REVIEW ARTICLE The Diagnosis of Glomerular Diseases Acute Glomerulonephritis and the Nephrotic Syndrome Michael P. Madaio, MD; John T. Harrington, MD apid and efficient diagnosis of diseases presenting as acute glomerulonephritis and/or nephrotic syndrome is critical for early and appropriate therapy aimed at preservation of renal function. Although there may be overlap in clinical presentation, and some patients present with clinical features of both syndromes, this analysis serves as an ini- Rtial framework to proceed with serologic testing and/or pathologic confirmation en route to final diagnosis. Efficient and timely diagnosis is essential in these situations because progression to end- stage renal disease may result if the underlying disease is not promptly treated. Arch Intern Med. 2001;161:25-34 Glomerular injury leads to impairment of ular injury in adults, focusing on glomeru- the selective filtering properties of the kid- lonephritis and nephrotic syndrome. Our ney and reduction in the glomerular fil- intent is to provide a framework that will tration rate (GFR).1-3 Consequently, blood enable efficient and timely diagnosis. A few constituents normally excluded from the introductory points warrant particular em- urinary space pass into the urine and are phasis. We do not discuss the evaluation excreted. The nature and severity of the of asymptomatic abnormalities discov- defect (ie, underlying disease and patho- ered on routine urinalysis (ie, isolated logic lesion) determine the quantity of red hematuria and/or non–nephrotic-range blood cells (RBC), white blood cells, and proteinuria). The clinician should be aware proteins lost in the urine and the extent that these manifestations may represent of functional impairment.4 These vari- less severe forms of the full-blown enti- ables determine the clinical presentation. ties. However, there are many nonglo- While the GFR is reduced initially in many merular causes of isolated hematuria and patients, the severity, reversibility, and pro- proteinuria that must also be considered gression of disease are dependent on many in these situations, and the reader is re- factors, including the nature, location, and ferred to recent reviews of these enti- extent of the insult and the renal and sys- ties.2,6-12 temic response to glomerular injury.3,4 Although our approach distinguishes Prompt recognition of the cause of glo- between nephritic and nephrotic states (the merular disease results in a more ratio- two classic clinical presentations of acute nal, safer, and effective therapeutic ap- glomerular injury), many of the underly- proach. Early diagnosis is especially ing diseases can produce nephritis or ne- important in patients with fulminant phrotic syndrome. Furthermore, this dis- disease, where delay in treatment greatly tinction is not always easily made in reduces the likelihood of a beneficial individual patients. For example, some pa- response.4,5 tients present with nephrotic-range pro- In this review, we delineate our ap- teinuria and active urine sediments, proach to the diagnosis of acute glomer- whereas others present with nephrotic- range proteinuria and acute renal failure. From the Renal Electrolyte and Hypertension Division, Department of Medicine, In some instances the clinical presenta- University of Pennsylvania, Philadelphia (Dr Madaio), and the Nephrology Division, tion represents the initial manifestation of Department of Medicine, New England Medical Center and Tufts University School of an acute disease, whereas in others the Medicine, Boston, Mass (Dr Harrington). physician initially detects a more chronic (REPRINTED) ARCH INTERN MED/ VOL 161, JAN 8, 2001 WWW.ARCHINTERNMED.COM 25 ©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 Table 1. Major Causes of Acute Nephritis* Table 2. Diagnostic Approach in Patients With Acute Normal Serum Glomerulonephritis* Low Serum Complement Level Complement Level Systemic Diseases Serologic Evaluation Systemic lupus erythematosus Polyarteritis nodosa C3, C4, CH50† (focal, approximately 75%; Wegener granulomatosis Anti-DNA antibodies‡ diffuse, approximately 90%) Hypersensitivity vasculitis Antineutrophil cytoplasmic antibodies Cryoglobulinemia (approximately 85%) Henoch-Schönlein purpura Cryoglobulins Subacute bacterial endocarditis (90%) Goodpasture’s syndrome Hepatitis B, C serolgic tests “Shunt”nephritis (90%) Visceral abscess Blood cultures§ Anti–glomerular basement membrane Renal Diseases (type a[3]IV collagen) antibodies Acute poststreptococcal glomerulonephritis IgG-IgA nephropathy Streptozyme\ (approximately 90%) Idiopathic rapidly progressive glomerulonephritis Membranoproliferative glomerulonephritis Anti-GBM disease Kidney Biopsy Type 1 (approximately 50%-80%)† Pauci-immune‡ (no immune deposits) Useful for establishing/confirming Type 2 (approximately 80%-90%) Immune-deposit disease diagnosis, determining degree of inflammation and fibrosis *Normal serum complement levels indicate that production of complement components is keeping up Sometimes, absence of findings are with consumption; it does not exclude participation of complement in the inflammatory process. helpful (eg, absence of immune Repeated measurements are useful (2-3 times, 1 week apart). Consistently normal serum levels are deposits suggests vasculitis) useful in narrowing the diagnostic possibilities. Percentages indicate the approximate frequencies of depressed C3 or hemolytic complement levels during the course of disease. GBM indicates glomerular *If rapidly progressive glomerulonephritis is 12 basement membrane. Adapted with permission from Madaio and Harrington. Copyright ©1983, present, empiric therapy (eg, pulse steroids) is Massachusetts Medical Society. All rights reserved. indicated before definitive diagnosis, to prevent †Most common pathologic findings are associated with hepatitis C infection. irreversible scarring. ‡Pauci-immune indicates lack of significant glomerular deposition of immunoglobulin by direct †Helpful in narrowing diagnostic possibilities immunofluorescence. Many patients have circulating antineutrophil cytoplasmic antibodies. (Table 1). ‡Serologic findings may be negative in . patients with nephrotic syndrome. disturbance. Simply stated, mul- phrotic-range proteinuria ( 3.5 g/d) §If endovascular or occult infection is tiple variables influence the final may be present. suspected (eg, endocarditis, abcess). clinical picture, including the incit- Acute glomerulonephritis can \If poststreptococcal glomerulonephritis is ing event and the host response to be due to a primary renal disease or suspected (Table 3). the immune reactants. Neverthe- a systemic disease. A thorough his- less, the clinical distinction be- tory and physical examination hour urine protein excretion rate or tween acute glomerulonephritis and should focus on identification of an urine protein:creatinine ratio) also nephrotic syndrome provides a rea- underlying systemic disease, and se- should be performed. If the GFR is sonable starting point to form an ini- rologic evaluation should be per- depressed, evaluation of renal size tial differential diagnosis, en route formed for a prompt diagnosis (eg, by ultrasound) is a useful guide to serologic and pathologic determi- (Table 1 and Table 2). Serologic to determine the extent of fibrosis. nation of the underlying glomeru- evaluation is essential and, to- Small kidneys (,9 cm) suggest ex- lar disease. Our discussion focuses gether with the clinical presenta- tensive scarring; reversibility is low on the initial diagnostic evaluation, tion, focuses the differential diag- in this setting, whatever the under- and not on either the pathogenesis nosis.12 The serum complement lying diagnosis. The presence of ne- or the subsequent management of levels provide useful information; if phrotic-range proteinuria is more the underlying diseases. The reader any component is depressed, assess- common in certain diseases. The use is referred to excellent recent re- ment of the levels of other compo- of renal biopsy will be discussed. views for these further consider- nents may be helpful. Initially de- 13-15 ations. termine the CH50 level; if results are Acute Glomerulonephritis With abnormal, proceed with evaluation Low Serum Complement Levels ACUTE of individual components (eg, C3 GLOMERULONEPHRITIS and C4 levels). If an abnormality of Low serum complement levels in pa- the alternate pathway is suspected, tients with glomerulonephritis most Acute glomerulonephritis is de- determine AH50 activity. often result from activation of fined as the sudden onset of hema- For the diagnostic approach, we complement within the kidney or turia, proteinuria, and RBC casts.12 arbitrarily divide the causes of glo- other sites. Most often production Although RBC casts are diagnostic merulonephritis into those with low does not keep up with consump- of glomerular bleeding, they may be and normal serum complement lev- tion,12 although patients with con- difficult to find. Visualization of dys- els. This provides for an efficient and genital or acquired complement de- morphic RBC under phase-contrast practical tool for the initial ap- ficiencies are more prone to develop microscopy by an experienced ob- proach to patients in clinical prac- glomerulonephritis.17 The sys- server is a useful surrogate.16 Pro- tice (Tables 1 and 2). temic diseases consistently produc- teinuria in patients with acute glo- Estimation of GFR (ie, serum ing hypocomplementemic glomeru- merulonephritis