INTRODUCTION
Mild renal disease is often clinically silent and patients may occasionally remain asymptomatic until their renal disease is so advanced as to cause near total loss of kidney function, resulting in volume overload and uremia. Moreover, a patient with minimal bladder inflammation will often have significant complaints of dysuria, whereas someone with renal parenchymal inflammation causing proteinuria, microscopic hematuria and renal insufficiency could remain silent for a long time. Often, renal disease is diagnosed incidentally because of elevated BUN and creatinine on routine blood chemistry profile. Therefore, the patients at risk for developing renal disease, as well as the patients with an already known renal diagnosis, should undergo periodic evaluation. This can be done with urinalysis, serum biochemistry and radiological tests that should be individualized to specific renal condition of a given patient.
URINALYSIS (UA)
Given its simplicity and clinical relevance, UA is one of the most commonly performed clinical laboratory tests throughout the world. It is often the starting point in the clinical evaluation of patients with hypertension, renal insufficiency, urinary tract symptoms, or proteinuria. For the experienced eye, it may help to differentiate between glomerular and tubulo-interstitial disorders in the patients with elevated serum creatinine levels and/or proteinuria. In addition, UA can help in following the activity of disease in a variety of renal disorders.
For collection of urine, a clean, disposable container should be used. It must be sterile, only if the sample will be sent for culture. The first urine void of the day is considered the best specimen for analysis. Urine obtained at this time is in its most concentrated form; its relative acidity aids in the preservation of casts and cellular elements. At least 10–15 mL of freshly collected urine is examined immediately, or stored briefly at 4°C to avoid bacterial overgrowth and chemical decomposition of the urinary sediment.
Routine UA consists of three parts:
- Evaluation of the physical characteristics of the urine.
- Chemical analysis using a dipstick consisting of multiple test reagents.
- Microscopic evaluation of the urinary sediment.
The microscopic examination is conducted on the pellet obtained after centrifugation at 200 rpm for 5 minutes. The supernatant should be saved for treatment with sulfosalicylic acid (SSA), if indicated.
The physical and chemical characteristics of urine and their significance are summarized in Table 1.1. Normal color of the urine can range from yellow to amber, as a function of concentration. The physiologic range of urine specific gravity is 1.003 to 1.035 (1.000 being the standard used for distilled water). The specific gravity is affected both by the particle weight and particle number (the latter affecting the urine osmolality also). Urinary pH is usually within the range of 4.5–7.9. It increases after a meal (the “posprandial alkaline tide”) and decreases with fasting.2
Persistently, acid urine is seen with protein intake (increased “fixed acid”), fever, gout, severe potassium depletion, hyper–aldosteronism, metabolic acidosis (but not renal tubular acidosis (RTA), and cranberry juice ingestion. Persistently alkaline urine is seen with distal RTA, urinary tract infection (UTI) with-producing organisms (e.g. Proteus), and metabolic alkalosis.
Proteinuria is an important marker of renal disease. Normal urinary protein excretion is less than 150 mg/day. Of this, 60 percent is derived from filtered serum proteins (approximately 40% albumin, 15% immunoproteins, and 5% other plasma proteins) and 40 percent comes from the cells of the thick ascending limb of the loop of Henle (Tamm Horsfall mucoprotein). Tamm-Horsfall protein forms the matrix of tubular casts. Transient proteinuria, independent of glomerular disease, can occur with fever, exercise, and upright posture (i.e. orthostatic proteinuria). Persistent proteinuria, however, has the significance of either glomerular or tubulo-interstitial renal disease. Glomerular proteinuria consists primarily of albumin and is often in the nephrotic range (> 3 gm/day). The term “microalbuminuria” is used for minor increases in urine albumin, whereas the sulfosalicylic acid method (using a 20% SSA solution) will precipitate all proteins (including Bence Jones proteins, glycoproteins, globulins, and albumin).
Findings on microscopic evaluation of the urine sediment reflect intrarenal pathology, and are summarized in Table 1.2.
Figure 1.1A shows examples of cellular elements found in the urinary sediment. Red blood cells are not normally found in the urine. When present, they have the appearance of pale, biconcave disks. The margin is smooth and regular, but in hypertonic urine the cells will shrink and have a crenated (i.e. spiky) appearance (Fig 1.1B). Dysmorphic erythrocytes are associated with glomerular bleeding and among them acanthocytes are the most specific. They are doughnut-shaped or spherical (but microcytic) and have membrane blebs (“Mickey Mouse ears” Fig. 1.1C). Leukocytes are larger in size and demonstrate the presence of cytoplasmic granules or lobulated nuclei (Fig. 1.1D). Epithelial cells may appear in the urine, and are derived either from renal tubular epithelium, transitional epithelium (from the ureters or bladder) or squamous epithelium (from the vaginal vault) (Figs 1.1E,1.1F).3
Fig. 1.1A to F: Cellular elements found in the urinary sedimen: (A) Normal erythrocytes. (B) The arrows labeled A and B point to the difference between a normal and a crenated erythrocyte. Note the difference between crenated erythrocytes (not indicative of GN, picture (B). (C) Dysmorphic erythrocytes. (D) Leukocytes. (E) Renal tubular epithelial cells are slightly larger than leukocytes and exhibit distinct, ecentric nuclei. (F) Squamous epithelial cells are large and irregularly shaped cells with nuclei that approximate the size of leukocytes. | |
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Urinary casts are formed in the distal tubule and collecting ducts. Tamm-Horsfall protein forms their matrix. They have a cylindrical shape, with parallel sides and rounded ends (Fig. 1.2A). Identification of specific types of casts helps in narrowing the differential diagnosis in patients with renal disease (Table 1.2). Examples of casts in the urinary sediment are shown in Figures 1.2B to 1.2 E.
Urinary electrolytes should be measured in a randomly obtained (spot) urine sample. These can provide important information regarding the renal tubular concentrating ability, volume status, and even some acid-base and electrolyte disturbances. However, these should be interpreted in the light of clinical setting and in the absence of diuretic use. Low urine sodium level (less than 10 mEq/L) in a spot specimen generally indicate volume depletion or other pre-renal cause of acute renal failure (ARF). In excess of 40 mEq/L, it could suggest loss of proximal tubular concentrating ability (e.g. physical damage to the tubules, as in patients with acute tubular necrosis), but also adrenal insufficiency, recent diuretic use or renal insufficiency. When the spot urine sodium concentration is in the range of 10 to 40 mEq/L, it is useful to calculate a fractional excretion of sodium (FENa). The FENa can be calculated as
FENa = (UNa) × (Pcreat/(PNa) × (Ucreat)
Where Ucreat and Pcreat represent the urinary and plasma creatinine concentrations and UNa and PNa, urinary and plasma sodium concentrations, respectively. Values less than 0.01 (or 1%, if above formula is multiplied by 100) indicate pre-renal acute renal failure.
Chloride levels, also measured by a spot test, may help differentiate between gastrointestinal and renal chloride wasting in the patients with metabolic alkalosis (values lower than 10 mEq/L suggest gastrointestinal losses). Although urinary chloride losses are usually associated with a spot urine chloride level in 5excess of 15 mEq/L, in cases of severe volume depletion associated with in long-term diuretic use, the concentration may be lower.
Another useful measurement is the urinary anion gap, which may be used to distinguish between gastrointestinal and urinary bicarbonate losses in patients with hyperchloremic (normal anion gap) metabolic acidosis. The urinary anion gap is calculated as follows:
Urinary anion gap = (UNa + UK)UCI
Which, as can be seen, is a function of the urinary concentrations (on spot urine test) of sodium, potassium and chloride, respectively. It is used to indirectly estimate the urinary ammonia (NH4+) excretion. Although direct urinary NH4+ measurement is possible, it is technically very difficult to perform and is not readily available. In chronic metabolic acidosis of non-renal origin (e.g. diarrhea), the kidney will respond by increasing NH4+ production. This will result in an increase in CI- concentration, which will exceed the sum of (Na+ + K+). The urinary anion gap will then take a negative value. In contrast, the kidneys may cause a metabolic acidosis by failing to excrete acid at a normal rate (i.e. renal tubular acidosis). Then urinary NH4+ is quite low, resulting in a positive urinary anion gap. This is further discussed in the chapter on metabolic acidosis.
Biochemical Evaluation of Renal Function
Incidental detection of abnormal renal function during routine lab work is not unusual. Serum BUN (blood urea nitrogen) and creatinine are commonly tested indicators of renal function, and the glomerular filtration rate can be estimated using these values
Glomerular filtration rate (GFR) is the Gold standard of renal function, measured by injecting inulin or iothalamate, which are freely filtered, but not reabsorbed or secreted by the tubules. These tests are cumbersome, time consuming and unsuitable for routine clinical use. Clinically, GFR can be estimated by using creatinine clearance (Ccr). For adults, commonly used formula of Cockcoft and Gault is as follows. Ccr (ml/minute) = (140-Age in years) × Weight (in kg)/72 × serum creatinine,
For females, this value should be multiplied by 0.85.
Serum creatinine is the most commonly utilized measure of creatinine clearance in day-to-day practice of medicine. It is subject to similar variations as BUN (discussed below), but to a lesser degree. It is perhaps more accurate to measure 24 hour urinary excretion of creatinine, simultaneously with serum creatinine measurement. The creatinine clearance can then be calculated as follows:
Ccr (ml/min) = UV/P, where
U = urine creatinine concentration (mg/deciliter),
V = volume of urine (ml per minute, i.e. 24 hour volume/1440), and
P = serum creatinine (mg/minute).
Creatinine clearance can also be calculated by simply calculating reciprocal of serum creatinine (i.e. 1/serum creatinine × 100). Thus, a serum creatinine of one in normal healthy adult is likely to reflect 100 percent renal function (or GFR). A rise in serum creatinine to 2.0 would then indicate reduction of the GFR by 50 percent, and so on. Serial follow-up of serum creatinine, rather than the absolute value of creatinine is more useful indicator of renal function in a given patient; since, the ‘normal’ creatinine could vary among individuals, in proportion to their muscle mass and diet. Thus, a low creatinine of 0.8 in an elderly, thin female may reflect severe renal insufficiency, while a creatinine of 2.0 in a bodybuilder may be associated with normal renal function.
BUN is a protein metabolite that is cleared by the kidneys via glomerular filtration. Since it is both secreted and reabsorbed by the tubules, it is poor marker of the renal function. Moreover, the BUN level in serum is also dependent upon rate of production and tubular reabsorption and secretion. A misleadingly high level of BUN can be found in the absence of abnormal renal function if the production is increased (e.g. gastrointestinal bleeding, burns, steroid therapy, sepsis, etc.) or if the tubular reabsorption is high (e.g. intravascular volume depletion, poor cardiac output etc.). On the other hand, BUN level can be misleadingly low despite poor renal function in elderly, malnourished and bedridden patients, who do not have enough muscle mass.
Serology to measure markers of immune function is often utilized in differential diagnosis of renal, especially glomerular diseases. These will be discussed in detail in the chapter on glomerular diseases.6
Fig. 1.2: Examples of casts found in the urinary sediment: Hyaline casts consist of Tamm-Horsfall protein and have no granularity or cellular elements (A). Red cell casts contain distinct erythrocytes (B), while the presence of nucleated or granular leukocytes help distinguish a leukocyte cast (C). A granular matrix within the borders of the cast and the lack of distinct cellular elements characterize a granular cast (D,E and F). | |
RADIOLOGIC STUDIES IN PATIENTS WITH RENAL DISEASES
Radiologic studies of renal patients should be individualized to obtain the most relevant information, depending upon the clinical circumstances. Similar information can obtained from different tests and there is no single best for every patient. The most useful tests are outlined below.
Urinary Tract Infection
Urinary tract infections (UTI) may involve the lower urinary tract, the upper urinary tract or both. Lower UTI usually responds quickly to antibiotic treatment and there is no need for diagnostic imaging studies. Most cases of upper UTI (i.e. pyelonephritis) are not complicated and are solely a clinical diagnosis. Radiologic studies are generally indicated only in patients suspected of having complicated pyelonephritis such as those with poor response to therapy, coexisting diabetes mellitus or altered immune state, know history of kidney stone or urinary tract abnormality and recurrent pyelonephritis.
Patients with diabetes and pyelonephritis are at increased risk of emphysematous pyelonephritis. This is an extremely severe infection, associated with air infiltration in a bubbled pattern in parenchyma and in Gerotta's fascia. Although the plain X-rays and renal ultrasound can show the intrarenal gas, an abdominal CT is the preferred imaging technique (Fig. 1.3), particularly for making a decision regarding therapy, since, often a nephrectomy is needed.
In patients with a known history of nephrolithiasis, as well as in patients with recurrent pyelonephritis or males with their first documented episode of pyelonephritis, the initial evaluation can include an intravenous pyelogram (IVP). Alternatively, if there is a contraindication to intravenous dye administration or if pyonephrosis is suspected, a renal ultrasound can be performed (Fig. 1.4).
Stone Disease
Urinary stones are a common diagnosis in clinical practice. Unless incidentally found during an abdominal imaging study, nephrolithiasis often presents first as renal colic. Most of the urinary stones (85–90%) are calcified and can be detected by a plain abdominal radiograph. An IVP can then confirm the location of the stone, show the presence or absence of urinary tract obstruction and define the anatomy of the urinary tract. The IVP has been the most frequently performed test for the initial evaluation of stone disease (Fig. 1.5).
Spiral CT scans (technique by which all the CT images are acquired in one breath-hold, usually 20 seconds) are becoming more common in patients with kidney stones because they will show virtually all kidney stones, do not require any injection of contrast, and can be done quickly. However, the dye dosage with a CT is about 30 percent more than with an IVP (Fig. 1.6)
Renal Masses
Most renal masses are incidentally detected on radiologic studies performed for a variety of unrelated reasons. Then, further imaging is frequently needed to determine if the incidentally found mass is malignant or not. To determine the nature of the mass, abdominal CT, ultrasound, or MRI can be used. To meet the criteria for a simple cyst (which then only requires periodic follow-up) on ultrasound, a lesion must have well-defined smooth walls, good and thorough enhancement, and no internal echoes. A lobular contour, poor enhancement from the surrounding renal parenchyma, and the presence of calcifications are suggestive of a solid mass (which is usually removed by either complete or partial nephrectomy, as it may represent a renal cell carcinoma). An abdominal CT is the preferred next diagnostic step. The CT criteria for a simple cyst include a round, well-defined lesion with internal density near that of water.
- Unfortunately, many lesions are not straight forward and fall in between these two categories (cystic or solid). They are then called indeterminate, and are best evaluated by a combination of ultrasound and CT studies.8Fig. 1.4: Pyonephrosis. Ultrasound showing echogenic (infected) material in a dilated and obstructed renal collecting system (arrow)Fig. 1.5: The abdominal radiograph (left panel) shows a large calcified stone in the left upper quadrant. The IVP (right panel) demonstrates obstruction of the left ureter (white arrows) by the stoneLesions that display only minimal noncystic features can be followed by repeat studies (at 3 months, 6 months, and 1 year) to ensure that they remain stable. More complex cystic lesions should probably be treated surgically, given the risk that they are or will become malignant. Indeterminate lesions should also be evaluated with a CT with intravenous contrast administration (as contrast enhancement is an important sign of malignancy); MRI can be substituted for patients at risk of radiologic contrast nephrotoxicity. Percutaneous needle biopsy of a renal mass is usually not done, except for the patients who are not surgical candidates and in whom a pathologic diagnosis is needed for management. The diagnostic yield is low and the risk of complications (e.g. bleeding or tumor seeding along the needle tract) is small but real. Figure 1.7 shows a simple renal cyst and polycystic kidney disease. Figure 1.8 shows a malignant renal mass.
Hematuria
The patients presenting with hematuria, but urinary sediment not suggestive of glomerulopathy, may have urinary stone, infection, or neoplasm. The preferred initial imaging study is an IVP. In addition, such patients should see a urologist to undergo a cystoscopy for further evaluation of the bladder. Retrograde pyelography is helpful in identifying and defining lesions in upper urinary tract.9
Fig. 1.7: Simple renal cyst (left panel) and multiple bilateral cysts of polycystic kidneys (right panel)
Fig. 1.8: Malignant renal mass. Note the complex lesion on unenhanced CT (left panel) and enhancement after intravenous contrast administration (right panel)
Fig. 1.9: Urinary tract obstruction. Renal ultrasound demonstrating a dilated renal collecting (left) and IVP showing dilated left renal collecting system (right)
Cytology of urine should also be done to exclude malignancy. If these tests have still not determined the diagnosis, an abdominal CT, or MRI with gadolinium can be performed as the next step. Studies are then indicated. Of note is urine reflux from the bladder into the ureter and renal collecting system that can produce an image on ultrasound very similar to that of obstruction. Another useful assessment with the ultrasound is the echogenicity of the kidneys. Increased echogenicity (brightness on ultrasound images), together with small size kidneys indicate that the renal failure is more chronic in nature. However, no further differentiation among various causes of chronic renal insufficiency is possible by ultrasound, since most chronic renal diseases are associated with shrunken kidneys.
Renal Artery Stenosis
Renal artery (RAS) is a common, and potentially correctable, cause of secondary hypertension (HTN). Many radiologic tests have been advocated as the preferred screening technique, but the results vary greatly in the hands of different investigators.
Doppler ultrasound is a relatively inexpensive and safe test (no exposure to radiation or dye), but it is difficult to visualize the entire main renal arteries, particularly in obese patients. Its accuracy is also highly variable and operator dependent. At this time it is nor recommended for screening except in those centers that have proven its utility. A regular renal ultrasound is often used to assess the renal echogenicity and also for renal a symmetry parenthesis.
In patients with unilateral RAS, increased renal parenchymal echogenicity and a difference in size between the affected (smaller) and unaffected kidney may be observed. Due to suboptimal sensitivity, this test is also not generally recommended for screening. Magnetic resonance (MR) angiography has recently shown great promise in the evolution of renal (especially proximal) artery stenosis. It also has the advantage of avoiding the use of intravenous radiologic contrast media. Captopril renogram is widely used in primary care setting as a useful and reliable (both sensitivity and specificity greater than 90–95%) screening technique of RAS. It will be discussed more in the section dealing with renovascular hypertension.
The gold standard for RAS evaluation remains conventional renal arteriography. It should probably be the first test when the clinical suspicion is high and the patient has normal renal function. It depicts the best anatomic detail of the renal arteries and provides an opportunity for treatment with balloon angioplasty. However, renal angiogram is an invasive procedure and has a relatively high cost. It has the risk of atheroembolism and radiologic contrast induced nephrotoxicity, particularly in diabetics, older patients, and patients with preexisting renal insufficiency. Therefore, it cannot be used as a screening test for all patients, but rather in those where the index of suspicion is high (Fig. 1.10).
Fig. 1.10: Tight right ostial renal artery stenosis (white arrow) on left. Same lesion after balloon angioplasty and intra-arterial stent placement (white arrow) on right
Nuclear Imaging in Patients with Renal Diseases
Nuclear imaging is a method that uses a radioactive tracer which, when introduced into the body, targets a specific organ. The tracer consists of a radionuclide (99mTc is the most commonly used) that is carried to the target organ by a nonradioactive pharmaceutical. From there it emits a type of radiation that can then be imaged and used for diagnostic purposes. Nuclear imaging does not provide the same anatomic detail seen with radiologic imaging of the urinary system; instead, it provides physiologic data about the function of the organ of interest.
Radiopharmaceuticals commonly used to target the genitourinary system are discussed in the Table 1.3.
Evaluation of the Renal Artery Flow
DTPA or MAG3 may be used for evaluation of the renal artery flow and excretion. Relative GFR or effective renal plasma flow (ERPF) can be calculated upon analyzing the flow down the aorta and into the renal arteries and the time taken for the radiopharmaceutical to concentrate into the renal cortex. Time-activity curves are also generated, showing the activity in each kidney during the time of the study.
Measurement of the Glomerular Filtration Rate (GFR)
GFR can be measured using 99mTcDTPA or MAG3, which is also used to assess ERPF. Using nuclear medicine techniques, isotope counts are taken at about 1–2 minutes post dosing. The contribution by each kidney to total GFR or ERPF can be quantified. The information is very helpful in assessing for asymmetrical renal disease as well as for monitoring changes in function over time. Although not commonly used for this purpose, GFR measurements using nuclear medicine techniques correlate well with the inulin clearance and 24 hour creatinine clearance measurements.
Allergic Interstitial Nephritis (AIN)
Gallium-67 citrate is a radiopharmaceutical that accumulates in the areas of inflammation; therefore it can be used to assess AIN, as well as renal infections (e.g. renal and perirenal abscess) and tumors. It is generally excreted by the kidneys within 24–48 hours from the time of administration. Retention beyond 72 hours, particularly in the setting of ARF, is suggestive (but not specific) of AIN. Indium scan also can be used to detect renal or perirenal abscess. The superiority of indium scan over gallium scan is not established.
Obstructive Uropathy
Sometimes the findings of a dilated renal pelvis and/or collecting system by anatomic imaging studies, such as ultrasound, abdominal CT scan, or IVP may reflect previous abnormality, rather than ongoing obstruction. Diuretic-augmented renal scintigraphy (e.g. Lasix renal scan) is then useful in differentiating dilation from obstruction versus non-obstructed renal collecting system. After the administration of the diuretic, the urine flow increases and should clear the scintigraphic activity caused by a non-obstructed system.
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Fig. 1.11: Renal scintigram showing a small right kidney and normal appearance of the left kidney (A). There is bilateral (worse on the left-white arrows) dilatation of the collecting system. There is prompt clearance (B) after administration of intravenous lasix (thus, no urodynamically significant obstruction)
Fig. 1.12: Captopril scan showing no difference in perfusion of both kidneys (left panel). After administration of captopril, the perfusion of left kidney decreases significantly, which is suggestive of renovascular disease
Time activity curves are generated for each kidney. Also, renal scintigraphic images can be analyzed and the clearance of nuclear “activity” is followed after the diuretic administration (Fig. 1.11).
Renal Artery Stenosis
Essential hypertension (HTN) accounts for most of the cases of hypertension. Secondary hypertension is uncommon and is often the result of renovascular disease, including major renal artery stenosis (RAS). RAS may be atherosclerotic in nature (usually in older patients) or a result of fibromuscular dysplasia. The resulting fall in GFR leads to activation of compensatory mechanism. This includes activation of renin-angiotensin system and maintenance of GFR via constriction of the efferent arteriole and increase in the intraglomerular pressure. This is a great autoregulatory mechanism for the kidney, but it also results in HTN (as a result of the vasoconstriction caused by angiotensin II). In such patients, the hypertension may be a clue to the presence of RAS. Even when diagnosed, however, RAS is not always the cause of the HTN. Recent prospective clinical trials have failed to always show improvement in blood pressure control after treatment (e.g. balloon angioplasty with or without intra-arterial stent placement) for RAS. The captopril renal scan has been used (sensitivity of 89–94% and specificity of 89–96%) as a screening measure for hemodynamically significant RAS. The test simply evaluates the response of the kidneys to ACE inhibition and helps to predict if RAS (when present) will respond to revascularization procedures. By blocking the conversion of angiotensin 1 to angiotensin II, captopril causes a fall in GFR in patients with renovascular HTN (Fig. 1.12). This is the rationale for performing the captopril renal scintigraphy.