Tag: Tuberculosis

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.