- ✦ Evaluation of Patients with Kidney Disease
- ✦ Physiology of Urinary Concentration and Dilution and Diabetes Insipidus
- ✦ Hyponatremia: Etiology, Pathophysiology, and Management
- ✦ Hypernatremia: Pathophysiology, Diagnosis and Management
- ✦ Hypokalemia: Prevention and Treatment
- ✦ Hyperkalemia: Pathophysiology, Diagnosis, Treatment, and Prevention
- ✦ Metabolic Acidosis and Metabolic Alkalosis
- ✦ Metabolic Alkalosis: Pathophysiology and Management
- ✦ Polyuria and Diabetes Insipidus
- ✦ Calcium and Phosphorus Metabolism Associated with Clinical Disorders in Pediatric and Adult Population
- ✦ Generalized Edema (Anasarca): A Systematic Approach to Diagnosis and Management
INTRODUCTION
In addition to the well-known excretory function, kidneys perform many other important metabolic and hormonal functions. They also play a vital role in regulating blood pressure. Thus, it is rather ironic that early stage kidney disease is often clinically silent. Even the biochemical abnormalities are subtle and symptoms curiously absent until late, when the dysfunction is rather advanced. For instance, even though proteinuria and hematuria signifying renal parenchymal damage may be present early on, symptoms of volume overload and uremia will only develop when the kidney damage is far advanced, often over extended period of time. Diagnosis of renal disease is frequently made incidentally when blood urea nitrogen (BUN) and serum creatinine (SCr) are found to be elevated on routine blood chemistry profile. If clinical symptoms or signs alone drive these or other diagnostic studies, most patients would be diagnosed with kidney disease in an advanced stage. Hence the cornerstone of the screening for kidney disease is identification of risk factors and risk stratification. Patients identified to have risk for developing kidney disease are examined in the clinic and tested in the laboratory periodically.
Since early kidney disease is asymptomatic, initial identification depends on laboratory parameters, such as elevated BUN and SCr, followed by the identification of the specific etiology by other diagnostic studies. This early diagnosis of kidney disease is critical in instituting disease specific treatment, reducing the progression of the chronic kidney disease (CKD), managing various complications of CKD (e.g., anemia, renal osteodystrophy), adjusting appropriate “renal dose” of various medications, avoiding nephrotoxins, and preparing for renal replacement therapy in timely fashion, if necessary.
Epidemiological studies over the past two decades have also identified several disconcerting phenomena that make screening for early stage CKD much more urgent. Many recent clinical trials identify that CKD is an independent risk factor for coronary artery disease and that the patients with CKD have a higher chance of dying with cardiovascular disease before reaching end stage renal disease (ESRD). Many national and international societies have now issued clinical practice guideline for large scale screening programs to identify patients with early CKD. It appears that renovascular disease and coronary vascular disease coexist.
These studies have also reported that the incidence and prevalence of CKD were vastly higher and rapidly increasing than previously thought. This “global epidemic” owes largely to the increasing burden of diabetes mellitus and hypertension. The economic impact of CKD and its treatment is enormous; as an example in United States alone it accounts for $25 billion annually.
The assessment of renal disease begins with estimation of glomerular filtration rate (GFR). Complete assessment of the patient with kidney disease can be accomplished by urinalysis, biochemical and immunological analyses, radiological tests and occasionally, a kidney biopsy. These tests are individualized to the specific renal condition of a given patient.4
ASSESSMENT OF GFR
The best measure of renal function is GFR, which is defined as the sum of the ultrafiltrate produced by all the glomeruli per unit of time. GFR differs in people based on age, gender, race and nutritional state. However, it remains quite constant in a given individual in the absence of renal disease except for slow, age related decline. Thus, it is important to measure it periodically in those at risk of developing renal disease, as well as in those who already have CKD. To account for the GFR differences based on individual's weight, all GFR measurements are reported after normalization to 1.73 m2 body surface area. This has allowed the novel staging system for the CKD based upon the level of GFR as introduced by National Kidney Foundation's ‘kidney disease clinical practice guidelines’ (Table 1). This staging system is now widely embraced internationally and includes a specific action plan of testing and treatment for each of the five stages.
There are various methods for measuring or estimating GFR. These are:
- Direct measurement methods which are considered the gold standard because they are highly accurate, but are expensive and time consuming.
- Radionuclide scintigraphy: Intravenous injection of a known quantity of a radionuclide tracer (e.g., DTPA), which is filtered by kidneys but neither secreted nor reabsorbed, and the amount concentrated in the kidney is measured by a gamma camera. This method not only measures GFR accurately but also provides a split function in each kidney.
- Measuring renal clearance of extrinsic substances (e.g., inulin, iothalamate): Intravenous injection of a known quantity of an extrinsic substance that is freely filtered by the kidneys but neither secreted nor reabsorbed. Urine is then collected to measure the quantity of the substance excreted and the ‘clearance’ is calculated by the equation described below.
- Measuring renal clearance of intrinsic substances (e.g., urea, creatinine) – A timed urine collection, typically 24-hour, for measuring the urea nitrogen or creatinine. The creatinine clearance (Ccl) (or urea clearance) is then derived from the clearance equation as below:Where,U = urine creatinine concentration (mg/deciliter),V = volume of urine (ml per minute, i.e., 24 hours volume/1440), andP = Serum creatinine (mg/dL).The average of urea and creatinine clearances is probably a more accurate method than either of the two alone. This is because of the compensation of the underestimation of GFR by the urea clearance by the overestimation of GFR by the Ccl.
- Estimation equations that incorporate Scr, age, gender and race (MDRD-4, Cockroft-Gault equation) C-G equation: Ccl (ml/minute)= (140-Age in years) x Weight (in kg)/72 × Scr (For females, this value should be multiplied by 0.85)
- Ccl can also be calculated by simply calculating reciprocal of Scr, i.e., Ccl = 1/Scr × 100
- For routine longitudinal follow up in any individual patient, simple Scr and BUN are adequate since in any individual with stable health and standard diet, these remain constant. But these measurements are unreliable in accurately predicting GFR.
It must be emphasized that in any acute illness, most of the above methods are unreliable because of the rapidly changing GFR. A 24-hour urine Ccl is probably the closest estimate of the true renal function in this situation.
BUN is a protein metabolite that is cleared by the kidneys via glomerular filtration. BUN level is dependent upon rate of production, tubular reabsorption and secretion, making it an unreliable marker of renal function. For example, a misleadingly high level of BUN can occur 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.).
A misleadingly low BUN level can be associated with advanced renal dysfunction in elderly, malnourished and bedridden patients, who do not have enough muscle mass (as in patients with cirrhosis).
SCr is the most commonly utilized measure of Ccl in day-to-day practice of medicine. Scr is also likely to be affected by many factors other than GFR, though to a lesser degree than BUN (Table 2).
Serial follow up of SCr, rather than the absolute value of creatinine, is more useful indicator of progression of renal function in a given patient, since the ‘normal’ creatinine could vary among individuals, in proportion of their muscle mass and diet. Thus, a low creatinine of 0.8 in an elderly, thin female may reflect advanced renal insufficiency, while a creatinine of 2.0 in a body builder may be associated with normal renal function.
In CKD, as the GFR declines, the tubular secretion of creatinine increases in a compensatory way, keeping the level of SCr unchanged. However, this compensatory mechanism gets saturated as GFR is reduced to 50 to 55 percent from baseline. At this point the SCr starts increasing gradually. Therefore, it can be surmised that a GFR change from 100 ml/min/m2 to 60 ml/min/m2 will not result in a change in the SCr. However, a change from 1.0 mg/dl to 1.2 mg/dl may signify that at least 50 percent GFR has been lost by that time, making it at least a stage 3 CKD.
Because of the compensatory tubular secretion of the creatinine, estimation of Ccl from spot SCr or total urine creatinine excretion in 24 hours usually overestimates GFR. Inhibition of tubular secretion of creatinine by cimetidine or trimethoprim can improve the accuracy of this estimation.
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The Cockcroft-Gault equation also modestly overestimates GFR. In children, Schwartz and Counahan-Barratt formulae are used similarly. A more accurate equation that applies to those with kidney disease is the Modification of Diet in Renal Disease (MDRD) equation, which calculates estimated GFR (eGFR). This is more difficult to calculate, but GFR calculators using this formula are widely available on various websites (e.g., www.kidney.org) and handheld devices. Even with this equation, concerns remain regarding its validity in diverse populations. It underestimates GFR in those without kidney disease.
Due to the fallacies of BUN and creatinine in estimating true GFR, and difficulty in measuring GFR by direct methods, there remains a need for a more accurate and easily available marker of kidney function to diagnose kidney disease early. Among several potential candidates, serum levels of cystatin C, a protein freely filtered and then metabolized by the tubules, is promising although still affected by factors other than GFR.
ASSESSMENT OF TUBULAR FUNCTION
The tubular function is responsible for dilution, concentration and acidification of urine.
This can be done by careful evaluation of osmolality, specific gravity, pH and anion gap of urine. The essentials of urinalysis are discussed below.
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. An expert evaluation of UA may distinguish glomerular from tubulo-interstitial disorders in the patients with elevated SCr levels and/or proteinuria. In addition, UA can help in following the activity of disease in a variety of renal disorders. UA is often called a ‘poor man's renal biopsy’. As mentioned above, UA can also help in evaluating tubular function with relatively simple testing.6
UA requires collection of 10 to 15 ml of fresh urine specimen in a clean, disposable container, which should be sterile if the sample is to 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. Urine should be 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 physical characteristics of urine, dipstick evaluation of urine, and microscopic examination of urine.
Evaluation of the Physical Characteristics of the Urine
The physical and chemical characteristics of urine and their significance are summarized in Table 3. Color of normal urine can range from yellow to amber, as a function of concentration of urine or osmolality. The osmolality of urine is determined by the number of particles in solution independent of their charge, size or density. This can be measured by freezing point depression by the lab, if needed. On the other hand, specific gravity of the urine can be measured relatively easily by refractometer, and depends upon number, relative size and density of particles in urine. It correlates with osmolality, but not in a mathematical fashion. The measurement of specific gravity by dipstick is not accurate. The physiologic range of urine specific gravity is 1.003 to 1.035 (compared to 1.000 for distilled water). Urine osmolality can ordinarily be increased by water deprivation, to a maximal capacity of 1200 mOsm/kg in a normal person, but cannot be achieved in states of deficiency of vasopressin. A good response to vasopressin will indicate deficiency of vasopressin (as in central diabetes insipidus) or resistance to action of vasopressin (as in nephrogenic diabetes insipidus). In those with low osmolality of plasma (due to relative excess of water compared to solutes), urine osmolality should be low, reflecting kidney's effort to excrete extra water. In the presence of hypoosmolar state, inability of kidney to dilute urine maximally (osmolality <100 or so), reflects presence of antidiuretic hormone, which may be appropriate (as in heart failure and cirrhosis) or inappropriate (as in those with syndrome of inappropriate antidiuretic hormone excess).
Semi-quantitative Chemical Analysis with a Dipstick Consisting of Multiple Test Reagents
Urinary pH can be measured rather accurately by dipstick and is usually within the range of 4.5 – 7.9. Urine pH can be alkaline after a meal (due to the “postprandial alkaline tide”) and decreases with fasting.
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Urinary tract infection (UTI) with urea splitting organisms (especially proteus) and systemic alkalosis due to vomiting, diuretics or alkali therapy can render urine alkaline. It can be a clue to the presence of renal tubular acidosis. Persistently acid urine is seen with high protein intake (increased “fixed acid” generation), fever, gout, severe potassium depletion, hyperaldosteronism, metabolic acidosis (but not renal tubular acidosis- RTA), and cranberry juice ingestion.
Microscopic Evaluation of the Urinary Sediment
The microscopic examination is conducted on the pellet obtained after centrifugation of urine at 2000 revolutions per minute for 5 minutes. The supernatant should be saved for treatment with sulfosalicylic acid (SSA), if indicated. It is very useful and provides important clues to presence of intrarenal pathology. The typical findings are summarized in Table 3. Figure 1 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. Dysmorphic (abnormally shaped) erythrocytes of acanthocyte variety indicate glomerular hematuria. Acanthocytes are doughnut-shaped or spherical (but microcytic) and have membrane blebs (“Mickey Mouse ears”). Leukocytes are larger in size and demonstrate the presence of cytoplasmic granules or lobulated nuclei. Presence of leukocytes usually indicates either infection (also associated with presence of bacteria) or interstitial nephritis. Epithelial cells may appear in the urine, and have different shapes according to the source they are derived from (renal tubular epithelium, transitional epithelium from the ureters or bladder, or squamous epithelium from the vaginal vault).
Urinary casts are formed in the distal tubule and collecting ducts. Particulate matter present in urine gets cast in the matrix of Tamm-Horsfall protein in the shape of renal tubules: cylindrical, with parallel sides and rounded ends. Identification of specific types of casts helps in narrowing the differential diagnosis in patients with renal disease (see Table 4). Granular or dense granular (muddy brown) casts signify tubular damage. Red cell casts (Fig. 2) or white cell casts (Fig. 3) indicate inflammation.
Measurement of Urine Electrolytes and Calculation of Urinary Anion Gap and Osmolal Gap
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 light of clinical setting. Low urine sodium level (less than 10 mEq/L) in a spot specimen generally indicates 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:
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 percent, if above formula is multiplied by 100) indicate low renal perfusion as in pre-renal ARF, sepsis, rhabdomyolysis, radiocontrast administration, nonsteroidal anti-inflammatory medicine use and acute glomerulonephritis.
Figure 1: Cellular elements in urine. Red blood cells (RBCs) present as rounded cells without nucleus. White blood cells (WBCs) are slightly larger than the RBC and have granular appearance. Squamous cells (SCs) are large, irregular cells
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Figure 2: Red blood cell cast. Note numerous small RBCs packed within the cast, indicative of glomerular hematuria
Values greater than 1 percent or even higher may indicate acute tubular necrosis in an appropriate clinical setting of ARF.
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 15 mEq/L suggest gastrointestinal losses). Although urinary chloride losses are usually associated with a spot urine chloride level in excess of 15 mEq/L, in cases of severe volume depletion associated with long-term diuretic use, the concentration may be lower.
Figure 3: White blood cell casts. Note presence of multiple WBCs within the proteinaceous material in the shape of tubules
Urine chloride less than 20 mmol/L or greater than 20 mmol/L help in determining therapy of metabolic alkalosis.
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:
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 nonrenal origin (e.g., diarrhea), the kidney will respond by increasing NH4+ production. This will result in an increase in Cl-concentration, which will exceed the sum of (Na+ + K+). The urinary anion gap will then take a negative value. In contrast, the failure of the kidneys to excrete acid at a normal rate will result in metabolic acidosis (i.e., renal tubular acidosis). Then, urinary NH4+ is quite low, resulting in a positive urinary anion gap. Presence of ketoacids, hippurate, benzoate or penicillin derivatives may also make the urine anion gap positive. This is further discussed under Metabolic Acidosis.
Urine osmolal gap may be useful in the presence of unmeasured anions. It can be calculated as –
Urine Osmolal gap = Measured—Calculated urine osmolality.
Where,
calculated osmolality = 2x (Na+K)+(urea/2.8) +(glucose/18)
This can be simplified as 2xNa++10 in those with relatively normal values of urea and glucose.
Proteinuria
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 percent albumin, 15 percent immunoproteins, and 5 percent 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 g/day). The term “microalbuminuria” is used for minor increases in urine albumin excretion (in excess of 30 mg/day). Albumin specific dipsticks can be used to detect microalbuminuria. First morning specimen is preferred for spot urine evaluation. Alternatively, spot urine albumin-creatinine ratio can be calculated. If the albumin excretion is in excess of 500 to 1000 mg/gm of creatinine, it is reasonable to follow proteinuria with spot urine protein-creatinine ratio. Quantitation of 24-hour urine protein excretion excludes the diurnal variation in protein excretion and remains the gold standard, though tedious and often impractical for the patient. SSA method (using a 20 percent SSA solution) precipitates all proteins present in urine (including Bence Jones proteins, glycoproteins, globulins, and albumin). It is important to do urine protein electrophoresis to rule out presence of monoclonal protein in most cases of proteinuria.
Immunologic Markers in Renal Disease
Autoimmunity is frequently involved in the pathogenesis of renal disease. Serology to measure markers of immune function is an important tool in differential diagnosis of renal, especially glomerular diseases. These will be discussed in detail in the chapter on glomerular diseases.
Radiologic Evaluation in Renal Disease
Radiologic studies are integral part of work up to define renal anatomy and perfusion. The studies should be chosen with discretion and should be individualized to obtain the most relevant information. Similar information can be obtained from different tests and there is no single best test for every patient.
In presence of renal insufficiency, it is important to consider the risks involved in a radiologic test. For example, use of radiocontrast media can result in loss of renal function and development of acute, and sometimes, permanent renal failure. Presence of renal insufficiency, older age, and amount and type of contrast are the most important risk factors for radiocontrast nephrotoxicity. Adequate hydration, use of isoosmolar contrast and premedication with certain medications 10may attenuate this insult. This will be dealt in more detail in the chapter on ARF.
Evaluation of Specific Renal Diseases
Depending upon the clinical circumstances, the most useful tests are outlined below:
Urinary Tract Infection
UTI, especially if confined to the lower tract, usually responds quickly to antibiotic treatment and there is no need for diagnostic imaging studies. The diagnosis of upper UTI (i.e., pyelonephritis) can usually be made clinically, but radiologic studies are needed in those with complicated pyelonephritis such as those with poor response to therapy, co-existing diabetes mellitus or altered immune state, known history of kidney stone or urinary tract abnormality with recurrent pyelonephritis. Patients with diabetes and pyelonephritis are at increased risk of emphysematous pyelonephritis, which is a particularly severe infection. Abdominal CT scan most effectively demonstrates the presence of air in a bubbled pattern in renal parenchyma and in Gerota's fascia. A nephrectomy is usually needed. Recurrent pyelonephritis in patients with a known history of stone disease can be evaluated by a renal ultrasound without using intravenous contrast.
Kidney Stone Disease
Asymptomatic urinary stones are often incidentally detected during an abdominal imaging study. Due to the presence of calcium in the urinary stones (85 to 90 percent), a plain abdominal radiograph of kidney, bladder and ureter (KUB) region can detect stones (Fig. 4), but has a low sensitivity and specificity. An IVP can also detect a radiolucent stone and presence or absence of obstruction, but has the disadvantage of using radiation and contrast.
Figure 4: Kidney, Ureter, Bladder (KUB) film showing right renal stone. Radioopaque stones (due to the presence of calcium in the stone) can be detected by plain films
In the setting of renal colic, spiral CT scan (technique by which all the CT images are acquired in one breath hold, usually 20 seconds) will show virtually all kidney stones: both radioopaque and radiolucent, does not require injection of contrast, and can be done quickly (Fig. 5). With evolving techniques, the dose of radiation with spiral CT is expected to decrease.
Renal Masses
Renal masses are also commonly detected on radiologic studies performed for unrelated reasons. Abdominal CT, ultrasound, or MRI can further delineate the nature of the mass, which will impact treatment strategy. For example, a simple cyst detected by ultrasound must have well-defined smooth walls, good enhancement, and no internal echoes; management consequently consists of periodic follow up only. Characteristics suggestive of malignancy such as lobular contour, poor enhancement from the surrounding renal parenchyma, and presence of calcifications warrant further investigation. An abdominal CT, by measuring the density of the mass as compared to that of water, can further define the cysts or masses.
Figure 5: Spiral CT stone study showing presence of stones in both kidneys. The CT study has the advantage of having high sensitivity and specificity, and no need of using radiocontrast
A combination of studies, such as ultrasound, CT or MRI can be used for indeterminate lesions: often requiring periodic follow up. Figure 6 shows a simple renal cyst and figure 7 shows polycystic kidney disease.
Hematuria
Hematuria can occur from upper or lower urinary tract due to a variety of causes, such as glomerular disease, urinary stone, infection, or neoplasm. Due to its noninvasive nature, ultrasound can easily be used for initial evaluation of renal anatomy and presence of a lesion such as stone or mass. Retrograde pyelography is helpful in identifying and defining lesions in upper urinary tract. Cytology of urine should also be done to exclude malignancy. Cystoscopy is indicated to further evaluate the bladder if the hematuria is not explained by other tests. If these tests have still not determined the diagnosis, an abdominal CT or MRI with gadolinium can be performed as the next step.
Acute Renal Failure
Clinical evaluation of renal failure is usually accomplished by determining the cause as prerenal, intrarenal, or postrenal. The cornerstone of initial diagnosis of postrenal failure is the renal ultrasound. Postrenal failure is caused by bladder outlet obstruction (e.g., prostatic hypertrophy or tumor, neurogenic bladder, or bladder tumor) or bilateral ureteric obstruction (e.g., abdominal/pelvic mass or retroperitoneal fibrosis). A renal ultrasound will identify dilatation of the renal collecting system upstream from the blockage in most cases. Absence of dilatation or only minimal dilatation, despite the presence of obstruction, may indicate very recent obstruction. Retroperitoneal fibrosis can prevent development of obvious dilatation of renal pelvis despite causing ureteral obstruction. Dilated pelvis may also be a result of reflux from the bladder into the ureter and renal collecting system in the absence of actual obstruction. Chronic renal diseases are characterized by increased parenchymal echogenicity (brightness on ultrasound images) and small size of kidneys.
Figure 6: Simple renal cyst seen on ultrasound of the kidney. The cyst has thin walls, without internal echo, and is clearly demarcated from surrounding tissue
Renal Artery Stenosis
Renal artery stenosis (RAS) is a common, and potentially correctable, condition in patients with uncontrolled or atypical hypertension (early or late onset hypertension, rise in creatinine with ACE inhibitor treatment, presence of abdominal bruits, asymmetric kidneys by imaging), and unexplained renal insufficiency. A variety of radiologic tests can be used to screen for this anatomical condition in such patients, though the sensitivities and specificities of the tests vary with experience of operators. It is very important to determine the functional significance of the anatomical finding of a narrow artery before treating every such finding. While correction of stenosis with an invasive procedure may improve hypertension or renal insufficiency in some, the correction may fail to improve hypertension or renal insufficiency in others if chosen indiscriminately, and even prove to be hazardous. The added risk of contrast-induced nephropathy superimposed on hypertensive damage is always a concern.
Figure 7: Bilateral multiple cysts shown by CT scan. The kidneys are enlarged with presence of innumerable cystscharacteristic of polycystic kidney disease
Duplex ultrasound is a relatively inexpensive and safe test (no exposure to radiation or dye), but it is difficult to visualize the entire main renal artery, particularly in obese patients. Vascular indices, such as resistive index of the blood vessel, have been suggested as a clue to the presence RAS. The accuracy of renal duplex ultrasound is highly variable and operator dependent and it is recommended for screening in those centers only that have proven its utility. Renal ultrasound in a patient with unilateral RAS may show increased renal parenchymal echogenicity and a difference in size between the affected (smaller) and unaffected kidney, but is not sensitive or specific. Magnetic resonance (MR) angiography has the advantage of avoiding the use of intravenous radiologic contrast media, but gadolinium-induced nephrogenic fibrosing dermopathy is a serious risk in those with decreased kidney function.
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. Figure 8 shows a renal arteriogram showing beaded appearance of bilateral renal arteries in fibromuscular dysplasia, a lesion found more commonly in young females, and amenable to renal 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 pre-existing 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.
Sampling of renal veins on both sides for measurement of renin can also be used to determine the site of production of renin.
Nuclear Imaging in Patients with Kidney Disease
Nuclear imaging is a method that uses a radioactive tracer which, when introduced into the body, targets a specific organ and emits a type of radiation that can be imaged and used for diagnostic purposes. The tracer consists of a radionuclide, most commonly 99mTc that is carried to the target organ by a nonradioactive pharmaceutical. Nuclear imaging provides physiologic data about the function of the organ of interest. Radiopharmaceuticals commonly used to target the genitourinary system are discussed in the Table 5.
Evaluation of the Renal Plasma Flow
DTPA or MAG3 may be used for evaluation of the renal artery flow and excretion. Relative GFR or 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 GFR
GFR can be measured using 99mTc –and DTPA is used to assess effective renal plasma flow (ERPF). Using nuclear medicine techniques, isotope counts are taken at about 1 to 2 minutes postdosing. The contribution by each kidney to total GFR or ERPF can be quantified. The information is very helpful in assessing differential function in asymmetrical renal disease as well as for monitoring changes in function over time. GFR measurements using nuclear medicine techniques correlate well with the inulin clearance and 24-hour Ccl measurements.
Figure 8: Renal arteriogram showing beaded appearance of bilateral renal areries. The lesion was successfully angioplastied, resulting in improvement in control of blood pressure
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Allergic Interstitial Nephritis (AIN)
Gallium-67 citrate is a radiopharmaceutical that accumulates in areas of inflammation; therefore it can be used to assess for AIN, as well as renal infections (e.g., renal and perirenal abscess) and tumors. The kidney usually excretes it 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.
Obstructive Uropathy
Presence 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. Presence of active obstruction can be assessed by diuretic-augmented renal scintigraphy (e.g., Lasix renal scan). After the administration of the diuretic, the urine flow increases and should clear the scintigraphic activity caused by a nonobstructed system. 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 (Figs 9A and B.)
Renal Artery Stenosis
Secondary hypertension is often the result of renovascular disease, including major RAS. RAS may be atherosclerotic in nature (usually in older patients) or due to fibromuscular dysplasia, which is common in young females. The resulting fall in GFR leads to activation of renin-angiotensin system and maintenance of GFR via constriction of the efferent arteriole and increase in the intraglomerular pressure. The increased production of Angiotensin II results in HTN. Even when diagnosed, 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 to 94 percent and specificity of 89 to 96 percent) 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 I to angiotensin II, captopril causes a fall in GFR in patients with renovascular HTN (Figs 10A and B). This is the rationale for performing the captopril renal scintigraphy. It will be discussed more in the section dealing with renovascular hypertension.
RENAL BIOPSY
Renal pathology can best be assessed by microscopic examination of renal tissue obtained by biopsy. The biopsy not only provides anatomical information, it provides diagnostic and prognostic information as well. Indications for renal biopsy include unexplained elevation of creatinine, proteinuria, hematuria, hereditary nephritis and in kidney transplant dysfunction.
The biopsy can be done by percutaneous technique using guidance of ultrasound or CT scan. Transjugular biopsy can be done in situations where it is not possible to reach the kidney from percutaneous route, or the patient is not able to cooperate during the procedure. Open surgical biopsy is needed in a patient with single kidney.14
Figures 9A and B: 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)
Figures 10A and B: 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
Biopsy sample is studied by three principal methods:
- Light microscopy typically employs hematoxylin and eosin stain to examine the various structures in the parenchyma. Special stains such as silver stain, Masson trichrome, PAS, etc. are used as needed.
- Immunofluorescence is a valuable method to detect immune complexes and antibodies mainly in the glomeruli, but in any part of the parenchyma. In some instances, this method may provide pathognomonic findings in certain diseases, e.g. anti-GBM antibody disease. Monoclonal antibodies labeled with fluorescent dyes are utilized to bind to various immune complexes or antibodies and studied under fluorescence microscope.
- Electron microscopy examines the ultrastructure of the renal tissue and the cytoskeleton. Among its many benefits, this technique can detect the specific location of immune complexes within the glomeruli, examine basement membrane pathologies, detect viral particles in infectious diseases, etc.
SUGGESTED READING
- Bazari H. Approach to the patient with renal disease. Cecil Medicine. Goldman L (ed) et al. 23rd edition. Saunders, Philadelphia: 2007: Chapter 115.
- Investigation of renal disease. section 2: comprehensive clinical nephrology. Feehally and Johnson (eds) Mosby 3rd edition, 2007.