I. OVERVIEW.
The glomerular diseases are defined by their clinical presentations and the histologic findings associated with the diseases. Glomerular diseases can also be categorized as primary processes in which the disease is confined to the kidney or as secondary processes in which a systemic disease impacts the kidney. Many glomerular diseases are autoimmune in nature. Injury to the kidney may be caused by the deposition of immune complexes within the glomeruli or by autoantibodies directed against antigens present within the kidney. The small vessels of the kidney and the glomerular capillaries are also frequently the target of small vessel vasculitides.
Clinically, the presence of a glomerular disease should be considered when proteinuria is present. Glomerulonephritis (GN) and vasculitis should be considered when hematuria and/or proteinuria is present. Therefore, the approach to the patient with possible glomerular disease should begin with an assessment of the protein excretion in the urine and a microscopic analysis of the urine for dysmorphic red blood cells and/or red blood cell casts.
When hematuria and/or proteinuria has been identified and glomerular disease is determined to be the most likely etiology, further clinical information and serologic testing can assist in the classification of the renal disorder before invasive testing. Although it is often difficult to predict the histologic pattern of injury in a patient with glomerular disease, patients frequently fall into two general clinical presentations—the nephritic syndrome and the nephrotic syndrome. The recognition of these syndromes can guide further serologic testing.
II. CLINICAL PATTERNS OF GLOMERULAR DISEASE
A. The Nephritic Syndrome. Patients with the nephritic syndrome typically present with hematuria, dysmorphic red blood cells and/or red blood cell casts, and proteinuria. The proteinuria can range from 200 mg/day to heavy proteinuria (greater than 10 g/day). Clinically, it is accompanied by hypertension and edema. Renal insufficiency is common and typically progressive. The term rapidly progressive glomerulonephritis (RPGN) refers to diseases with a nephritic syndrome that lead to a rapid deterioration in renal function, defined as a doubling of serum creatinine or a 50% decrease in glomerular filtration rate (GFR) over 3 months or less.
B. The Nephrotic Syndrome. Patients with the nephrotic syndrome present with proteinuria, hypoalbuminemia (serum albumin less than 3.0 mg/dL), and edema. Nephrotic range proteinuria (often defined as greater than 3.5 g
of proteinuria per day) is usually the most prominent renal abnormality. Dysmorphic red blood cells and casts are typically absent, but exceptions do exist. Focal segmental glomerulosclerosis (FSGS), for example, usually presents with nephrotic range proteinuria but can be associated with low-grade hematuria. Additional complications of the nephrotic syndrome include hyperlipidemia, thrombosis, and infection. The diseases that cause the nephrotic syndrome can lead to chronic, progressive renal injury, but typically are more slowly progressive than diseases presenting as the nephritic syndrome.
C. Clinicopathologic Correlation. The pathologic diagnosis of glomerular diseases incorporates the histologic pattern defined by light microscopy, immunofluorescence staining for immunoglobulins (Igs) and complement proteins, and examination of the glomerular ultrastructure by electron microscopy. The primary glomerular diseases are listed in
Table 9-1, with the prominent histologic findings on biopsy that define the disorder. There is a general correlation between the pattern of histologic injury and the clinical presentation. Thus, the clinical findings can suggest the underlying pathologic process, although definitive diagnosis requires a biopsy. The clinician must also consider if there is a systemic process that may be causing the proteinuria. Primary glomerular diseases can often not be distinguished histologically from the injury pattern seen in systemic diseases, so this distinction is usually made clinically.
The nephritic syndrome is usually caused by glomerular inflammation and manifests with an “active” urine sediment (e.g., cells and/or casts). Immune complexes which deposit in the mesangium or in the subendothelial space [membranoproliferative glomerulonephritis (MPGN), IgA nephropathy, and many forms of lupus nephritis] generate inflammatory mediators that have access to the circulation and can cause an influx of inflammatory cells. Glomerular endothelial injury is also caused by autoantibodies to the glomerular basement membrane (anti-GBM), and with necrotizing injury of the glomerular capillaries as occurs in the antineutrophil cytoplasmic antibody (ANCA)—mediated vasculitides. These two diseases frequently present with glomerular crescents and RPGN (
Table 9-2).
Diseases that present with the nephrotic syndrome disrupt the size and charge-selective barriers that ordinarily prevent the ultrafiltration of macromolecules across the glomerular capillary wall. In general, these diseases disrupt the glomerular capillary wall without causing overt inflammation (FSGS, diabetic nephropathy, and amyloidosis), or they affect the epithelial cells without causing endovascular inflammation [membranous nephropathy (MN) and minimal change disease (MCD)].
III. CLINICAL ASSESSMENT OF GLOMERULAR DISEASE
A. The Nephritic Syndrome. In cases in which the nephritic syndrome is the predominant clinical presentation, a search for systemic diseases is warranted (
Table 9-3). The history and physical examination should particularly focus on the assessment of rashes, lung disease, neurologic abnormalities, evidence of viral or bacterial infections, and musculoskeletal and hematologic abnormalities. Laboratory assessment should be tailored to the clinical findings in the history and physical examination. A complete blood count (CBC), electrolyte panel, 24-hour urine collection for protein and creatinine clearance, and liver function tests should be obtained initially. Serum complement (C3) levels are often clinically helpful to assist in the diagnosis of a specific renal disease (
Table 9-4). Further laboratory assessment may be performed based on these findings, and may include an antistreptolysin titer, antinuclear antibody (ANA), ANCA, cryoglobulins, and/or an anti-GBM antibody (
Table 9-3). These early assessments may provide a presumptive diagnosis and should lead the clinician to an appropriate therapeutic intervention while awaiting renal biopsy results, but they are not a substitute for renal biopsy. Proper management of the glomerular diseases requires a tissue diagnosis to confirm the clinical findings and provide information regarding the acuity and chronicity of the disease process.
B. The Nephrotic Syndrome. With the identification of significant proteinuria, with or without other features of the nephrotic syndrome, secondary causes of proteinuria should be considered (
Table 9-5). History and physical examination should evaluate for the presence of viral and bacterial infections, malignancies (particularly lung, breast, and lymphomas), and chronic diseases (such as diabetes), and medications should be reviewed for their potential to cause glomerular proteinuria. Laboratory assessment initially includes CBC, electrolyte panel, 24-hour urine collection for protein and creatinine clearance, liver function tests, and a cholesterol panel. Further assessment may include hepatitis and human immunodeficiency virus (HIV) serologies, ANA, rapid plasma reagin, and serum and urine electrophoresis (
Table 9-5). Renal biopsy should be performed in all cases in which no cause is evident, or to determine the extent of renal disease to guide therapy or prognosis.
IV. THERAPY FOR GLOMERULAR DISEASE.
Treatment of glomerular disorders can be approached by management of the nephrotic syndrome and immunomodulatory therapies for specific glomerular diseases and vasculitides. The management of systemic diseases that cause secondary glomerular injury is rapidly changing (e.g., new antiviral therapies for HIV and hepatitis B and C, and clinical trials using chemotherapeutic regimens for malignancies and vasculitides). Therefore, the reader is encouraged to refer to recent disease-specific reviews of the literature for current management strategies for these systemic diseases.
A. General Management of Proteinuric Glomerular Disease. Untreated nephrotic syndrome is associated with significant morbidity due to
accelerated atherosclerosis, dyslipidemia, thromboembolic events, and infections. Often treatment requires both general management and disease-specific treatment to achieve remission and lessen morbidity. The general treatment strategies that should be considered in the patient with nephrotic syndrome include management of proteinuria, hypertension, edema, hyperlipidemia, and hypercoagulability.
