844
Readers of this chapter are assumed already to be competent
medical historians and to be very familiar with the essent...
Chapter 24  Approach to the Patient with Kidney Disease   845
studies and the sequence in which they should be performed.
...
846   Section IV  Evaluation of the Patient with Kidney Disease
red or brown urine. Many chemicals, medications, and food
...
Chapter 24  Approach to the Patient with Kidney Disease   847
Imaging
When hematuria is not believed to be of glomerular o...
848   Section IV  Evaluation of the Patient with Kidney Disease
high-grade proteinuria and even full-blown nephrotic syn-
...
Chapter 24  Approach to the Patient with Kidney Disease   849
Sedimentation rate and C-reactive protein level are often el...
850   Section IV  Evaluation of the Patient with Kidney Disease
suggests an underlying systemic illness causing secondary ...
Chapter 24  Approach to the Patient with Kidney Disease   851
Alport’s disease and nail-patella syndrome.Some patients can...
852   Section IV  Evaluation of the Patient with Kidney Disease
extremities must be carefully evaluated for evidence of ar...
Chapter 24  Approach to the Patient with Kidney Disease   853
sodium concentration may be artifactually reduced (pseudo-
h...
854   Section IV  Evaluation of the Patient with Kidney Disease
can include suprapubic fullness, frequency, polyuria, or n...
Chapter 24  Approach to the Patient with Kidney Disease   855
a similar degree of hypertension but with coexistent diabete...
856   Section IV  Evaluation of the Patient with Kidney Disease
The next very important element of the physical examina-
t...
Chapter 24  Approach to the Patient with Kidney Disease   857
pain, which frequently radiates into the testicle or labia. ...
858   Section IV  Evaluation of the Patient with Kidney Disease
increasingly insoluble as the pH falls below 6.5). When ba...
Chapter 24  Approach to the Patient with Kidney Disease   859
4 mm in diameter will pass spontaneously. As stone size
incr...
860   Section IV  Evaluation of the Patient with Kidney Disease
History and Review of Systems
The initial goal of history ...
Enfermedad renal
Enfermedad renal
Enfermedad renal
Enfermedad renal
Enfermedad renal
Enfermedad renal
Enfermedad renal
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Enfermedad renal

  1. 1. 844 Readers of this chapter are assumed already to be competent medical historians and to be very familiar with the essentials of the general physical examination. Furthermore, many of the topics that are briefly reviewed in this chapter are addressed in much greater detail in other parts of this textbook. Con- sequently, the focus here is on certain features of the history, physical examination, and laboratory testing that might be of specific utility to nephrologists and nephrology trainees. The chapter is divided into nine broad areas of kidney disorder and addresses those features of greatest importance to the early diagnostic and therapeutic phases of the patient’s workup. Hematuria Hematuria is the excretion of abnormal amounts of red blood cells (RBCs) into the urine. Normal individuals excrete about 1 million RBCs per day in their urine. When translated to the sediment of a spun urine specimen, this equates to about 1 to 3 RBCs per high-power field (HPF). Therefore excretion of more than 3 RBCs per HPF is abnormal and may warrant further evaluation. Asymptomatic “microscopic hematuria” is very common; it may be detected in up to 13% of adults.1 Although it is most often of no consequence, hematuria can be a sign of serious disease and should never be ignored. Gross hematuria occurs when enough blood is present in the urine to turn it red or brown. Although microscopic and gross hema- turia are generally caused by the same conditions, there are marked differences in the relative frequencies with which vari- ous pathologic conditions manifest these two presentations. Therefore, the diagnostic approaches to these two conditions are different. Routine screening of healthy individuals for the presence of hematuria is not recommended by the U.S. Preventive Services Task Force.2 However, asymptomatic microscopic hematuria may be detected when a urinalysis is performed during the evaluation of a patient for nonurinary complaints. Furthermore, despite official recommendations, urinalyses are nonetheless frequently ordered as a screening test. When such testing reveals hematuria, the person’s age, gender, race, medical history, and physical findings should be considered in deciding whether to further evaluate this find- ing and, if so, in determining the most appropriate diagnostic Hematuria,  844 History and Review of Systems,  845 Physical Examination,  845 Laboratory Tests,  845 Imaging,  847 Nephritic Syndrome,  847 History and Review of Systems,  848 Physical Examination,  848 Laboratory Tests,  848 Imaging,  849 Renal Biopsy,  849 Nephrotic Syndrome,  850 History and Review of Systems,  850 Physical Examination,  851 Laboratory Tests,  852 Imaging,  853 Renal Biopsy,  853 Obstructive Uropathy,  853 History and Review of Systems,  853 Physical Examination,  854 Laboratory Tests,  854 Imaging,  854 Hypertension,  854 History and Review of Systems,  855 Physical Examination,  855 Laboratory Tests,  856 Imaging,  856 Other Studies,  856 Nephrolithiasis,  856 History and Review of Systems,  856 Physical Examination,  857 Laboratory Tests,  857 Imaging,  858 Differential Diagnosis,  858 Initial Treatment,  858 Acute Kidney Injury,  859 History and Review of Systems,  860 Physical Examination,  860 Laboratory Tests,  860 Imaging,  861 Renal Biopsy,  861 Chronic Kidney Disease   and Chronic Kidney Failure,  861 History and Review of Symptoms,  862 Physical Examination,  863 Laboratory Tests,  863 Imaging,  864 Urinary Tract Infection,  864 History and Review of Systems,  864 Physical Examination,  865 Laboratory Tests,  865 Imaging,  865 Approach to the Patient with Kidney Disease Michael Emmett, Andrew Z. Fenves, and John C. Schwartz Chapter 24
  2. 2. Chapter 24  Approach to the Patient with Kidney Disease   845 studies and the sequence in which they should be performed. Asymptomatic microscopic hematuria should be confirmed in at least two of three midstream clean-catch voidings before the physician embarks on a potentially expensive workup, which can have significant adverse impact and complications. If microscopic hematuria spontaneously resolves, evaluation decisions are strongly influenced by the clinician’s index of suspicion (see later). Microscopic hematuria associated with symptoms such as urinary frequency or pain is more worri- some and mandates further evaluation. Gross hematuria, especially if clots are passed, usually indicates a urologic source of bleeding. Even a single episode of gross hematuria man- dates evaluation. The most common cause of gross hematuria in young women (<40 years of age) is urinary tract infection (UTI). Malignancy must be strongly considered and ruled out by appropriate studies in older patients.3 Brown, “Coca- Cola”–colored, or smoky urine with RBCs present on micros- copy is very suggestive of a glomerular source of bleeding. History and Review of Systems Three major factors influencing the workup are the patient’s gender,race,and age.The common causes of hematuria in chil- dren and young adults are much different than those in older individuals. Hematuria in adults older than 40 years (some experts propose an age cutoff of older than 50 years) must be considered a sign of malignancy (of the bladder, upper urinary tract, or kidney) until proved otherwise. Although malignancy is much less frequent in young patients with hematuria, a Wilms’ tumor should be considered. Bladder cancer is much more common in men and in whites. Hypercalciuria, and less commonly hyperuricosuria, cause hematuria frequently in children but less commonly in adults. Hematuria due to UTI is much more common in women, whereas older men may bleed from the prostate. In women, cyclic gross hematu- ria concurrent with the menses raises the strong possibility of genitourinary (GU) tract endometriosis. The combination of hematuria with fever, dysuria, or flank pain, or a prior history of these symptoms raises the likelihood of infection, stones, or malignancy. Colicky pain suggests ureteral ­obstruction from a stone, blood clot, or sloughed renal papilla. This is especially the case if the pain radiates to the testicle or labia. A family history of renal dysfunction or renal stones should be sought. When a patient with hematuria has family members with renal failure, polycystic kidney disease or Alport’s disease should be considered. Familial hearing loss, especially in male relatives, also suggests Alport’s disease. A very common cause of otherwise unexplained asymptomatic familial hematuria is thin basement membrane disease.4 Sickle cell trait is a very common cause of hematuria in African Americans. Sickle cell anemia can also cause hematuria.5 Hematuria sometimes occurs after vigorous exercise or participation in contact or noncontact sports.6 Mechanisms include direct recurrent trauma to the bladder or kidneys and pathologic renal hemodynamic effects. However, the fact that hematuria occurs after completing a long bicycle ride or running a marathon does not exclude the possibil- ity of other potentially serious pathologic conditions, and generally a complete evaluation is necessary. Exercise-related hemoglobinuria, such as march hemoglobinuria, and postex- ercise myoglobinuria result in excretion of globin pigments and positive results on dipstick testing without RBCs in the urine. Travel history may be very important as, for example, when hematuria develops in patients who have traveled to areas where Schistosoma haematobium infection or tuberculo- sis is endemic. Although otherwise unexplained bleeding into the urine can occur in patients with hereditary or acquired coagulation disorders or in patients who take therapeutic anti- coagulants, these conditions and drugs should not preclude consideration of other important underlying etiologies. Bleed- ing disorders and anticoagulants will cause any pathologic GU structures such as malignancies to bleed more readily. This is especially common in older patients.7 A history of cigarette smoking (or second-hand smoke exposure) increases the risk of bladder cancer twofold to fourfold.8 Occupational exposure to aniline dyes and aromatic amines and amides; treatment with some chemotherapeutic agents such as cyclophospha- mide and mitotane; and radiation to the pelvis increase the risk for uroepithelial cancers. In the past, long-term use of analgesics did increase the risk of bladder cancer, but this was probably due to the presence of phenacetin, which has now been removed from these medications. Indeed, the use of aspi- rin and other nonsteroidal antiinflammatory drugs (NSAIDs) has been shown to reduce the likelihood of bladder cancer in some epidemiologic studies.9 A recent history of pharyngitis followed by hematuria raises the possibility of glomerulonephritis with synpharyn- gitic bleeding. Chronic glomerulonephritis, most commonly immunoglobulin A (IgA) nephropathy, is often exacerbated by an upper respiratory tract infection and may result in gross hematuria. This is distinct from poststreptococcal glomerulo- nephritis, which occurs 2 to 6 weeks following the infection. With gross hematuria, it is useful to determine if the bleed- ing is more pronounced at the very beginning or at the termina- tion of voiding. Although formal “three-glass” urine collections are rarely performed, a history of initiation hematuria suggests a urethral source, whereas termination hematuria is suggestive of bladder neck or prostatic urethra pathology. Blood clots in some the urine usually denote structural urologic pathology. Physical Examination Evaluation of blood pressure and volume status is especially important when glomerulonephritis is a consideration. If pal- pation of the abdomen reveals a mass, a renal tumor or hydro- nephrosis may exist. A palpable bladder after voiding indicates obstruction or retention. Atrial fibrillation raises the possibil- ity of renal embolic infarction, especially if the patient has flank pain. Costovertebral angle tenderness is also suggestive of pyelonephritis, nephrolithiasis, or ureteropelvic junction obstruction. A bruit over the kidney suggests a vascular cause. Careful genital and rectal examination is necessary to diag- nose prostatitis, prostate cancer, epididymitis, meatal stenosis, and other structural causes of hematuria. Laboratory Tests A diagnosis of gross hematuria is suggested by red or brown urine. Only about 1 mL of blood causes 1 L of urine to become red. However, many substances other than RBCs can produce
  3. 3. 846   Section IV  Evaluation of the Patient with Kidney Disease red or brown urine. Many chemicals, medications, and food metabolites can produce a spectrum of urine colors. A chemi- cal test for hemoglobin is very helpful in distinguishing among these possibilities. The most commonly used method of test- ing the urine for blood is the urine test strip or dipstick, which utilizes the peroxidase-like activity of hemoglobin to gener- ate a color change. The test strip does not react with most nonhemoglobin pigments that can color the urine. In addi- tion to detecting the hemoglobin within RBCs, however, the test reaction yields a positive result with free hemoglobin and myoglobin. Also, hypochlorite solutions, which are sometimes used to clean urine collection containers, can produce a false- positive test strip reaction for blood. Therefore, a positive test strip result must be followed by a microscopic examination of the urine to confirm the presence of RBCs. Some of the causes of red or brown urine are shown in Table 24-1. It is crucial to separate hematuria caused by glomerular abnormalities from bleeding due to other pathologic kidney conditions (tumors or cysts) or pathologic processes distal to the glomerulus (interstitial disease, stones, or tumors, or other processes affecting the renal pelvis, ureters, bladder, urethra, prostate, or other lower GU system structures). When blood originates from glomeruli,the RBCs pass through the length of the renal tubules, where they are subjected to marked changes in osmolality, ionic strength, pH, and other forces. Compres- sion of the RBCs together with urine proteins creates RBC casts (Figure 24-1), and identification of these casts on micro- scopic examination is excellent evidence of glomerular bleed- ing. Although quite specific, RBC casts often are not seen even with definite glomerular bleeding. A more common helpful finding in glomerular bleeding is the identification of dysmor- phic RBCs of varying shape and sizes with blebs, budding, and especially the vesicle-shaped protrusions that characterize acanthocytes (i.e., “Mickey Mouse ears”; see Figure 24-1). For dysmorphic RBCs to be an excellent indicator of glomerular bleeding, most of the urine RBCs should be affected.10 Acan- thocytes are quite specific, however, and if they represent more than 5% of the RBCs, this is very a suggestive sign of glomeru- lar bleeding. Another indication that bleeding is more likely of glomerular origin is coexistent significant proteinuria (>0.5 g/day or >0.5 g protein per gram of creatinine). The presence of pyuria with hematuria suggests inflammation or infection and warrants a urine culture.Table 24-2 highlights some of the features that can be used to differentiate glomerular and non- glomerular, or urologic, hematuria. Urine cytologic analysis is indicated when otherwise unexplained hematuria is docu- mented. It has good specificity when results are positive and a sensitivity of about 80% for bladder cancer but a much lower sensitivity for upper tract malignancy.11 TABLE 24-1  Causes of Red or Brown Urine ENDOGENOUS SUBSTANCES FOODS DRUGS Red blood cells Artificial food coloring Adriamycin Hemoglobin Beets Chloroquine Myoglobin Blackberries Deferoxamine Bilirubin Blueberries Levodopa Porphyrins Fava beans Methyldopa Melanin Paprika Metronidazole Rhubarb Nitrofurantoin Phenazopyridine (Pyridium) Phenolphthalein Phenytoin Prochlorperazine Quinine Rifampin Sulfonamides FIGURE 24-1  Red blood cell cast and acanthocytes consistent with glomerular bleeding (diffusion interference contrast optics). (Courtesy of Dr. Rajiv Agarwal, Nephrology Division, Indiana University School of ­Medicine.) TABLE 24-2  Differentiation of Glomerular from Urologic Bleeding GLOMERULAR HEMATURIA NONGLOMERULAR/  UROTHELIAL/­ UROLOGIC ­HEMATURIA Urine color Dark red, brown, cola colored, smoky Bright red Clots − + Proteinuria + − Red blood cell ­morphology Dysmorphic (espe- cially acanthocytes) Isomorphic Hypertension + − Edema + − Urinary voiding symptoms − + Back pain, flank pain + + Renal function Reduced Normal Family history + + Trauma − + Upper respiratory tract infection + − Fever, rash + −
  4. 4. Chapter 24  Approach to the Patient with Kidney Disease   847 Imaging When hematuria is not believed to be of glomerular origin, then computed tomography (CT) with and without intrave- nous (IV) contrast is currently the preferred initial imaging modality to evaluate microscopic and gross hematuria and has largely replaced intravenous pyelography (IVP). CT urogra- phy has excellent sensitivity for stones, identifies most kidney tumors, and reveals other non–GU tract abdominal pathologic processes. The major downside of a CT scan is the need for IV contrast and the significant radiation exposure. If CT cannot be done, then renal ultrasonography is the next best initial imag- ing test. If the explanation for hematuria is not evident on the initial study, the next diagnostic imaging test to perform is cys- toscopy. Direct visualization of the bladder requires cystoscopy. Abnormal areas or lesions can be biopsied. Performing cystos- copy at the time of bleeding may localize the bleeding site. If no abnormality is noted and there is any suspicion of upper tract disease, retrograde pyelography may be performed. One diag- nostic approach is illustrated in Figure 24-2. A major decision branch is based on the patient’s age and other risk factors for bladder cancer.There is controversy about the specific age to be used for diagnostic stratification. Some experts believe it should be 40 years and others argue for 50 years. Figure 24-3 shows the frequency of renal, uroepithelial, and bladder cancers separated by gender and age in 1930 patients evaluated for hematuria.3 Nephritic Syndrome Classic nephritic syndrome is characterized by glomerular hematuria and an active urine sediment, manifested by dys- morphic RBCs (especially acanthocytes) and RBC casts, and often white blood cells (WBCs) and WBC casts. In general, these are the result of an inflammatory process in the glomerulus. Usually, glomerular filtration rate (GFR) is reduced, and variable degrees of hypertension, oliguria, and edema occur. Proteinuria is common but often of relatively low magnitude. In many cases the degree of proteinuria is limited by the accompanying reduction in GFR. However, Microscopic hematuria (Dipstick positive and RBCs in urine) History, physical exam, careful UA, urine culture Non-glomerular bleeding Sx of UTI and positive culture Rx and reevaluate No UTI CT scan Mass or lesion Refer Neg Further W/U, serology studies, kidney Bx, etc as indicated Age >40 y OR age <40 y + high index suspicion Age <40 y Low index suspicion Urine cytology Pos Cystoscopy ? Repeat W/U* Neg Cytology and cystoscopy Quantitate proteinuria and GFR Consider thin BM disease, IgA nephropathy, other GN Glomerular bleeding (Proteinuria/RBC casts/dysmorphic RBCs) FIGURE 24-2  Diagnostic scheme for evaluation of microscopic hematuria.*Workup should be repeated if the patient develops new symptoms of gross hematuria.
  5. 5. 848   Section IV  Evaluation of the Patient with Kidney Disease high-grade proteinuria and even full-blown nephrotic syn- drome can coexist with nephritic syndrome in some patients. The hematuria can be sporadic, intermittent, or persistent. It can be microscopic or gross. Isolated glomerular hematuria without inflammation (e.g., that which occurs with thin base- ment membrane disease) is generally not considered to be the result of a nephritic process. The character of the glomerular hematuria does not always predict the underlying cause of the disorder, nor does it predict the long-term renal outcome of the process. Nephritic syndrome can occur as an isolated renal process or as a feature of a systemic disease or a hereditary disorder. Glomerular hematuria due to nephritic syndrome must be distinguished from bleeding caused by other kidney, intersti- tial, or lower GU tract pathology, including stones, benign or malignant mass lesions, and infections. The features that help differentiate these classes of hematuria have been discussed in the previous hematuria section and are listed in Table 24-2. When nephritic hematuria is identified, additional renal eval- uation is required. History and Review of Systems The patient’s history often helps to distinguish glomerular hematuria from urothelial or urologic hematuria. Glomerular hematuria, when visible, is often described as dark brown, tea or cola colored, or smoky as opposed to the overtly red color often seen with urologic pathology. Clots are almost never formed with glomerular hematuria.The patient may also note that the urine has become foamy as a result of the excretion of albumin, which has a soaplike action and reduces the sur- face tension of urine. Urinary voiding symptoms are distinctly uncommon. Back, flank, or abdominal pain does not distin- guish glomerular hematuria from urothelial hematuria. There may be a history of an antecedent upper respiratory tract or skin infection in patients with poststreptococcal glomerulo- nephritis (postpharyngitic hematuria). In other patients with an underlying form of chronic glomerulonephritis, such as IgA glomerulonephritis, gross hematuria may occur simulta- neously with, or immediately after, an episode of pharyngitis (synpharyngitic hematuria). There may be a family history of glomerular disease. A history of hypertension, fluid reten- tion, and/or edema formation suggests glomerular hematuria, particularly if renal function is reduced. Fever, skin rash, and joint symptoms raise the possibility of a systemic disease caus- ing glomerular hematuria. Hearing loss and visual symptoms related to lens abnormalities can be seen with Alport’s disease. Hemoptysis raises the possibility of vasculitis or anti–glomer- ular basement membrane (anti-GBM) disease. Physical Examination Hypertension is very frequent with glomerular hematuria. Most often this is due to renal salt retention and volume expan- sion. The salt retention is caused by enhanced reabsorption in the distal nephron, especially the cortical collecting tubule.12 The renin-angiotensin-aldosterone system in most patients with nephritic syndrome is functioning normally.13 Malignant hypertension with vital organ injury occurs in some patients. Careful eye-retinal examination may yield a specific diagnosis. High-frequency sensorineural hearing loss strongly suggests Alport’s disease. Typical skin rashes and other abnormalities can be seen in systemic lupus erythematous, vasculitis, Fabry’s disease, and Henoch-Schönlein purpura. Joint findings may suggest a rheumatologic–collagen vascular disease or vasculi- tis. Examination of the suprapubic area, the back, or the flanks is generally unrevealing. Laboratory Tests Urine Studies The hallmark of nephritic syndrome is glomerular hematu- ria. Hematuria is most easily recognized by a positive result on a urine dipstick test for blood. See the preceding section on hematuria for further discussion. Proteinuria is a frequent accompaniment to hematuria in patients with nephritic syn- drome but is usually absent in patients with urothelial hema- turia.The proteinuria can range from low grade (<500 to 1000 mg/day) to overt nephrotic levels (>3000 mg/day). Protein excretion can be quantitated with 24-hour urine collection. Alternatively, a spot urine protein/creatinine ratio can be determined, which gives a reasonable estimate of the magni- tude of proteinuria.14 Microscopic examination of the urine in the nephritic state reveals a variable number of free RBCs. Often a small pellet of RBCs can be noted at the bottom of a test tube of centrifuged urine. RBC casts are the definitive finding in the nephritic syndrome but very often cannot be seen. A more commonly identified characteristic of glomerular bleeding is dysmorphic urine RBCs with blebs, budding, and vesicle-shaped protru- sions10 (see Figure 24-1). Examination of the urine sediment with phase-contrast microscopy can be especially helpful. Kidney inflammation also generates pyuria and WBC casts. Hyaline casts can be seen, especially with marked proteinuria. Blood Studies Routine laboratory studies should include a complete blood count (CBC), electrolyte levels, blood urea nitrogen (BUN) concentration, creatinine concentration, and liver panel. 20–29 30–39 40–49 50–59 60–69 70–79 80–89 0 5 10 15 20 25 30 %withmalignancy 35 40 45 Age by decade Gross Hematuria-Men Gross Hematuria-Women Micro-Hematuria-Men Micro-Hematuria-Women FIGURE 24-3  Prospectiveanalysisoftheriskofmalignancyin1930patients undergoing workup for hematuria. (Adapted from Khadra MH, Pickard RS, Charlton M, et al: A prospective analysis of 1,930 patients with hematuria to evaluate current diagnostic practice, J Urol 163:524-527, 2000.)
  6. 6. Chapter 24  Approach to the Patient with Kidney Disease   849 Sedimentation rate and C-reactive protein level are often ele- vated regardless of the cause of nephritic syndrome. A deter- mination of the GFR is required. Usually this is accomplished with a quantitative urine collection for measurement of cre- atinine clearance. Iothalamate clearance, if available, provides the most accurate measurement. Various formulas, such as the Cockcroft-Gault equation or one of the equations developed by the Modification of Diet in Renal Disease (MDRD) study, can estimate the GFR based on a single and presumably sta- ble serum creatinine measurement (Table 24-3). However, all methods that rely on a single serum creatinine measurement will give erroneous results when renal function is rapidly changing and the serum creatinine concentration is not relatively stable. Measurements of complement levels can be very helpful in patients with nephritic syndrome.15 It is generally best to begin with a measure of total hemolytic complement (CH50) and then proceed to measurement of C3 (a component of both the classic and alternative complement pathways) and C4 (a component of the classic pathway only). Table 24-4 separates the various forms of acute nephritic glomerulonephritis into those with normal and those with reduced complement levels. Low C3 with normal C4 levels suggest poststreptococcal glo- merulonephritis or membranoproliferative glomerulonephri- tis, whereas low C3 and C4 levels are more consistent with postinfectious glomerulonephritis, systemic lupus erythema- tous, hepatitis C–associated membranoproliferative glomeru- lonephritis (type I), or mixed cryoglobulinemia. Other serologic studies,mainly to measure various autoanti- bodies, are ordered when specific underlying systemic diseases are considered the possible cause. The antinuclear antibody (ANA) and anti-DNA, anti-Smith, and anti-Rho antibodies help confirm the diagnosis of systemic lupus erythematosus and other collagen vascular diseases. The perinuclear anti- neutrophil cytoplasmic antibody (P-ANCA) and cytoplasmic antineutrophil cytoplasmic antibody (C-ANCA) tests help to establish a diagnosis of vasculitis. Anti-GBM antibodies are seen in patients with Goodpasture’s syndrome. A number of infectious diseases can produce an acute nephritic syndrome. It is also important to consider viral hepatitis, both B and C, as well as human immunodeficiency virus (HIV) infection and syphilis and, if plausible, to send blood specimens for diagnostic studies. Other infectious diseases that must always be considered are infectious endocarditis or another persis- tent bacterial infection such as an abscess or infected vascular shunt. Blood cultures must be ordered for all patients with otherwise unexplained fever, heart murmurs, or leukocytosis. The commonly ordered laboratory studies for patients with nephritic syndrome are shown in Table 24-5. Imaging Renal size is a very important parameter to define in patients with nephritic syndrome.This is most easily accomplished with renal ultrasonography. Although normal-sized kidneys do not definitively predict reversibility (even irreversible end-stage kid- neys can be of normal size as a result of swelling or infiltration in patients with diabetes mellitus or amyloidosis), small kidneys do indicate that irreversible fibrosis and atrophy are probably pres- ent.The assessment of renal size is therefore especially important for determining renal prognosis and making decisions regarding renal biopsy. If the kidneys are small (<9 cm in a normal-sized adult) the likelihood of reversible disease decreases markedly, and the difficulty and risk of the biopsy procedure increase. Renal Biopsy Patients with glomerular hematuria who have normal blood pressure, normal renal function, and minimal proteinuria rarely require a renal biopsy unless the clinical presentation TABLE 24-4  Complement Levels in Acute Nephritic Syndromes Low Serum Complement Levels Systemic Diseases (Low C3 and C4) Systemic lupus erythematosus Cryoglobulinemia (hepatitis C) Bacterial endocarditis Shunt nephritis Renal Localized Diseases Acute poststreptococcal glomerulonephritis (low C3; normal C4) Membranoproliferative glomerulonephritis Type I (low C3 and C4) Type II (dense deposit disease) (low C3; normal C4) Normal Serum Complement Levels Systemic Diseases Polyarteritis nodosa Antineutrophil cytoplasmic antibody–positive granulomatosis vasculitis (Wegener’s granulomatosis) Hypersensitivity vasculitis Henoch-Schönlein purpura Goodpasture’s syndrome Renal Localized Diseases Immunoglobulin A nephropathy Rapidly progressive glomerulonephritis Anti–glomerular basement membrane disease isolated to kidney Pauci-immune glomerulonephritis (kidney localized) TABLE 24-3  Glomerular Filtration Rate (GFR)/Creatinine Clearance Estimating Formulas Cockcroft-Gault Equation (estimates creatinine clearance) eGFR = (140 − age) × wt (kg) Cr × 72 × .85 (if female) Abbreviated MDRD Equation (estimates body surface area–corrected GFR in mL/min/1.73 m2) eGFR = 186 × Cr − 1.154 × Age − 0.203 × 1.21 (if black) × .742 (if female) Cr, Serum creatinine concentration (measured as mg/dL); eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease study. Data from National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification, Am J Kidney Dis 39(2 suppl 1):S1-S266, 2002.
  7. 7. 850   Section IV  Evaluation of the Patient with Kidney Disease suggests an underlying systemic illness causing secondary glo- merular disease. Renal biopsy may be helpful when glomeru- lar hematuria is associated with abnormal renal function and is especially so when it is important to establish the specific diagnosis to guide therapy.16 When renal function is decreas- ing rapidly (rapidly progressive glomerulonephritis) and a nephritic picture exists, the biopsy may need to be obtained very rapidly. Nephrotic Syndrome Nephrotic syndrome has historically been considered to include five principal clinical findings: 1. High-grade, albumin-dominant proteinuria (generally 3 to 3.5 g/day or spot urine protein/creatinine ratio of 3 to 3.5 [grams of protein per gram of creatinine]) 2. Hypoalbuminemia 3. Edema 4. Hyperlipidemia 5. Lipiduria However, milder and earlier forms of many clinical dis- orders that can generate the full nephrotic syndrome may produce lower degrees of albuminuria in the range between 30 mg/day to 3500 mg/day with or without the other fea- tures. Also, the full spectrum of nephrotic syndrome may not develop in some patients despite high-grade albumin- uria. The principal underlying abnormality responsible for all the other clinical features of nephrotic syndrome is increased permeability of the glomerular capillaries. Nephrotic syndrome may occur as an idiopathic and iso- lated condition, may be an inherited disorder, or may be a complication of an underlying systemic disease or allergic or immunologic disorder. It is always imperative to identify any underlying cause, when one exists (Table 24-6). This is accomplished by recognizing clues from the history and physical examination, reviewing a routine set of laboratory studies, and performing more specific tests suggested by the initial findings. History and Review of Systems The patient’s history often helps elucidate the cause of nephrotic syndrome. The most common underlying systemic disease causing nephrotic syndrome is diabetes mellitus, and the syndrome can develop in those with all subtypes of this disorder. Although other glomerulopathies can also occur in patients with diabetes, atypical historical, physical, and labo- ratory findings usually cause the physician to consider another cause for nephrotic syndrome.17 The history may also point to other relatively common disorders that generate nephrotic syndrome. These include systemic lupus erythematosus and the various forms of systemic amyloidosis—primary, sec- ondary or reactive, and familial-hereditary. Infectious causes including viral hepatitis, HIV infection, Mycoplasma infec- tion, and syphilis as well as parasitic causes such as malaria, schistosomiasis, filariasis, and toxoplasmosis must be consid- ered. Many drugs can cause the syndrome, so it is extremely important to obtain a complete list of medications, includ- ing legally prescribed and over-the-counter medications, herbal or “natural” products, and illicit drugs. Drugs and drug classes that have been linked to nephrotic syndrome are the NSAIDs, penicillamine, several antibiotics, and, much more rarely, angiotensin converting enzyme inhibitors, tamoxifen, and lithium. A paraneoplastic nephrotic syndrome can be the presenting complaint with a variety of solid malignancies, lymphomas, and leukemias or can develop during treatment, sometimes as a treatment complication. Familial forms of nephrotic syndrome often present in infancy.18 The nephrotic syndrome may rarely be a prominent feature in patients with TABLE 24-5  Blood Studies for Acute Nephritic Syndrome Routine Complete blood count Electrolyte levels Blood urea nitrogen and creatinine concentrations Liver function studies Complement levels (total hemolytic complement [CH50], C3, C4) As Clinical Findings Suggest Anti-DNA antibody test Antineutrophil cytoplasmic antibody (ANCA) titer Anti–glomerular basement membrane antibody test Antistreptolysin O titer or streptozyme test Cryoglobulin titer Hepatitis B and C antibody assay and viral load determination Human immunodeficiency virus test Blood cultures TABLE 24-6  Causes of Secondary Nephrotic Syndrome Systemic Diseases Diabetes mellitus Systemic lupus erythematosus Amyloidosis Carcinoma Lymphoma and myeloma Preeclampsia Drugs Gold Antibiotics Nonsteroidal antiinflammatory drugs Penicillamine Heroin Infections Human immunodeficiency virus infection Hepatitis B and C Malaria Syphilis Congenital/Inherited Disorders Alport’s syndrome Congenital nephrotic syndrome Nail-patella syndrome
  8. 8. Chapter 24  Approach to the Patient with Kidney Disease   851 Alport’s disease and nail-patella syndrome.Some patients can date the onset of major proteinuria, because they notice that their urine has become foamy. This phenomenon, which is most readily noticed by men, occurs because albumin has a soaplike effect that reduces the surface tension of urine. This can be a very useful sign in patients with recurring episodes of nephrotic syndrome. Physical Examination Edema is a major characteristic of nephrotic syndrome. The development of hypoalbuminemia reduces the oncotic pressure within the capillaries, and this favors the net translocation of fluid into the interstitial spaces. To the extent that this occurs, intravascular volume and blood pressure fall, and this triggers the sympathetic nervous system, activates the renin-angioten- sin-aldosterone axis, elevates vasopressin levels, and modulates many other control systems that act together to promote net renal salt and water retention. This pathogenic sequence has been termed the underfill mechanism of salt and water retention in nephrotic syndrome. However, edema formation in many, perhaps most, nephrotic patients cannot be fully explained by underfill mechanisms. Although reduced intravascular oncotic pressures certainly exist in nephrotic patients, the net hydro- static gradient for water movement across capillary beds is also influenced by the interstitial oncotic pressure, and this generally falls in parallel with reductions in plasma oncotic pressure. Consequently, the net hydrostatic pressure gradient from the intravascular compartment to the interstitial space may not significantly increase. Edema formation under these conditions may be the consequence of a primary form of renal salt and water retention. This pathogenic sequence for edema formation is called the overfill mechanism. Undoubtedly each of these mechanisms plays a role in various phases and forms of nephrotic syndrome. The mechanism that predominates is probably related to the specific renal lesion causing the nephrotic syndrome.19,20 Also, these mechanisms may evolve from one form to the other. Regardless of which mechanism occurs initially, either will likely progress to a steady-state con- dition in which the initial effective arterial volume status is difficult or impossible to discern. Whether the initiating event is “underfill” of the effective arterial space leading to renal salt and water retention or “overfill” of this compartment causing excess salt and water to enter the interstitial spaces, the devel- opment of clinically apparent edema in an adult requires the net retention of about 8 to 10 pounds of fluid, which is equiva- lent to more than 4 L of normal saline. Nephrotic edema is a form of pitting edema. When the thumb is pushed against a bony structure such as the tibia or sacrum, the resulting “pit” remains visible for a short period of time. Pitting edema is graded on a scale of 1 to 4 (from very slight to more apparent to deep pitting that persists for longer than 2 minutes). Nephrotic edema is diffuse and to some degree probably affects virtually all tissues, but it is not equally distributed. The interstitial pressure in various locations has a major impact on edema formation. Thus the low ambient interstitial pressure often results in prominent periorbital edema.Gravitational force also causes nephrotic edema to accumulate in dependent body parts. Edema is generally worse in the lower legs and feet at the end of the day and becomes more prominent in the face after nocturnal recumbency. Bedfast patients accumulate edema fluid in their back and sacral areas. The diurnal variation of edema formation becomes less prominent when the degree of edema worsens. Edema that is massive and generalized is termed ana- sarca. Dropsy is a historical term for generalized edema. Nephrotic edema is usually symmetric (after adjustment for gravitational dependency), and unilateral edema should raise the possibility of edema due to local anatomic abnor- malities such as venous thromboses, varicosities, or lym- phatic obstruction. However, asymmetric nephrotic edema can be caused by upon an anatomic condition that generates greater local or asymmetrical edema. Severe edema can result in skin breakdown, blisters, weeping, and superinfection. Chronic (months to years) severe edema of any cause, includ- ing nephrotic syndrome, can produce fibrosis of the skin and subcutaneous tissues. The resulting “brawny” edema is usually pigmented, is very firm, and often will not pit. Physical clues to other disorders that produce generalized edema should be sought during physical examination. The neck veins must be carefully evaluated to determine whether right-sided cardiac pressures are increased due to cardiac, pul- monary, or pericardial abnormalities. Elevated jugular venous pressures, pericardial knock, Kussmaul’s sign (absence of inspiratory decline in jugular pressure), and prominent x and y descents suggest pericardial disease. Pulsus paradoxus (an exaggerated fall in systemic blood pressure of 10 mm Hg or more with inspiration) suggests pericardial or pulmonary dis- ease. Although prominent ascites often indicates liver disease, whereas pulmonary congestion and pleural effusions suggest cardiac or pulmonary pathology, fluid may accumulate in these locations in patients with severe nephrotic syndrome in the absence of cardiac or liver abnormalities. Many skin findings other than edema are associated with nephrotic syndrome itself and some suggest underlying primary diseases. Xanthelasma palpebrarum (periorbital-eyelid xantho- mas) is associated with hypercholesterolemia about 50% of the time and may become very prominent in nephrotic patients. Eruptive xanthomas, usually associated with extreme hyper- triglyceridemia, are much rarer but may also occur in patients with nephrotic syndrome. A number of relatively specific skin, nail, and scalp abnormalities are associated with various rheu- matolgic conditions.These include a malar facial rash, scarring alopecia, mat telangiectasia, nail bed telangiectasia and nail fold capillary loops and vascular infarcts, and erythema nodosum. Sarcoidosis is also frequently associated with erythema nodo- sum and skin papules. Jaundice, angiomata, telangiectasia, and palmar erythema raise the likelihood of hepatic disorders. The vasculitides produce a number of skin manifestations, includ- ing leukocytoclastic rashes and skin infarctions. Several nail findings occur in nephrotic patients.Transverse white lines, or leukonychia (sometimes called Muehrcke’s lines) can develop during periods of marked hypoalbuminemia. Chronic hypoalbuminemia may cause more diffuse white nails (Terry’s or half-and-half nails) or yellow nails.21 None of these nail findings is specific, however, and they can also occur with other debilitating diseases, after chemotherapy, and so on. Nail-patella syndrome—characterized by dystro- phic nails, hypoplastic patellae, and iliac horns—may present with nephrotic syndrome. The eyes, in addition to being swollen, may be inflamed or show evidence of scleritis with systemic vasculitic disease. Of course the heart and liver must be carefully examined and the
  9. 9. 852   Section IV  Evaluation of the Patient with Kidney Disease extremities must be carefully evaluated for evidence of arthri- tis and for deep vein thrombi, which occur with increased fre- quency in these patients.22 Laboratory Tests Urine Studies Proteinuria is readily detected using a semiquantitative urine dipstick test. The protein-detecting pad is impregnated with a protein-sensitive pH indicator dye and a strong pH buffer (which keeps the pad’s pH constant independent of the actual urine pH). The pH indicator changes color when moistened with urine containing dissolved proteins (the phenomenon is called the protein error of pH indicators). Dipstick protein tests are most sensitive to albumin and react poorly to urine globulins and immunoglobulin light chains (Bence Jones pro- tein).The dipstick results have the following approximate cor- relations with protein concentration: Negative:15mg/dL Trace: 15-30 mg/dL 1+: 30-100 mg/dL 2+: 100-300 mg/dL 3+: 300-1000 mg/dL 4+: 1000 mg/dL Extremely alkaline urine (i.e., infected urine) can overwhelm the acid buffer and thereby produce a false-positive dipstick protein test. More recently albumin-specific urine dipstick tests have been marketed specifically to detect low-grade albuminuria (i.e., microalbuminuria). Some can simultaneously measure creatinine concentrations so that the albumin/creatinine ratio can be determined. Albumin-specific dipstick tests are generally not used to diagnosis or follow patients with overt (macro) albuminuria or nephrotic syndrome. Sulfosalicylic acid precipitates most urine proteins, and the resulting turbidity is proportional to the protein concentration. The sulfosalicylic acid turbid- ity test detects albumin, globulins, and Bence Jones proteins. Although it was a very useful test, environmental safety con- cerns have eliminated it from most physician’s offices. If a high urine protein concentration is documented, a quantitative measurement of protein excretion will be required. This is usually achieved with a 24-hour urine col- lection. Alternatively, the protein/creatinine ratio (grams pro- tein/gram creatinine) in a single morning specimen may be used.14 If the creatinine excretion rate is assumed to be about 1 g/day, then the ratio of grams protein to 1 gram of creatinine will approximate the 24-hour protein excretion. Approximate corrections can be made depending on the patient’s gender and body habitus. A timed quantitative urine collection has the advantage of permitting measurement of creatinine clear- ance, and this may be very useful. The urine dipstick protein test, sulfosalicylic acid turbidity test, 24-hour protein excretion, and protein/creatinine ratio are all measures of total protein concentration or excretion. None of these will characterize the specific urine proteins (except that the urine dipstick tests are more sensitive to albumin, and the albumin sticks are specific to that class). Agarose gel protein electrophoresis of the urine defines the urine protein classes (i.e.,albumin,α1-globulin,α2-globulin,β-globulin,γ-globulin), and monoclonal immunoglobulins and light chains can be identified. Electrophoresis results also allow stratification of nephrotic patients into those with selective proteinuria (mainly albumin) and those with nonselective proteinuria (both heavy albuminuria and globulinuria). This differentiation may have prognostic implications. Characterization of intact immuno- globulins, heavy chains, and light chains is also accomplished with either immunoelectrophoresis or immunofixation. Hyaline casts are common in patients with nephrotic syn- drome and represent precipitated Tamm-Horsfall protein together with abnormally filtered and excreted serum pro- teins.23,24 Cellular casts are usually indicative of renal infection and/or interstitial inflammation (WBC casts) or glomerular inflammation, proliferation, and/or necrosis (when RBC casts are seen; see Figure 24-1). Such disorders may be idiopathic and isolated to the kidney, associated with systemic vasculitis, or related to another systemic inflammatory disease process such as systemic lupus erythematosus. Lipiduria is a characteristic feature of nephrotic syndrome. The lipids in the urine sediment can be found in excreted tubule cells (oval fat bodies), within fatty casts, and/or as free- floating lipid globules. Some, but not all, of the urinary lipid is esterified cholesterol, and this component is birefringent and therefore is best seen with a polarizing microscope, which demonstrates their characteristic bright crosslike appearance25 (Figure 24-4). Much of the urine fat originates from filtered high-density lipoprotein. The high-density lipoprotein is small enough to be filtered by “leaky” glomerular epithelial and is then partially reabsorbed by renal tubule epithelial cells, which subsequently degenerate and slough into the urine.26 Blood Studies Initial studies should include a routine chemical profile (elec- trolytes, glucose, BUN, creatinine, total protein, albumin, calcium, phosphate, and liver enzymes), a lipid panel (total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), and a CBC. The FIGURE 24-4  Lipiduria. Birefringent cholesterol crystals seen with polar- izing light microscopy.
  10. 10. Chapter 24  Approach to the Patient with Kidney Disease   853 sodium concentration may be artifactually reduced (pseudo- hyponatremia) as a result of a displacement error caused by hyperlipidemia. This error occurs with flame photometry and with indirect potentiometry but not with direct potentiom- etry. The calcium concentration must also be corrected for the low albumin concentration, and measurement of ionized calcium concentration may be helpful. Additional testing is directed by the patient’s clinical presentation and findings and the suspicions of the physician. Testing for syphilis and HIV and screening studies for viral hepatitis (hepatitis B and C) are generally performed. If a collagen vascular disease is sus- pected, then an ANA assay, anti–double-stranded DNA anti- body assay, complement levels, and other more specific tests for autoimmune disorders are indicated. Although determina- tion of sedimentation rate is sometimes helpful, it is usually elevated in all patients with nephrotic syndrome, regardless of cause.27 If a paraproteinemia disorder (including primary amyloidosis) is suspected, a serum immunoelectrophoresis or immunofixation study should be performed (in addition to qualitative and quantitative urine protein studies). When clinical and historical features are suggestive, cryoglobulin and antistreptolysin O titers are obtained. Assessment of the GFR is mandatory and is usually accomplished with a timed urine collection for calculation of the creatinine clearance. Although estimation of GFR from the serum creatinine concentration using one of several equations, such as the MDRD equation, can be very helpful, collection of a timed urine specimen for measurement of protein and creatinine excretion is indicated in all nephrotic patients who are considered to be compliant and who can understand the instructions for accurate col- lection of such a specimen. When available, an iothalamate clearance may be very helpful; this remains the “gold standard” measure for GFR. Imaging A chest radiograph (CXR) is required to assess cardiac size and evaluate for pericardial disease, pleural effusions, and so on. A renal sonogram with Doppler study is required to determine the renal anatomy and status of the collection sys- tem and renal vasculature. Special attention is directed to the possibility of renal vein thrombosis. The finding of a single kidney, asymmetrical kidney size, or bilaterally small kidneys will direct subsequent evaluation. Patients should have routine age-indicated screening studies for malignancy such as mam- mography and colonoscopy. However, extensive studies to rule out occult malignancy are not indicated. Renal Biopsy Renal biopsy is not always indicated in patients with nephrotic syndrome. If the cause seems apparent, then treatment can be initiated without histologic confirmation. For example, biopsy is not usually required in a patient with long-standing diabetes mellitus who develops nephrotic syndrome after the expected time period. However, if atypical features exist, such as very active sediment with RBC casts, a very short time course, or absence of retinopathy and other end-organ involvement, then a biopsy may be required to rule out other causes of the syn- drome. In young children with a classic clinical presentation, the diagnosis of minimal change disease can be assumed and therapy initiated without histologic confirmation. This diag- nosis is not as frequent in adults, and empiric therapy is less commonly initiated. Nonetheless, this course may be appro- priate when contraindications to a biopsy exist or the patient is very reluctant to undergo an invasive procedure, and the clini- cal features are consistent with minimal change nephropathy. In the majority of adults with nephrotic syndrome, however, a biopsy is appropriate to define the disease, improve prognosti- cation, and direct therapeutic intervention. Obstructive Uropathy Obstructive uropathy refers to structural or functional interfer- ence with normal urine flow anywhere from the renal pelvis to the urethra. The resultant increase in pressure within the urinary tract proximal to the obstruction leads to a number of structural and physiologic changes. The anatomic outcome of an obstructive process often includes dilatation of the calyces and renal pelvis, termed hydronephrosis, and, if the obstruction is distal to the ureteropelvic junction, hydroureter. Obstructive uropathy is a common cause of acute or sub- acute renal failure. The early recognition of this clinical entity is essential both to improve prognosis and to identify the most appropriate therapy, which is quite different than that used to treat other forms of acute kidney injury. Untreated obstructive uropathy can result in a progressive and irrevers- ible loss of renal function and eventually lead to end-stage renal disease. However, early recognition and treatment can allow a potentially full renal recovery. Obstructive uropathy is often described as acute (hours to a few days), subacute (several days to weeks), and chronic (months to years). The obstruction may be unilateral or bilateral, and either partial or complete. The clinician should establish the severity and chronicity of the condition so that appropriate therapy can be instituted. This is accomplished by means of careful his- tory taking and physical examination, appropriate laboratory tests, and selected imaging studies depending on the clinical circumstances. History and Review of Systems Patients with acute obstructive uropathy may report abrupt onset of severe flank pain (if the obstruction is at the level of the ureter or above) or suprapubic pain and fullness (if there is lower-level obstruction). The pain is often colicky when the intraluminal process is due to nephrolithiasis or papillary necrosis. The pain may be accompanied by urinary frequency and urgency if there is partial urinary tract obstruction. Occa- sionally, nausea and even vomiting may occur when severe pain is present. A history of complete anuria should always alert the physician to the possibility of obstruction, especially in the appropriate clinical setting, for example, in an elderly man with a history of prostate cancer or prostatic hypertrophy. Gross hematuria may occur when obstructive uropathy is due to nephrolithiasis, papillary necrosis, or neoplasms of the uri- nary tract. Rarely, patients may report the passage of renal cal- culi or small pieces of tissue with the sudden cessation of pain after such an event. The history in patients with subacute or chronic obstruction is often negative or vague, but symptoms
  11. 11. 854   Section IV  Evaluation of the Patient with Kidney Disease can include suprapubic fullness, frequency, polyuria, or noctu- ria. Patients may also complain of difficulty with initiating or stopping micturition if bladder outlet obstruction is present. Occasionally, urinary tract obstruction leads to an infection such as pyelonephritis, with accompanying high fever, flank pain, and dysuria. Physical Examination The physical examination can be very informative when blad- der obstruction exists. The enlarged bladder may be detected with palpation and percussion. In rare cases a flank mass may be palpable from a hydronephrotic kidney. Prostatic enlargement and other prostatic pathology that may produce obstruction, such as malignancy or infection, can be detected via rectal examination. The physical examination is usually of limited value, however, for detecting obstruction of the ureters or pelvis of the kidney. Hypertension is occasionally caused by urinary tract obstruction. Several mechanisms have been proposed for this development. In acute, unilateral obstruc- tion there can be activation of the renin-angiotensin system, with increased renin secretion by the obstructed kidney.28,29 The plasma renin activity is typically normal with bilateral obstruction or with chronic unilateral obstruction.The hyper- tension that may occur in this setting has been attributed to renal failure with extracellular fluid (ECF) volume expan- sion.30 In these instances, the diuresis that follows the correc- tion of the obstruction often, but not always, eliminates the hypertension. Fever may be present if infection complicates obstruction. Laboratory Tests The initial laboratory evaluation may provide clues to the presence of obstructive uropathy. The urinalysis may reveal a few RBCs and WBCs. There may be evidence of impaired renal function in patients with complete or severe partial bilateral obstruction or in those with obstruction of a soli- tary kidney. The plasma creatinine concentration is usually normal in patients with unilateral obstruction due to the presence of the normal contralateral kidney. However, uni- lateral renal obstruction can very rarely lead to anuria and acute renal failure. This has been attributed to vascular or ureteral spasm.31 Renal tubular acidosis with hyperkale- mia is well described with obstructive uropathy.32 Multiple defects in renin, aldosterone, and distal tubule function have been described. In some patients renin and aldosterone lev- els are reduced and the electrolyte abnormalities resolve in response to exogenous mineralocorticoids. In others, distal tubule injury diminishes sodium reabsorption and potas- sium secretion. The hyperchloremic acidosis is due to both hyperkalemia-induced suppression of ammoniagenesis and directly impaired proton secretion. Consequently, obstruc- tive uropathy is a common cause of hyperkalemia and type 4 renal tubular acidosis.32,33 Often, maximal urine concentrat- ing capacity is also reduced.33 Acute obstruction causes an initial increase in renal blood flow, but this is soon followed by a reduction attributed to vasoconstriction.33 This can sometimes increase the BUN/ creatinine ratio similar to that seen in prerenal azotemia. Imaging Renal ultrasonography is the test of choice to diagnose obstructive uropathy. This modality avoids IV contrast expo- sure. It has an extremely high sensitivity (95%) and very good specificity (75%) for the diagnosis of hydronephrosis.34,35 In early obstruction (first 1 to 3 days), however, the collecting system can be relatively noncompliant, and therefore overt hydronephrosis may not occur. Furthermore, when extrin- sic compression of the ureter exists, obstructive uropathy can develop without overt dilation of the ureter or the renal pel- vis. This most often occurs in elderly men with malignancy involving the retroperitoneum or prostate or when retroperi- toneal fibrosis exists.36 Furthermore, hydronephrosis or hydro- ureter should not be equated with obstruction. Nonobstructive hydronephrosis can occur as a result of neuromuscular abnor- malities of the bladder and/or ureters (megacystis-megaureter syndrome) and in other conditions such as vesicoureteral reflux and pregnancy.37 Examination of the resistive index of the renal vasculature (vasoconstriction occurs with obstruction) and the response of the resistive index to a diuretic challenge can be a very helpful differentiator.37 As Ellenbogen and colleagues stated, “It should be clear that the degree of hydronephrosis does not always correspond with the degree of obstruction.”35 When ultrasonographic results are inconclusive or the suspi- cion of obstruction is very high despite a nondiagnostic sono- gram, CT scanning should be performed. The combination of renal ultrasonography and CT of the kidneys will establish the diagnosis of obstructive uropathy in the overwhelming major- ity of cases.34,37 CT scans have generally replaced the IVP. In some cases a retrograde study or percutaneous nephros- tomy is necessary. Although much more invasive studies, they do not require IV contrast material, have a very high diag- nostic yield, and also often treat the obstruction. Whenever a high degree of clinical suspicion of bladder obstruction exists, bladder catheterization, both a diagnostic and a therapeutic procedure, should be performed. Hypertension Systemic hypertension is one of the most common disorders seen in clinical practice. In the United States it affects about 20% of white adults, 40% of African American adults, and more than 80% of those older than 80 years of age. In addi- tion, it is extremely common in patients with virtually any type of renal disease. The nephrologist must be an expert in the diagnosis and treatment of this disease and should have a rigorous and systematic approach for the diagnosis and treat- ment of hypertension. Over time the definition and classifica- tion of adult hypertension has been a moving target.The most recent diagnostic classification and therapeutic guidelines were published in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treat- ment of High Blood Pressure.38 Table 24-7 shows how this report classifies blood pressure, but these guidelines should always be viewed in the context of the individual patient’s history and clinical circumstances. Also these blood pres- sure levels are for patients who are not acutely ill and are not taking antihypertensive medications. A patient with a con- sistently elevated blood pressure and no comorbid conditions is obviously treated quite differently than an individual with
  12. 12. Chapter 24  Approach to the Patient with Kidney Disease   855 a similar degree of hypertension but with coexistent diabetes mellitus or other cardiovascular or renal disease. Chronic sys- temic hypertension is also associated with the development of cardiovascular disease, congestive heart failure, stroke, and chronic kidney disease (CKD). Appropriate treatment of the hypertension clearly reduces the risk of development of these complications, and it is therefore imperative to carefully evaluate and classify hypertensive patients so that appropriate therapy can be rendered. History and Review of Systems The evaluation of patients with hypertension should include an assessment of target organ function and/or damage, con- comitant risk factors, and comorbid conditions, as well as a search to detect causes of secondary forms of hypertension, especially reversible conditions.39 Obviously, a complete and detailed medical history is the first step in the evaluation. Particular attention should be paid to the presence of other cardiovascular risk factors such as age, African American ethnicity, underlying CKD, dyslipidemia, history of smok- ing, obesity, microalbuminuria, left ventricular hypertrophy, a family history of a myocardial infarction before age 50, and coincident arterial disease.The clinician should determine the duration and degree of hypertension and assess for any symp- toms of severe hypertension such as blurry vision, visual loss, headaches, encephalopathy, or nausea. A thorough dietary his- tory is also essential and should include an estimate of sodium, potassium, calcium, and fat intake. Other important factors to identify include tobacco use, alcohol consumption, all pre- scribed and over-the-counter medications taken, illicit drug use, the efficacy of previous antihypertensive drug therapy and any adverse effects, and the presence (or absence) of sexual dysfunction. It is remarkable that patients (and many physi- cians) remain unaware of the potential hypertensive effects of many over-the-counter medications, particularly the NSAID class of drugs. A family history of hypertension is also very important for the diagnosis of both familial monogenetic forms of hypertension and essential hypertension. Nephrologists are very often asked to evaluate and treat hypertensive patients who are referred for a second opinion, particularly those with poor blood pressure control. In this population it is particularly important to identify any poten- tial primary (and hopefully reversible) cause for secondary hypertension (Table 24-8). In this regard, symptoms charac- teristic of certain underlying causes of hypertension should be sought. Examples include paroxysmal hypertension, sweating, palpitations, and severe headache for pheochromocytomas; sweating, palpitations, and weight loss for thyrotoxicosis; and weight gain, edema, and polyuria for Cushing’s syndrome. A common form of secondary hypertension is that due to atherosclerotic renal artery stenosis. These patients may relate a history of recent worsening of their blood pressure control despite adherence to the antihypertensive medication regi- men. They also very frequently have a history of generalized vascular disease. Primary hyperaldosteronism is now recog- nized as a very common condition, especially in patients with difficult to control or severe hypertension. Prevalence among hypertensive patients may be as high as 10%. Although spon- taneous or drug-related hypokalemia suggests this diagnosis, it often presents with normal electrolytes. Physical Examination The physical examination begins with careful blood pressure measurement in the office setting. Patients should not smoke or ingest caffeine for at least 30 minutes prior to the examina- tion. They should be comfortably seated in a chair with back support with the arm resting at heart level. An appropriately sized cuff must be used. Its width should be at least 40 percent of arm circumference and its length at least 80 percent of arm circumference.40 Two or more readings should be taken 2 to 5 minutes apart and averaged. Blood pressure should also be measured in the supine and standing position if orthostatic hypotension is likely. When a coarctation is considered, blood pressure should be measured in each arm and also in the legs. Use of incorrect cuff size in obese individuals causes an over- estimation of blood pressure. Although the use of mercury manometers is encouraged, these have largely been eliminated due to the environmental toxicity of mercury. A regularly cali- brated aneroid or electronic device is acceptable. Overestima- tion of systolic blood pressure is common in elderly patients who have calcified and stiff arteries that cannot be com- pressed.This condition, called pseudohypertension, is suspected when the radial artery remains palpable after the cuff has been inflated above systolic blood pressure. TABLE 24-7  Classification of Blood Pressure in Adults HYPERTENSION CLASSIFICATION SYSTOLIC PRES- SURE (mm Hg) DIASTOLIC PRES- SURE (mm Hg) Normal 120 and 80 Prehypertension 120-139 or 80-89 Stage 1 hypertension 140-159 or 90-99 Stage 2 hypertension ≥160 or ≥100 TABLE 24-8  Causes of Secondary Hypertension Renal parenchymal disease Renovascular hypertension Fibromuscular dysplasia Atherosclerotic renal artery disease Renal vasculitis Renal infarction Primary hyperaldosteronism Renin-secreting tumor Pheochromocytoma Cushing’s syndrome Liddle’s syndrome Apparent mineralocorticoid excess Geller’s syndrome Aortic coarctation Thyroid disease Drugs (e.g., corticosteroids, cocaine, amphetamines, oral contraceptives) Sleep apnea
  13. 13. 856   Section IV  Evaluation of the Patient with Kidney Disease The next very important element of the physical examina- tion is a thorough funduscopic evaluation. The presence and severity of hypertensive retinopathy provides an important clue to the duration and severity of the hypertension. Spe- cial note should be made of hemorrhage, arteriolar narrowing, papilledema, and/or cotton-wool spots. The cardiovascular and pulmonary examination may reveal evidence of carotid and/or peripheral vascular disease, left ventricular hypertrophy (e.g., hyperdynamic precordium and the presence of a fourth heart sound), or congestive heart fail- ure (e.g., jugular venous distention, peripheral edema, third heart sound, and/or rales). Coarctation of the aorta is sug- gested by differences in the intensity of the radial pulses or a radial-femoral arterial pulsation difference or temporal delay. The abdominal and flank examination may reveal abdomi- nal bruits suggesting renal artery stenosis. Neurologic exami- nation in severely hypertensive patients may reveal findings consistent with encephalopathy. Abnormal findings on thy- roid examination may suggest otherwise occult thyroid dis- ease. The presence of hyperpigmentation and striae raises the possibility of Cushing’s syndrome. Neurofibroma and café au lait spots suggest the possibility of neurofibromatosis (and either pheochromocytoma or renal vascular disease). Laboratory Tests The extent of laboratory evaluation depends on the clinical circumstances of the individual patient. The initial evaluation of a person with stage 1 hypertension includes measurement of serum electrolytes, BUN, creatinine, calcium, and glucose; a lipid profile; urinalysis; and CBC. If warranted by the clinical history and physical examination findings, additional testing such as thyroid studies, urine albumin/creatinine ratio, and quantitation of GFR with a timed urine collection for mea- surement of creatinine clearance or iothalamate clearance are measured. When a pheochromocytoma is suspected, 24-hour urine catecholamines and fractionated metanephrines, or frac- tionated plasma catecholamines or free metanephrines should be measured. A plasma aldosterone/plasma renin activity ratio is a reasonable screening test for the detection of primary hyperaldosteronism if this condition is clinically suspected. This test should be ordered for patients with unprovoked hypokalemia; those with severe diuretic-induced hypoka- lemia, unexpected metabolic alkalosis, or severe or resistant hypertension; or hypertensive patients with an incidentally discovered adrenal mass (“incidentaloma”). Imaging A baseline CXR is appropriate for all hypertensive patients. Other imaging modalities are required when the history, physical examination, and laboratory results suggest that the hypertension may be secondary to anatomic abnormalities or when pathologic end-organ changes due to the hypertension must be determined. Renal sonography is an excellent non- invasive test for assessing renal size, identifying cysts, and detecting hydronephrosis. It is obviously indicated whenever enlarged kidneys or a mass can be palpated. When there is strong clinical suspicion of renovascular hypertension, several options are available to establish the diagnosis. They include spiral CT angiography, magnetic resonance angiography, and duplex Doppler ultrasonography. Which screening test is best is determined by the specific features of each patient and the skill of the imaging center that is used. Renal artery Doppler studies are very operator dependent, and results are often sub- optimal in large patients. CT angiography of the renal arteries is an excellent diagnostic tool but carries the risk of contrast- related kidney injury in susceptible patients as well as consid- erable radiation exposure. Gadolinium-enhanced magnetic resonance angiography also yields excellent results, but is con- traindicated in patients with reduced kidney function because of concerns about nephrogenic systemic fibrosis. Also it can- not be used when patients are claustrophobic or have metallic implants. Captopril renal perfusion scans are no longer recom- mended as a screening test because of their relatively low pre- dictive value. It should be emphasized that one should proceed directly to catheter angiography if the clinical suspicion is very high, no matter what any screening tests show. Other Studies An electrocardiogram is necessary to screen for left ventricular hypertrophy and cardiac arrhythmias and to provide a baseline for future comparison. Nephrolithiasis Nephrolithiasis, or kidney stones, is an increasingly prevalent medical problem. Over 5% of the U.S. population is affected, and the lifetime risk of developing a stone is between 10% and 15%.41 Patients who develop a first stone are very likely to have a second one (50% within 5 years and 80% within 20 years).41 Therefore, every physician is likely to encounter patients with this problem. History and Review of Systems Kidney stones are strongly suspected when patients present with classic signs and symptoms such as gross hematuria associated with waves of flank and/or lower abdominal pain (colic), which may radiate into the genital region. However, symptoms are sometimes very vague. Either gross hematu- ria or microscopic hematuria is usually, but not always, pres- ent. The absence of hematuria does not exclude a diagnosis of nephrolithiasis.42 Poorly localized abdominal pain, nausea, vomiting, and urinary frequency may occur. Often, patients are entirely asymptomatic, and the stones are noted inciden- tally when an imaging study is done for a different reason. When painful symptoms do develop, they generally indicate that an asymptomatic stone has passed from the renal pel- vis into the ureter where it has caused obstruction, inflam- mation, and/or bleeding. These symptoms often first occur during the night or in the early morning, beginning abruptly with rapidly worsening pain. The paroxysms of pain prob- ably reflect hyperperistalsis of the renal calyces, pelvis, and ureter. The site of pain and its referral pattern are clues to the stone’s location. Upper ureteral obstruction usually produces flank pain and tenderness, and anterior abdominal radiation of pain. Lower ureteral obstruction produces lower abdominal
  14. 14. Chapter 24  Approach to the Patient with Kidney Disease   857 pain, which frequently radiates into the testicle or labia. Very often stones lodge near the ureterovesical junction where they irritate the bladder, which produces urinary frequency, uri- nary urgency, suprapubic tenderness, and dysuria. If the stone enters the bladder and then obstructs its outlet, suprapubic pain and anuria may develop. Potential kidney stone risk factors should be identified. The patient should be questioned about unusual dietary hab- its. Does the patient consume large amounts of oxalate-rich foods such as spinach, rhubarb, beets, or black tea? Is intake of animal protein, which reduces urine citrate excretion, excessive? High salt ingestion increases urine calcium excre- tion. Sardines, anchovies, and organ meat are rich sources of purines and thereby increase urine uric acid excretion. The medication history may reveal other important clues to stone pathogenesis. Some medications increase the risk of stones by reducing urine citrate excretion—carbonic anhydrase inhibi- tors such as acetazolamide and topiramate are important examples. Other medications that may directly precipitate as stones are the protease inhibitor indinavir, triamterene, and some sulfonamides.43 Dietary supplements, vitamins, and minerals such as calcium salts and vitamin D can produce hypercalciuria. A number of underlying medical conditions can generate kidney stones. These include most chronic disorders associ- ated with hypercalciuria, such as hyperparathyroidism and sarcoidosis. Hypercalcemia-hypercalciuria of malignancy usually does not result in kidney stones because of its acute presentation and relatively short course. Any medical or sur- gical condition associated with significant steatorrhea (short gut disorders, cystic fibrosis, bile salt depletion from ileal dis- ease, gastrointestinal bypass) may generate stones as a result of hyperoxaluria and reduced urine volume. Chronic diarrhea without steatorrhea causes chronic metabolic acidosis and persistent aciduria—a risk factor for uric acid stones. Strong epidemiologic associations with both calcium and uric acid kidney stones have been demonstrated for obesity, weight gain, diabetes mellitus, and metabolic syndrome.44 The impact of occupations associated with reduced fluid intake and/or excessive sweating should be considered, because low urine volume is a major risk factor for stone formation. A his- tory of recurrent kidney infections raises concern for infec- tion (struvite) stones (see later).The age when the first kidney stone develops is also a clue to the etiologic diagnosis. Kidney stones associated with inherited disorders such as cystinuria and congenital hyperoxaluria often present in the young. Eth- nicity has a major impact on risk. Over a 6-year period (1988 to 1994) in the United States, whites had the highest risk of kidney stones (5.9%), African Americans the lowest risk (1.7%), and Mexican Americans intermediate risk (2.6%).41 The family history also may be helpful; first-degree relatives of patients with stones very often also have had stones.45 Physical Examination The presence of fever is a sign of possible infection, which must be rapidly addressed. It is of critical importance to rec- ognize an infection proximal to an obstructing stone. This is a medical-urologic emergency requiring urgent drainage of the renal pelvis (surgically or via interventional radiology) and appropriate antibiotic therapy. Fever and/or leukocytosis, which do not usually occur with uncomplicated kidney stones, are red flags for this condition. The skin is generally pale and cool, and often clammy. The patient should be examined for costovertebral angle tenderness. Hypoactive bowel sounds and ileus may develop in these patients, but abdominal tenderness is unusual, and if rebound tenderness is present another cause should be sought. Bruits over the abdominal aorta and iliac vessels may be indicative of a leaking aortic abdominal aneu- rysm, which can mimic the symptoms of renal colic. In men, a rectal examination may reveal prostatitis, and in women, a pelvic examination may suggest ovarian pathology or an ecto- pic pregnancy. Laboratory Tests The routine initial laboratory battery includes a CBC. The WBC count may be slightly increased with an uncompli- cated stone, but leukocytosis of more than 15,000 cells/mm3 and a left shift suggests a complicating infection. The BUN and creatinine values are important markers of GFR, espe- cially if renal mass is reduced, severe obstruction exists, or the patient is volume depleted. An electrolyte panel may provide clues that distal renal tubular acidosis exists (hyperchloremic acidosis and hypokalemia). The serum calcium, phosphate, and uric acid levels can indicate the existence of a hypercal- cemic-hypercalciuric condition, renal phosphate wasting, or a hyperuricosuric condition. In women of childbearing age a pregnancy test must be performed. Urine Studies Hematuria with isomorphic RBCs is very common but not universal.42 RBC casts should not be seen. Proteinuria should be absent or low grade. Although pyuria may occur without infection, it should always raise suspicion, and a urine culture should be performed.The urine pH may provide a helpful clue. A very high pH of freshly voided urine (i.e.,7.5) almost always indicates the existence of a UTI. Chronic UTIs may lead to the development of struvite stones, also called triple phosphate, urease-related, or infection stones. When the infecting bacteria produce the enzyme urease, the urea in urine is split into two molecules of NH3 and one of CO2.The CO2 escapes from the urine, whereas each NH3 molecule binds a proton and thereby elevates the urine pH above that under usual physiologic con- ditions. Abundant ammonium in an alkaline urine tends to precipitate with magnesium and phosphate to form struvite (MgNH4PO4 · 6H2O). Note that struvite is really a double phosphate crystal. The term triple phosphate derives from the fact that carbonate-apatite (Ca10[PO4]6 · CO3) commonly coprecipitates with struvite, which results in a combination of three cations—calcium, magnesium, and ammonium—and the phosphate anion. Struvite stones often grow to large stag- horn shapes. Urease-producing bacteria include Ureaplasma urealyticum, most Proteus species, and many Staphylococcus, Klebsiella, and Pseudomonas species. Escherichia coli does not generate urease. A urine pH that is not appropriately acidic (5.5) in a patient with hyperchloremic acidosis suggests distal renal tubular acidosis, a disorder often associated with calcium phosphate stones. Conversely, persistently acidic urine is associated with uric acid stones (because uric acid becomes
  15. 15. 858   Section IV  Evaluation of the Patient with Kidney Disease increasingly insoluble as the pH falls below 6.5). When bac- teriuria is identified, a urine sample must be sent for culture. If overt signs of infection exist, then hospital admission for additional evaluation is generally required. Identification of crystals in the urine sediment can be helpful and sometimes diagnostic. Recognition of the “ben- zene ring” cysteine is virtually diagnostic of cystinuria. The “coffin lid” crystals of struvite are also very characteristic and indicate that an infection-related stone is likely. Although uric acid and calcium oxalate crystals are very common and relatively nonspecific, they may be helpful clues to etiology when kidney stones are recognized.46 Twenty-four-hour urine collection for quantitation of nephrolithiasis-relevant chemicals can be very helpful. Several commercial laborato- ries offer stone risk profile or metabolic stone risk testing. These studies may identify abnormally high (e.g., calcium, oxalate, urate) and/or low (e.g., citrate) chemical concen- trations and excretion rates. The saturation-supersaturation state of the urine for various stone-forming crystals is also routinely calculated. In general at least two samples should be collected for such studies because of significant day-to- day variation in excretion rates. Specimens should be sent for these studies whenever recurrent stones develop or when a first stone is documented in a patient with a higher than usual risk for recurrence (e.g., those with a family history of stones, patients with gastrointestinal disorders). Some suggest that 24-hour urine studies should be performed after the first kid- ney stone in all patients. Imaging The imaging procedure of choice is a noncontrast helical CT scan with relatively thin (3- to 5-mm) cuts. This modality has replaced IVP as the preferred imaging procedure. Although a plain radiograph of the abdomen (kidneys, ureters, bladder) is very inexpensive and may be diagnostic, it has generally also been replaced by the CT scan as the initial screening test.47 The CT scan can detect radiopaque calculi as small as 1 mm in diameter. Calcium stones are opaque; cysteine and struvite stones are slightly radiopaque; and pure uric acid stones are radiolucent. Stones comprised of indinavir or triamterene are also radiolucent. The CT scan will also reveal renal anatomy, the presence of hydronephrosis, other abdominal and pelvic pathology, and other potential causes of the patient’s symp- toms. Although a renal-abdominal sonogram will demon- strate renal anatomy and reveal the presence of hydronephrosis and most stones in the renal pelvis, it will miss most ureteral stones. Therefore sonography is generally used to follow the progress of known stone disease but not as an initial study. However, sonography is indicated as the initial procedure in pregnant women and others for whom radiation exposure must be minimized. Magnetic resonance imaging (MRI) is generally not very good for the diagnosis of kidney stones. Differential Diagnosis Many conditions can mimic nephrolithiasis. Any form of renal bleeding associated with blood clots can cause ure- teral obstruction and produce symptoms identical to those of a kidney stone. Other clinical mimics of kidney stones are acute abdominal aneurysm, pyelonephritis, renal can- cer, renal tuberculosis, papillary necrosis, renal infarction, and renal vein thrombosis. Papillary necrosis, which is more likely in patients with diabetes or sickle cell disease, can cause true renal colic when sloughed papillae obstruct the ureter. Ectopic pregnancy, appendicitis, and bowel obstruc- tion must be considered. Finally, some patients complain of kidney stone symptoms because they are seeking anal- gesic drugs. Table 24-9 shows the differential diagnosis of ­urolithiasis-like pain. Initial Treatment Patients with renal colic can often be managed conserva- tively as outpatients with analgesics and fluids. However, admission and urgent urologic consultation is required if the patient is septic, has an infection proximal to an obstruc- tion, has obstruction of a solitary kidney (including a renal transplant) or bilateral kidney obstruction, has high-grade obstruction with a large ( 7-mm) stone, has acute kidney failure, has urine extravasation, or has unrelenting pain despite analgesic use or pain responsive only to parenteral analgesics. The most important determinant of the likelihood that a stone will pass is its size. Most kidney stones smaller than TABLE 24-9  Differential Diagnosis of Urolithiasis-Like Pain CATEGORY DISORDERS Renal Pyelonephritis Blood clot Renal infarction Tumor (kidney or pelvis) Papillary necrosis Ureteral Tumor Blood clot Stricture Bladder Tumor Blood clot Urinary retention Intraabdominal Peritonitis Appendicitis Biliary disease Bowel obstruction Vascular disorder Aortic aneurysm Mesenteric insufficiency Retroperitoneal Lymphadenopathy Fibrosis Tumor Gynecologic Ectopic or tubal pregnancy Ovarian torsion/cyst rupture Pelvic inflammatory disease Cervical cancer Endometriosis Ovarian vein syndrome Neuromuscular Muscle pain Rib fracture Radiculitis Infectious Herpes zoster Pleuritis/pneumonia Fungal bezoar
  16. 16. Chapter 24  Approach to the Patient with Kidney Disease   859 4 mm in diameter will pass spontaneously. As stone size increases beyond a diameter of 4 mm, the chance of pass- ing falls progressively until it becomes very unlikely at a diameter of 10 mm. Consequently, conservative outpatient therapy becomes less likely to be successful as the stone size increases beyond 4 to 5 mm.48,49 Narcotics and/or NSAIDs are used for analgesia. If the patient is to be managed as an outpatient then NSAIDs are the preferred agents. If nau- sea and vomiting are prominent, a parenteral NSAID such as ketorolac can be used.50 For severe pain IV morphine is generally given.51 If the stone has a reasonable chance of passing without urologic intervention, then glucocorticoste- roids, calcium channel blockers (usually nifedipine), and/or α1-adrenergic antagonists (usually tamsulosin, which is used to treat benign prostatic hyperplasia) are often employed to relax ureteral muscles and thereby assist stone passage. Patients should always attempt to retrieve the passed stone for analysis. This can be accomplished by urinating through a filter or fine screen (an aquarium net is a good option). If none is available, the patient can urinate through a fine gauze pad or simply void into a glass jar so the calculus will be visible. Acute Kidney Injury Acute kidney injury (AKI) is a clinical syndrome broadly defined as an abrupt decline in renal function occurring over a period of hours to days resulting in the retention of nitrog- enous and metabolic waste products and ECF volume. Very often, electrolyte and acid-base disorders also develop (hyper- kalemia, hyponatremia, and metabolic acidosis). AKI develops as a result of a variety of pathophysiologic influences and may lead to varying degrees of damage to one or more anatomic divisions of the nephron with subsequent adverse functional consequences. Although the initial clinical manifestation of AKI may be oliguria, urine volume can remain normal or even increase, and patients can be completely asymptomatic. The diagnosis is often made when routine biochemical screen- ing reveals a recent increase in serum creatinine and/or BUN concentrations. There is no universally accepted operational defini- tion of AKI, and more than 30 different criteria have been employed in various clinical studies.52 Commonly used definitions include an absolute increase in serum creatinine concentration of 0.5 to 1.0 mg/dL, and relative increases of 25% to 100% over a period of 1 to several days. Although far from perfect, these approaches have proved to be useful in identifying patients with AKI in clinical practice. More recently a new classification and diagnostic system known by the acronym RIFLE (Risk, Injury, Failure, Loss, End stage) has been introduced.52 Table 24-10 shows this diagnostic and classification system. The incidence of AKI depends greatly on the patient population studied and the criteria used to identify affected patients. The incidence of AKI in ambulatory patients is very low, but AKI develops in up to 7% of hospitalized patients and about 30% of those admitted to intensive care units.53,54 United Kingdom population studies report that the annual incidence of AKI is between 486 and 620 per million.54 Out- comes associated with AKI have changed little over the past 50 years.The in-hospital mortality rate of critically ill patients with AKI is higher than 50%. Older age, female gender, respi- ratory failure, liver failure, sepsis, and impaired consciousness all correlate with higher in-hospital mortality rates. The causes of AKI can be broadly divided into three cat- egories: prerenal azotemia (a disorder characterized by renal hypoperfusion in which renal parenchymal tissue integrity is preserved), intrinsic renal failure with parenchymal tissue injury, and postrenal failure (dysfunction due to acute obstruc- tion of the urinary tract) (Table 24-11). Appropriate catego- rization of AKI requires the clinician to integrate the findings and results from a careful history, physical examination, and appropriate laboratory and imaging studies. TABLE 24-10  RIFLE Criteria for Acute Kidney Injury (AKI) CLASS GFR URINE OUTPUT Risk Creatinine increase ×1.5 or GFR fall of 25% 0.5 mL/kg/hr 6 hr Injury Creatinine increase ×2 or GFR fall of 50% 0.5 mL/kg/hr 12 hr Failure Creatinine increase ×3 or GFR fall of 75% or Creatinine ≥4 mg% (acute increase ≥0.5 mg%) 0.3 mL/kg/hr 24 hr or Anuria 12 hr Loss Persistent AKI = complete loss of renal function 4 wk End stage End-stage renal disease 3 mo GFR, Glomerular filtration rate. TABLE 24-11  Causes of Acute Kidney Injury Prerenal Gastrointestinal hemorrhage Burns Pancreatitis Capillary leak Diarrhea, vomiting, nasogastric suction, fistula fluid loss Excessive sweating Diuretics, nonsteroidal antiinflammatory drugs Congestive heart failure Cirrhosis Intrinsic Ischemia (e.g., postoperative acute tubular necrosis) Nephrotoxins (e.g., radiocontrast agents, aminoglycosides) Sepsis Acute interstitial nephritis Acute glomerulonephritis Acute vascular syndrome (e.g., bilateral renal artery thromboembolism or dissection) Atheroembolic disease Postrenal Bilateral upper tract obstruction (e.g., nephrolithiasis, papillary necrosis) or obstruction of solitary functioning kidney Lower tract obstruction (e.g., prostatic hypertrophy, urethral stricture, bladder mass or stone, obstructed urinary catheter)
  17. 17. 860   Section IV  Evaluation of the Patient with Kidney Disease History and Review of Systems The initial goal of history taking is to establish whether the patient actually has AKI. In this regard, a careful review of clinical, pharmacy, nursing, and radiologic records is necessary. A relatively recent serum creatinine determination is invalu- able but not always available. In some cases the clinician must make a presumptive diagnosis of AKI pending further data collection and investigation. A diagnosis of AKI can usually be more readily established when it occurs during a hospital- ization because urine output is often recorded and laboratory values are measured frequently. A history of anuria should raise the possibility of obstruc- tive uropathy. The historical features that assist in the differ- entiation of AKI into the categories shown in Table 24-11 should be identified. One of the risk factors that most strongly predicts the development of AKI is the presence of CKD.55 A history of salt and fluid losses such as occur with diarrhea, vomiting, or ECF loss into a third space as is seen with exten- sive burns, pancreatitis, or leaky capillaries suggests a prerenal etiology. NSAIDs, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers, especially when combined with diuretics, can generate a renal hypoperfusion state and AKI.Therefore medication review is essential to identify such drugs and also any other potential nephrotoxic agents. A history of heart failure or liver disease increases the like- lihood that AKI is the result of reduced effective arterial vol- ume. Often, the cause of AKI is multifactorial (e.g., a patient with a gastrointestinal hemorrhage may undergo a radiologic study with IV contrast). It is also critically important to iden- tify any history of underlying CKD. Often, such patients develop superimposed AKI due to a variety of renal insults. A history of decreased urine output or anuria is important, but, as noted earlier, many patients have normal urine output despite AKI. A history of voiding symptoms such as urinary frequency, hesitancy, or incontinence suggests the possibility of obstruc- tive uropathy. Many patients with renal artery emboli and some with bilateral renal vein thrombosis may present with flank pain and a history of hematuria. It is also important to elicit any history of a recent interventional procedure, which raises the possibility of AKI as a result of IV or intraarterial contrast infusion or atheroembolic disease. A history of fever, skin rash, arthralgias, sinusitis, and/or hemoptysis raises the possibility of glomerulonephritis related to infection, collagen vascular disease, or vasculitis. Physical Examination An extremely important aspect of the physical examination in every patient with AKI is an assessment of ECF and effec- tive arterial volume status. Overt hypotension is the strongest indicator of potential renal underperfusion. Less severe vol- ume depletion is suggested by an orthostatic pulse increase of more than 30 beats/min (measured 1 minute after standing). Of note, orthostatic hypotension, defined as a drop in systolic blood pressure of more than 20 mm Hg after standing, is less helpful because it occurs in 10% of normal subjects.56 Dry axillae and dry mucous membranes with a furrowed tongue are useful signs of volume depletion. However, poor skin tur- gor and slow capillary refill have not been shown to be helpful signs in adults.56 The neck veins are usually flat when volume contraction exists. Renal perfusion is reduced as a result of heart failure or hepatic cirrhosis. Signs of the former condition include dis- tended neck veins, pulmonary rales, an S3 gallop, and pitting peripheral edema. Stigmata of chronic liver disease, includ- ing jaundice, hepatosplenomegaly, ascites, gynecomastia, nail clubbing, palmar erythema, vascular spiders, and testicular atrophy, should be sought. The presence of either true ECF volume depletion or reduced effective arterial volume raises the very strong possibility of a prerenal (and potentially readily reversible) cause of the AKI. The physical examination may suggest a systemic disease associated with an intrinsic AKI, such as vasculitis, endocar- ditis, thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, and so on. An important cause of AKI in the hospitalized or recently hospitalized patient is athero- embolic (cholesterol embolic) disease. This often overlooked condition generally occurs following an invasive procedure that requires intraarterial catheterization (e.g., cardiac cath- eterization, angiography) or cardiac or aortic surgeries. Skin findings include livedo reticularis, ulcers, purpura, petechiae, painful erythematous nodules, cyanosis, and gangrene. Retinal examination may reveal arterial atheroemboli (Hollenhorst plaques). Flank tenderness or an enlarged palpable bladder indicates possible postrenal causes for AKI. A digital examination of the prostate should be performed in all men with AKI, and a bimanual pelvic examination to detect pelvic masses should be considered in women. If lower tract obstruction is a seri- ous consideration in-and-out diagnostic postvoid bladder catheterization should be done. The normal postvoid residual urine volume is less than 50 mL. Any urine collected should be saved for potential additional studies. Laboratory Tests Initial testing in AKI must include urinalysis and an estimate of the GFR. ECF volume contraction causes marked urine concentration, which increases the urine specific gravity and may generate positive dipstick protein results. Microscopy often reveals hyaline casts, but there should be few cells and no cellular casts. Quantitative protein excretion is relatively low (1 g/day). A “bland” finding on urinalysis is also consistent with an obstructive or postrenal cause for AKI, unless a com- plicating infection produces pyuria and bacteriuria, or hema- turia results from stone disease. AKI due to intrinsic damage such as tubular necrosis will generate a “dirty” urinalysis with many epithelial cells and muddy brown granular and epithe- lial cell casts. The urine is generally isosthenuric (i.e., specific gravity is 1.010). Rhabdomyolysis causes myoglobinuria, and pigmented granular casts are seen. Acute glomerulonephritis produces proteinuria, hematuria, and RBC casts. Acute inter- stitial nephritis causes pyuria and white cell casts. If it is due to an allergic reaction, then urine eosinophils are often seen, but this is not a specific finding.57 Estimation of the GFR gives an approximate measure of the number of functioning nephrons. In the setting of AKI the GFR is, by definition, not in a steady state. This makes GFR estimates, especially those based on plasma cre- atinine, unreliable. However, a rising creatinine concentration

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