Glomerular disease
Diseases of the glomerulus can present as one of five clinical syndromes: chronic glomerulonephritis, nephrotic syndrome, acute glomerulonephritis, rapidly progressive glomerulonephri-tis, or asymptomatic hematuria or proteinuria [see Figure 1]. The clinical characteristics and the urinalysis results are useful for determining which syndrome is present in a patient with suspected glomerular disease [see Table 3].
Diseases that cause active inflammation in the glomerulus are typically associated with a constellation of clinical features referred to as the nephritic syndrome. This syndrome is characterized by signs and symptoms suggestive of primary salt retention by the kidney, resulting in volume overload and circulatory congestion. Manifestations include hypertension, congestive heart failure, and peripheral edema. The urinalysis result also reflects active glomerular inflammation and is described as nephritic in nature. A nephritic urinary sediment is characterized by a variable number of red blood cells (RBCs), WBCs, and RBC casts [see Figure 2]. The finding of RBC casts is pathognomonic of active glomerulonephritis. Proteinuria is usually modest, ranging from 2 to 6 g in a 24-hour collection, and the GFR is often severely reduced.
The nephrotic syndrome results from diseases that produce little in the way of active glomerular inflammation but, instead, cause massive leakage of protein across the glomerular basement membrane. The development of hypoalbuminemia and subsequent decline in oncotic pressure cause intravascular fluid to translocate into the extravascular compartment, giving rise to a contracted EABV. In turn, the decline in EABV results in secondary renal salt retention. Unlike the nephritic syndrome, hypertension is less prominent and findings of circulatory congestion are absent. Typically, the GFR is only mildly reduced. The urinalysis result also reflects the lack of inflammation in the glomerulus. Characteristic findings include free-fat droplets,oval fat bodies, fatty casts, and only minimal amounts of cellu-larity. These findings, along with large amounts of protein in the urine, constitute a nephrotic urinary sediment.
Figure 2 Components of urinary sediment.
Chronic Glomerulonephritis
Chronic glomerulonephritis describes a patient with evidence of chronic renal failure who shows characteristics of glomerular disease. The urinalysis demonstrates a few RBCs and WBCs but is mostly nonspecific. A variable amount of pro-teinuria is present. Kidney size is typically small, reflecting the presence of advanced fibrosis and glomerulosclerosis. Patients with this syndrome presumably have a glomerular disease that has progressed to end stage, leaving the kidneys irreversibly damaged.
Nephrotic Syndrome
The nephrotic syndrome describes a patient who presents with a nephrotic clinical picture and a nephrotic urinary sediment. In addition to edema, hypoalbuminemia, and large amounts of protein in the urine, a number of other findings are typical of the nephrotic syndrome. These include hyperlipi-demia, hypercoagulability, and a predisposition to infection with encapsulated gram-positive organisms because of hy-pogammaglobulinemia. As with other clinical syndromes, the underlying cause of the nephrotic syndrome can be a primary renal disease or secondary kidney involvement as part of a systemic disorder. Because the kidney can respond to injury in only a few ways, systemic disorders often cause the same histo-logic picture as primary renal disease. For example, membranous glomerulopathy is a primary renal disease, but this same histologic pattern can develop as a result of systemic lupus ery-thematosus or exposure to gold in the treatment of rheumatoid arthritis.
The approach to the patient with nephrotic syndrome is directed toward distinguishing primary from secondary glomeru-lar diseases. Routine clinical evaluation may be sufficient to make this distinction, but in many cases, additional laboratory tests are required [see 10:V Glomerular Diseases].
Acute Glomerulonephritis
Acute glomerulonephritis describes a patient who presents with the abrupt onset of a nephritic clinical syndrome accompanied by a nephritic urinary sediment. There is evidence of circulatory congestion, manifested by hypertension and occasionally by pulmonary congestion. Examination of the urine demonstrates RBCs, WBCs, and RBC casts. The GFR is relatively stable, in contrast to the rapid fall in GFR seen with the syndrome of rapidly progressive glomerulonephritis. Acute glomeru-lonephritis is often associated with a preceding infection and can resolve spontaneously. The workup is designed to determine whether the underlying disorder is a primary renal disease or a systemic disorder affecting the kidney [see 10:V Glomerular Diseases].
Rapidly Progressive Glomerulonephritis
Rapidly progressive glomerulonephritis should be considered in patients who present with a nephritic clinical picture and who have a nephritic urinary sediment. This condition is distinguished from acute glomerulonephritis by the rapid loss of renal function, which is defined as a rise in the serum creati-nine concentration of more than 2 mg/dl over a 3-month period. This syndrome has a much less consistent temporal relationship with infection, and there is little tendency for spontaneous recovery.
This syndrome needs to be recognized early so that renal biopsy can be done and therapy instituted immediately, if indicated. With patients in whom renal biopsy shows a crescentic glomerulonephritis, immunofluorescent studies provide a useful classification of the diseases that most commonly give rise to this clinical syndrome.
Asymptomatic Hematuria or Proteinuria
Asymptomatic hematuria or proteinuria describes a patient who has hematuria or proteinuria, or both, but who is otherwise without clinical symptoms. The approach to these patients is described below.
Asymptomatic Urinary Sediment Abnormalities Proteinuria
Proteinuria is relatively common, with 5% to 10% of urine dipstick tests showing positive results in adults during screening examinations.14 Because many disease states and mechanisms can underlie proteinuria, it is important to review renal handling of protein under normal conditions to formulate a differential diagnosis on the basis of structural-functional abnormalities.
Transient and Orthostatic Proteinuria
Two types of asymptomatic, isolated proteinuria warrant consideration: transient or functional proteinuria and orthostat-ic proteinuria. The underlying mechanism for transient protein-uria is not yet understood. Common factors such as fever, heart failure, seizure activity, pancreatitis, and exercise are frequently associated with transient proteinuria.15 The proteinuria resolves with treatment of the underlying cause. Orthostatic proteinuria occurs in up to 5% of adolescents but is uncommon in older age groups.16 Typically, such patients demonstrate proteinuria while in the upright position, which then resolves when the recumbent position is assumed. Long-term follow-up studies demonstrate no deterioration in renal function over time. Generally, or-thostatic proteinuria resolves spontaneously.16
Persistent Proteinuria
Persistent proteinuria generally connotes significant renal pathophysiology. Renal protein excretion is determined primarily by three factors: the characteristics of the protein (its size and charge, as well as its concentration in the blood); the permeability of the glomerular capillary wall; and tubular reabsorption of filtered protein. Smaller and more positively charged proteins have greater rates of filtration into the urinary space than do larger and more negatively charged proteins. Normally, 1 to 3 g of protein (approximately two thirds globulin and one third albumin) are filtered daily. Over 90% of the filtered load is reabsorbed by the tubule, so that 150 mg of protein is maximally excreted each day.
There are three categories of persistent proteinuria: overflow, glomerular, and tubulointerstitial. In overflow proteinuria, proteins that are normally filtered are produced in such high quantities that they overwhelm the reabsorptive capacity of the tubule and are spilled into the urine. The glomerular filtration barrier is intact and functions normally. Paraprotein disorders such as multiple myeloma, in which excess immunoglobulin light chains are produced, result in Bence-Jones proteins in the urine. Lysozymuria, which occurs in patients with myelogenous leukemia, and myoglobinuria caused by rhabdomyolysis are two additional examples of overflow proteinuria. Standard urine dipsticks will react positively only with albumin (and other negatively charged proteins) and thus will be negative in dys-proteinemic states when paraproteins (positively charged proteins) appear in the urine. When such disorders are suspected, sulfosalicylic acid or heat acetic precipitation methods should be used to detect nonalbumin species.
In glomerular proteinuria, the glomerular filtration barrier is structurally abnormal (as in diabetic nephropathy, amyloidosis, and membranous lesions) or loses its fixed negative charge (as in minimal change disease). Both the filtration barrier of the glomerular basement membrane and the reabsorptive capacity of the tubule are exceeded. As a result, proteinuria is often heavy, with albumin being the most prevalent protein. When urinary protein excretion exceeds 3.5 g in a 24-hour collection, nephrotic-range proteinuria is said to be present.
Tubulointerstitial proteinuria occurs when tubular dysfunction and injury preclude normal reabsorptive pathways for filtered proteins, primarily low-molecular-weight globulins. Additionally, damaged tubules may secrete excess proteinaceous material into the urinary space (Tamm-Horsfall mucoprotein). Typically, protein excretion amounts to 1 to 2 g/24 hr but can exceed 3 g/24 hr as tubulointerstitial disease progresses, causing secondary glomerular injury. Acute tubulointerstitial nephritis, tubular toxins such as aminoglycosides, and Fanconi syndrome can underlie this type of proteinuria. So-called indeterminate proteinuria (0.3 to 3.0 g/24 hr, primarily albumin) can be seen in diseases such as hypertensive nephrosclerosis, obstructive uropathy, and chronic tubulointerstitial nephritis.
Diagnosis of Proteinuria
Quantifying the amount of protein excreted by a patient is conventionally done with a 24-hour urine collection. An efficient and accurate alternative is measurement of the protein-to-creati-nine ratio in a spot urine specimen.17 The numerical value of this ratio represents the amount of urinary protein excreted in grams per day. For example, if a patient has 150 mg/dl of protein and 50 mg/dl of creatinine in a spot urine specimen, a total protein excretion rate of 3 g/24 hr would be expected. This simple procedure is accurate and independent of the amount of proteinuria, degree of renal insufficiency, or underlying disease state.
The urine dipstick test for protein can give false positive results when various pharmacologic agents and gross hematuriaare present or when urine pH is high (> 7.0). False negative results highlight the fact that dipstick testing primarily detects albumin but misses positively charged proteins such as parapro-teins (e.g., Bence-Jones immunoglobulin light chains).
Figure 3 Approach to the patient with hematuria.
Hematuria
Hematuria is defined as an RBC count greater than 1 RBC per high-power field for men and a count greater than 3 RBCs per high-power field for women. Alternatively, urinary tract blood loss that is greater than 8,000 to 15,000 RBCs/ml of urine is considered abnormal. Hematuria can be microscopic or gross, but the degree of hematuria is generally of little diagnostic or prognostic value. As little as 1 ml of blood per liter of urine can cause a visible color change. Not all reddish-brown urine is the result of hematuria. Hemoglobinuria and myoglobinuria can cause similar discoloration, but only the supernatant of a spun urine sample is discolored; RBCs are absent on urine microscopy in these conditions. Drugs such as rifampin, sulfasalazine, and the pheno-thiazines can also cause red discoloration of urine [see Figure 3].
Hematuria is a relatively common clinical finding. Froom and colleagues reported a 40% incidence on routine urinalysis in 1,000 men between 18 and 33 years of age; 13% of postmeno-pausal women were reported to have hematuria on routine screening.18,19 Crystalluria caused by hypercalciuria or hyperuri-cosuria may often account for so-called idiopathic hematuria in asymptomatic persons. Crystal aggregates or microcalculi are thought to injure tubular epithelium, resulting in hematuria. Andres and colleagues found that more than 30% of children with isolated hematuria had hypercalciuria and a positive family history of nephrolithiasis.20 If left untreated, these children have an increased risk of kidney stones later in life. Similar patterns have been observed in adults; correction of hypercalciuria or hyper-uricosuria leads to resolution of hematuria in most cases.
Differential Diagnosis
The differential diagnosis of hematuria is extensive but can be divided into two broad categories: renal, or so-called upper tract, sources; and nonrenal, or so-called lower tract, sources.21 In most cases, hematuria is nonrenal in origin. Mariani and colleagues determined the etiology for asymptomatic, isolated hematuria in adults in 1,000 consecutive cases.22 Of 883 cases in which causes were identified, only 13 (1.5%) were glomerular in origin, whereas urethritis, prostate disease, bladder carcinoma, and cystitis accounted for more than 75% of cases.
RBCs originating from the glomerulus have a distinctive dys-morphic appearance when viewed on phase-contrast microscopy, whereas hematuria originating from the lower urinary tract (nonglomerular hematuria) is characterized by uniform, intact RBCs similar to those seen on a peripheral smear. Diagnos-tically, the use of RBC dysmorphism is somewhat limited by the need for phase-contrast microscopy and a trained urine microscopist.
If glomerulonephritis appears to be an unlikely diagnosis on the basis of clinical findings, serial urinalyses should be done to determine whether hematuria is transient or persistent. Transient hematuria, particularly in young persons, is quite common and rarely indicative of significant pathology.23 When present in patients older than 50 years, however, transient hematuria warrants a comprehensive evaluation to rule out malignancy. Persistent hematuria in patients of any age mandates a thorough diagnostic workup.
Historical clues can provide key diagnostic information in the evaluation of patients with hematuria. For example, inherited forms of renal disease are likely if a patient has a family history of autosomal dominant polycystic kidney disease, deafness (Alport disease), or sickle cell trait or disease. Flank pain radiating to the groin may indicate urinary tract obstruction caused by stones or blood clots. Dysuria, urinary frequency, and urgency are consistent with an infectious source. A recent upper respiratory tract infection may have triggered IgA nephropathy or postinfectious glomerulonephritis. Hematuria may develop spontaneously in patients receiving anticoagulants. Finally, in-tense exercise, such as long-distance running, can precipitate hematuria, as can prostate enlargement.
