Acute Glomerulonephritis and the Nephrotic Syndrome

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

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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 ␣[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 Ͼ 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 (Ͻ9 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 typically ranges creatinine level) and quantitation of lonephritis include systemic lupus from 500 mg/d to 3 g/d, but ne- urine protein excretion (ie, 24- erythematosus, subacute bacterial

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Downloaded From: https://jamanetwork.com/ on 09/24/2021 endocarditis, shunt nephritis, and nephritis (MPGN) usually is pres- tinguishing glomerulonephritis af- cryoglobulinemia. These diseases ent. Most cases of essential mixed ter streptococcal infections from usually are apparent from the his- cryoglobulinemia and associated glo- IMPGN (Table 3). These serologic tory and results of physical exami- merulonephritis are associated with determinations are especially useful nation, and serologic testing is per- hepatitis C infection,26-28 and the ma- in situations where the distinction be- formed to confirm these diagnoses jority of these patients have hepati- tween glomerulonephritis after strep- (Table 2). Some patients (approxi- tis C RNA or anti–hepatitis C anti- tococcal infections and MPGN is dif- mately 10%) with heavy protein- bodies in the serum.25 Therefore ficult on clinical grounds alone (eg, uria may have negative serologic hepatitis C assays (ie, polymerase where there is persistent or recur- findings at initial presentation due chain reaction and antibody evalua- rent disease). to loss of antibodies in the urine, tis- tions) should be performed in pa- sue deposition, or other factors.18,19 tients with undiagnosed glomerulo- Acute Glomerulonephritis Blood cultures should be obtained nephritis.29 Liver enzyme levels and With Normal Serum in all febrile patients to exclude in- other liver function tests may be nor- Complement Levels fection, since endovascular infec- mal at disease onset.25,28,29 Charac- tion must be treated promptly. teristic lesions on kidney biopsy One should initially consider glo- (eg, intraluminal thrombi or “fin- merulonephritis associated with sys- Systemic Diseases. The diagnosis of gerprint” pattern of the electron- temic diseases, then evaluate the pos- lupus usually is determined by the dense deposits) also should raise sibility of primary renal diseases presence of extrarenal disease (eg, suspicion of hepatitis C–associated (Table 1). arthritis or rash) and serologic find- disease. ings (eg, anti–double-stranded DNA Systemic Diseases. Multi-organ in- antibodies; Table 2). Nephrotic- Primary Renal Diseases. Primary re- volvement strongly suggests a sys- range proteinuria and reduced GFR nal diseases associated with glomeru- temic process, and typical symp- are indicative of a more severe pro- lonephritis and low serum comple- toms of an underlying disease may liferative lupus nephritis. Renal bi- ment levels include acute post- be useful in narrowing the diagnos- opsy is, however, necessary to dis- infectious glomerulonephritis and id- tic possibilities, eg, sinusitis, pul- tinguish the disease subtype in more iopathic MPGN (IMPGN). The monary infiltrates (Wegener granu- severe forms,18 and therefore is rec- former has been most extensively lomatosis),42 pulmonary hemorrhage ommended in patients with lupus studied after streptococcal infec- (Goodpasture’s syndrome),43 nau- and decreased GFR and/or ne- tions, although the syndrome has sea, vomiting and abdominal pain, phrotic syndrome. Renal biopsy elu- been reported after other bacterial, vi- and purpura (Henoch-Scho¨nlein cidates the degree of inflammation ral, parasitic, rickettsial, and fungal purpura).12 Serologic evaluation, in- (ie, assessment of disease activity and infections.30 Although IMPGN re- cluding measurement of anti- confirmation of diagnosis) and the mains an important cause of glomer- neutrophil cytoplasmic antibodies level of fibrosis (eg, scarring or ular disease in children, the inci- (ANCA) and anti–glomerular base- chronicity).20-24 With clinical assess- dence of primary disease in adults has ment membrane (GBM) antibod- ment of extrarenal lupus activity, declined.31,32 Secondary forms of the ies, along with hepatitis serologic these pathologic variables are use- disease may be associated with au- evaluation, is essential, especially for ful in guiding administration and toimmune diseases, chronic infec- prompt diagnosis in patients with withdrawal of immunosuppressive tions, microangiopathies, and para- rapidly progressive glomerulone- therapy. protein deposition diseases.33 Most phritis (RPGN). Purpura, arthralgias, and other patients with IMPGN have recur- A few caveats warrant men- signs of vasculitis in patients with glo- rent bouts of glomerulonephritis tion. Most patients with polyarteri- merulonephritis and low serum (and/or nephrotic syndrome). By tis associated with hepatitis B or C complement levels raise the suspi- contrast, with glomerulonephritis af- display normal or near-normal cion of cryoglobulinemia. Patients ter streptococcal infections, recov- complement levels (Ͼ80%); how- may present with clinical features as- ery (lack of progression to end- ever, decreased levels occur more sociated with glomerulonephritis stage renal disease) is the rule, frequently in patients with cryo- or/and nephrotic syndrome, al- especially in children (Ͻ2% progres- globulinemia. The liver enzyme lev- though the former is more com- sion to end-stage renal disease), and, els and liver function tests may be mon. Cryoglobulinemia (75%) and thus the disease course is helpful in normal at disease onset, although the rheumatoid factor activity (70%) are confirming the diagnosis. Neverthe- serologic findings are typically posi- frequently present; however, the lev- less, persistent urinary abnormali- tive.25,28,29 Patients with hepatitis B els fluctuate, and they may not be de- ties may last for years, and a small and glomerulonephritis typically tectable at initial presentation.25 More percentage of adults develop slowly have positive findings for hepatitis than 80% will have reduced serum progressive renal failure.30 For diag- B surface antigen and antibodies to complement levels sometime dur- nosis, repeated evaluation of serum hepatitis B core, and negative finding the course of disease, and C4 and complement levels, determination of ings for antibodies to hepatitis B sur- C2 complement levels may be mark- autoantibodies to complement path- face antigen in serum.29,44 Among edly depressed.25 Pathologically, way components, and renal biopsy this group, the incidence of sys- membranoproliferative glomerulo- findings are especially helpful in dis- temic involvement (ie, polyarteri-

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Downloaded From: https://jamanetwork.com/ on 09/24/2021 Table 3. Complement Levels and Kidney Deposits to Distinguish Idiopathic Membranoproliferative Glomerulonephritis (MPGN) and Poststreptococcal Glomerulonephritis (GN)*

MPGN

Type 1 Type 2 Type 3 Poststreptococcal GN Immunofluorescence IgG, C3 C3 predominates C3ϾIgG IgG, C3 (glomeruli) Electron dense Subendothelial mesangial Dense BM deposits Like type I, Subendothelial mesangial deposits often thickened BM subepithelial (humps) C3 Levels fluctuate Persists low Levels fluctuate Low for 2-4 wk, then normal C4 Normal or reduced Normal Normal Normal to low normal (alternate C path) Autoantibodies C3NeFI/III C4NeF NFI C3NeFII C3NeFI/III Antistreptoccal antibodies

*C3NeFII binds to C3 convertase and blocks its inactivation by factor H; this results in alternative pathway activation.34 It is present in more than 75% of patients with MPGN type II but is infrequent in MPGN type I.35 C3NEFI/III converts C3 and the terminal components via properdin, activating complement (found in approximately 25% of type I and Ͼ75% of type III).35,36 C4NeF type binds to the C3 convertase, C4b2a, and a C3bBb stabilizing factor, NFI; it was discovered in the serum of MPGN type I patients.37 Patients with lipodystophy are more prone to MPGN and some of them produce autoantibodies vs complement component (nephritic factors).38 Glomorulonephritis after streptococcal infection may occur in sporadic or epidemic form and evidence of recent infection may not be obtained. In the first few weeks, C4 and C2 levels are usually normal or near normal, with profound depression of C3 reflecting alternative pathway activation.39 In most patients, the levels return to normal within a month, although they may take up to 3 months to normalize.40 Serum antibodies to streptococcal cell wall proteins (eg, streptozyme assay) are positive in more than 95% of patients with pharyngitis and 80% of patients with skin infections.41 However, since the prevalence of streptococcal infections in the general population is high, their detection is not diagnostic.

tis) varies widely by geography, from neys. Occasionally ANCA may be most all patients with idiopathic, as high as 84% in cities with in- found in patients with lupus nephri- pauci-immune glomerulonephritis creased drug use, to a much lower tis, although its significance is un- have ANCA; however, 75% of this incidence in rural areas.29 Patients clear.56 group express pANCA.58 In the clini- with glomerulonephritis associ- cal setting of RPGN, these assays are ated with abscess typically have nor- Serologic Evaluation, Use of the especially useful, with high positive mal complement levels (unless there Kidney Biopsy in Clinical and negative predictive values is endocarditis), and the site of in- Practice, Referral to a (Ͼ90%).57 However, they have much fection is usually apparent from the Nephrologist lower predictive values in other clini- history and results of physical ex- cal settings (eg, hematuria or non- amination.39,45 The clinical presentation provides nephrotic-range proteinuria with nor- clues, but serologic testing facili- mal serum creatinine levels), and the Primary Renal Diseases. The clini- tates rapid diagnosis, especially in utility of ANCA vs other intracellu- cal presentation of IgA nephropa- patients without systemic symp- lar antigens is less clear. thy varies considerably (eg, asymp- toms. We recommend initially ob- Pathologic evaluation also is tomatic hematuria, RPGN, nephrotic taining C3 and C4 levels, along with useful for rapid diagnosis, for dis- syndrome).46 Most often it is idio- determination of serum ANCA, anti– tinguishing primary renal diseases, pathic, although liver disease is the DNA, and anti–GBM antibody lev- and for determining disease sever- most frequent association.47-51 Re- els (Table 2). The perinuclear ity.58 In most cases, systemic dis- nal biopsy is required for definitive (pANCA) and cytoplasmic (cANCA) eases associated with glomerulone- diagnosis. patterns of staining for ANCA should phritis are apparent from the clinical Rapidly progressive glomeru- be determined. These serologic presentation, and serologic testing lonephritis may be associated with evaluations are especially impor- confirms the diagnosis. In some in- any form of glomerulonephritis, in- tant in patients with RPGN and stances, however, the serologic find- cluding those associated with low should be determined immediately ings are not diagnostic or not readily complement levels. Most patients, in this situation. The results may available, and histologic examina- however, present without systemic obviate the need for immediate tion of the kidney is required. Al- symptoms and with normal levels kidney biopsy, and the serologic re- though the pathologic findings are (Ͼ95% have normal complement sults should dictate initial ther- not always diagnostic, they help to levels).52 The majority of patients apy.52,53 Determination of hepatitis narrow the differential diagnosis. with idiopathic RPGN are ANCA serologies and evaluation of cryo- The pathologic findings also are positive. Less commonly (10%-20%), globulin levels also should be per- helpful in determining the degree of patients have anti-GBM disease (eg, formed. disease activity (eg, the level of in- linear GBM deposits and crescentic Patients with Wegener granu- flammation or the extent of fibro- glomerulonephritis); occasionally lomatosis typically have serum ANCA sis), and this information may help (5%-10%), patients will have posi- (80%-95%), and the most common guide therapy. tive findings for ANCA and anti- pattern is cANCA, with antigenic Renal biopsy may be espe- GBM antibodies.53-56 The latter group specificity for proteinase 3. Most of cially important for patients with is more likely to have vasculitis in the rest of the ANCA are directed at RPGN, where prompt diagnosis and organs other than the lungs and kid- myeloperoxidase (pANCA).57 Al- treatment are essential.52 For ex-

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Downloaded From: https://jamanetwork.com/ on 09/24/2021 ample, in a patient with RPGN (cres- interstitial fibrosis will be present, ally leads to hypoalbuminemia, centic glomerulonephritis) for whom whatever the underlying cause of the resulting in edema. Furthermore, we serologic findings are not rapidly primary renal disease, and diagnos- have known for more than 20 years available, the absence of immune de- tic interpretation will be limited. that patients with urinary protein ex- posits (ie, pauci-immune glomeru- Furthermore, the probability of re- cretion rates of less than 2 g/d have lonephritis) on evaluation of biopsy sponse to subsequent therapeutic in- a better prognosis.60 The clinical is consistent only with vasculitis or tervention is greatly reduced.59 complex referred to as nephrotic Wegener granulomatosis; anti-GBM In situations where the patient syndrome results from heavy pro- disease (ie, linear immune deposits) is asymptomatic (eg, RBC and RBC teinuria and includes edema, hypo- and the major immune deposit–med- casts present on urinalysis, without albuminemia, hyperlipidemia, and iated diseases are excluded by that systemic findings) and the GFR is lipiduria. Many factors influence the finding. In this regard, if systemic vas- normal, the physician should ob- onset and severity of edema, includ- culitis is suspected, angiography or serve the serum creatinine level ing the degree and duration of pro- biopsy of other affected organs pro- closely over time, while proceeding teinuria, the serum albumin level, vides a more specific diagnosis.58 As with the evaluation. We emphasize the patient’s underlying renal dis- mentioned previously, the extent of that in cases of isolated hematuria (ie, ease (ie, sodium retentive state and disease activity in this situation is without casts or proteinuria), the renal function), dietary sodium in- also useful in guiding therapy. source of bleeding from other sites take, accompanying cardiovascular Pathologic evaluation is also within the urinary tract (eg, blad- and liver function, etc. The pres- particularly helpful in diagnosing glo- der, prostate, or ureters), should be ence or severity of nephrotic syn- merulonephritis in patients with un- explored by means of visualization of drome does not predict the under- explained, acute renal failure, when the kidney and the collecting sys- lying pathological disturbance, and the diagnosis is uncertain from the tem (ie, cystoscopy and intravenous the syndrome can be due to a pri- clinical findings. For example, in pa- pyelogram and/or computed tomo- mary renal or a systemic disease. The tients with progressive renal failure graphic scan). Depending on the re- incidence of diseases associated with without significant urinary or sys- sults, renal biopsy may be per- the nephrotic syndrome varies mark- temic symptoms, the pathologic find- formed to confirm or elucidate the edly with age, thus providing im- ings may be very helpful in confirm- diagnosis of glomerulonephritis and portant diagnostic information. In ing or excluding a diagnosis. The to determine the level of disease ac- most children and adults, the ini- results derived from the biopsy are tivity. Sometimes, lack of abnormal tial manifestation of disease is pe- also very useful in patients with findings on histologic evaluation is ripheral edema. The elderly (aged slowly progressive renal failure due helpful in excluding a renal cause of Ͼ65 years) may be misdiagnosed to glomerular disease, where it is dif- the bleeding. with congestive heart failure. Many ficult to determine the level of dis- The urgency for referral to a ne- patients are asymptomatic. ease activity (eg, the extent of fibro- phrologist for further consider- sis and irreversible disease) from the ation and renal biopsy depends on Systemic Diseases clinical presentation alone.59 For ex- the GFR. For example, in situa- ample, in some instances it may be tions where there are isolated uri- Initial diagnostic evaluation in- difficult to distinguish disease activ- nary abnormalities, history and cludes consideration of systemic dis- ity (ie, exacerbation amenable to fur- physical examination are unreveal- eases and drugs; the most common ther immunosuppression) from pro- ing, and serum creatinine level is associations are listed in Table 4. gressive fibrosis, unassociated with a normal and stable (ie, Ͻ88.4 µmol/L Diabetes mellitus is the most com- disease flare. Treatment in the latter [1.0 mg/dL] in a 70-kg man), pro- mon cause of nephrotic syndrome in situation would not be specific to the ceed with the serologic workup adults in the United States.62-64 Ap- underlying disease, but it would in- while closely monitoring renal func- proximately one third of patients with clude control of systemic hyperten- tion, before consultation, consider- juvenile-onset (type 1) diabetes melli- sion (preferably by use of an angio- ation of biopsy, and treatment. How- tus develop nephrotic syndrome, pre- tensin-converting enzyme inhibitor) ever, if the GFR is abnormal or dictably leading to renal failure,65 and and hyperlipidemia. rapidly deteriorating, or if there are recent evidence indicates that there Nevertheless, the clinician must systemic symptoms, immediate con- is genetic susceptibility to the devel- be aware of limitations of the use and sultation (ie, that day) is advisable opment of nephropathy.66 In pa- interpretation of the kidney biopsy for clinical decisions regarding treat- tients with type 1 diabetes mellitus results. If the kidneys are small (eg, ment, biopsy, need for dialysis, etc. in whom nephropathy develops, the Ͻ9 cm in length for a 70-kg pa- natural history of the disease is fairly tient), the risk associated with bi- NEPHROTIC SYNDROME predictable and has diagnostic util- opsy (ie, major bleeding requiring ity. Asymptomatic microalbumin- transfusion and other interven- Nephrotic-range proteinuria in uria, the initial manifestation, oc- tion) is increased, and the probabil- adults is defined as urinary excre- curs 5 to 10 years into the illness; ity of obtaining clinically useful, di- tion of more than 3.5 g protein per overt proteinuria (0.5-3.0 g/d) oc- agnostic information is substantially 1.73 m2 in 24 hours. Although an ar- curs 13 to 20 years after disease on- reduced.59 In this setting, severe and bitrary definition, persistent pro- set, and nephrotic-range protein- irreversible glomerulosclerosis and teinuria at or above this level usu- uria (Ͼ3.5 g/d) develops a few years

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Downloaded From: https://jamanetwork.com/ on 09/24/2021 sions), and those without retinopa- Table 4. Major Causes of Nephrotic Syndrome thy are more likely to have nondia- betic glomerular disease. We reserve Primary renal diseases renal biopsy for diabetic patients with Membrane nephropathy (MN) (33%) Focal glomerulosclerosis (FSGS) (33%) nephrotic syndrome with atypical IgA nephropathy (IgA) (10%) history, examination results, or clini- Minimal-change disease (MCD) (15%) cal course for diabetic nephropathy Membranoproliferative glomerulonephritis (MPGN) (2%-5%) (eg, early-onset renal failure, rapid Other (eg, proliferative glomerulonephritis) (5%-7%) progression of renal failure, lack of Systemic diseases* evidence of microvascular disease Diabetes Amyloidosis elsewhere, or evidence of overt glo- Systemic lupus erythematosus merulonephritis). Dysproteinemias Nephrotic syndrome in pa- Multiple myeloma tients with lupus nephritis is most of- Immunotactoid/fibrillary glomerulonephritis ten indicative of a severe prolifera- Light chain–deposition disease tive or inflammatory lesion.20-24 Heavy chain–deposition disease However, some patients develop non- Infections Human immunodeficiency virus disease (FSGS) inflammatory, membranous, lupus Hepatitis B (MN) lesions and present with a normal Hepatitis C (MPGN) GFR and heavy proteinuria. Acute re- Syphilis (MN) nal failure for another reason (eg, use Malaria (MN) of nonsteroidal anti-inflammatory Schistosomiasis (MN) drugs or interstitial nephritis) in a pa- Tuberculosis (Amyloid) Leprosy (MN) tient with membranous lupus ne- Malignant neoplasms phropathy may confuse the situa- Solid adenocarcinomas, eg, lung, breast, colon (MN) tion.19 As discussed previously, loss Hodgkin lymphoma (MCD) of autoantibodies in the urine can re- Other malignant neoplasms sult in negative serologic findings Drugs or toxins and delay diagnosis. However, de- Nonsteroidal anti-inflammatory drugs (MCD) Gold (MN) pressed serum complement levels Penicillamine (MN) or/and other clinical features of sys- Probenecid (MN) temic lupus should raise suspicion of Mercury (MN) this disorder. Pathological evalua- Captopril (MN) tion of the kidney is necessary for Heroin (intravenous, FSGS) determination of disease activity and Heroin (“skin poppers,” amyloid) the extent of fibrosis. Less common- Other Preeclampsia ly, nephrotic syndrome has been as- Chronic allograft rejection sociated with other rheumatologic Vesicoureteral reflux (FSGS) diseases5,52,59,70 (Table 4). Bee sting Amyloidosis and the dysproteinemias should be considered in pa- *Lesions that resemble primary glomerular diseases are indicated in parentheses. Table modified with tients older than 40 years, although permission from Koenig and Bolton.61 most patients are older than 50 years. Eighty percent of patients with amy- thereafter. The period between onset Diabetic retinopathy is a useful loidosis have proteinuria, and the ne- of microalbuminuria and renal failure marker of diabetic nephropathy in pa- phrotic syndrome occurs in about one can be extended by rigorous control tients with nephrotic syndrome, es- third.71 Amyloidosis may be idio- of blood glucose level and blood pres- pecially in patients with type 1 dia- pathic or associated with multiple my- sure, use of angiotensin-converting betes (Ͼ90% of patients with eloma, long-standing rheumatoid ar- enzyme inhibitors, and, perhaps, re- nephropathy have retinopathy); mi- thritis, or chronic infections, although striction of dietary protein and reduc- crovascular disease in the retina is in- the latter are much less common in tion of hyperlipidemia.67,68 Neverthe- dicative of diabetic nephropathy and recent decades.71,72 Most patients with less,progressiontoend-stagerenalfail- usually precedes it.63,64 Fluorescein an- amyloidosis in the United States have ure is fairly predictable within a few giography is necessary to adequately immunoglobulin light chain–asso- years after the onset of nephrotic syn- evaluate the retinal microvascula- ciated disease.73 Accompanying sys- drome.69 In patients with type 2 dia- ture, and it should be performed in temic symptoms (eg, fatigue or betes mellitus, the prevalence and patients with diabetes and protein- weight loss) and/or cardiac involve- expression of diabetic nephropathy uria when the diagnosis is uncer- ment are common, although other or- are more variable, as the nephropathy tain. Nevertheless, retinopathy is less gans may be affected. A monoclonal is often complicated by hypertensive predictable in patients with type 2 dis- spike is found in the serum or urine and atherosclerotic disease in older ease and proteinuria (approximately by electrophoresis in more than 80% patients.63 50%-80% will have diabetic le- of proteinuric individuals and more

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Downloaded From: https://jamanetwork.com/ on 09/24/2021 than 90% of patients with nephrotic syndrome; approximately 20% of Table 5. Human Immunodeficiency Virus Glomerulopathies* these patients will have free light chains.71,72 The yield of abdominal Renal Abnormalites Clinical Features fat-pad biopsy is approximately 75% FSGS (collapsing more common) Proteinuria in this group, and the procedure Nephrotic syndrome should be performed in patients Progressive renal insufficiency HUS/TTP/TMA Progressive renal insufficiency older than 40 years with unex- Microangiopathic hemolytic anemia 73 plained proteinuria. Skin, gingi- Thrombocytopenia val, and rectal biopsy findings are Systemic involvement less sensitive, unless there is overt (eg, central nervous system) clinical involvement.73,74 Results of IgA/IgG Acute glomerulonephritis bone marrow examination may dem- Predominantly IgA and/or IgG deposits Membranous/MPGN Associated with hepatitis B, hepatitis C onstrate evidence of monoclonal re- Syphilis 73 striction. APSGN Post infectious glomerulonephritis, associated Other related disorders, includ- with bacterial or other infections ing immunotactoid and/or fibrillary glomerulopathy and heavy *FSGS indicates focal segmental glomerulosclerosis; HUS, hemolytic uremic syndrome; TTP, thrombotic thrombocytopenic purpura; TMA, thrombotic microangiography; Ig, immunoglobulin; MPGN, chain–deposition disease, may pre- membranoproliferative glomerulonephritis; and APSGN, glomerulonephritis after streptococcal infection. sent as nephrotic syndrome (with or Clinical presentation may be complicated by drug-induced disease (eg, elevated creatinine level without progressive renal failure). secondary to trimethoprim sulfamethoxazole on other nephrotoxins) and/or the presence of These entities are difficult to diag- tubulointerstitial disease (including acute tubular necrosis), etc. nose on clinical grounds alone, and renal biopsy is required for diagno- proteinuria should raise suspicion of edema and heavy proteinuria.91 The sis.75-81 The size, shape, and nature the diagnosis.89 Less common forms cause of these entities is uncertain, of the immune deposits and micro- of glomerulopathies associated with although circumstantial evidence of fibrils distinguish these entities from HIV include IgA deposition, micro- an immune-mediated pathogenesis amyloid deposits and each other. angiopathy, and acute renal fail- exists in most instances. The terms Recognition of the association of ure.85 Regarding the latter, renal bi- used to categorize these patients re- nephrotic syndrome with infections opsy may be necessary to distinguish fer to the typical pathologic descrip- has been rekindled with the epi- the cause of acute renal failure in these tion of the light microscopy find- demic of acquired immunodefi- individuals. Other infections associ- ings of kidney tissue (Table 4). ciency syndrome (AIDS).82-84 Pa- ated with the nephrotic syndrome are Accordingly, histologic evaluation of tients with AIDS may present with a given in Table 4.30 kidney biopsy specimens is re- variety of nephrologic syndromes A variety of neoplasms and quired to make a definitive diagno- (Table 5).85 The varied clinical pre- drugs have been linked to the ne- sis. These lesions usually are indis- sentations and pathologic entities ob- phrotic syndrome; the more com- tinguishable from those of patients served in these patients likely reflect mon pathologic associations are in- with systemic diseases. In fact, kid- differences in pathogenesis and host dicated in Table 4.61,90 In most cases, ney biopsy specimens from pa- response to viral infection. Renal in- the neoplasm is obvious from the tients with systemic diseases fre- volvement may occur at any stage of history and results of physical and quently are categorized as having infection, although the entity oc- laboratory examinations, although “disease like” the idiopathic varie- curs more commonly in patients with occasionally the nephrotic syn- ties (ie, membranous-like or mini- established AIDS. The pathologic ab- drome represents the initial mani- mal change–like lesions). Neverthe- normality in patients with ne- festation of disease. Nonsteroidal less, although the causes of these phrotic syndrome is typically focal anti-inflammatory drugs are the entities are uncertain, identifica- and segmental glomerulosclerosis.86 most common drugs associated with tion of the abnormality using re- A more severe form, termed collaps- the nephrotic syndrome, probably sults of kidney biopsy has utility in ing glomerulopathy, more common in the result of their widespread use. classifying the disease and in pre- patients who are seropositive for hu- With drug-induced disease, deter- dicting outcome and response to man immunodeficiency virus (HIV), mining causality may be difficult, as therapy. is associated with rapid progression resolution of nephrosis may take to end-stage renal failure within weeks to months after discontinu- Diagnosis of Nephrotic months.87 It has been postulated that ation of use of the offending agent. Syndrome HIV infection of renal cells (eg, mesangial or epithelial) contributes to Primary Glomerular Diseases Because of these considerations, our fibrosis and the more rapid progres- recommendations for the initial sion to renal failure observed in these Idiopathic nephrotic syndrome is the workup of adults with nephrotic patients.88 Urinary protein excre- term used to describe nonsystemic syndrome are outlined in Table 6. tion can exceed 20 g/d in some pa- disease or disease without another Unless the GFR is abnormal or rap- tients (ie, supernephrotic syn- pathogenically relevant associa- idly deteriorating, proceed with the drome), and therefore this level of tion. Patients typically present with diagnostic evaluation and subse-

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Downloaded From: https://jamanetwork.com/ on 09/24/2021 biopsy findings also provide prog- Table 6. Evaluation of Nephrotic Syndrome in Adults* nostic information, thereby influ- encing therapeutic decisions.59 Thus, History we recommend renal biopsy when Family history and history of drug use or toxin exposure Physical examination the diagnosis is uncertain or knowl- If patient Ͼ50 y, usual recommendations for age, including stool examination edge of the severity of disease will (hemoccult testing 3×) influence therapy. Nevertheless, if If stool examination is negative, perform flexible sigmoidoscopy the probability of a specific disease If stool examination is positive, perform standard gastrointestinal tract workup or group of diseases is high, the risk Laboratory testing of complication due to biopsy is Complete blood cell count; measurement of serum creatinine, glucose, liver enzymes, lactate dehydrogenase, alkaline phosphatase, and albumin; lipid profile; and chest x-ray high, and the risks of therapy ap- Consider systemic diseases pear reasonable (eg, short course of Fluorescein angiography (for diabetes mellitus) high-dose oral steroids), then em- Antinuclear antibodies (for systemic lupus erythematosus) pirical therapy without biopsy Consider malignant neoplasms, eg, amyloid or light chain disease or myeloma should be strongly considered.60 Em- Ͼ If either patient 50 y or initial evaluation raises suspicion, perform pirical use of steroids in children Serum protein electophoresis Serum immunoelectrophoresis with minimal-change disease is a Urine protein electrophoresis good example of this approach. Abdominal fat-pad biopsy As noted in the discussion of Consider infection glomerulonephritis, pathological Perform hepatitis C, hepatitis B, human immunodeficiency virus serologic testing evaluation of the kidney also has utility in defining the disease subtype and Renal biopsy To distinguish primary glomerular disease determining the severity of disease. For diagnosis of unsuspected secondary glomerular disease The results of renal biopsy are also (eg, amyloid) very helpful when attempting to sort To determine disease severity out the potential contribution of 2 or more diseases. In this regard, it is *If the initial workup is negative, stop looking for other causes; reevaluate in 6 to 12 months. sometimes difficult to determine whether activity of the underlying Table 7. Other Considerations in the Diagnosis disease or superimposition of an- of Glomerular Diseases* other primary disease is the cause of the worsening situation. For ex- Hereditary nephritis (including thin basement membrane disease)92 ample, nephrotic syndrome in a pa- Typically X-linked, rarely autosomal recessive tient with well-controlled diabetes Family history, males severly affected without retinopathy or other mani- Female carriers develop hematuria but not renal failure Type ␣(5)IV collagen abnormality or impaired assembly of ␣(3), ␣(4), and ␣(5) collagen festations of microvascular disease Patients who have undergone transplantation may develop anti–glomerular basement should raise suspicion of another membrance (type ␣[3]IV collagen) cause. The pathological results often are very helpful in the setting of Hemolytic uremic syndrome93,94 rapidly progressive renal failure in an Spontaneous form HIV-seropositive patient; this clini- Autoantibodies to inhibitor of von Willebrand factor cleaving protease Familial form cal presentation should evoke a di- Deficiency of von Willebrand factor cleaving protease agnostic workup for other causes of glomerular disease. Thrombotic thrombocytopenic purpura93,94 RENAL DISORDERS THAT Malignant hypertension MASQUERADE AS ACUTE Interstitial nephritis (eg, drug induced) GLOMERULONEPHRITIS AND/OR NEPHROTIC Acute tubular necrosis SYNDROME

Atheroembolic renal disease Patients with the diseases listed in Table 7 may present with signifi- *Previous history of severe hypertension or hypertensive retinopathy, systemic features (eg, rash, arthritis), or associated complications leading to disseminated intravascular coagulation (eg, sepsis) may cant hematuria, RBC casts, and/or ne- be helpful in distinguishing from glomerulonephritis. phrotic-range proteinuria, thus mim- icking acute glomerulonephritis or quently refer the patient to a ne- mal, the patient most likely has nephrotic syndrome. These condi- phrologist to assist with manage- idiopathic nephrotic syndrome. The tions should be considered in pa- ment. Further evaluation (and results of the kidney biopsy distin- tients without an obvious disease as- therapy) should be driven by the re- guish among primary renal dis- sociation. The clinical history, results sults of the initial studies. If the re- eases and occasionally uncover un- of physical examination, and labora- sults of the initial workup are nor- suspected systemic diseases. Kidney tory findings are useful in construct-

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