InternalMed_Harrison

InternalMed_Harrison. FIguRE 59-2 CT of a patient with peritoneal carcinomatosis (white arrow) and ascites (yellow arrow). Cirrhosis accounts for 84% of cases of ascites. Cardiac ascites, peritoneal carcinomatosis, and “mixed” ascites resulting from cirrhosis and a second disease account for 10–15% of cases. Less common causes of ascites include massive hepatic metastasis, infection (tuberculosis, Chlamydia infection), pancreatitis, and renal disease (nephrotic syndrome). Rare causes of ascites include hypothyroidism and familial Mediterranean fever. Once the presence of ascites has been confirmed, the etiology of the ascites is best determined by paracentesis, a bedside procedure in which a needle or small catheter is passed transcutaneously to extract ascitic fluid from the peritoneum. The lower quadrants are the most frequent sites for paracentesis. The left lower quadrant is preferred because of the greater depth of ascites and the thinner abdominal wall.


InternalMed_Harrison

InternalMed_Harrison. Paracentesis is a safe procedure even in patients with coagulopathy; 287 complications, including abdominal wall hematomas, hypotension, hepatorenal syndrome, and infection, are infrequent. Once ascitic fluid has been extracted, its gross appearance should be examined. Turbid fluid can result from the presence of infection or tumor cells. White, milky fluid indicates a triglyceride level >200 mg/ dL (and often >1000 mg/dL), which is the hallmark of chylous ascites. Chylous ascites results from lymphatic disruption that may occur with trauma, cirrhosis, tumor, tuberculosis, or certain congenital abnormalities. Dark brown fluid can reflect a high bilirubin concentration and indicates biliary tract perforation. Black fluid may indicate the presence of pancreatic necrosis or metastatic melanoma.


InternalMed_Harrison

InternalMed_Harrison. The ascitic fluid should be sent for measurement of albumin and total protein levels, cell and differential counts, and, if infection is suspected, Gram’s stain and culture, with inoculation into blood culture bottles at the patient’s bedside to maximize the yield. A serum albumin level should be measured simultaneously to permit calculation of the serum-ascites albumin gradient (SAAG).


InternalMed_Harrison

InternalMed_Harrison. The SAAG is useful for distinguishing ascites caused by portal hypertension from nonportal hypertensive ascites (Fig. 59-3). The SAAG reflects the pressure within the hepatic sinusoids and correlates with the hepatic venous pressure gradient. The SAAG is calculated by subtracting the ascitic albumin concentration from the serum albumin level and does not change with diuresis. A SAAG ≥1.1 g/dL reflects the presence of portal hypertension and indicates that the ascites is due to increased pressure in the hepatic sinusoids. According to Starling’s law, a high SAAG reflects the oncotic pressure that counterbalances the portal pressure. Possible causes include cirrhosis, cardiac ascites, hepatic vein thrombosis (Budd-Chiari syndrome), sinusoidal obstruction syndrome (veno-occlusive disease), or massive liver metastases. A SAAG <1.1 g/dL indicates that the ascites is not related to portal hypertension, as in tuberculous peritonitis, peritoneal carcinomatosis, or pancreatic ascites.


InternalMed_Harrison

InternalMed_Harrison. For high-SAAG (≥1.1) ascites, the ascitic protein level can provide further clues to the etiology (Fig. 59-3). An ascitic protein level of ≥2.5 g/dL indicates that the hepatic sinusoids are normal and are allowing passage of protein into the ascites, as occurs in cardiac ascites, early Budd-Chiari syndrome, or sinusoidal obstruction syndrome. An ascitic protein level <2.5 g/dL indicates that the hepatic sinusoids have been damaged and scarred and no longer allow passage of protein, as occurs with cirrhosis, late Budd-Chiari syndrome, or massive liver metastases. Pro-brain-type natriuretic peptide (BNP) is a natriuretic hormone released by the heart as a result of increased volume and ventricular wall stretch. High levels of BNP in serum occur in heart failure and may be useful in identifying heart failure as the cause of high-SAAG ascites.


InternalMed_Harrison

InternalMed_Harrison. Further tests are indicated only in specific clinical circumstances. When secondary peritonitis resulting from a perforated hollow viscus is suspected, ascitic glucose and lactate dehydrogenase (LDH) levels can < 1.1 g/dL Ascitic protein ˜ 2.5 g/dL Cirrhosis Late Budd-Chiari syndrome Massive liver metastases ˜ 1.1 g/dL Heart failure/constrictive pericarditis Early Budd-Chiari syndrome IVC obstruction Sinusoidal obstruction syndrome Biliary leak Nephrotic syndrome Pancreatitis Peritoneal carcinomatosis Tuberculosis Ascitic protein < 2.5 g/dL SAAG FIguRE 59-3 Algorithm for the diagnosis of ascites according to the serum-ascites albumin gradient (SAAG). IVC, inferior vena cava.


InternalMed_Harrison

InternalMed_Harrison. 288 be measured. In contrast to “spontaneous” bacterial peritonitis, which may complicate cirrhotic ascites (see “Complications,” below), secondary peritonitis is suggested by an ascitic glucose level <50 mg/dL, an ascitic LDH level higher than the serum LDH level, and the detection of multiple pathogens on ascitic fluid culture. When pancreatic ascites is suspected, the ascitic amylase level should be measured and is typically >1000 mg/dL. Cytology can be useful in the diagnosis of peritoneal carcinomatosis. At least 50 mL of fluid should be obtained and sent for immediate processing. Tuberculous peritonitis is typically associated with ascitic fluid lymphocytosis but can be difficult to diagnose by paracentesis. A smear for acid-fast bacilli has a diagnostic sensitivity of only 0 to 3%; a culture increases the sensitivity to 35–50%. In patients without cirrhosis, an elevated ascitic adenosine deaminase level has a sensitivity of >90% when a cut-off value of 30–45 U/L is used. When


InternalMed_Harrison

InternalMed_Harrison. a culture increases the sensitivity to 35–50%. In patients without cirrhosis, an elevated ascitic adenosine deaminase level has a sensitivity of >90% when a cut-off value of 30–45 U/L is used. When the cause of ascites remains uncertain, laparotomy or laparoscopy with peritoneal biopsies for histology and culture remains the gold standard.


InternalMed_Harrison

InternalMed_Harrison. The initial treatment for cirrhotic ascites is restriction of sodium intake to 2 g/d. When sodium restriction alone is inadequate to control ascites, oral diuretics—typically the combination of spironolactone and furosemide—are used. Spironolactone is an aldosterone antagonist that inhibits sodium resorption in the distal convoluted tubule of the kidney. Use of spironolactone may be limited by hyponatremia, hyperkalemia, and painful gynecomastia. If the gynecomastia is distressing, amiloride (5–40 mg/d) may be substituted for spironolactone. Furosemide is a loop diuretic that is generally combined with spironolactone in a ratio of 40:100; maximal daily doses of spironolactone and furosemide are 400 mg and 160 mg, respectively.


InternalMed_Harrison

InternalMed_Harrison. Refractory cirrhotic ascites is defined by the persistence of ascites despite sodium restriction and maximal (or maximally tolerated) diuretic use. Pharmacologic therapy for refractory ascites includes the addition of midodrine, an α1-adrenergic antagonist, or clonidine, an α2-adrenergic antagonist, to diuretic therapy. These agents act as vasoconstrictors, counteracting splanchnic vasodilation. Midodrine alone or in combination with clonidine improves systemic hemodynamics and control of ascites over that obtained with diuretics alone. Although β-adrenergic blocking agents (beta blockers) are often prescribed to prevent variceal hemorrhage in patients with cirrhosis, the use of beta blockers in patients with refractory ascites is associated with decreased survival rates.


InternalMed_Harrison

InternalMed_Harrison. When medical therapy alone is insufficient, refractory ascites can be managed by repeated large-volume paracentesis (LVP) or a transjugular intrahepatic peritoneal shunt (TIPS)—a radiologically placed portosystemic shunt that decompresses the hepatic sinusoids. Intravenous infusion of albumin accompanying LVP decreases the risk of “post-paracentesis circulatory dysfunction” and death. Patients undergoing LVP should receive IV albumin infusions of Part 2 Cardinal Manifestations and Presentation of Diseases 6–8 g/L of ascitic fluid removed. TIPS placement is superior to LVP in reducing the reaccumulation of ascites but is associated with an increased frequency of hepatic encephalopathy, with no difference in mortality rates. Malignant ascites does not respond to sodium restriction or diuretics. Patients must undergo serial LVPs, transcutaneous drainage catheter placement, or, rarely, creation of a peritoneovenous shunt (a shunt from the abdominal cavity to the vena cava).


InternalMed_Harrison

InternalMed_Harrison. Ascites caused by tuberculous peritonitis is treated with standard antituberculosis therapy. Noncirrhotic ascites of other causes is treated by correction of the precipitating condition. Spontaneous bacterial peritonitis (SBP; Chap. 159) is a common and potentially lethal complication of cirrhotic ascites. Occasionally, SBP also complicates ascites caused by nephrotic syndrome, heart failure, acute hepatitis, and acute liver failure but is rare in malignant ascites. Patients with SBP generally note an increase in abdominal girth; however, abdominal tenderness is found in only 40% of patients, and rebound tenderness is uncommon. Patients may present with fever, nausea, vomiting, or the new onset of or exacerbation of preexisting hepatic encephalopathy.


InternalMed_Harrison

InternalMed_Harrison. SBP is defined by a polymorphonuclear neutrophil (PMN) count of ffi250/ L in the ascitic fluid. Cultures of ascitic fluid typically reveal one bacterial pathogen. The presence of multiple pathogens in the setting of an elevated ascitic PMN count suggests secondary peritonitis from a ruptured viscus or abscess (Chap. 159). The presence of multiple pathogens without an elevated PMN count suggests bowel perforation from the paracentesis needle. SBP is generally the result of enteric bacteria that have translocated across an edematous bowel wall. The most common pathogens are gram-negative rods, including Escherichia coli and Klebsiella, as well as streptococci and enterococci.


InternalMed_Harrison

InternalMed_Harrison. Treatment of SBP with an antibiotic such as IV cefotaxime is effective against gram-negative and gram-positive aerobes. A 5-day course of treatment is sufficient if the patient improves clinically. Nosocomial or health care–acquired SBP is frequently caused by multidrug-resistant bacteria, and initial antibiotic therapy should be guided by the local bacterial epidemiology. Cirrhotic patients with a history of SBP, an ascitic fluid total protein concentration <1 g/dL, or active gastrointestinal bleeding should receive prophylactic antibiotics to prevent SBP; oral daily norfloxacin is commonly used. Diuresis increases the activity of ascitic fluid protein opsonins and may decrease the risk of SBP.


InternalMed_Harrison

InternalMed_Harrison. Hepatic hydrothorax occurs when ascites, often caused by cirrhosis, migrates via fenestrae in the diaphragm into the pleural space. This condition can result in shortness of breath, hypoxia, and infection. Treatment is similar to that for cirrhotic ascites and includes sodium restriction, diuretics, and, if needed, thoracentesis or TIPS placement. Chest tube placement should be avoided. Dysuria, Bladder Pain, and the Interstitial Cystitis/Bladder Pain Syndrome John W. Warren Dysuria and bladder pain are two symptoms that commonly call atten-60e SEC TION 7 tion to the lower urinary tract. Dysuria, or pain that occurs during urination, is commonly perceived as burning or stinging in the urethra and is a symptom of several syndromes. The presence or absence of other symptoms is often helpful in distinguishing among these conditions. Some of these syndromes differ in men and women.


InternalMed_Harrison

InternalMed_Harrison. Approximately 50% of women experience dysuria at some time in their lives; ∼20% report having had dysuria within the past year. Most dysuria syndromes in women can be categorized into two broad groups: bacterial cystitis and lower genital tract infections. Bacterial cystitis is usually caused by Escherichia coli; a few other gram-negative rods and Staphylococcus saprophyticus can also be responsible. Bacterial cystitis is acute in onset and manifests not only as dysuria but also as urinary frequency, urinary urgency, suprapubic pain, and/or hematuria.


InternalMed_Harrison

InternalMed_Harrison. The lower genital tract infections include vaginitis, urethritis, and ulcerative lesions; many of these infections are caused by sexually transmitted organisms and should be considered particularly in young women who have new or multiple sexual partners or whose partner(s) do not use condoms. The onset of dysuria associated with these syndromes is more gradual than in bacterial cystitis and is thought (but not proven) to result from the flow of urine over damaged epithelium. Frequency, urgency, suprapubic pain, and hematuria are reported less frequently than in bacterial cystitis. Vaginitis, caused by Candida albicans or Trichomonas vaginalis, presents as vaginal discharge or irritation. Urethritis is a consequence of infection by Chlamydia trachomatis or Neisseria gonorrhoeae. Ulcerative genital lesions may be caused by herpes simplex virus and several other specific organisms.


InternalMed_Harrison

InternalMed_Harrison. Among women presenting with dysuria, the probability of bacterial cystitis is ∼50%. This figure rises to >90% if four criteria are fulfilled: dysuria and frequency without vaginal discharge or irritation. Present standards suggest that women meeting these four criteria, if they are otherwise healthy, are not pregnant, and have an apparently normal urinary tract, can be diagnosed with uncomplicated bacterial cystitis and treated empirically with appropriate antibiotics. Other women with dysuria should be further evaluated by urine dipstick, urine culture, and a pelvic examination. Dysuria is less common among men. The syndromes presenting as dysuria are similar to those in women but with some important distinctions.


InternalMed_Harrison

InternalMed_Harrison. In the majority of men with dysuria, frequency, urgency, and/or suprapubic, penile, and/or perineal pain, the prostate is involved, either as the source of infection or as an obstruction to urine flow. Bacterial prostatitis is usually caused by E. coli or another gram-negative rod, with one of two presentations. Acute bacterial prostatitis presents with fever and chills; prostate examination should be gentle or not performed at all, as massage may result in a wave of bacteremia. Chronic bacterial prostatitis presents as recurrent episodes of bacterial cystitis; prostate examination with massage demonstrates prostatic bacteria and leukocytes. Benign prostatic hyperplasia (BPH) can obstruct urine flow, with consequent symptoms of weak stream, hesitancy, and dribbling. If a bacterial infection develops behind the obstructing prostate, dysuria and other symptoms of cystitis will occur. Men whose symptoms are consistent with bacterial cystitis should be evaluated with urinalysis and urine


InternalMed_Harrison

InternalMed_Harrison. develops behind the obstructing prostate, dysuria and other symptoms of cystitis will occur. Men whose symptoms are consistent with bacterial cystitis should be evaluated with urinalysis and urine culture.


InternalMed_Harrison

InternalMed_Harrison. Several sexually transmitted infections can manifest as dysuria. Urethritis (usually without urinary frequency) presents as a urethral discharge and can be caused by C. trachomatis, N. gonorrhoeae, Mycoplasma genitalium, Ureaplasma urealyticum, or T. vaginalis. Herpes simplex, chancroid, and other ulcerous lesions may present as dysuria, again without urinary frequency. For further discussion, see Chaps. 162 and 163. Other causes of dysuria may be found in patients of either sex. Some cases are acute and include lower urinary tract stones, trauma, and urethral exposure to topical chemicals. Others may be relatively chronic and attributable to lower urinary tract cancers, certain medications, Behçet’s syndrome, reactive arthritis, a poorly understood entity known as chronic urethral syndrome, and interstitial cystitis/bladder pain syndrome (see below).


InternalMed_Harrison

InternalMed_Harrison. Studies indicate that patients perceive pain as coming from the urinary bladder if it is suprapubic in location, alters with bladder filling or emptying, and/or is associated with urinary symptoms such as urgency and frequency. Bladder pain occurring acutely (i.e., over hours or a day or two) is helpful in distinguishing bacterial cystitis from urethritis, vaginitis, and other genital infections. Chronic or recurrent bladder pain may accompany lower urinary tract stones; bladder, uterine, cervical, vaginal, urethral, or prostate cancer; urethral diverticulum; cystitis induced by radiation or certain medications; tuberculous cystitis; bladder neck obstruction; neurogenic bladder; urogenital prolapse; or BPH. In the absence of these conditions, the diagnosis of interstitial cystitis/bladder pain syndrome (IC/BPS) should be considered.


InternalMed_Harrison

InternalMed_Harrison. Most clinicians with outpatient practices see undiagnosed cases of IC/BPS. This chronic condition is characterized by pain perceived to be from the urinary bladder, urinary urgency and frequency, and nocturia. The majority of cases are diagnosed in women. Symptoms wax and wane for months or years or possibly even for the rest of the patient’s life. The spectrum of symptom intensity is broad. The pain can be excruciating, urgency can be distressing, frequency can be up to 60 times per 24 h, and nocturia can cause sleep deprivation. These symptoms can disrupt daily activities, work schedules, and personal relationships; patients with IC/BPS report less life satisfaction than do those with end-stage renal disease.


InternalMed_Harrison

InternalMed_Harrison. IC/BPS is not a new disease, having first been described in the late nineteenth century in a patient with the symptoms mentioned above and a single ulcer visible on cystoscopy (now called a Hunner’s lesion after the urologist who first reported it). Over the ensuing decades, it became clear that many patients with similar symptoms had no ulcer. It is now appreciated that only up to 10% of patients with IC/BPS have a Hunner’s lesion. The definition of IC/BPS, its diagnostic features, and even its name continue to evolve. The American Urological Association has defined IC/BPS as “an unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder, associated with lower urinary tract symptoms of more than six weeks’ duration, in the absence of infection or other identifiable causes.”


InternalMed_Harrison

InternalMed_Harrison. CHAPTER 60e Dysuria, Bladder Pain, and the Interstitial Cystitis/Bladder Pain Syndrome 60e-2 Many patients with IC/BPS also have other syndromes, such as fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and migraine. These syndromes collectively are known as functional somatic syndromes (FSSs): chronic conditions in which pain and fatigue are prominent features but laboratory tests and histologic findings are normal. Like IC/BPS, the FSSs often are associated with depression and anxiety. The majority of FSSs affect more women than men, and more than one FSS can affect a single patient. Because of its similar features and comorbidity, IC/BPS sometimes is considered an FSS.


InternalMed_Harrison

InternalMed_Harrison. Contemporary population studies of IC/BPS in the United States indicate a prevalence of 3–6% among women and 2–4% among men. For decades, it was thought that IC/BPS occurred mostly in women. These prevalence findings, however, have generated research aimed at determining the proportion of men who have symptoms usually diagnosed as chronic prostatitis (now known as chronic prostatitis/chronic pelvic pain syndrome) but who actually have IC/BPS. Among women, the average age at onset of IC/BPS symptoms is the early forties, but the range is from childhood through the early sixties. Risk factors (antecedent features that distinguish cases from controls) primarily have been FSSs. Indeed, the odds of IC/BPS increase with the number of such syndromes present. Surgery was long thought to be a risk factor for IC/BPS, but analyses adjusting for FSSs refuted that association. About one-third of patients appear to have bacterial cystitis at the onset of IC/BPS.


InternalMed_Harrison

InternalMed_Harrison. The natural history of IC/BPS is not known. Although studies from urology and urogynecology practices have been interpreted as showing that IC/BPS lasts for the lifetime of the patient, population studies suggest that some individuals with IC/BPS do not consult specialists and may not seek medical care at all, and most prevalence studies do not show an upward trend with age—a pattern that would be expected with incident cases throughout adulthood followed by lifetime persistence of a nonfatal disease. It may be reasonable to conclude that patients in a urology practice represent those with the most severe and recalcitrant IC/BPS.


InternalMed_Harrison

InternalMed_Harrison. For the ≤10% of IC/BPS patients who have a Hunner’s lesion, the term interstitial cystitis may indeed describe the histopathologic picture. Most of these patients have substantive inflammation, mast cells, and granulation tissue. However, in the 90% of patients without such lesions, the bladder mucosa and interstitium are relatively normal, with scant inflammation.


InternalMed_Harrison

InternalMed_Harrison. Numerous hypotheses about the pathogenesis of IC/BPS have been put forward. It is not surprising that most early theories focused on the bladder. For instance, IC/BPS has been investigated as a chronic bladder infection. Sophisticated technologies have not identified a causative organism in urine or in bladder tissue; however, the patients studied by these methods had IC/BPS of long duration, and the results do not preclude the possibility that infection may trigger the syndrome or may be a feature of early IC/BPS. Other inflammatory factors, including a role for mast cells, have been postulated, but (as noted above) the 90% of patients without a Hunner’s ulcer have little bladder inflammation and do not have a prominence of mast cells in bladder tissue. Autoimmunity has been considered, but autoantibodies are low in titer, nonspecific, and thought to be a result rather than a cause of IC/BPS. Increased permeability of the bladder mucosa due to defective epithelium or


InternalMed_Harrison

InternalMed_Harrison. considered, but autoantibodies are low in titer, nonspecific, and thought to be a result rather than a cause of IC/BPS. Increased permeability of the bladder mucosa due to defective epithelium or glycosaminoglycan (the bladder’s mucous coating) has been studied frequently, but the findings have been inconclusive.


InternalMed_Harrison

InternalMed_Harrison. Investigations of causes outside the bladder have been prompted by the presence of comorbid FSSs. Many patients with FSSs have abnormal pain sensitivity as evidenced by (1) low pain thresholds in body areas unrelated to the diagnosed syndrome, (2) dysfunctional descending neurologic control of tactile signals, and (3) enhanced brain responses to touch in functional neuroimaging studies. Moreover, in patients with IC/BPS, body surfaces remote from the bladder are more sensitive to pain than is the case in individuals without IC/BPS. All PART 2 Cardinal Manifestations and Presentation of Diseases these findings are consistent with upregulation of sensory processing in the brain. Indeed, a prevailing theory is that these concomitantly occurring syndromes have in common an abnormality of brain processing of sensory input. However, antecedence is a critical criterion for causality, and no study has demonstrated that abnormal pain sensitivity precedes either IC/BPS or the FSSs.


InternalMed_Harrison

InternalMed_Harrison. In some patients, IC/BPS has a gradual onset, and/or the cardinal symptoms of pain, urgency, frequency, and nocturia appear sequentially in no consistent order. Other patients can identify the exact date of onset of IC/BPS symptoms. More than half of the latter patients describe dysuria beginning on that date. As stated, only a minority of IC/BPS patients who obtain medical care soon after symptom onset have uropathogenic bacteria or leukocytes in the urine. These patients—and many others with new-onset IC/BPS—are treated with antibiotics for presumptive bacterial cystitis or, if male, chronic bacterial prostatitis. Persistent or recurring symptoms without bacteriuria eventually prompt a differential diagnosis, and IC/BPS is considered. Traditionally, the diagnosis of IC/BPS has been delayed for years, but recent interest in the disease has shortened this interval.


InternalMed_Harrison

InternalMed_Harrison. The pain of IC/BPS includes suprapubic prominence and changes with the voiding cycle. Two-thirds of women with IC/BPS report two or more sites of pain. The most common site (involved in 80% of women) and generally the one with the most severe pain is the supra-pubic area. About 35% of female patients have pain in the urethra, 25% in other parts of the vulva, and 30% in nonurogenital areas, mostly the low back and also the anterior or posterior thighs or the buttocks. The pain of IC/BPS is most commonly described as aching, pressing, throbbing, tender, and/or piercing. What may distinguish IC/BPS from other pelvic pain is that, in 95% of patients, bladder filling exacerbates the pain and/or bladder emptying relieves it. Almost as many patients report a puzzling pattern in which certain dietary substances worsen the pain of IC/BPS. Smaller proportions—but still the majority—of patients report that their IC/BPS pain is worsened by menstruation, stress, tight clothing, exercise, and


InternalMed_Harrison

InternalMed_Harrison. dietary substances worsen the pain of IC/BPS. Smaller proportions—but still the majority—of patients report that their IC/BPS pain is worsened by menstruation, stress, tight clothing, exercise, and riding in a car as well as during or after vaginal intercourse.


InternalMed_Harrison

InternalMed_Harrison. The urethral and vulvar pains of IC/BPS merit special mention. In addition to the descriptive adjectives for IC/BPS mentioned above, these pains commonly are described as burning, stinging, and sharp and as being worsened by touch, tampons, and vaginal intercourse. Patients report that urethral pain increases during urination and generally lessens afterward. These characteristics have commonly resulted in diagnosis of the urethral pain of IC/BPS as chronic urethral syndrome and the vulvar pain as vulvodynia.


InternalMed_Harrison

InternalMed_Harrison. In many patients with IC/BPS, there is a link between pain and urinary urgency; that is, two-thirds of patients describe the urge to urinate as a desire to relieve their bladder pain. Only 20% report that the urge stems from a desire to prevent incontinence; indeed, very few patients with IC/BPS are incontinent. As mentioned above, urinary frequency can be severe, with ∼85% of patients voiding more than 10 times per 24 h and some as often as 60 times. Voiding continues through the night, and nocturia is common, frequent, and often associated with sleep deprivation.


InternalMed_Harrison

InternalMed_Harrison. Beyond these common symptoms of IC/BPS, additional urinary and other symptoms may be present. Among the urinary symptoms are difficulty in starting urine flow, perceptions of difficulty in emptying the bladder, and bladder spasms. Other symptoms include the manifestations of comorbid FSSs as well as symptoms that do not constitute recognized syndromes, such as numbness, muscle spasms, dizziness, ringing in the ears, and blurred vision. The pain, urgency, and frequency of IC/BPS can be debilitating. Proximity to a bathroom is a continual focus, and patients report difficulties in the workplace, leisure activities, travel, and simply leaving home. Familial and sexual relationships can be strained.


InternalMed_Harrison

InternalMed_Harrison. Traditionally, IC/BPS has been considered a rare condition that is diagnosed by urologists at cystoscopy. However, this disorder is much more common than once was thought; it is now being considered earlier in its course and is being diagnosed and managed more often by primary care clinicians. Results of physical examination, urinalysis, and urologic procedures are insensitive and/or nonspecific. Thus, diagnosis is based on the presence of appropriate symptoms and the exclusion of diseases with a similar presentation.


InternalMed_Harrison

InternalMed_Harrison. Three categories of disorders can be considered in the differential diagnosis of IC/BPS. The first comprises diseases that manifest as bladder pain (see above) or urinary symptoms. Among the latter diseases is overactive bladder, a chronic condition of women and men that presents as urgency and frequency and that can be distinguished from IC/BPS by the patient’s history: pain is not a feature of overactive bladder, and its urgency arises from the need to avoid incontinence. Endometriosis is a special case: it can be asymptomatic or can cause pelvic pain, dysmenorrhea, and dyspareunia—i.e., types of pain that mimic IC/BPS. Endometrial implants on the bladder (although uncommon) can cause urinary symptoms, and the resulting syndrome can mimic IC/BPS. Even if endometriosis is identified, it is difficult in the absence of bladder implants to determine whether it is causative of or incidental to the symptoms of IC/BPS in a specific woman.


InternalMed_Harrison

InternalMed_Harrison. The second category of disorders encompasses the FSSs that can accompany IC/BPS. IC/BPS can be misdiagnosed as gynecologic chronic pelvic pain, irritable bowel syndrome, or fibromyalgia. The correct diagnosis may be entertained only when either changes of pain with altered bladder volume or urinary symptoms become more prominent.


InternalMed_Harrison

InternalMed_Harrison. The third category involves syndromes that IC/BPS mimics by way of its referred pain, such as vulvodynia and chronic urethral syndrome. Therefore, IC/BPS should be considered in the differential diagnosis of persistent or recurrent “urinary tract infection” (UTI) with sterile urine cultures; overactive bladder with pain; chronic pelvic pain, endometriosis, vulvodynia, or FSSs with urinary symptoms; and “chronic prostatitis.” As mentioned above, important clues to the diagnosis of IC/BPS are pain that changes with bladder volume or with certain foods or drinks. Common among these are chilies, chocolate, citrus fruits, tomatoes, alcohol, caffeinated drinks, and carbonated beverages; full lists of common trigger foods are available at the websites cited in the treatment section below.


InternalMed_Harrison

InternalMed_Harrison. Cystoscopy under anesthesia formerly was thought to be necessary for the diagnosis of IC/BPS because of its capacity to reveal a Hunner’s lesion or—in the 90% of patients without an ulcer—petechial hemorrhages after bladder distention. However, because Hunner’s lesions are uncommon in IC/BPS and petechiae are nonspecific, cystoscopy is no longer necessary for diagnosis. Accordingly, the indications for urologic referral have evolved toward the need to rule out other diseases or to administer more advanced treatment.


InternalMed_Harrison

InternalMed_Harrison. A typical patient presents to the primary clinician after days, weeks, or months of pain, urgency, frequency, and/or nocturia. The presence of urinary nitrites, leukocytes, or uropathogenic bacteria should prompt treatment for UTI in women and chronic bacterial prostatitis in men. Persistence or recurrence of symptoms in the absence of bacteriuria should prompt a pelvic examination for women, an assay for serum prostate-specific antigen for men, and urine cytology and inclusion of IC/BPS in the differential diagnosis for both sexes.


InternalMed_Harrison

InternalMed_Harrison. In the diagnosis of IC/BPS, inquiries about pain, pressure, and discomfort are useful; IC/BPS should be considered if any of these sensations are noted in one or more anterior or posterior sites between the umbilicus and the upper thighs. Nondirective questions about the effect of bladder volume changes include “As your next urination approaches, does this pain get better, get worse, or stay the same?” and “After you urinate, does this pain get better, get worse, or stay the same?” Establishing that the pain is exacerbated by the consumption of certain foods and drinks not only supports the diagnosis of IC/BPS but also serves as the basis for one of the first steps in managing this syndrome. A nondirective way to ask about urgency is to describe it to the patient as a compelling urge to urinate that is difficult to postpone; follow-up questions can determine whether this urge is intended to relieve pain or prevent incontinence. To assess severity and provide quantitative baseline


InternalMed_Harrison

InternalMed_Harrison. to urinate that is difficult to postpone; follow-up questions can determine whether this urge is intended to relieve pain or prevent incontinence. To assess severity and provide quantitative baseline measures, pain and urgency should be estimated by the patient on a scale of 0–10, with 0 being none and 10 the worst 60e-3 imaginable. Frequency per 24-h period should be determined and nocturia assessed as the number of times per night the patient is awakened by the need to urinate.


InternalMed_Harrison

InternalMed_Harrison. About half of patients with IC/BPS have intermittent or persistent microscopic hematuria; this manifestation and the need to exclude bladder stones or cancer require urologic or urogynecologic referral. Initiation of therapy for IC/BPS does not hamper subsequent urologic evaluation. The goal of therapy is to relieve the symptoms of IC/BPS; the challenge lies in the fact that no treatment is uniformly successful. However, most patients eventually obtain relief, generally with a multifaceted approach. The American Urological Association’s guidelines for management of IC/BPS are an excellent resource. The correct strategy is to begin with conservative therapies and proceed to riskier measures only if necessary and under the supervision of a urologist or urogynecologist. Conservative tactics include education, stress reduction, dietary changes, medications, pelvic-floor physical therapy, and treatment of associated FSSs.


InternalMed_Harrison

InternalMed_Harrison. Months or even years may have passed since the onset of symptoms, and the patient’s life may have been disrupted continually, with repeated medical visits provoking frustration and dismay in both patient and physician. In this circumstance, simply giving a name to the syndrome is beneficial. The physician should discuss the disease, the diagnostic and therapeutic strategies, and the prognosis with the patient and with the spouse and/or other pertinent family members, who may need to be made aware that although IC/BPS has no visible manifestations, the patient is undergoing substantial pain and suffering. This information is particularly important for sexual partners, as exacerbation of pain during and after intercourse is a common feature of IC/BPS. Because stress can worsen IC/ BPS symptoms, stress reduction and active measures such as yoga or meditation exercises may be suggested. The Interstitial Cystitis Association (http://www.ichelp.com) and the Interstitial Cystitis Network


InternalMed_Harrison

InternalMed_Harrison. stress reduction and active measures such as yoga or meditation exercises may be suggested. The Interstitial Cystitis Association (http://www.ichelp.com) and the Interstitial Cystitis Network (http://www.ic-network.com) can be useful in this educational process.


InternalMed_Harrison

InternalMed_Harrison. In constructing a benign diet, some of the many patients who identify particular foods and drinks that exacerbate their symptoms find it useful to exclude all possible offenders and add items back into the diet one at a time to confirm which ones worsen their symptoms. Patients also should experiment with fluid volumes; some find relief with less fluid, others with more. The pelvic floor is often tender in IC/BPS patients. Two randomized controlled trials showed that weekly physical therapy directed at relaxation of the pelvic muscles yielded significantly more relief than a similar schedule of general body massage. This intervention can be initiated under the direction of a knowledgeable physical therapist who recognizes that the objective is to relax the pelvic floor, not to strengthen it.


InternalMed_Harrison

InternalMed_Harrison. Among oral medications, nonsteroidal anti-inflammatory drugs are commonly used but are controversial and often unsuccessful. Two randomized controlled trials showed that amitriptyline can diminish IC/BPS symptoms if an adequate dose (≥50 mg per night) can be given. This drug is used not for its antidepressant activity but because of its proven effects on neuropathic pain; however, it is not approved by the U.S. Food and Drug Administration for treatment of IC/BPS. An initial dose of 10 mg at bedtime is increased weekly up to 75 mg (or less if a lower dose adequately relieves symptoms). Side effects can be expected and include dry mouth, weight gain, sedation, and constipation. If this regimen does not control symptoms adequately, pentosan polysulfate, a semisynthetic polysaccharide, can be added at a dose of 100 mg three times a day. Its theoretical effect is to replenish a possibly defective glycosaminoglycan layer over the bladder mucosa; randomized controlled trials suggest only


InternalMed_Harrison

InternalMed_Harrison. CHAPTER 60e Dysuria, Bladder Pain, and the Interstitial Cystitis/Bladder Pain Syndrome 60e-4 a modest benefit over placebo. Adverse reactions are uncommon and include gastrointestinal symptoms, headache, and alopecia. Pentosan polysulfate has weak anticoagulant effects and perhaps should be avoided by patients with coagulation abnormalities. Anecdotal reports suggest that successful therapy for one FSS is accompanied by diminished symptoms of other FSSs. As has been noted here, IC/BPS often is associated with one or several FSSs. Thus, it seems reasonable to hope that, to the extent that accompanying FSSs are treated successfully, the symptoms of IC/BPS will be relieved as well. If several months of these therapies in combination do not relieve symptoms adequately, the patient should be referred to a urologist or urogynecologist who has access to additional modalities. Cystoscopy under anesthesia allows distention of the bladder with water, a procedure that provides ∼40% of patients


InternalMed_Harrison

InternalMed_Harrison. referred to a urologist or urogynecologist who has access to additional modalities. Cystoscopy under anesthesia allows distention of the bladder with water, a procedure that provides ∼40% of patients with several months of relief and can be repeated. For those few patients with a Hunner’s lesion, fulguration may offer relief. Bladder instillation of solutions containing lidocaine or dimethyl sulfoxide can be administered. Physicians experienced in the care of IC/BPS patients have used anticonvulsants, narcotics, and cyclosporine as components of therapy. Pain specialists can be of assistance. Sacral neuromodulation with a temporary percutaneous electrode can be tested and, if effective, can then be performed with an implanted device. In a very small number of patients with recalcitrant symptoms, surgeries, including cystoplasty, partial or total cystectomy, and urinary diversion, may provide relief.


InternalMed_Harrison

InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases


InternalMed_Harrison

InternalMed_Harrison. Azotemia and urinary Abnormalities Julie Lin, Bradley M. Denker Normal kidney functions occur through numerous cellular pro-cesses to maintain body homeostasis. Disturbances in any of these 61 functions can lead to abnormalities that may be detrimental to survival. Clinical manifestations of these disorders depend on the pathophysiology of renal injury and often are identified as a complex of symptoms, abnormal physical findings, and laboratory changes that constitute specific syndromes. These renal syndromes (Table 61-1) may arise from systemic illness or as primary renal disease. Nephrologic syndromes usually consist of several elements that reflect the underlying pathologic processes, typically including one or more of the following: (1) reduction in glomerular filtration 289 rate (GFR) (azotemia), (2) abnormalities of urine sediment (red blood cells [RBCs], white blood cells [WBCs], casts, and crystals), abnormal excretion of serum proteins (proteinuria), (4) disturbances in urine


InternalMed_Harrison

InternalMed_Harrison. (azotemia), (2) abnormalities of urine sediment (red blood cells [RBCs], white blood cells [WBCs], casts, and crystals), abnormal excretion of serum proteins (proteinuria), (4) disturbances in urine volume (oliguria, anuria, polyuria), (5) presence of hypertension and/or expanded total body fluid volume (edema), (6) electrolyte abnormalities, and (7) in some syndromes, fever/pain. The specific combination of these findings should permit identification of one of the major nephrologic syndromes (Table 61-1) and allow differential diagnoses to be narrowed so that the appropriate diagnostic and therapeutic course can be determined. All these syndromes and their associated diseases are discussed in more detail in subsequent chapters. This chapter focuses on several aspects of renal abnormalities that are critically important for distinguishing among those processes: (1) reduction in GFR leading to azotemia, alterations of the urinary sediment and/or protein excretion, and abnormalities of


InternalMed_Harrison

InternalMed_Harrison. that are critically important for distinguishing among those processes: (1) reduction in GFR leading to azotemia, alterations of the urinary sediment and/or protein excretion, and abnormalities of urinary volume.


InternalMed_Harrison

InternalMed_Harrison. Monitoring the GFR is important in both hospital and outpatient settings, and several different methodologies are available. GFR is the primary metric for kidney “function,” and its direct measurement involves administration of a radioactive isotope (such as inulin or iothalamate) that is filtered at the glomerulus into the urinary space but is neither reabsorbed nor secreted throughout the tubule. GFR—i.e., the clearance of inulin or iothalamate in milliliters per minute—is calculated from the rate of appearance of the isotope in the urine over several hours. In most clinical circumstances, direct GFR measurement is not feasible, and the plasma creatinine level is used as a surrogate to estimate GFR. Plasma creatinine (PCr) is the most widely used marker for GFR, which is related directly to urine creatinine (UCr) excretion and inversely to PCr. On the basis of this relationship (with some important caveats, as discussed below), GFR will fall in roughly inverse proportion to the rise


InternalMed_Harrison

InternalMed_Harrison. to urine creatinine (UCr) excretion and inversely to PCr. On the basis of this relationship (with some important caveats, as discussed below), GFR will fall in roughly inverse proportion to the rise in PCr. Failure to account for GFR reductions in drug dosing can lead to significant morbidity and death from drug toxicities (e.g., digoxin, aminoglycosides). In the outpatient setting, PCr serves as an estimate for GFR (although much less accurate; see below). In patients with chronic progressive renal disease, there is an approximately linear relationship between 1/PCr (y axis) and time (x axis). The slope of that line will remain constant for an individual;


InternalMed_Harrison

InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases when values deviate, an investigation for a superimposed acute process (e.g., volume depletion, drug reaction) should be initiated. Signs and symptoms of uremia develop at significantly different levels of PCr, depending on the patient (size, age, and sex), underlying renal disease, existence of concurrent diseases, and true GFR. Generally, patients do not develop symptomatic uremia until renal insufficiency is severe (GFR <15 mL/min).


InternalMed_Harrison

InternalMed_Harrison. A significantly reduced GFR (either acute or chronic) is usually reflected in a rise in PCr, leading to retention of nitrogenous waste products (defined as azotemia) such as urea. Azotemia may result from reduced renal perfusion, intrinsic renal disease, or postrenal processes (ureteral obstruction; see below and Fig. 61-1). Precise determination of GFR is problematic, as both commonly measured indices (urea and creatinine) have characteristics that affect their accuracy as markers of clearance. Urea clearance may underestimate GFR significantly because of urea reabsorption by the tubule. In contrast, creatinine is derived from muscle metabolism of creatine, and its generation varies little from day to day.


InternalMed_Harrison

InternalMed_Harrison. Creatinine clearance (CrCl), an approximation of GFR, is measured from plasma and urinary creatinine excretion rates for a defined period (usually 24 h) and is expressed in milliliters per minute: CrCl = (Uvol × UCr)/(PCr × Tmin). Creatinine is useful for estimating GFR because it is a small, freely filtered solute that is not reabsorbed by the tubules. PCr levels can increase acutely from


InternalMed_Harrison

InternalMed_Harrison. AZOTEMIA Urinalysis and Renal ultrasound HydronephrosisRenal size parenchyma Urinalysis Urologic evaluation Relieve obstruction Small kidneys, thin cortex, bland sediment, isosthenuria <3.5 g protein/24 h Normal size kidneys Intact parenchyma Bacteria Pyelonephritis Chronic Renal Failure Symptomatic treatment delay progression If end-stage, prepare for dialysis Normal urinalysis with oliguria Abnormal urinalysis WBC, casts eosinophils Interstitial nephritis Red blood cells Renal artery or vein occlusion Urine electrolytes Muddy brown casts, amorphous sediment + protein RBC casts Proteinuria Angiogram FeNa <1% U osmolality > 500 mosmol FeNa >1% U osmolality < 350 mosmol Renal biopsy Prerenal Azotemia Volume contraction, cardiac failure, vasodilatation, drugs, sepsis, renal vasoconstriction, impaired autoregulation Acute Tubular Necrosis Glomerulonephritis or vasculitis Immune complex, anti-GBM disease Acute Renal Failure


InternalMed_Harrison

InternalMed_Harrison. FIguRE 61-1 Approach to the patient with azotemia. FeNa, fractional excretion of sodium; GBM, glomerular basement membrane; RBC, red blood cell; WBC, white blood cell. dietary ingestion of cooked meat, however, and creatinine can be secreted into the proximal tubule through an organic cation pathway (especially in advanced progressive chronic kidney disease), leading to overestimation of GFR. When a timed collection for CrCl is not available, decisions about drug dosing must be based on PCr alone. Two formulas are used widely to estimate kidney function from PCr: (1) Cockcroft-Gault and (2) four-variable MDRD (Modification of Diet in Renal Disease). Cockcroft-Gault: CrCl (mL/min) = (140 − age (years) × weight (kg) ×[0.85 if female])/(72 × PCr (mg/dL). MDRD: eGFR (mL/min per 1.73 m2) = 186.3 × PCr (e−1.154) × age (e−0.203) ×(0.742 if female)×(1.21 if black).


InternalMed_Harrison

InternalMed_Harrison. Numerous websites are available to assist with these calculations (www.kidney.org/professionals/kdoqi/gfr_calculator.cfm). A newer CKDEPI eGFR, which was developed by pooling several cohorts with and without kidney disease who had data on directly measured GFR, appears to be more accurate: CKD-EPI: eGFR = 141 × min (PCr/k, 1)a × max (PCr/k, 1)−1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black], where PCr is plasma creatinine, k is 0.7 for females and 0.9 for males, a is −0.329 for females and −0.411 for males, min indicates the minimum of PCr/k or 1, and max indicates the maximum of PCr/k or 1 (http:// www.qxmd.com/renal/Calculate-CKD-EPI-GFR.php).


InternalMed_Harrison

InternalMed_Harrison. There are limitations to all creatinine-based estimates of GFR. Each equation, along with 24-h urine collection for measurement of creatinine clearance, is based on the assumption that the patient is in steady state, without daily increases or decreases in PCr as a result of rapidly changing GFR. The MDRD equation is better correlated with true GFR when the GFR is <60 mL/min per 1.73 m2. The gradual loss of muscle from chronic illness, chronic use of glucocorticoids, or malnutrition can mask significant changes in GFR with small or imperceptible changes in PCr. Cystatin C, a member of the cystatin superfamily of cysteine protease inhibitors, is produced at a relatively constant rate from all nucleated cells. Serum cystatin C has been proposed to be a more sensitive marker of early GFR decline than is PCr; however, like serum creatinine, cystatin C is influenced by the patient’s age, race, and sex and also is associated with diabetes, smoking, and markers of inflammation.


InternalMed_Harrison

APPROACH TO THE PATIENT:

InternalMed_Harrison. APPROACH TO THE PATIENT:


InternalMed_Harrison

InternalMed_Harrison. Once GFR reduction has been established, the physician must decide if it represents acute or chronic renal injury. The clinical situation, history, and laboratory data often make this an easy distinction. However, the laboratory abnormalities characteristic of chronic renal failure, including anemia, hypocalcemia, and hyperphosphatemia, often are present as well in patients presenting with acute renal failure. Radiographic evidence of renal osteodystrophy (Chap. 335) can be seen only in chronic renal failure but is a very late finding, and these patients are usually undergoing dialysis. The urinalysis and renal ultrasound can facilitate distinguishing acute from chronic renal failure. An approach to the evaluation of azotemic patients is shown in Fig. 61-1. Patients with advanced chronic renal insufficiency often have some proteinuria, nonconcentrated urine (isosthenuria; isosmotic with plasma), and small kidneys on ultrasound, characterized by increased echogenicity and cortical


InternalMed_Harrison

InternalMed_Harrison. renal insufficiency often have some proteinuria, nonconcentrated urine (isosthenuria; isosmotic with plasma), and small kidneys on ultrasound, characterized by increased echogenicity and cortical thinning. Treatment should be directed toward slowing the progression of renal disease and providing symptomatic relief for edema, acidosis, anemia, and hyperphosphatemia, as discussed in Chap. 335. Acute renal failure (Chap. 334) can result from processes that affect renal blood flow (prerenal azotemia), intrinsic renal diseases (affecting small vessels, glomeruli, or tubules), or postrenal processes (obstruction of urine flow in ureters, bladder, or urethra) (Chap. 343).


InternalMed_Harrison

InternalMed_Harrison. Decreased renal perfusion accounts for 40–80% of cases of acute renal failure and, if appropriately treated, is readily reversible. The etiologies of prerenal azotemia include any cause of decreased circulating blood volume (gastrointestinal hemorrhage, burns, diarrhea, diuretics), volume sequestration (pancreatitis, peritonitis, rhabdomyolysis), or decreased effective arterial volume (cardiogenic shock, sepsis). Renal perfusion also can be affected by reductions in cardiac output from peripheral vasodilation (sepsis, drugs) or profound renal vasoconstriction (severe heart failure, hepatorenal syndrome, agents such as nonsteroidal anti-inflammatory drugs [NSAIDs]). True or “effective” arterial hypovolemia leads to a fall in mean arterial pressure, which in turn triggers a series of neural and humoral responses, including activation of the sympathetic nervous and renin-angiotensin-aldosterone systems and antidiuretic hormone (ADH) release. GFR is maintained by prostaglandin-mediated


InternalMed_Harrison

InternalMed_Harrison. and humoral responses, including activation of the sympathetic nervous and renin-angiotensin-aldosterone systems and antidiuretic hormone (ADH) release. GFR is maintained by prostaglandin-mediated relaxation of afferent arterioles and angiotensin II–mediated constriction of efferent arterioles. Once the mean arterial pressure falls below 80 mmHg, GFR declines steeply.


InternalMed_Harrison

InternalMed_Harrison. Blockade of prostaglandin production by NSAIDs can result in severe vasoconstriction and acute renal failure. Blocking angiotensin action with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) decreases efferent arteriolar tone and in turn decreases glomerular capillary perfusion pressure. Patients taking NSAIDs and/or ACE inhibitors/ARBs are most susceptible to hemodynamically mediated acute renal failure when blood volume is reduced for any reason. Patients with bilateral renal artery stenosis (or stenosis in a solitary kidney) are dependent on efferent arteriolar vasoconstriction for maintenance of glomerular filtration pressure and are particularly susceptible to a precipitous decline in GFR when given ACE inhibitors or ARBs.


InternalMed_Harrison

InternalMed_Harrison. Prolonged renal hypoperfusion may lead to acute tubular necrosis (ATN), an intrinsic renal disease that is discussed below. The urinalysis and urinary electrolyte measurements can be useful in distinguishing prerenal azotemia from ATN (Table 61-2). The urine Na and osmolality of patients with prerenal azotemia can be predicted from the stimulatory actions of norepinephrine, angiotensin II, ADH, and low tubule fluid flow rate. In prerenal conditions, the tubules are intact, leading to a concentrated urine (>500 mosmol), avid Na retention (urine Na concentration, <20 mmol/L; fractional excretion of Na, <1%), and UCr/PCr >40 (Table 61-2). The prerenal urine sediment is usually normal or has hyaline and granular casts, whereas the sediment of ATN usually is filled with cellular debris, tubular epithelial casts, and dark (muddy brown) granular casts.


InternalMed_Harrison

InternalMed_Harrison. Urinary tract obstruction accounts for <5% of cases of acute renal failure but is usually reversible and must be ruled out early in the evaluation (Fig. 61-1). Since a single kidney is capable of adequate BUN/PCr ratio Urine sodium UNa, meq/L Urine osmolality, mosmol/L H2O Fractional excretion of sodiuma Urine/plasma creatinine UCr/PCr Urinalysis (casts) FENa = . PNa × >20:1 granular 10–15:1 >40 <350 >2% <20 Muddy brown Abbreviations: BUN, blood urea nitrogen; PCr, plasma creatinine concentration; PNa, plasma sodium concentration; UCr, urine creatinine concentration; UNa, urine sodium concentration.


InternalMed_Harrison

InternalMed_Harrison. Abbreviations: BUN, blood urea nitrogen; PCr, plasma creatinine concentration; PNa, plasma sodium concentration; UCr, urine creatinine concentration; UNa, urine sodium concentration. clearance, obstructive acute renal failure requires obstruction at the urethra or bladder outlet, bilateral ureteral obstruction, or unilateral obstruction in a patient with a single functioning kidney. Obstruction is usually diagnosed by the presence of ureteral and renal pelvic dilation on renal ultrasound. However, early in the course of obstruction or if the ureters are unable to dilate (e.g., encasement by pelvic or periureteral tumors), the ultrasound examination may be negative. The specific urologic conditions that cause obstruction are discussed in Chap. 343.


InternalMed_Harrison

InternalMed_Harrison. When prerenal and postrenal azotemia have been excluded as etiologies of renal failure, an intrinsic parenchymal renal disease is present. Intrinsic renal disease can arise from processes involving large renal vessels, intrarenal microvasculature and glomeruli, or the tubulointerstitium. Ischemic and toxic ATN account for ~90% of cases of acute intrinsic renal failure. As outlined in Fig. 61-1, the clinical setting and urinalysis are helpful in separating the possible etiologies. Prerenal azotemia and ATN are part of a spectrum of renal hypoperfusion; evidence of structural tubule injury is present in ATN, whereas prompt reversibility occurs with prerenal azotemia upon restoration of adequate renal perfusion. Thus, ATN often can be distinguished from prerenal azotemia by urinalysis and urine electrolyte composition (Table 61-2 and Fig. 61-1). Ischemic ATN is observed most frequently in patients who have undergone major surgery, trauma, severe hypovolemia, overwhelming sepsis, or


InternalMed_Harrison

InternalMed_Harrison. urine electrolyte composition (Table 61-2 and Fig. 61-1). Ischemic ATN is observed most frequently in patients who have undergone major surgery, trauma, severe hypovolemia, overwhelming sepsis, or extensive burns. Nephrotoxic ATN complicates the administration of many common medications, usually by inducing a combination of intrarenal vasoconstriction, direct tubule toxicity, and/ or tubule obstruction. The kidney is vulnerable to toxic injury by virtue of its rich blood supply (25% of cardiac output) and its ability to concentrate and metabolize toxins. A diligent search for hypo-tension and nephrotoxins usually uncovers the specific etiology of ATN. Discontinuation of nephrotoxins and stabilization of blood pressure often suffice without the need for dialysis while the tubules recover. An extensive list of potential drugs and toxins implicated in ATN is found in Chap. 334.


InternalMed_Harrison

InternalMed_Harrison. Processes involving the tubules and interstitium can lead to acute kidney injury (AKI), a subtype of acute renal failure. These processes include drug-induced interstitial nephritis (especially by antibiotics, NSAIDs, and diuretics), severe infections (both bacterial and viral), systemic diseases (e.g., systemic lupus erythematosus), and infiltrative disorders (e.g., sarcoidosis, lymphoma, or leukemia). A list of drugs associated with allergic interstitial nephritis is found in Chap. 340. Urinalysis usually shows mild to moderate proteinuria, hematuria, and pyuria (~75% of cases) and occasionally WBC casts. The finding of RBC casts in interstitial nephritis has been reported but should prompt a search for glomerular diseases (Fig. 61-1). Occasionally, renal biopsy will be needed to distinguish among these possibilities. The finding of eosinophils in the urine is suggestive of allergic interstitial nephritis or atheroembolic renal disease and is optimally observed with Hansel staining.


InternalMed_Harrison

InternalMed_Harrison. among these possibilities. The finding of eosinophils in the urine is suggestive of allergic interstitial nephritis or atheroembolic renal disease and is optimally observed with Hansel staining. The absence of eosinophiluria, however, does not exclude these etiologies.


InternalMed_Harrison

InternalMed_Harrison. Occlusion of large renal vessels, including arteries and veins, is an uncommon cause of acute renal failure. A significant reduction in GFR by this mechanism suggests bilateral processes or, in a patient with a single functioning kidney, a unilateral process. Renal arteries can be occluded with atheroemboli, thromboemboli, in situ thrombosis, aortic dissection, or vasculitis. Atheroembolic renal failure can occur spontaneously but most often is associated with recent aortic instrumentation. The emboli are cholesterol-rich and lodge in medium and small renal arteries, with a consequent eosinophil-rich inflammatory reaction. Patients with atheroembolic acute renal failure often have a normal urinalysis, but the urine may contain eosinophils and casts. The diagnosis can be confirmed by renal biopsy, but this procedure is often unnecessary when other stigmata of atheroemboli are present (livedo reticularis, distal peripheral infarcts, eosinophilia). Renal artery thrombosis may lead


InternalMed_Harrison

InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases HEMATURIA Proteinuria (>500 mg/24 h), Dysmorphic RBCs or RBC casts Pyuria, WBC casts Urine culture Urine eosinophils Hemoglobin electrophoresis Urine cytology UA of family members 24 h urinary calcium/uric acid IVP +/Renal ultrasound As indicated: retrograde pyelography or arteriogram, or cyst aspiration Cystoscopy Urogenital biopsy and evaluation Renal CT scan Renal biopsy of mass/lesion Follow periodic urinalysis Renal biopsy FIguRE 61-2 Approach to the patient with hematuria. ANCA, antineutrophil cytoplasmic antibody; ASLO, antistreptolysin O; CT, computed tomography; GBM, glomerular basement membrane; IVP, intravenous pyelography; RBC, red blood cell; UA, urinalysis; VDRL, Venereal Disease Research Laboratory; WBC, white blood cell.


InternalMed_Harrison

InternalMed_Harrison. Serologic and hematologic evaluation: blood cultures, anti-GBM antibody, ANCA, complement levels, cryoglobulins, hepatitis B and C serologies, VDRL, HIV, ASLO to mild proteinuria and hematuria, whereas renal vein thrombosis typically induces heavy proteinuria and hematuria. These vascular complications often require angiography for confirmation and are discussed in Chap. 341.


InternalMed_Harrison

InternalMed_Harrison. Diseases of the glomeruli (glomerulonephritis and vasculitis) and the renal microvasculature (hemolytic-uremic syndromes, thrombotic thrombocytopenic purpura, and malignant hypertension) usually present with various combinations of glomerular injury: proteinuria, hematuria, reduced GFR, and alterations of sodium excretion that lead to hypertension, edema, and circulatory congestion (acute nephritic syndrome). These findings may occur as primary renal diseases or as renal manifestations of systemic diseases. The clinical setting and other laboratory data help distinguish primary renal diseases from systemic diseases. The finding of RBC casts in the urine is an indication for early renal biopsy (Fig. 61-1), as the pathologic pattern has important implications for diagnosis, prognosis, and treatment. Hematuria without RBC casts can also be an indication of glomerular disease; this evaluation is summarized in Fig. 61-2. A detailed discussion of glomerulonephritis and diseases of the


InternalMed_Harrison

InternalMed_Harrison. and treatment. Hematuria without RBC casts can also be an indication of glomerular disease; this evaluation is summarized in Fig. 61-2. A detailed discussion of glomerulonephritis and diseases of the microvasculature is found in Chap. 340.


InternalMed_Harrison

InternalMed_Harrison. Oliguria refers to a 24-h urine output <400 mL, and anuria is the complete absence of urine formation (<100 mL). Anuria can be caused by total urinary tract obstruction, total renal artery or vein occlusion, and shock (manifested by severe hypotension and intense renal vasoconstriction). Cortical necrosis, ATN, and rapidly progressive glomerulonephritis occasionally cause anuria. Oliguria can accompany acute renal failure of any etiology and carries a more serious prognosis for renal recovery in all conditions except prerenal azotemia. Nonoliguria refers to urine output >400 mL/d in patients with acute or chronic azotemia. With nonoliguric ATN, disturbances of potassium and hydrogen balance are less severe than in oliguric patients, and recovery to normal renal function is usually more rapid.


InternalMed_Harrison

InternalMed_Harrison. The evaluation of proteinuria is shown schematically in Fig. 61-3 and typically is initiated after detection of proteinuria by dipstick examination. The dipstick measurement detects only albumin and gives false-positive results at pH >7.0 or when the urine is very concentrated or contaminated with blood. Because the dipstick relies on urinary albumin concentration, a very dilute urine may obscure significant proteinuria on dipstick examination. Quantification of urinary albumin on a spot urine sample (ideally from a first morning void) by measurement of an albumin-to-creatinine ratio (ACR) is helpful in approximating a 24-h albumin excretion rate (AER), where ACR (mg/g) ≈AER (mg/24 h). Furthermore, proteinuria that is not predominantly due to albumin will be missed by dipstick screening. This information is particularly important for the detection of Bence-Jones proteins in the urine of patients with multiple myeloma. Tests to measure total urine protein concentration accurately rely


InternalMed_Harrison

InternalMed_Harrison. This information is particularly important for the detection of Bence-Jones proteins in the urine of patients with multiple myeloma. Tests to measure total urine protein concentration accurately rely on precipitation with sulfosalicylic or trichloracetic acid (Fig. 61-3).


InternalMed_Harrison

InternalMed_Harrison. The magnitude of proteinuria and its composition in the urine depend on the mechanism of renal injury that leads to protein losses. Both charge and size selectivity normally prevent virtually all plasma albumin, globulins, and other high-molecular-weight proteins from crossing the glomerular wall; however, if this barrier is disrupted, plasma proteins may leak into the urine (glomerular proteinuria; Fig. 61-3). Smaller proteins (<20 kDa) are freely filtered but are readily reabsorbed by the proximal tubule. Traditionally, healthy individuals excrete <150 mg/d of total protein and <30 mg/d of albumin. However, even at albuminuria levels <30 mg/d, risk for progression to overt nephropathy or subsequent cardiovascular disease is increased. The remainder of the protein in the urine is secreted by 293 the tubules (Tamm-Horsfall, IgA, and urokinase) or represents small amounts of filtered β2-microglobulin, apoproteins, enzymes, and peptide hormones. Another mechanism of proteinuria entails


InternalMed_Harrison

InternalMed_Harrison. by 293 the tubules (Tamm-Horsfall, IgA, and urokinase) or represents small amounts of filtered β2-microglobulin, apoproteins, enzymes, and peptide hormones. Another mechanism of proteinuria entails excessive production of an abnormal protein that exceeds the capacity of the tubule for reabsorption. This situation most commonly occurs with plasma cell dyscrasias, such as multiple myeloma, amyloidosis, and lymphomas, that are associated with monoclonal production of immunoglobulin light chains.


InternalMed_Harrison

InternalMed_Harrison. The normal glomerular endothelial cell forms a barrier composed of pores of ~100 nm that retain blood cells but offer little impediment to passage of most proteins. The glomerular basement membrane traps most large proteins (>100 kDa), and the foot processes of epithelial cells (podocytes) cover the urinary side of the glomerular basement membrane and produce a series of narrow channels (slit diaphragms) to allow molecular passage of small solutes and water but not proteins. Some glomerular diseases, such as minimal change disease, cause fusion of glomerular epithelial cell foot processes, resulting in predominantly “selective” (Fig. 61-3) loss of albumin. Other glomerular diseases can present with disruption of the basement membrane and slit diaphragms (e.g., by immune complex deposition), resulting in losses of albumin and other plasma proteins. The fusion of foot processes causes increased pressure across the capillary basement membrane, resulting in areas with larger pore sizes


InternalMed_Harrison

InternalMed_Harrison. resulting in losses of albumin and other plasma proteins. The fusion of foot processes causes increased pressure across the capillary basement membrane, resulting in areas with larger pore sizes (and more severe “nonselective” proteinuria (Fig. 61-3).


InternalMed_Harrison

InternalMed_Harrison. When the total daily urinary excretion of protein is >3.5 g, hypoalbuminemia, hyperlipidemia, and edema (nephrotic syndrome; Fig. 61-3) are often present as well. However, total daily urinary protein excretion >3.5 g can occur without the other features of the nephrotic syndrome in a variety of other renal diseases, including diabetes (Fig. 61-3). Plasma cell dyscrasias (multiple myeloma) can be associated with large amounts of excreted light chains in the urine, which may not be detected by dipstick. The light chains are filtered by the glomerulus and overwhelm the reabsorptive capacity of the proximal tubule. Renal failure from these disorders occurs through a variety of mechanisms, including proximal tubule injury, tubule obstruction (cast nephropathy), and light chain deposition (Chap. 340). However, not all excreted light chains are nephrotoxic.


InternalMed_Harrison

InternalMed_Harrison. PROTEINURIA ON URINE DIPSTICK Quantify by 24-h urinary excretion of protein and albumin or first morning spot albumin-to-creatinine ratio RBCs or RBC casts on urinalysis In addition to disorders listed under microalbuminuria consider Myeloma-associated kidney disease (check UPEP) Intermittent proteinuria Postural proteinuria Congestive heart failure Fever Exercise Go to Fig. 61-2 Macroalbuminuria 300-3500 mg/d or 300-3500 mg/g Microalbuminuria 30-300 mg/d or 30-300 mg/g Nephrotic range > 3500 mg/d or > 3500 mg/g + Consider Early diabetes Essential hypertension Early stages of glomerulonephritis (especially with RBCs, RBC casts)Consider Early diabetes Essential hypertension Early stages of glomerulonephritis (especially with RBCs, RBC casts) Nephrotic syndrome Diabetes Amyloidosis Minimal change disease FSGS Membranous glomerulopathy IgA nephropathy


InternalMed_Harrison

InternalMed_Harrison. FIguRE 61-3 Approach to the patient with proteinuria. Investigation of proteinuria is often initiated by a positive dipstick on routine urinalysis. Conventional dipsticks detect predominantly albumin and provide a semiquantitative assessment (trace, 1+, 2+, or 3+), which is influenced by urinary concentration as reflected by urine specific gravity (minimum, <1.005; maximum, 1.030). However, more exact determination of proteinuria should employ a spot morning protein/creatinine ratio (mg/g) or a 24-h urine collection (mg/24 h). FSGS, focal segmental glomerulosclerosis; RBC, red blood cell; UPEP, urine protein electrophoresis.


InternalMed_Harrison

InternalMed_Harrison. Hypoalbuminemia in nephrotic syndrome occurs through excessive urinary losses and increased proximal tubule catabolism of filtered albumin. Edema forms from renal sodium retention and reduced plasma oncotic pressure, which favors fluid movement from capillaries to interstitium. To compensate for the perceived decrease in effective intravascular volume, activation of the renin-angiotensin system, stimulation of ADH, and activation of the sympathetic nervous system take place, promoting continued renal salt and water reabsorption and progressive edema. Despite these changes, hypertension is uncommon in primary kidney diseases resulting in the nephrotic syndrome (Fig. 61-3 and Chap. 338). The urinary loss of regulatory proteins and changes in hepatic synthesis contribute to the other manifestations of the nephrotic syndrome. A hypercoagulable state may arise from urinary losses of antithrombin III, reduced serum levels of proteins S and C, hyperfibrinogenemia, and enhanced platelet


InternalMed_Harrison

InternalMed_Harrison. of the nephrotic syndrome. A hypercoagulable state may arise from urinary losses of antithrombin III, reduced serum levels of proteins S and C, hyperfibrinogenemia, and enhanced platelet aggregation. Hypercholesterolemia may be severe and results from increased hepatic lipoprotein synthesis. Loss of immunoglobulins contributes to an increased risk of infection. Many diseases (some listed in Fig. 61-3) and drugs can cause the nephrotic syndrome; a complete list is found in Chap. 338.


InternalMed_Harrison

HEMATuRIA, PYuRIA, AND CASTS

InternalMed_Harrison. HEMATuRIA, PYuRIA, AND CASTS


InternalMed_Harrison

InternalMed_Harrison. Isolated hematuria without proteinuria, other cells, or casts is often indicative of bleeding from the urinary tract. Hematuria is defined as two to five RBCs per high-power field (HPF) and can be detected by dipstick. A false-positive dipstick for hematuria (where no RBCs are seen on urine microscopy) may occur when myoglobinuria is present, often in the setting of rhabdomyolysis. Common causes of isolated hematuria include stones, neoplasms, tuberculosis, trauma, and prostatitis. Gross hematuria with blood clots usually is not an intrinsic renal process; rather, it suggests a postrenal source in the urinary collecting system. Evaluation of patients presenting with microscopic hematuria is outlined in Fig. 61-2. A single urinalysis with hematuria is common and can result from menstruation, viral illness, allergy, exercise, or mild trauma. Persistent or significant hematuria (>3 RBCs/ HPF on three urinalyses, a single urinalysis with >100 RBCs, or gross hematuria) is associated with


InternalMed_Harrison

InternalMed_Harrison. viral illness, allergy, exercise, or mild trauma. Persistent or significant hematuria (>3 RBCs/ HPF on three urinalyses, a single urinalysis with >100 RBCs, or gross hematuria) is associated with significant renal or urologic lesions in 9.1% of cases. The level of suspicion for urogenital neoplasms in patients with isolated painless hematuria and nondysmorphic RBCs increases with age. Neoplasms are rare in the pediatric population, and isolated hematuria is more likely to be “idiopathic” or associated with a congenital anomaly. Hematuria with pyuria and bacteriuria is typical of infection and should be treated with antibiotics after appropriate cultures. Acute cystitis or urethritis in women can cause gross hematuria. Hypercalciuria and hyperuricosuria are also risk factors for unexplained isolated hematuria in both children and adults. In some of these patients (50–60%), reducing calcium and uric acid excretion through dietary interventions can eliminate the microscopic hematuria.


InternalMed_Harrison

InternalMed_Harrison. Isolated microscopic hematuria can be a manifestation of glomerular diseases. The RBCs of glomerular origin are often dysmorphic when examined by phase-contrast microscopy. Irregular shapes of RBCs may also result from pH and osmolarity changes produced along the distal nephron. Observer variability in detecting dysmorphic RBCs is common. The most common etiologies of isolated glomerular hematuria are IgA nephropathy, hereditary nephritis, and thin basement membrane disease. IgA nephropathy and hereditary nephritis can lead to episodic gross hematuria. A family history of renal failure is often present in hereditary nephritis, and patients with thin basement membrane disease often have family members with microscopic hematuria. A renal biopsy is needed for the definitive diagnosis of these disorders, which are discussed in more detail in Chap. 338. Hematuria with dysmorphic RBCs, RBC casts, and protein excretion >500 mg/d is virtually diagnostic of glomerulonephritis. RBC casts form


InternalMed_Harrison

InternalMed_Harrison. disorders, which are discussed in more detail in Chap. 338. Hematuria with dysmorphic RBCs, RBC casts, and protein excretion >500 mg/d is virtually diagnostic of glomerulonephritis. RBC casts form as RBCs that enter the tubule fluid and become trapped in a cylindrical mold of gelled Tamm-Horsfall protein. Even in the absence of azotemia, these patients should undergo serologic evaluation and renal biopsy as outlined in Fig. 61-2.


InternalMed_Harrison

InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases Isolated pyuria is unusual since inflammatory reactions in the kidney or collecting system also are associated with hematuria. The presence of bacteria suggests infection, and WBC casts with bacteria are indicative of pyelonephritis. WBCs and/or WBC casts also may be seen in acute glomerulonephritis as well as in tubulointerstitial processes such as interstitial nephritis and transplant rejection. Casts can be seen in chronic renal diseases. Degenerated cellular casts called waxy casts or broad casts (arising in the dilated tubules that have undergone compensatory hypertrophy in response to reduced renal mass) may be seen in the urine.


InternalMed_Harrison

InternalMed_Harrison. By history, it is often difficult for patients to distinguish urinary frequency (often of small volumes) from true polyuria (>3 L/d), and a quantification of volume by 24-h urine collection may be needed (Fig. 61-4). Polyuria results from two potential mechanisms: excretion of nonabsorbable solutes (such as glucose) or excretion of water (usually from a defect in ADH production or renal responsiveness). To distinguish a solute diuresis from a water diuresis and to determine whether the diuresis is appropriate for the clinical circumstances, urine osmolality is measured. The average person excretes between 600 and 800 mosmol of solutes per day, primarily as urea and electrolytes. If the urine output is >3 L/d and the urine is dilute (<250 mosmol/L), total mosmol excretion is normal and a water diuresis is present. This circumstance could arise from polydipsia, inadequate secretion of vasopressin (central diabetes insipidus), or failure of renal tubules to respond to vasopressin


InternalMed_Harrison

InternalMed_Harrison. and a water diuresis is present. This circumstance could arise from polydipsia, inadequate secretion of vasopressin (central diabetes insipidus), or failure of renal tubules to respond to vasopressin (nephrogenic diabetes insipidus). If the urine volume is >3 L/d and urine


InternalMed_Harrison

InternalMed_Harrison. POLYURIA (>3 L/24 h) Urine osmolality < 250 mosmol History, low serum sodium Water deprivation test or ADH level Primary polydipsia Psychogenic Hypothalamic disease Drugs (thioridazine, chlorpromazine, anticholinergic agents) > 300 mosmol Diabetes insipidus (DI) Solute diuresis Glucose, mannitol, radiocontrast, urea (from high protein feeding), medullary cystic diseases, resolving ATN, or obstruction, diuretics posthypophysectomy, trauma, histiocystosis or granuloma, encroachment by aneurysm, Sheehan's syndrome, infection, Guillain-Barré, fat embolus, Acquired tubular diseases: pyelonephritis, analgesic nephropathy, multiple myeloma, amyloidosis, obstruction, sarcoidosis, hypercalcemia, hypokalemia, Sjren’s syndrome, sickle cell anemia Drugs or toxins: lithium, demeclocycline, methoxyflurane, ethanol, diphenylhydantoin, propoxyphene, amphotericin Congenital: hereditary, polycystic or medullary cystic disease


InternalMed_Harrison

InternalMed_Harrison. Drugs or toxins: lithium, demeclocycline, methoxyflurane, ethanol, diphenylhydantoin, propoxyphene, amphotericin Congenital: hereditary, polycystic or medullary cystic disease FIguRE 61-4 Approach to the patient with polyuria. ADH, antidiuretic hormone; ATN, acute tubular necrosis. osmolality is >300 mosmol/L, a solute diuresis is clearly present and a search for the responsible solute(s) is mandatory.


InternalMed_Harrison

InternalMed_Harrison. Excessive filtration of a poorly reabsorbed solute such as glucose or mannitol can depress reabsorption of NaCl and water in the proximal tubule and lead to enhanced excretion in the urine. Poorly controlled diabetes mellitus with glucosuria is the most common cause of a solute diuresis, leading to volume depletion and serum hypertonicity. Since the urine sodium concentration is less than that of blood, more water than sodium is lost, causing hypernatremia and hypertonicity. Common iatrogenic solute diuresis occurs in association with mannitol administration, radiocontrast media, and high-protein feedings (enteral or parenteral), leading to increased urea production and excretion. Less commonly, excessive sodium loss may result from cystic renal diseases or Bartter’s syndrome or may develop during a tubulointerstitial process (such as resolving ATN). In these so-called salt-wasting disorders, the tubule damage results in direct impairment of sodium reabsorption and indirectly reduces


InternalMed_Harrison

InternalMed_Harrison. during a tubulointerstitial process (such as resolving ATN). In these so-called salt-wasting disorders, the tubule damage results in direct impairment of sodium reabsorption and indirectly reduces the responsiveness of the tubule to aldosterone. Usually, the sodium losses are mild, and the obligatory urine output is <2 L/d; resolving ATN and postobstructive diuresis are exceptions and may be associated with significant natriuresis and polyuria.


InternalMed_Harrison

InternalMed_Harrison. Formation of large volumes of dilute urine is usually due to polydipsic states or diabetes insipidus. Primary polydipsia can result from habit, psychiatric disorders, neurologic lesions, or medications. During deliberate polydipsia, extracellular fluid volume is normal or expanded and plasma vasopressin levels are reduced because serum osmolality tends to be near the lower limits of normal. Urine osmolality is also maximally dilute at 50 mosmol/L.


InternalMed_Harrison

InternalMed_Harrison. Central diabetes insipidus may be idiopathic in origin or secondary to a variety of conditions, including hypophysectomy, trauma, neoplastic, inflammatory, vascular, or infectious hypothalamic diseases. Idiopathic central diabetes insipidus is associated with selective destruction of the vasopressin-secreting neurons in the supraoptic and paraventricular nuclei and can either be inherited as an autosomal dominant trait or occur spontaneously. Nephrogenic diabetes insipidus can occur in a variety of clinical situations, as summarized in Fig. 61-4. A plasma vasopressin level is recommended as the best method for distinguishing between central and nephrogenic diabetes insipidus. Alternatively, a water deprivation test plus exogenous vasopressin may distinguish primary polydipsia from central and nephrogenic diabetes insipidus. For a detailed discussion, see Chap. 404.


InternalMed_Harrison

InternalMed_Harrison. Atlas of Urinary Sediments and Renal Biopsies Agnes B. Fogo, Eric G. Neilson Key diagnostic features of selected diseases in renal biopsy are illus-trated, with light, immunofluorescence, and electron microscopic 62e images. Common urinalysis findings are also documented. Figure 62e-1 Minimal-change disease. In minimal-change disease, light microscopy is unremarkable (A), whereas electron microscopy (B) reveals podocyte injury evidenced by complete foot process effacement. (ABF/Vanderbilt Collection.) CHAPTER 62e Atlas of Urinary Sediments and Renal Biopsies Figure 62e-2 Focal segmental glomerulosclerosis (FSGS). There is a well-defined segmental increase in matrix and obliteration of capil-lary loops (arrow), the sine qua non of segmental sclerosis not other-wise specified (NOS) type. (EGN/UPenn Collection.)


InternalMed_Harrison

InternalMed_Harrison. Figure 62e-3 Collapsing glomerulopathy. There is segmental col-lapse (arrow) of the glomerular capillary loops and overlying podocyte hyperplasia. This lesion may be idiopathic or associated with HIV infec-tion and has a particularly poor prognosis. (ABF/Vanderbilt Collection.) Figure 62e-4 Hilar variant of FSGS. There is segmental sclerosis of the glomerular tuft at the vascular pole with associated hyalinosis, also present in the afferent arteriole (arrows). This lesion often occurs as a secondary response when nephron mass is lost due to, e.g., scar-ring from other conditions. Patients usually have less proteinuria and less steroid response than FSGS, NOS type. (ABF/Vanderbilt Collection.) Figure 62e-5 Tip lesion variant of FSGS. There is segmental scle-rosis of the glomerular capillary loops at the proximal tubular outlet (arrow). This lesion has a better prognosis than other types of FSGS. (ABF/Vanderbilt Collection.)


InternalMed_Harrison

InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases Figure 62e-6 Postinfectious (poststreptococcal) glomerulonephritis. The glomerular tuft shows proliferative changes with numerous poly-morphonuclear leukocytes (PMNs), with a crescentic reaction (arrow) in severe cases (A). These deposits localize in the mesangium and along the capillary wall in a subepithelial pattern and stain dominantly for C3 and to a lesser extent for IgG (B). Subepithelial hump-shaped deposits are seen by electron microscopy (arrow) (C). (ABF/Vanderbilt Collection.)


InternalMed_Harrison

InternalMed_Harrison. Figure 62e-7 Membranous glomerulopathy. Membranous glomerulopathy is due to subepithelial deposits, with resulting basement membrane reaction, resulting in the appearance of spike-like projections on silver stain (A). The deposits are directly visualized by fluorescent anti-IgG, revealing diffuse granular capillary loop staining (B). By electron microscopy, the subepithelial location of the deposits and early surrounding basement membrane reaction is evident, with overlying foot process effacement (C). (ABF/Vanderbilt Collection.) Figure 62e-8 IgA nephropathy. There is variable mesangial expansion due to mesangial deposits, with some cases also showing endocapillary proliferation or segmental sclerosis (A). By immunofluorescence, mesangial IgA deposits are evident (B). (ABF/Vanderbilt Collection.) CHAPTER 62e Atlas of Urinary Sediments and Renal Biopsies


InternalMed_Harrison

InternalMed_Harrison. CHAPTER 62e Atlas of Urinary Sediments and Renal Biopsies Figure 62e-9 Membranoproliferative glomerulonephritis. There is mesangial expansion and endocapillary proliferation with cellular interposition in response to subendothelial deposits, resulting in the “tram-track” of duplication of glomerular basement membrane. (EGN/ UPenn Collection.) Figure 62e-10 Dense deposit disease (membranoproliferative glomerulonephritis type II). By light microscopy, there is a membranoproliferative pattern. By electron microscopy, there is a dense transformation of the glomerular basement membrane with round, globular deposits within the mesangium. By immunofluorescence, only C3 staining is usually present. Dense deposit disease is part of the group of renal diseases called C3 glomerulopathy, related to underlying complement dysregulation. (ABF/Vanderbilt Collection.)


InternalMed_Harrison

InternalMed_Harrison. Figure 62e-12 C3 glomerulonephritis. By immunofluorescence, only C3 staining is usually present, with occasional minimal immu-noglobulin, in an irregular capillary wall and mesangial distribution. (ABF/Vanderbilt Collection.) PART 2 Cardinal Manifestations and Presentation of Diseases Figure 62e-11 C3 glomerulonephritis. By light microscopy, there is a membranoproliferative pattern. C3 glomerulonephritis is part of the group of renal diseases called C3 glomerulopathy, related to underlying complement dysregulation. (ABF/ Vanderbilt Collection.) Figure 62e-13 C3 glomerulonephritis. By electron microscopy, usual density deposits are present (arrows), including mesangial, subendothelial, and occasional hump-type subepithelial deposits. (ABF/ Vanderbilt Collection.)


InternalMed_Harrison

InternalMed_Harrison. (ABF/ Vanderbilt Collection.) Figure 62e-14 Mixed proliferative and membranous glomerulonephritis. This specimen shows pink subepithelial deposits with spike reaction, and the “tram-track” sign of reduplication of glomerular basement membrane, resulting from subendothelial deposits, as may be seen in mixed membranous and proliferative lupus nephritis (International Society of Nephrology [ISN]/Renal Pathology Society [RPS] class V and IV). (EGN/UPenn Collection.) Figure 62e-16 Granulomatosis with polyangiitis (Wegener’s). This pauci-immune necrotizing crescentic glomerulonephritis shows numerous breaks in the glomerular basement membrane with associated segmental fibrinoid necrosis and a crescent formed by proliferation of the parietal epithelium. Note that the uninvolved segment of the glomerulus (at ∼5 o’clock) shows no evidence of proliferation or immune complexes. (ABF/Vanderbilt Collection.) CHAPTER 62e Atlas of Urinary Sediments and Renal Biopsies


InternalMed_Harrison

InternalMed_Harrison. CHAPTER 62e Atlas of Urinary Sediments and Renal Biopsies Figure 62e-15 Lupus nephritis. Proliferative lupus nephritis, ISN/RPS class III (focal) or IV (diffuse), manifests as endocapillary proliferation, which may result in segmental necrosis due to deposits, particularly in the subendothelial area (A). By immunofluorescence, chunky irregular mesangial and capillary loop deposits are evident, with some of the peripheral loop deposits having a smooth, molded outer contour due to their subendothelial location. These deposits typically stain for all three immunoglobulins, IgG, IgA, IgM, and both C3 and C1q (B). By electron microscopy, subendothelial (arrow), mesangial (white rim arrowhead), and rare subepithelial (black arrowhead) dense immune complex deposits are evident, along with extensive foot process effacement (C). (ABF/Vanderbilt Collection.) PART 2 Cardinal Manifestations and Presentation of Diseases


InternalMed_Harrison

InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases Figure 62e-17 Anti–glomerular basement membrane antibody-mediated glomerulonephritis. There is segmental necrosis with a break of the glomerular basement membrane (arrow) and a cellular crescent (A), and immunofluorescence for IgG shows linear staining of the glomerular basement membrane with a small crescent at ∼1 o’clock (B). (ABF/Vanderbilt Collection.) Figure 62e-18 Amyloidosis. Amyloidosis shows amorphous, acellular expansion of the mesangium, with material often also infiltrating glomerular basement membranes, vessels, and the interstitium, with apple-green birefringence by polarized Congo red stain (A). The deposits are composed of randomly organized 9to 11-nm fibrils by electron microscopy (B). (ABF/Vanderbilt Collection.)


InternalMed_Harrison

InternalMed_Harrison. Figure 62e-19 Light chain deposition disease. There is mesangial expansion, often nodular by light microscopy (A), with immunofluorescence showing monoclonal staining, more commonly with kappa than lambda light chain, of tubules (B) and glomerular tufts. By electron microscopy (C), the deposits show an amorphous granular appearance and line the inside of the glomerular basement membrane (arrows) and are also found along the tubular basement membranes. (ABF/Vanderbilt Collection.) Figure 62e-20 Light chain cast nephropathy (myeloma kidney). Monoclonal light chains precipitate in tubules and result in a syncytial giant cell reaction (arrow) surrounding the casts and a surround-ing chronic interstitial nephritis with tubulointerstitial fibrosis. (ABF/ Vanderbilt Collection.) CHAPTER 62e Atlas of Urinary Sediments and Renal Biopsies


InternalMed_Harrison

InternalMed_Harrison. CHAPTER 62e Atlas of Urinary Sediments and Renal Biopsies Figure 62e-21 Fabry’s disease. Due to deficiency of α-galactosidase, there is abnormal accumulation of glycolipids, resulting in foamy podocytes by light microscopy (A). These deposits can be directly visualized by electron microscopy (B), where the glycosphingolipid appears as whorled so-called myeloid bodies, particularly in the podocytes. (ABF/Vanderbilt Collection.) Cardinal Manifestations and Presentation of Diseases Figure 62e-22 Alport’s syndrome and thin glomerular basement membrane lesion. In Alport’s syndrome, there is irregular thinning alternating with thickened so-called basket-weaving abnormal organization of the glomerular basement membrane (A). In benign familial hematuria, or in early cases of Alport’s syndrome or female carriers, only extensive thinning of the glomerular basement membrane is seen by electron microscopy (B). (ABF/Vanderbilt Collection.)


InternalMed_Harrison

InternalMed_Harrison. Figure 62e-23 Diabetic nephropathy. In the earliest stage of diabetic nephropathy, only mild mesangial increase and prominent glomerular basement membranes (confirmed to be thickened by electron microscopy) are present (A). In slightly more advanced stages, more marked mesangial expansion with early nodule formation develops, with evident arteriolar hyaline (B). In established diabetic nephropathy, there is nodular mesangial expansion, so-called Kimmelstiel-Wilson nodules, with increased mesangial matrix and cellularity, microaneurysm formation in the glomerulus on the left, and prominent glomerular basement membranes without evidence of immune deposits and arteriolar hyalinosis of both afferent and efferent arterioles (C). (ABF/Vanderbilt Collection.)


InternalMed_Harrison

InternalMed_Harrison. Figure 62e-24 Arterionephrosclerosis. Hypertension-associated injury often manifests extensive global sclerosis of glomeruli, with accompanying and proportional tubulointerstitial fibrosis and pericapsular fibrosis, and there may be segmental sclerosis (A). The vessels show disproportionately severe changes of intimal fibrosis, medial hypertrophy, and arteriolar hyaline deposits (B). (ABF/Vanderbilt Collection.) Figure 62e-26 Hemolytic-uremic syndrome. There are character-istic intraglomerular fibrin thrombi, with a chunky pink appearance (thrombotic microangiopathy) (arrow). The remaining portion of the capillary tuft shows corrugation of the glomerular basement mem-brane due to ischemia. (ABF/Vanderbilt Collection.)


InternalMed_Harrison

InternalMed_Harrison. B Figure 62e-27 Progressive systemic sclerosis. Acutely, there is fibrinoid necrosis of interlobular and larger vessels, with intervening normal vessels and ischemic change in the glomeruli (A). Chronically, this injury leads to intimal proliferation, the so-called onion-skinning appearance (B). (ABF/Vanderbilt Collection.) CHAPTER 62e Atlas of Urinary Sediments and Renal Biopsies Figure 62e-25 Cholesterol emboli. Cholesterol emboli cause cleft-like spaces (arrow) where the lipid has been extracted during processing, with smooth outer contours and surrounding fibrotic and mononuclear cell reaction in these arterioles. (ABF/Vanderbilt Collection.) Figure 62e-28 Acute pyelonephritis. There are characteristic intra-tubular plugs and casts of PMNs (arrow) with inflammation extending into the surrounding interstitium and accompanying tubular injury. (ABF/ Vanderbilt Collection.)


InternalMed_Harrison

InternalMed_Harrison. (ABF/ Vanderbilt Collection.) Figure 62e-29 Acute tubular injury. There is extensive flattening of the tubular epithelium and loss of the brush border, with mild intersti-tial edema, characteristic of acute tubular injury due to ischemia. (ABF/ Vanderbilt Collection.) Figure 62e-30 Acute interstitial nephritis. There is extensive interstitial lymphoplasmocytic infiltrate with mild edema and associated tubular injury (A), which is frequently associated with interstitial eosinophils (B) when caused by a drug hypersensitivity reaction. (ABF/Vanderbilt Collection.) B Figure 62e-31 Oxalosis. Calcium oxalate crystals have caused extensive tubular injury, with flattening and regeneration of tubular epithelium (A). Crystals are well visualized as sheaves when viewed under polarized light (B). (ABF/Vanderbilt Collection.)


InternalMed_Harrison

InternalMed_Harrison. Figure 62e-32 Acute phosphate nephropathy. There is extensive acute tubular injury with intratubular nonpolarizable calcium phos-phate crystals. (ABF/Vanderbilt Collection.) Figure 62e-35 Coarse granular cast. (ABF/Vanderbilt Collection.) Figure 62e-33 Sarcoidosis. There is chronic interstitial nephritis with numerous, confluent, nonnecrotizing granulomas. The glomeruli are unremarkable, but there is moderate tubular atrophy and interstitial fibrosis. (ABF/Vanderbilt Collection.) Figure 62e-36 Fine granular casts. (ABF/Vanderbilt Collection.) CHAPTER 62e Atlas of Urinary Sediments and Renal Biopsies Figure 62e-34 Hyaline cast. (ABF/Vanderbilt Collection.) Figure 62e-37 Red blood cell cast. (ABF/Vanderbilt Collection.) Figure 62e-38 White blood cell cast. (ABF/Vanderbilt Collection.) Figure 62e-40 “Maltese cross” formation in an oval fat body. (ABF/Vanderbilt Collection.)


InternalMed_Harrison

InternalMed_Harrison. Figure 62e-39 Triple phosphate crystals. (ABF/Vanderbilt Collection.) Figure 62e-41 Uric acid crystals. (ABF/Vanderbilt Collection.) 295 fluid and Electrolyte Disturbances David B. Mount SODIuM AND WATER COMPOSITION OF BODY FLuIDS Water is the most abundant constituent in the body, comprising approximately 50% of body weight in women and 60% in men. Total-63 body water is distributed in two major compartments: 55–75% is intracellular (intracellular fluid [ICF]), and 25–45% is extracellular (extracellular fluid [ECF]). The ECF is further subdivided into intravascular (plasma water) and extravascular (interstitial) spaces in a ratio of 1:3. Fluid movement between the intravascular and interstitial spaces occurs across the capillary wall and is determined by Starling forces, i.e., capillary hydraulic pressure and colloid osmotic pressure. The transcapillary hydraulic pressure gradient exceeds the corresponding oncotic pressure gradient, thereby favoring the movement of plasma


InternalMed_Harrison

InternalMed_Harrison. capillary hydraulic pressure and colloid osmotic pressure. The transcapillary hydraulic pressure gradient exceeds the corresponding oncotic pressure gradient, thereby favoring the movement of plasma ultrafiltrate into the extravascular space. The return of fluid into the intravascular compartment occurs via lymphatic flow.


InternalMed_Harrison

InternalMed_Harrison. The solute or particle concentration of a fluid is known as its osmolality, expressed as milliosmoles per kilogram of water (mOsm/kg). Water easily diffuses across most cell membranes to achieve osmotic equilibrium (ECF osmolality = ICF osmolality). Notably, the extracellular and intracellular solute compositions differ considerably owing to the activity of various transporters, channels, and ATP-driven membrane pumps. The major ECF particles are Na+ and its accompanying anions Cl– and HCO3–, whereas K+ and organic phosphate esters (ATP, creatine phosphate, and phospholipids) are the predominant ICF osmoles. Solutes that are restricted to the ECF or the ICF determine the “tonicity” or effective osmolality of that compartment. Certain solutes, particularly urea, do not contribute to water shifts across most membranes and are thus known as ineffective osmoles.