of kidney stones (Fig. 15.9). CT scanning may differentiate malignant from nonmalignant renal masses. CT scanning is essential to evaluate local spread of renal tumors. High-resolution CT angiography is excellent at defining the anatomy of the renal arteries and veins (eg, renal vein thrombosis). CT scanning is superior at identifying renal cysts compared to ultrasonography, since it is capable of detecting small cysts of 2-3 mm diameter. Because of safety and cost, the renal ultrasound is still used to screen for polycystic kidney disease.
Magnetic Resonance Imaging
Magnetic resonance imaging provides a useful alternative to computed tomography in individuals at risk for toxicity from intravenous contrast. It may also offer an advantage in the evaluation of small renal masses. Magnetic resonance angiography has proven useful in the evaluation of stenosis in the mid and proximal renal arteries.
19
Why is gadolinium contrast avoided in patients with a serum creatinine > 2?
Recently, several reports of progressive systemic fibrosis in patients with kidney failure have emerged (nephrogenic systemic fibrosis [NSF]). This disorder has only been reported in patients receiving gadolinium, a contrast agent used to enhance the standard MRI. Although rare, these cases invariably progressed to death. To date all of these cases have occurred in patients with advanced renal disease. Therefore, MRI with gadolinium contrast is typically avoided in patients with a serum creatinine that exceeds 2.0 mg/dL, unless deemed urgent. Newer contrast agents at very low doses are under investigation as an alternate approach.
20
When is radionuclide scanning useful? When is renal angiography useful? When is retrograde pyelography useful?
Radionuclide Scanning
This imaging technique has been successfully used to evaluate renal perfusion in a variety of settings, including renal artery stenosis and thrombosis. Although, a radionuclide study can provide an assessment of renal tubular function, it is nonspecific and, therefore, cannot establish a definitive renal diagnosis. Radionuclide cystograms are widely employed by pediatric nephrologists to detect early reflux and scarring in children with vesicoureteral reflux.
Renal Angiography
Renal angiography is the gold standard for direct visualization of the renal vasculature. It is invaluable in the diagnosis and treatment of renal artery stenosis and renal vein thrombosis (Fig. 15.10). Renal arteriography may also provide complementary information in the evaluation of a renal mass.
Retrograde Pyelography
Retrograde pyelography is an essential tool for localizing the site of a urinary tract obstruction. It may also prove therapeutic (eg, ureteral stents can be placed to relieve an obstruction).
21
What serologic markers are important in serologic examination of the urine? What do they signify?
Determination of serum complement components (C3, C4) constitutes an important step in the evaluation of patients with suspected glomerular disease. Other serologic markers useful in the evaluation of glomerular disease include serum cryoglobulins (essential mixed cryoglobulinemia), hepatitis serologies (membranous glomerulonephritis), human immunodeficiency virus (focal segmental glomerulosclerosis), serum and urine immunoelectrophoresis (myeloma, amyloidosis), and quantitative determination of antinuclear antibodies (lupus nephritis).
In addition, the presence of circulating antibodies to specific cytoplasmic antigens (antineutrophil cytoplasmic antibodies [ANCAs]) have been described in association with renal vasculitis and rapidly progressive glomerulonephritis. These antibodies possess several different antigenic specificities, although two major classes are routinely reported using indirect immunofluorescence staining. Antibodies with a cytoplasmic pattern of staining (c-ANCA) are directed toward proteinase-3 and are commonly found in Wegener granulomatosus. In contrast, antibodies with specificity to myeloperoxidase demonstrate a perinuclear staining pattern (p-ANCA). The p-ANCA is often present in patients with systemic vasculitis. These antibodies have also been described in several nonrenal diseases such as inflammatory bowel disease and, therefore, cannot be considered absolutely specific for kidney disease.
22
When is a renal biopsy necessary? Describe the process of obtaining it?
The renal biopsy remains the “gold standard” for establishing the diagnosis of parenchymal kidney disease. When the clinical description and laboratory features are insufficient to arrive at a definitive diagnosis, a renal biopsy is necessary to delineate the underlying disease. The procedure is safe and can be performed at the bedside. It requires <30 minutes to complete. A small-bore biopsy needle is introduced into the lower pole of kidney under ultrasound or CT guidance. The patient is typically kept at bedrest overnight and discharged the next day. The principal complications are bleeding and infection. Although, some bleeding invariably occurs after the procedure, it is rarely clinically significant. Renal tissue is fixed and examined by an experienced nephropathologist.
23
What are the three techniques used in the pathologic examination of a renal biopsy? What can be seen and done in each?
Typically, the pathologic examination involves three techniques (Fig. 15.11):
1. Light microscopy (LM) provides information about all major components of the renal parenchyma including glomeruli, tubules, interstitium, and vessels. Special stains are employed to highlight specific components of the glomerulus (eg, the silver stain highlights the glomerular basement membrane and mesangial matrix, the trichrome stain highlights type I and III collagen).
2. Transmission electron microscopy (EM) has much greater resolution than light microscopy, although the area that can be seen at one time is less. EM provides information on glomerular ultrastructure, specifically detailing the microarchitecture of the podocyte, endothelial cell, mesangium, and the basement membrane. EM also permits identification and localization of immune complexes as well as nonimmune deposits (eg, amyloid).
3. Direct immunofluorescence (IF) involves coating the tissue with fluorescinated anti-immunoglobulin and anticomplement antibodies. These antibodies will bind to immune complexes. Immune complexes appear as granular deposits in glomeruli using an immunofluorescence microscope with a fluorescence light source. IF also provides information on the location of immune complexes in the kidney.
24
What are two general models used to explain the pathogenesis of kidney injury?
The pathogenesis of kidney injury varies depending on the underlying cause. In some instances, the etiology is obvious and quickly reversible with the appropriate intervention. For example, relief of mechanical obstruction is followed by resolution of impaired renal function (although residual tubular dysfunction may persist). Over the past 50 years two general models have evolved to explain the pathogenesis of renal injury involving the glomerulus, tubules, interstitium, or renal microvessels: (1) immune-mediated renal damage and (2) nonimmune mechanisms of kidney injury. These two constructs will be briefly discussed. Additional details will be described in conjunction with specific diseases in subsequent sections.
25
What are two types of immune mediated renal injury? What happens in each? What determines the structural and functional consequences? What can help treat them?
Immunologic mechanisms of kidney damage have been studied for more than 50 years. These studies have largely been restricted to animal models of glomerular injury. However, similar findings have been described in diseases that affect the interstitium and renal microvasculature. In general, two types of immune-mediated renal injury have been characterized:
1. Visceral epithelial cell (podocyte) injury secondary to cytokine release from activated T-lymphocytes. Minimal change disease and focal segmental glomerulosclerosis are examples of glomerular disease resulting from injury to the podocyte.
2. Immune complex formation secondary to antibodies directed toward intrinsic renal antigens (eg, membranous glomerulonephritis) or trapping of circulating immune-complexes within the renal parenchyma (lupus or post-streptococcal glomerulonephritis).
The structural (inflammatory cell infiltrates, crescent formation, fibrosis) and functional (decrease in GFR, proteinuria, hematuria) manifestations of renal injury depend, in part, on the location and extent of immune deposition within the kidney.
Drugs that alter the immune response have proven useful in the treatment of renal diseases secondary to immune-mediated injury.
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