Tag: Pregnancy

  • Pregnancy Tests

    Most pregnancy tests are based on the fact that the placenta secretes human chorionic gonadotropin (hCG), a hormone that has a luteinizing action on ovarian follicles and probably has other functions that are not completely known. Serum hCG levels of about 25 milli-international units (mIU)/ ml (IU/L) are reached about 8-10 days after conception. The hCG levels double approximately every 2 days (various investigators have reported doubling times ranging from 1-3 days) during approximately the first 6 weeks of gestation. Levels of about 500 mIU/ml are encountered about 14-18 days after conception (28-32 days after the beginning of the last menstrual period). Serum levels are generally higher than urine levels for about the first 2 weeks after conception and about the same as urine levels during the third week. Thereafter, urine levels are higher than serum. The serum (and urine) hCG levels peak about 55-70 days (8-10 weeks) after conception (literature range, 40-77 days). Peak serum values are about 30,000 mIU/ml (range, 20,000-57,000 mIU/ml). Serum and urine levels then decline rather rapidly during the last part of the first trimester, with serum levels eventually stabilizing at about 10,000 mIU/ml. These levels are maintained for the remainder of pregnancy, although some investigators describe a brief rise and fall in the third trimester. Urine levels generally parallel serum levels, but the actual quantity of urine hCG obtained in terms of milliinternational units per milliliter is considerably dependent on technical aspects of the kit method being used (discussed later).

    The hCG molecule is composed of two subunits, alpha and beta. The alpha subunit is also a part of the pituitary hormones LH, FSH, and TSH. The beta subunit, however, is different for each hormone. The hCG molecule in serum becomes partially degraded or metabolized to beta subunits and other fragments that are excreted in urine.

    Biologic tests. The first practical biologic test for pregnancy was the Ascheim-Zondek test, published in 1928. Urine was injected into immature female mice, and a positive result was indicated by corpus luteum development in the ovaries. This took 4-5 days to perform. The next major advance took place in the late 1950s when frog tests were introduced. These took about 2 hours to complete. The result was almost always positive by the 40th day after the last menses, although it could become positive earlier.

    Immunologic tests. In the 1960s it was learned that antibodies to hCG could be produced by injecting the hCG molecule into animals. This was the basis for developing immunologic pregnancy tests using antigen-antibody reactions. In the late 1960s and during the 1970s, both latex agglutination slide tests and hemagglutination tube tests became available. The slide tests took about 2 minutes to perform and had a sensitivity of 1,500-3,000 mIU/ml, depending on the manufacturer. The tube tests required 2 hours to complete and had a sensitivity of 600-1,500 mIU/ml. The antibody preparations used at that time were polyclonal antibodies developed against the intact hCG molecule, and they cross-reacted with LH and TSH. This did not permit tests to be sensitive enough to detect small amounts of hCG, because urine LH could produce false positive results.

    Beta subunit antibody tests. In the late 1970s, methods were found to develop antibodies against the beta subunit of hCG rather than against the whole molecule. Antibody specific against the beta subunit could greatly reduce or even eliminate the cross-reaction of hCG with LH. However, the degree of current beta subunit antibody specificity varies with different commercial companies. By 1980, sensitivity of the slide tests using beta hCG antibody had reached 500-1,500 mIU/ml, and sensitivity of the beta hCG tube tests was approximately 200 mIU/ml. Both the slide and the tube tests required a urine specimen. In the 1980s, standard immunoassay methods were developed for beta hCG in serum that provide a sensitivity of 3-50 mIU/ml. These methods detect pregnancy 1-2 weeks after conception. The great majority of current tests use monoclonal antibodies, either alone or with a polyclonal antibody that captures the hCG molecule and a monoclonal antibody that identifies it. Several manufacturers developed abbreviated serum pregnancy immunoassays that compared patient serum with a single standard containing a known amount of beta hCG (usually in the range of 25 mIU/ml). A result greater than the standard means that beta hCG is present in a quantity greater than the standard value, which in usual circumstances indicates pregnancy. Current serum immunoassay procedures take between 5 minutes and 2 hours to perform (depending on the manufacturer). The abbreviated method is much less expensive and is usually quicker. Several urine tests are available that detect 50 mIU/ml of hCG.

    Technical problems with human chorionic gonadotropin. Some (not all) of the kits that detect less than 25 mIU/ml of hCG may have problems with false-positive results of several different etiologies. First, of course, there may be incorrect performance of the test or patient specimen mishandling. The antibodies used in the different manufacturer’s tests have different specificities. Serum hCG molecules may exist in different forms in some patients: whole (“intact”) molecule, free beta subunit, free alpha subunit, or other degraded hCG fragments. Considerable quantities of serum free beta or alpha subunits are more often seen with tumors. Different antibodies may detect different amounts of hCG material depending on whether the antibody detects only the whole molecule, the beta subunit on the whole molecule, or the free beta subunit only (including in urine a partially degraded free beta subunit known as the “core beta fragment”). Most anti-beta antibodies actually detect both whole molecule (because of the structural beta subunit), free beta subunit, and core beta fragments. Therefore, the amount of hCG (in mIU/ml) detected in urine depends on several factors: (1) whether a specific whole-molecule or a beta-hCG method is used. The specific whole-molecule method reports about the same quantity of intact hCG in serum or urine, whereas the beta-specific assay would report higher amounts of hCG in urine than in serum since it detects intact hCG plus the beta subunits and fragments that are present in greater quantities in urine than serum; (2) degree of urine concentration or dilution; (3) stage of pregnancy, since more beta fragments appear in urine after the first few weeks; (4) how the particular kit is standardized (discussed later). Some beta-hCG antibodies have a certain degree of cross-reaction with LH, although theoretically a beta-specific antibody should not do so. The serum of occasional patients contains heterophil-type antibodies capable of cross-reacting with monoclonal test antibodies (HAMA) that were produced in mouse tissue cells and could produce a false positive result. This most often happens with double antibody “sandwich” test methods. Some kits are affected in a similar way by renal failure.

    Another confusing aspect of pregnancy testing relates to standardization of the tests by the manufacturers (that is, adjusting the test method to produce the same result as a standard, which is a known quantity of the material being assayed). In hCG testing, the manufacturers use a standard from the World Health Organization (WHO). The confusion arises because the earliest WHO standard used for this purpose (Second International Standard; second IS) was composed of a mixture of whole-molecule hCG, free beta subunits, and other hCG fragments. When the supply of second IS was exhausted, the WHO developed the first (and then the third) International Reference Preparation (IRP), which is mostly whole-molecule hCG without free beta subunit. However, hCG kits standardized with the original second IS give results about half as high as current kits standardized against the first or third IRP. Also, certain current kits specific for whole-molecule hCG would not detect some of the hCG fragments in the original second IS. This difference in antibody behavior may at least partially explain discrepant reports in the literature of equal quantities of hCG in pregnancy serum and urine and other reports of urine values as high as 10 times serum values. After the first few weeks of pregnancy, maternal serum contains primarily intact hCG; maternal urine contains some intact hCG but much larger quantities of free beta subunits and core beta fragments.

    Finally, it has been reported in several studies that occasionally normal nonpregnant women may have low-level circulating levels of an hCG-like substance, usually less than 25 mIU/ml. This was reported in about 2.5% (range, 0%-14%) of patients in these studies, although most evaluations of hCG test kits have not reported false positive results. When one kit was reactive, sometimes one or more different kits would also be reactive, but usually some kits do not react with these substances. At present, in most laboratories there is no satisfactory way to know immediately whether a positive result is due to pregnancy, is due to hCG-producing tumor, or is false positive, especially when the test is a yes-no method. Although there are ways to investigate possible discrepancies, it usually takes considerable time and retesting to solve the problem or it may necessitate consultation with a reference laboratory.

    Other uses for hCG assay. Pregnancy tests are useful in certain situations other than early diagnosis of normal pregnancy. These conditions include ectopic pregnancy, spontaneous abortion (which occurs in about 15% of all pregnancies; literature range, 12%-31%), and hCG-producing neoplasms. Ectopic pregnancy and neoplasms will be discussed in detail later. When the differential diagnosis includes normal intrauterine pregnancy, ectopic pregnancy, and threatened, incomplete, or complete abortion, the pattern obtained from serum quantitative beta-hCG assays performed every other day may be helpful. During the first 4 weeks of pregnancy (beginning at conception), there is roughly a doubling of hCG every 2 days (range, 1-3 days). As noted earlier, serum beta hCG by immunoassay first detects embryonic placental hCG in titers of 2-25 IU/L between 1 and 2 weeks after conception. Ectopic pregnancy and abortions may demonstrate an increase in their hCG levels at the same rate as in normal pregnancy up to a certain point. In the case of ectopic pregnancy, that point is usually less than 4 weeks (possibly as long as 6 weeks) after conception, since the ectopic location usually limits placental growth or rupture occurs. The typical pattern of ectopic pregnancy is a leveling off (plateau) at a certain time. The usual pattern of abortion is either a decrease in beta-hCG levels as abortion takes place or a considerable slowing in the rate of increase. However, these are only rules of thumb. About 15% of normal intrauterine pregnancies display less increase (decreased rate of increase) than expected, and thus could be mistaken for beginning abortion by this criterion alone. Also, ectopic pregnancy values may sometimes decline rather than plateau if the fetus dies.

    Ectopic pregnancy

    Ectopic pregnancy is a common gynecologic problem, either by itself or in differential diagnosis. Symptoms include abdominal pain of various types in about 97% of patients (literature range, 91%-100%), abnormal uterine bleeding in about 75% (54%-80%), delayed menses in about 75% (68%-84%), adnexal tenderness on palpation in about 90%-95%, unilateral adnexal mass in about 50% (30%-76%), and fever (usually lowgrade) in about 5% (3%-9%). Hypovolemic shock is reported as the presenting symptom in about 14%. It is obvious that these signs and symptoms can suggest a great number of conditions. In one study, 31% of patients with ectopic pregnancy in the differential diagnosis had a strongly suggestive triad of abdominal pain, uterine bleeding, and an adnexal mass. Only 14% of these patients were found to have ectopic pregnancy. Some conditions that frequently mimic ectopic pregnancy are pelvic inflammatory disease; threatened, incomplete, or complete abortion; corpus luteum rupture; dysfunctional uterine bleeding; and bleeding ovarian cyst. Among routine laboratory tests, a hemoglobin value less than 10 gm/100 ml is reported in about 40% of ectopic pregnancy cases (28%-55%) and leukocytosis in about 50%. Among other diagnostic procedures, culdocentesis for fresh blood is reported to produce about 10% false negative results (5%-18%). Pregnancy test results vary according to the sensitivity of the test. Urine or serum pregnancy tests with a sensitivity of 500-1,000 mIU/ml result in about 25% false negative results (8%-60%). Tests with a sensitivity of 50 mIU/ml yield about 5%-10% false negative results (0%-13%). Serum tests with a sensitivity of 25 IU/L or better have a false negative rate of about 1%-2% (range, 0%-3%). A positive pregnancy test result is not a diagnosis of ectopic pregnancy but signifies only that the patient has increased levels of hCG, for which there could be several possible causes. Also, some manufacturers’ kits are subject to a certain number of false positive results. Interpretation of a negative test result depends on the sensitivity of the test. If the test is a serum hCG immunoassay with a sensitivity of 25 mIU/ml (IU/L) or better, a negative test result is about 98%-99% accurate in excluding pregnancy. However, there are rare cases in which the specimen might be obtained 2-4 days before the patient hCG reaches detectable levels or there could be a technical laboratory error. A repeat test 48 hours later helps to exclude these possibilities.

    As noted previously, failure to double hCG values in 24 hours at gestational age 4-8 weeks occurs in about 66% of ectopic pregnancies, about 85% of spontaneous abortion cases, and about 15% of normal pregnancies. Such an abnormally slow hCG increase rate would warrant closer followup or possibly other diagnostic tests, such as a quantitative serum hCG assay if the 48-hour increase is considerably low. A substantially low serum hCG level for gestational age suggests abnormal pregnancy. Another use for quantitative hCG assay in appropriate cases is to see if the “discriminatory zone” of Kadar has been reached. Originally, this was the range of 6,000-6,500 mIU/ml (IU/L, IRP standard) above which standard transabdominal ultrasound (TAUS) can visualize a normal pregnancy gestational sac in the uterus in about 94% of cases (although TAUS could detect an intrauterine gestational sac below 6,000 mIU/ml in some cases, failure to do so gives no useful information). With more sensitive ultrasound equipment and use of a vaginal transducer, it has been reported that the discriminatory zone upper limit can be reduced to the area of 1,000-1,500 mIU/ml (IU/L), but the exact value must be established by each institution using its particular pregnancy test and ultrasound equipment. Transvaginal ultrasound is more sensitive than TAUS in detecting an adnexal mass or free cul-de-sac fluid that would suggest ectopic pregnancy.

    Neoplasms producing human chorionic gonadotropin

    Neoplasms arising from chorionic villi, the fetal part of the placenta, are known as gestational trophoblastic neoplasms and include hydatidiform mole (the counterpart in tumor classification of benign adenoma) and choriocarcinoma (chorioepithelioma, the equivalent of carcinoma). Hydatidiform mole also has a subdivision, chorioadenoma destruens, in which the neoplasm invades the placenta but there is no other evidence of malignancy. The major importance of hydatidiform mole is a very high (і 10%) incidence of progression to choriocarcinoma.

    Several hormone assays have been proposed as aids in diagnosis. By far the most important is hCG, which is produced by the trophoblast cell component of fetal placental tissue. Current pregnancy tests using monoclonal antibodies to beta subunit of hCG or to the whole molecule can detect levels of 25 mIU/ml (IU/L), sometimes less, without interference by LH, permitting detection of nearly all gestational tumors (except a very few that predominately secrete the free beta fragment of hCG, which would necessitate an assay that would detect this hCG metabolite). Since normal placental tissue secretes hCG, the problem then is to differentiate normal pregnancy from neoplasm. Suspicion is raised by clinical signs and also by finding hCG levels that are increased more than expected by the duration of pregnancy or that persist after removal of the placenta. Twin or other multiple pregnancies can also produce hCG levels above expected values. Although serum levels of hCG greater than 50,000 mIU/ml (or urine levels > 300,000 mIU/ml) are typically associated with gestational neoplasms, especially if these levels persist, a considerable number of patients with gestational tumors have hCG values less than this level. About 25% of patients in one report had values less than 1,000 mIU/ml. In normal pregnancies, serum hCG levels become nondetectable by about 14 days (range, 3-30 days) after delivery. In one study of elective abortions, it took 23-52 days for hCG levels to become nondetectable. After removal of a hydatidiform mole, hCG levels should become nondetectable in about 2-3 months (range, 21-278 days). Once neoplasm is diagnosed and treated, hCG measurement is a guideline for success of therapy and follow-up of the patient for possible recurrence.

    Other hormones useful in possible gestational neoplasms. Fetal and placental tissue produces other hormones that may be useful. Progesterone (or its metabolite pregnanediol) and estradiol are secreted by the placenta in slowly increasing quantity throughout most of pregnancy. It has been reported that during the first 20 weeks of gestation, hydatidiform moles are associated with serum estradiol-17b values that are increased from values expected in normal pregnancy, with good separation of normal pregnancy from molar pregnancy. Serum progesterone levels were increased in about 75% of nonaborted moles up to the 20th week. Urinary pregnanediol levels, on the other hand, are frequently decreased. Finding increased serum progesterone and estradiol-17b levels during the time that peak hCG values are expected (between the 50th and 80th days after the last menstrual period), accompanied by a decreased urine pregnanediol level, would suggest a hydatidiform mole or possibly a choriocarcinoma. Serum human placental lactogen (hPL), or somatomammotropin, is another placental hormone whose level rises during the first and second trimesters and then reaches a plateau during the last 2-3 months. The association of decreased levels of hPL in the first and second trimesters with increased hCG levels suggests neoplasm. There is, however, a small degree of overlap of hPL level in patients with mole and the normal range for pregnancy. One report suggests a possible inverse ratio between hPL values and degree of malignancy (the greater the degree of malignancy, the less serum hPL produced).

    Production of hCG has been reported to occur in nearly two thirds of testicular embryonal cell carcinomas and in about one third of testicular seminomas. Instances of hCG secretion by adenocarcinomas from other organs and, rarely, from certain other tumors have been reported.

  • Viral Diseases

    Viral upper respiratory tract diseases

    Respiratory disease may take several forms, and the predominant etiologies are different in different age groups. Incidence statistics also vary depending on the geographic area and the population selected. Of the known viruses, rhinoviruses are predominantly associated with acute upper respiratory tract disease (including the common cold) in adults, whereas in children, rhinovirus, adenovirus, parainfluenza virus, and the enteroviruses are important. Acute bronchitis in children is most often due to respiratory syncytial virus and parainfluenza virus. In croup, parainfluenza is said to be the most important virus.

    Viral pneumonia

    Respiratory syncytial virus is the predominant cause of pneumonia in infants and young children, beginning at age 1 month with a peak incidence at about age 6 months, followed by adenovirus or parainfluenza virus. In older children or adults, bacterial pneumonia (most often due to Pneumococcus or Mycoplasma pneumoniae) is more common than viral pneumonia. Among viral agents known to cause pneumonia in adults, the most common is probably influenza. In any study, a large minority of cases do not yield a specific etiologic agent.

    Viral meningitis

    Viruses are an important cause of meningitis, especially in children. They typically produce the laboratory picture of aseptic meningitis: the classic cerebrospinal fluid (CSF) findings are variable, but often include mildly increased protein levels, increased cell counts with mononuclear cells predominating, normal glucose levels, and no organisms found on culture. It should be remembered, however, that tuberculous meningitis gives similar findings, except for a decreased CSF glucose level, and likewise shows a sterile culture on ordinary bacterial culture media. Some patients with mumps meningoencephalitis may have decreased CSF glucose levels in addition to CSF lymphocytosis. Enteroviruses are the largest etiologic group causing aseptic meningitis. Among the enteric viruses, poliomyelitis used to be the most common organism, but with widespread polio vaccination programs, echovirus and coxsackievirus have replaced polio in terms of frequency.

    After the enteroviruses, mumps is the most important. A small but significant number of patients with mumps develop clinical signs of meningitis, and a large number show CSF changes without demonstrating enough clinical symptoms to warrant a diagnosis and workup for meningitis. Changes in CSF or the clinical picture of meningitis may occur in patients without parotid swelling or other evidence of mumps. Lymphocytic choriomeningitis and leptospirosis are uncommon etiologies for aseptic meningitis.

    Encephalitis is a syndrome that frequently has CSF alterations similar to those of meningitis. The two cannot always be separated, but the main difference is clinical; encephalitis features depression of consciousness (lethargy, coma) over a prolonged period, whereas meningitis usually is a more acute illness with manifestations including fever, headache, vomiting, lethargy, stiff neck, and possibly convulsions. In severe bacterial infection, encephalitis may follow meningitis. Encephalitis is most often caused by viruses, of which the more common are mumps, herpes simplex type 1 (HSV-1), measles, and the arboviruses. Sometimes encephalitis is a complication of vaccination.

    Viral gastroenteritis

    Viruses are likely to be blamed for diarrhea that cannot be explained otherwise. In most cases, definitive evidence is lacking because enteric virus is present in a significant number of apparently healthy children. Bacterial infection should always be carefully ruled out. Two clinical types of viral gastroenteritis have been described. One type usually occurs in epidemics, more often in older children and in adults, with clinical signs of an acute self-limited gastroenteritis of 1-2 days’ duration. The most commonly associated etiology is the Norwalk-type group of viruses. The other type of illness is sporadic and affects mostly infants and younger children. There is severe diarrhea, usually accompanied by fever and vomiting, which lasts for 5-8 days. Rotavirus is the most frequently isolated virus in these patients. About 5%-10% of gastroenteritis in infants less than 2 years old is said to be caused by adenovirus types 40 and 41

    Viral infections in pregnancy

    By far the most dangerous viral disease during pregnancy is rubella. Statistics are variable, but they suggest about a 15%-25% risk of fetal malformation when rubella infection occurs in the first trimester (literature range, 10%-90%). The earlier in pregnancy that maternal infection occurs, the greater the risk that the fetus will be infected. However, not all infected fetuses develop congenital malformation. When the fetus is infected early in the first trimester, besides risk of congenital malformation, as many as 5%-15% of fetuses may die in utero. Risk of fetal malformation in second trimester infections is about 5%. After the fourth month of pregnancy, there is no longer any danger to the fetus. Cytomegalovirus (CMV) infection is more frequent than rubella, but CMV has a lower malformation rate. Cytomegalovirus damage is more severe in the first two trimesters. Other viruses may cause congenital malformations, but evidence is somewhat inconclusive as to exact incidence and effects. Herpes simplex and the hepatitis viruses are in this group.

  • The Kidney in Disease

    Primary glomerular renal disease for a long time was subdivided into glomerulonephritis (acute, subacute, chronic) and the nephrotic syndrome, based on clinical and light microscopic findings. With the advent of renal biopsy, electron microscopy, and immunoglobulin fluorescent staining of tissue sections, the clinical categories are being reclassified on the basis of ultrastructure and immunologic characteristics (see Table 37-5). Diseases in some of the immunohistopathologic subdivisions have different prognoses (and, in some cases, different responses to certain therapeutic agents) and therefore could logically be regarded as separate entities. Nevertheless, I have chosen to describe laboratory findings in terms of the original clinical syndromes, since this is the way most clinicians encounter primary renal disease. A morphologic classification of glomerular disease is given in Table 37-5.

    Glomerulonephritis

    Acute glomerulonephritis. Classic acute glomerulonephritis (AGN) corresponds to a subcategory of proliferative glomerulonephritis that is considered a hypersensitivity reaction, usually associated with concurrent or recent infection. The most common organism incriminated is the beta-hemolytic Lancefield group A Streptococcus. Only a relatively small number of specific group A strains are known to cause AGN in contrast to the large number that initiate acute rheumatic fever.

    Clinically, onset of the disease is frequently manifested by gross hematuria. The urine may be red or may be the color of coffee grounds (due to breakdown of hemoglobin to brown acid hematin). In mild cases, gross hematuria may be less evident, or the hematuria may be microscopic only. Varying degrees of peripheral edema, especially of the upper eyelids, are often present. Hypertension of varying degree is a frequent initial finding.

    Laboratory features usually include an elevated erythrocyte sedimentation rate and frequently a mild to moderate normocytic-normochromic (or slightly hypochromic) anemia. There is mild to moderate proteinuria (0.5-3.0 gm/24 hours). The urinary sediment reflects varying degrees of hematuria, often with WBCs also present. RBC casts are characteristic and are the most diagnostic laboratory finding. They may be present only intermittently, may be few in number, and may be degenerated enough to make recognition difficult. Although RBC casts are not specific for AGN, relatively few diseases are consistently associated with RBC casts. These conditions include AGN, subacute and occasionally chronic glomerulonephritis, subacute bacterial endocarditis, some of the collagen diseases (especially systemic lupus), and hemoglobinuric acute tubular necrosis.

    Renal function tests. Prolonged azotemia is not common in poststreptococcal AGN (5%-10% of cases), despite hypertension, although as many as 50% of affected persons have some BUN elevation initially. Renal function tests are said to be essentially normal in nearly 50% of patients; the rest have varying degrees of impairment for varying time intervals, and a small percentage show renal insufficiency with uremia. Urine concentrating ability is generally maintained for the first few days; in some patients, it may then be impaired for a considerable time. Function tests in general tend to reflect (although not exclusively) the primarily glomerular lesion found in AGN, manifested on light microscopy by increased glomerular cellularity and swelling and proliferation of capillary endothelial cells and on electron microscopy by subepithelial “humps.”

    Antistreptococcal antibodies. In addition to urinalysis, the antistreptolysin-O (ASL or ASO) titer may be helpful, since a significant titer (>200 Todd units) suggests recent or relatively recent group A streptococcal infection. However, since up to 20% of AGN patients have ASO titers in the normal range, a normal ASO titer does not rule out the diagnosis, nor does a high titer guarantee that the condition is indeed AGN (the group A streptococcal infection may be unrelated to the renal disease). Measurement of other streptococcal enzyme antibodies, such as anti-deoxyribonuclease B (ADN-B), in addition to ASO, will improve sensitivity of the test. Several commercial kits have combined reagents active against several of the antistreptococcal antibodies (Chapter 23). The third component (C3) of serum complement is nearly always depressed in streptococcal AGN and returns to normal in 6-8 weeks. Consistently normal early C3 levels are evidence against streptococcal etiology, and failure of C3 to become normal in 8 weeks also suggests a different etiology.

    Acute glomerulonephritis is a relatively benign disease in childhood, since mortality is only about 1%, and an even smaller percentage suffer permanent damage. In adults, the incidence of the disease is much lower, but 25%-50% of adult patients develop chronic renal disease.

    Rapidly progressive glomerulonephritis. Rapidly progressive glomerulonephritis may follow the acute stage of AGN but much more commonly appears without any previous clinical or serologic evidence of AGN. It is more common in older children and adults. The original term “subacute glomerulonephritis” was misleading; originally it referred to the duration of the clinical course, longer than that of AGN in the average patient but much shorter than that of chronic glomerulonephritis. Histologically, the glomeruli show epithelial cell proliferation with resultant filling in of the space between Bowman’s capsule and the glomerular tuft (epithelial crescent). The urine sediment includes many casts of hyaline and epithelial series; RBCs and often WBCs are present in varying numbers, often with a few RBC casts. There is moderately severe to marked proteinuria, and both the degree of proteinuria and the urinary sediment may sometimes be indistinguishable from similar findings in the nephrotic syndrome, even with fatty casts present. Clinically, rapidly progressive glomerulonephritis behaves as a more severe form of AGN and generally leads to death in weeks or months. It is not the same process as the nephrotic episodes that may form part of chronic glomerulonephritis. In addition to urinary findings, anemia is usually present. Renal function tests demonstrate both glomerular and tubule destruction, although clinically there is usually little additional information gained by extensive renal function studies. Serum complement C3 is temporarily depressed in cases of poststreptococcal origin but otherwise is usually normal.

    Chronic glomerulonephritis. Chronic glomerulonephritis infrequently is preceded by AGN, but usually there is no antecedent clinical illness or etiology. It most often runs a slowly progressive or intermittent course over many years. During the latent phases there may be very few urinary abnormalities, but RBCs are generally present in varying small numbers in the sediment. There is almost always proteinuria, generally of mild degree, and rather infrequent casts of the epithelial series. Disease progression is documented by a slowly decreasing ability to concentrate the urine, followed by deterioration in creatinine clearance. Intercurrent streptococcal upper respiratory tract infection or other infections may occasionally set off an acute exacerbation. There may be one or more episodes of the nephrotic syndrome, usually without much, if any, hematuria. The terminal or azotemic stage produces the clinical and laboratory picture of renal failure. Finely granular and waxy casts predominate, and broad casts are often present. There is moderate proteinuria.

    Nephrotic syndrome

    The criteria for diagnosis of the nephrotic syndrome include high proteinuria (>3.5 gm/24 hours), edema, hypercholesterolemia, and hypoalbuminemia. However, one or occasionally even more of these criteria may be absent. The level of proteinuria is said to be the most consistent criterion. In addition, patients with the nephrotic syndrome often have a characteristic serum protein electrophoretic pattern, consisting of greatly decreased albumin and considerably increased alpha-2 globulin. However, in some cases the pattern is not marked enough to be characteristic. The nephrotic syndrome is one of a relatively few diseases in which the serum cholesterol level may substantially contribute toward establishing the diagnosis, especially in borderline cases.

    The nephrotic syndrome has nothing in common with the entity formerly called hemoglobinuric nephrosis (or lower nephron nephrosis), despite the unfortunate similarity in names. The term hemoglobinuric nephrosis has generally been discarded, since it is only a subdivision of acute tubular necrosis, due to renal tubule damage from hemoglobin derived from marked intravascular hemolysis. Even the term “nephrotic syndrome” as it is currently used is actually a misnomer and dates from the time when proteinuria was thought primarily to be due to a disorder of renal tubules. The word “nephrosis” was then used to characterize such a situation. It is now recognized that various glomerular lesions form the actual basis for proteinuria in the nephrotic syndrome, either of the primary or the secondary type. The nephrotic syndrome as a term is also confusing because it may be of two clinical types, described in the following section.

    Primary (or lipoid) nephrosis. Primary nephrosis is the idiopathic form and is usually found in childhood. The etiology of primary (idiopathic or lipoid) nephrosis is still not definitely settled. Renal biopsy has shown various glomerular abnormalities, classified most easily into basement membrane and focal sclerosis varieties. In most children the basement membrane changes may be so slight (null lesion) as to be certified only by electron microscopy (manifested by fusion of the footplates of epithelial cells applied to the basement membrane). The null lesion is associated with excellent response to steroids, a great tendency to relapse, and eventually relatively good prognosis. Focal sclerosis most often is steroid resistant and has a poor prognosis.

    In lipoid nephrosis, the urine contains mostly protein. The sediment may contain relatively small numbers of fatty and granular casts, and there may be small numbers of RBCs. Greater hematuria or cylindruria suggests greater severity but not necessarily a worse prognosis. Renal function tests are normal in most patients; the remainder have various degrees of impairment.

    Nephrotic syndrome. Although lipoid nephrosis may be found in adults, the nephrotic syndrome is more common and may be either idiopathic or secondary to a variety of diseases. The most common idiopathic lesions include a diffuse light microscope “wire loop” basement membrane thickening, which has been termed membranous glomerulonephritis, and a type that has been called membranoproliferative. Prognosis in these is worse than in childhood lipoid nephrosis.

    The most common etiologies of secondary nephrotic syndrome are chronic glomerulonephritis, Kimmelstiel-Wilson syndrome, systemic lupus, amyloid and renal vein thrombosis. In the urine, fat is the most characteristic element, appearing in oval fat bodies and fatty casts. Also present are variable numbers of epithelial and hyaline series casts. Urine RBCs are variable; usually only few, but sometimes many. Significant hematuria suggests lupus; the presence of diabetes and hypertension suggests Kimmelstiel-Wilson syndrome; a history of previous proteinuria or hematuria suggests chronic glomerulonephritis; and the presence of chronic long-standing infection suggests an amyloid etiology. About 50% of cases are associated with chronic glomerulonephritis. Renal function tests in the nephrotic syndrome secondary to lupus, Kimmelstiel-Wilson syndrome, and amyloid generally show diffuse renal damage. The same is true of chronic glomerulonephritis in the later stages; however, if the nephrotic syndrome occurs relatively early in the course of this disease, test abnormalities may be minimal, reflected only in impaired concentrating ability, Histologically, renal glomeruli in the nephrotic syndrome exhibit lesions that vary according to the particular disease responsible.

    Membranoproliferative glomerulonephritis occurs in older children and teenagers and displays some features of AGN as well as nephrotic syndrome. Hematuria and complement C3 decrease occur, but the C3 decrease usually is prolonged beyond 8 weeks (60% or more cases). However, C3 levels may fluctuate during the course of the disease.

    Malignant hypertension (accelerated arteriolar nephrosclerosis)

    Malignant hypertension is most common in middle age, with most patients aged 30-60 years. There is a tendency toward males and an increased incidence in blacks. The majority of patients have a history of preceding mild or benign hypertension, most often for 2-6 years, although the disease can begin abruptly. The syndrome may also be secondary to severe chronic renal disease of several varieties. Clinical features are markedly elevated systolic and diastolic blood pressures, papilledema, and evidence of renal damage. Laboratory tests show anemia to be present in most cases, even in relatively early stages. Urinalysis in the early stages most often shows a moderate proteinuria and hematuria, usually without RBC casts. The sediment thus mimics to some extent the sediment of AGN. Later the sediment may show more evidence of tubular damage. There usually develops a moderate to high proteinuria (which uncommonly may reach 5-10 gm/24 hours) accompanied by considerable microscopic hematuria and often many casts, including all those of the hyaline and epithelial series—even fatty casts occasionally. In the terminal stages, late granular or waxy casts and broad renal failure casts predominate. The disease produces rapid deterioration of renal function, and most cases terminate in azotemia. Nocturia and polyuria are common owing to the progressive renal damage. If congestive heart failure is superimposed, there may be a decreased urine volume plus loss of ability to concentrate urine.

    Pyelonephritis (renal infection)

    Acute pyelonephritis often elicits a characteristic syndrome (spiking high fever, costovertebral angle tenderness, dysuria, back pain, etc.). Proteinuria is mild, rarely exceeding 2 gm/24 hours. Pyuria (and often bacteriuria) develops. The presence of WBC casts is diagnostic, although they may have to be carefully searched for or may be absent. Urine culture may establish the diagnosis of urinary tract infection but cannot localize the area involved. Hematogenous spread of infection to the kidney tends to localize in the renal cortex and may give fewer initial urinary findings; retrograde ascending infection from the lower urinary tract reaches renal medulla areas first and shows early pyuria.

    In chronic low-grade pyelonephritis, the urine may not be grossly pyuric, and sediment may be scanty. In some cases, urine cultures may contain fewer than 100,000 organisms/mm3 (100 Ч 109/L) or may even be negative. Very frequently, however, there is a significant increase in pus cells; they often, but not invariably, occur in clumps when the process is more severe. Casts other than the WBC type are usually few or absent in pyelonephritis until the late or terminal stages, and WBC casts themselves may be absent.

    A urine specimen should be obtained for culture in all cases of suspected urinary tract infection to isolate the organism responsible and determine antibiotic sensitivity (Chapter 14).

    Tuberculosis is a special type of renal infection. It involves the kidney in possibly 25% of patients with chronic or severe pulmonary tuberculosis, although the incidence of clinical disease is much less. Hematuria is frequent; it may be gross or only microscopic. Pyuria is also common. Characteristically, pyuria is present without demonstrable bacteriuria (of ordinary bacterial varieties), but this is not reliable due to a considerable frequency of superinfection by ordinary bacteria in genitourinary tuberculosis. Dysuria is also present in many patients. If hematuria (with or without pyuria) is found in a patient with tuberculosis, genitourinary tract tuberculosis should be suspected. Urine cultures are said to be positive in about 7% of patients with significant degrees of active pulmonary tuberculosis. At least three specimens, one obtained each day for 3 days, should be secured, each one collected in a sterile container. A fresh early morning specimen has been recommended rather than 24-hour collections. Acid-fast urine smears are rarely helpful. If suspicion of renal tuberculosis is strong, intravenous pyelography should be done to assess the extent of involvement.

    Renal papillary necrosis is a possible complication of acute pyelonephritis, particularly in diabetics.

    Renal papillary necrosis (necrotizing papillitis)

    As the name suggests, this condition results from necrosis of a focal area in one or more renal pyramids. Papillary necrosis is most frequently associated with infection but may occur without known cause. It is much more frequent in diabetics. A small minority of cases are associated with sickle cell hemoglobin diseases or phenacetin toxicity. The disease usually is of an acute nature, although some patients may have relatively minor symptoms or symptoms overshadowed by other complications or disease. The patients are usually severely ill and manifest pyuria, hematuria, and azotemia, especially when renal papillary necrosis is associated with infection. Drip-infusion intravenous (IV) pyelography is the diagnostic test of choice. Naturally, urine culture should be performed.

    Renal embolism and thrombosis

    Renal artery occlusion or embolism most often affects the smaller renal arteries or the arterioles. Such involvement produces renal infarction in that vessel’s distribution, usually manifested by hematuria and proteinuria. Casts of the epithelial series may also appear. Renal infarction frequently produces elevation of serum lactic dehydrogenase (LDH), with the LDH-1 isoenzyme typically greater than LDH-2 (Chapter 21). Aspartate aminotransferase (serum glutamic oxaloacetic transaminase) may also be increased but less frequently. Alkaline phosphatase is temporarily increased in some patients after 5-10 days (range 3-15 days), possibly related to the granulation tissue healing process.

    Acute tubular necrosis

    This syndrome may result from acute or sudden renal failure of any cause, most often secondary to hypotension, although intravascular hemolysis from blood transfusion reactions is probably the most famous cause. Acute tubular necrosis begins with a period of oliguria or near anuria and manifests subsequent diuresis if recovery ensues. Urinalysis demonstrates considerable proteinuria with desquamated epithelial cells and epithelial hyaline casts. There are usually some RBCs (occasionally many) and often large numbers of broad and waxy casts (indicative of severe urinary stasis in the renal parenchyma). Hemoglobin casts are usually present in cases due to intravascular hemolysis. Specific gravity is characteristically fixed at 1.010 after the first hours, and the BUN level begins rising shortly after onset. In cases of acute tubular necrosis not due to intravascular hemolysis, the pathogenesis is that of generalized tubular necrosis, most often anoxic.

    Congenital renal disease

    Polycystic kidney. There are two clinical forms of polycystic kidney, one fatal in early infancy and the other (adult type) usually asymptomatic until the third or fourth decade. The urinary sediment is highly variable; microscopic intermittent hematuria is common, and gross hematuria may occasionally take place. Cysts may become infected and produce symptoms of pyelonephritis. In general, the rate of proteinuria is minimal or mild but may occasionally be higher. Symptoms may be those of hypertension (50%-60% of cases) or renal failure. If the condition does progress to renal failure, the urinary sediment is nonspecific, reflecting only the presence of end-stage kidneys of any etiology. Diagnosis may be suggested by family history and the presence of bilaterally palpable abdominal masses and is confirmed by radiologic procedures, such as IV pyelography. Ultrasound can also be useful.

    Renal developmental anomalies. This category includes horseshoe kidney, solitary cysts, reduplication of a ureter, renal ptosis, and so forth. There may be no urinary findings or, sometimes, a slight proteinuria. In children, urinary tract anomalies often predispose to repeated urinary tract infection. Recurrent urinary tract infection, especially in children, should always be investigated for the possibility of either urinary tract obstruction or anomalies. Diagnosis is by IV pyelography.

    Renal neoplasia

    The most common sign of carcinoma anywhere in the urinary tract is hematuria, which is present in 60%-80% of patients with primary renal adenocarcinoma and (according to one report) in about 95% of bladder, ureter, and renal pelvis carcinoma. In renal cell carcinoma, hematuria is most often visible grossly and is intermittent. In persons over age 40 a neoplasm should be suspected if increased urine RBCs are not explained by other conditions known to produce hematuria. Even if such diseases are present, this does not rule out genitourinary carcinoma. The workup of a patient with hematuria is discussed in Chapter 13. Methods for detecting renal cell carcinoma are described in Chapter 33.

    Lupus erythematosus or polyarteritis nodosa

    About two thirds of lupus patients have renal involvement. Generally, there is microscopic hematuria; otherwise there may be a varying picture. In the classic case of lupus (much less often in polyarteritis), one finds a “telescoped sediment,” that is, a sediment containing the characteristic elements of all three stages of glomerulonephritis (acute, subacute, and chronic) manifest by fatty, late granular, and RBC casts. Usually, hematuria is predominant, especially in polyarteritis. In lupus, RBC casts are more commonly found. Up to one third of lupus patients develop the nephrotic syndrome. Complement C3 levels are frequently decreased in active lupus nephritis.

    Embolic glomerulonephritis

    Embolic glomerulonephritis is most commonly associated with subacute bacterial endocarditis. Scattered small focal areas of necrosis are present in glomerular capillaries. There is some uncertainty whether the lesions are embolic, infectious, or allergic in origin. Since the glomerular lesions are sharply focal, there usually is not much pyuria. Hematuria is usually present and may be pronounced. If localized tubular stasis occurs in addition, RBC casts may appear, with resultant simulation of latent glomerulonephritis or AGN. The rate of proteinuria often remains relatively small, frequently not more than 1 gm/24 hours.

    Diabetes

    The kidney may be affected by several unrelated disorders, including (1) a high incidence of pyelonephritis, sometimes renal papillary necrosis; (2) a high incidence of arteriosclerosis with hypertension; and (3) Kimmelstiel-Wilson syndrome (intercapillary glomerulosclerosis). The nephrotic syndrome may occur in the late stages of the Kimmelstiel-Wilson syndrome. Otherwise, only varying degrees of proteinuria are manifest, perhaps with a few granular casts. Diabetic microalbuminuria, a stage that precedes overt diabetic renal disease, was discussed in the earlier section on urine protein.

    Pregnancy

    Several abnormal urinary findings are associated with pregnancy.

    Benign proteinuria. Proteinuria may appear in up to 30% of otherwise normal pregnancies during labor but surpasses 100 mg/100 ml in only about 3% of these cases. It is unclear whether proteinuria must be considered pathologic if it occurs in uncomplicated pregnancy before labor. Some authorities believe that proteinuria is not found in normal pregnancy; others report an incidence of up to 20%, which is ascribed to abdominal venous compression.

    Eclampsia. This condition, also known as toxemia of pregnancy, denotes a syndrome of severe edema, proteinuria, hypertension, and convulsions associated with pregnancy. This syndrome without convulsions is called preeclampsia. In most cases, onset occurs either in the last trimester or during labor, although uncommonly the toxemic syndrome may develop after delivery. The etiology is unknown, despite the fact that delivery usually terminates the signs and symptoms. Pronounced proteinuria is the rule; the most severe cases may have oval fat bodies and fatty casts. Other laboratory abnormalities include principally an elevated serum uric acid level in 60%-70% of cases and a metabolic acidosis. The BUN level is usually normal. Diagnosis at present depends more on physical examination, including ophthalmoscopic observation of spasm in the retinal arteries and blood pressure changes, than on laboratory tests, except tests for proteinuria. Gradual onset of eclampsia may be confusing, since some degree of edema is common in pregnancy, and proteinuria (although only slight or mild) may appear during labor.

    Glucosuria. Glucosuria occurs in 5%-35% of pregnancies, mainly in the last trimester. Occasional reports state an even higher frequency. It is not completely clear whether this is due to increased glucose filtration resulting from an increased GFR, a decreased renal tubular transport maximum (reabsorptive) capacity for glucose, a combination of the two, or some other factor. Lactosuria may also occur in the last trimester and may be mistaken for glucosuria when using copper sulfate reducing tests for urine glucose.

    Renal function tests. The glomerular filtration rate is increased during pregnancy. Because of this, the BUN level may be somewhat decreased, and clearance tests are somewhat increased. Renal concentration may appear falsely decreased because of edema fluid excretion that takes place during sleep.

    Infection. Bacteriuria has been reported in 4%-7% of pregnant patients, whereas the incidence in nonpregnant healthy women is approximately 0.5%. It is believed that untreated bacteriuria strongly predisposes to postpartum pyelonephritis.

  • Pregnancy

    Do discuss both your plans and any worries that you have with doctors, and other professional staff looking after you. Pregnancy and childbirth is a time for continuing support. You can receive good advice, and possibly information about sympathetic obstetricians, from the local branch of the Multiple Sclerosis Society or other MS support groups.
    In the past there was often very clear and very negative advice given about pregnancy to someone with MS. In general now this view has changed. A useful way to proceed is to discuss with your partner and/or family and close friends, a series of ‘What if ?’ questions, considering, for example, some of the problems that might occur financially or in relation to child care. Through these means you can rehearse some of the ways of managing potential difficulties, in the hope, and in many cases the expectation, that such problems will not occur.
    Relapses tend to be lower in number during pregnancy, and overall most women find their pregnancy is relatively uneventful from an MS point of view.

    Feeling good

    Many women with MS feel really well while pregnant and would like that feeling to continue afterwards! What is almost certainly happening is that some immunosuppression is occurring naturally in your pregnancy, and lowering the levels of Multiple Sclerosis activity. So far it has not been possible to identify any of the specific hormones or proteins produced in pregnancy that produce this ef fect, although one pregnancy hormone has been identified, which suppresses an experimental form of MS in the guinea pig. So there is some basis for optimism in this line of research. However, applying animal-based research to humans has been a notoriously fickle and unpredictable process, so it would be unwise to expect immediate developments as far as people with MS are concerned. On the other hand there is an increased risk of relapse of your MS after delivery and if you should suffer a miscarriage (see below).

    Taking drugs

    As an important general rule you should not take any drug, even an over-the-counter drug, during pregnancy, or indeed when you are considering becoming pregnant, without discussing this first with your doctor. For many drugs used to treat the everyday symptoms of MS, there is substantial information available about the consequences of their use during pregnancy, and many of them are safe to use.
    Those drugs that are now being used to treat the disease itself, rather than any one specific symptom, such as the interferon-based drugs (such as Avonex, Betaferon and Rebif) and Copaxone, are powerful immuno- suppressants, and it is still not clear what effects they will have on an unborn baby. You should stop taking such drugs once you have started trying for a baby, for it will be some time before you know you are pregnant and in the meantime the fertilized egg could be developing. It is a question of balancing your own concerns about the effects of Multiple Sclerosis on you, and the health of your unborn baby. The decision may not be an easy one to make, but most mothers treat the health of their unborn baby as their main concern at this time.

  • Pregnancy, childbirth and the menopause

    Issues concerning pregnancy and childbirth often worry people with MS and their partners, as many will have recently embarked on relationships in which they will be considering the possibility of having children. Bringing up children is also another area that concerns both people with Multiple Sclerosis and those close to them. We also discuss problems older women might encounter.