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- tial 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, Glomerular injury leads to impairment of theselective filtering properties ofthe kid- ney and reduction in the glomerular fie tration rate (GFR). Consequently, blood juents normally exelided from the space pass into the urine and are excreted. The nature and severity of the defeet (ie, underlying disease and patho- logic lesion) determine the quantity of red blood cells (RBC), white blood cells, and proteins lost in the urine and the extent of functional impairment.’ These var ables determine the clinical presentation While the GFRis reduced initially in many patients, the severity, reversibility, and pro- gression of disease are dependent on many factors including the nature, location, and extent of the insult and the renal and sys- temic response to glomerular injury.”* Prompt recognition of the eause of glo- rmerular disease results in a more ratio- nal, safer, and effective therapeutic ap- proach. Early diagnosis is especially important in patients with fulminant disease, where delay in treatment greatly reduces the likelihood of a benelicial In this review, we delineate our ap- proach to the diagnosis of acute glomer- From the Renal Electrolyte and Hypertension Division, Department of Medicine, Univers of Pennsylvania, Philadelphia (Dr Madaio), andthe Nephrology Division, Department of Medicine, New England Medical Center and Tats University School of Medicine, Boston, Mass (Dr Harrington) Downloaded From: on 0192/2018 (agen ED) ARCHINTERN MEDIVOL OTN OT Arch Intern Med. 2001;161:25-34 ular injury in adults, focusing on glomeru- lonephritis and nephrotic syndrome. Our {intent is to provide a framework that will enable efficientand timely diagnosis. A few introductory points warrant particular em- phasis. We do not discuss the evaluation of asymptomatic abnormalities discov- ered on routine urinalysis (ie, isolated hematuria and/or non-nephrotic-range proteinuria). The clinician should be aware that these manifestations may represent forms of the full-blown enti- 1, there are many nonglo- rmerular causes of isolated hematuria and proteinuria that must also be considered. less sever Hes. Howe in these situations, and the reader is re- ferred to recent reviews of these enti Although our approach distinguishes between nephriticand nephrotic states (the ‘wo classic clinical presentations of acute glomerular injury), many of the underly {ng diseases ean produce nephritis or ne- phrotic syndrome. Furthermore, this dis- Linction is not always easily made in individual patients. For example, some p tents present with nephrotic-range pro- teinuria and active urine sediments, whereas others present with nephrotic- range proteinuria and acute renal failure. In some instances the clinical presenta- ton represents the initial manifestation of fan acute disease, whereas in others the physician initially detects a more chronic (©2001 American Medical Association. Al rights reserved,Table 1. Major Cuses of Acute Nephriis™ Table 2. Diagnose Approach ‘in Pationts With Acute a Glomeruonephrtis® tow ser conpamen Lovet compte ae a (focal, approximately 75%: ‘Wegener granulomatosis: ‘Anti-DNA antibodies Seeoy ae Ma oan en eee) See a Ser roma cone | a ee ‘Renal OF 9¢ c_[3} collagen) antibodies eee en set a S Ta eereme yin” helt! ftom pe) baw aut ssemerme at bs erento cme es Seen ee ee, yy ecaameumrat Feral ety eee er oe Ia oc ‘Massachusetts Medical Society. All rights reserved. ‘indicated before definitive dlagnosis, to prevent Stance tu tan a See a sa yess ee saponwnauns dca et eer er ee ee vege rn step Selo fangs may be negative n disturbance. Simply stated, mul- phroticrangeproteimuria (>3.5 fd) Palen ih nepotesndome ‘if endovasclar roc cto tiple variables influence the final may be present. susyeted edocs aces) clinical picture, ineluding the ineit- ‘Acute glomerulonephitis can lifpattepacoclglomertonepts is ing event and the host response tobe due toa primary renal disease or std ble) the immune reactants, Neverth systemic disease. A thorough his- less, the clinical distinction be- tory and physical examination hour urine protein excretion rate or tween acute glomerulonephritisand should focus on identification ofan__urine protein:creatinine ratio) also nephroticsyndrome providesarea- underlying systemic disease, and: should be performed. If the GER is sonablestarting point to form anini- _rologie evaluation should be per- depressed, evaluation of renal size tial differential diagnosis, en route formed for a prompt diagnosis (eg, by ultrasound) isa useful guide toserologicand pathologic determi- (Rabe ¥ and Table 2). Serologic to determine the extent of fibrosis. nation of the underlying glomeru- evaluation is essential and, to- Small kidneys (<9 em) suggest ex- lar disease. Our discussion focuses gether with the clinical presenta- tensive searring; reversibility is low onthe initial diagnostic evaluation, tion, focuses the differential diag- in this setting, whatever the undei and not on either the pathogenesis nosis."? 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 cerlain diseases. The use fs 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- ations." termine the CHyy level; ifresultsare Acute Glomerulonephritis With abnormal, proceed with evaluation _Low Serum Complement Levels ACUTE of individual components (eg, C3 GLOMERULONEPHRITIS and C4 levels). Ifanabnormality of Low serum complement levelsin pa the alternate pathway is suspected, ents with glomerulonephritis most Acute glomerulonephritis is determine AHL, activity often result from activation of fined as the sudden onset of hema- For thediagnosticapproach, we complement within the kidney or turia, proteinuria, and RBC casts."* arbitrarily divide the causes of glo- other sites. Most often production Although RBC casts are diagnostic merulonephriisinto those withlow does not keep up with consump- of glomerular bleeding, they maybe and normalserum complement lev-__tion,"* although patients with con- difficult ofind. Visualizationofdys- els. Thisprovides foranefficientand genital or acquired complement de- morphic RBC under phase-contrist practical tool for the initial ap-__ ficiencies are more prone to develop microscopy by an experienced ob- proach to patients in clinical prac- _glomerulonephritis.7 The sys- server is a useful surrogate." Pro- tice (Tables 1 and 2). temic diseases consistently produc teinuria in patients with acute glo- Estimation of GFR (je, 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 (nEPRINTED) XRCHINTERN MEDIVOL ToT, JAN DOT WWW ARCHNTERNOIED COM (©2001 American Medical Association. Al rights reserved, Downloaded From: on 0192/2018endocarditis, shunt nephritis, and ceryoglobulinemia, These diseases usually are apparent from the his tory and resulls of physical exami nation, and serologic testing is pe formed to confirm these diagnoses (Fable 2). Some patients (approxi- mately 10%) with heavy protein- uuria may have negative serologic findings at initial presentation due to loss of antibodies in the urine, tis- sue deposition, or other factors."*"" Blood cultures should be obtained {nall febrile patients to exelude in- fection, since endovascular infec- ton must be treated promptly ‘Systemic Diseases. The diagnosis of Iypus usually is determined by the presence of extrarenal disease (cg, arthritis or rash) and serologic find ings (eg, anti~double-stranded DNA. antibodies; Table 2). Nephrotic- range proteinuria and reduced GFR are indicative of a more severe pro- IMferative lupus nephritis. Renal bi psy is, however, necessary to dis tinguish the disease subtype in more severe forms,” and therefore is rec- ‘ommended in patients with lupus and decreased GER and/or ne- phrotic syndrome. Renal biopsy elu- cidates the degree of inflammation (Ge, assessment of disease activity and confirmation of diagnosis) and the level of fibrosis (eg, scarring or chronicity) 2 With clinical assess- ‘ment of extrarenal lupus activity these pathologic variables are use ful in guiding administration and withdrawal of immunosuppressive therapy. Purpura, arthralgias, and other signs of vasculitis in patients with glo- merulonephritis and low serum complement levels raise the suspi- cion of eryoglobulinemis, Patients ‘may present with clinical featuresas- sociated with glomerulonephritis or/and nephrotic syndrome, al- though the former is more com- ‘mon. Cryoglobulinemia (75%) and rheumatoid factor activity (70%) are frequently present; however, the lev- els fluctuate, and they may not be de- tcctable at inital presentation.” More than 80% will have reduced serum complement levels sometime dur- ing the course of disease, and C4and C2 complement levels may be mark- edly depressed. Pathologtcally membranoproliferative glomerulo- (aepRuy ED) ARGTINTERN MEDIVOL a] TAN ana WHWAR nephritis (MPGN) usually is pres ‘ent. Most cases of essential mixed ‘eryoglobulinemia and associated glo- merulonephritis are associated with hepatitis Cinfection,*™and the ma- jority of these patients have hepati- lis C RNA oF anti-hepatitis C ant- bodies in the serum.”* Therefore hepatitis C assays (ie, polymerase ‘chain reaction and antibody evalus- tions) should be performed in pa- lients with undiagnosed glomerulo- nephritis.” Liver enzyme levels and ‘other liver fanction tests may be nor- mal at disease onset" Charac- teristic lesions on kidney biopsy (eg, intraluminal thrombi or “fin- gerprint” pattern of the electron dense deposits) also should raise suspicion of hepatitis C-associated disease Primary Renal Diseases. Primary re- nal diseases associated with glomen lonephritis and low serum compl ment levels include acute post- infectious glomerulonephritis and id- lopathic MPGN (IMPGN). The former has been most extensively studied alter streptococcal infec tions, although the syndrome has been reportedalter other bacterial, vi- ral, parasitic, rickettsial, and fungal infections." Although IMPGN r. mains an important cause of glomer ular disease in children, the inel- dence of primary disease in adults has declined." Secondary forms of the disease may be associated with att- toimmune diseases, chronic infee- tions, microangiopathies, and para- protein deposition diseaces.”” Most patients with IMPGN have recur- rent bouts of glomerulonephritis (and/or nephrotic syndrome). By ‘contrast, with glomerulonephritisal- ter streptococcal infections, recov- ery (lack of progression to end- stage renal disease) is the rule. ‘especially in children (<2% progres sion to end-stage renal disease), and, thus the disease course is helpful in ‘confirming the diagnosis, Neverthe less, persistent urinary abnormali- ties may last for years, and a small percentage of adults develop slowly progressive renal failure.” For diag- nosis, repeated evaluation of serum ‘complement levels, determination of ‘autoantibodies to complement path= ‘way components, and renal biopsy findings re especially helpful in dis- Linguishing glomerulonephritis af ter streptococcal infections from IMPGN (fable 3). These serologic determinations are especially useful {msituations where the distinction be ‘ween glomerulonephritisalterstrep- tococcal infections and MPGN is dif ficult on clinical grounds alone (eg, where there is persistent oF recur rent disease). Acute Glomerulonephritis, With Normal Serum Complement Levels (One should initially consider glo- ‘merulonephritis associated with sys- temic diseases, then evaluate the pos- sibility of primary renal diseases (Table D. Systemic Diseases. Multi-organ in- volvement strongly suggests a sys- temic process, and typical symp- toms of an underlying disease may be useful in narrowing the diagnos- tic possibilities, eg, sinusitis, pul- ‘monary infiltrates (Wegener gram Jomatosis), pulmonary hemorrhage (Goodpasture’s syndrome), nau- sea, vomiting and abdominal pain, and purpura (Henoch-Schonle purpura). Serologte evaluation, in- cluding measurement of anti- neutrophil cytoplasmic antibodies (ANCA) and anti-glomerular base- ment membrane (GBM) antibod- fes, along with hepatitis serologic evaluation, is essential, especially for prompt diagnosis in patients with rapidly progressive glomerulone- phritis (RPGN), A few caveats warrant men- tion, Most patients with polyarteri- tis associated with hepatitis B or display normal or near-normal complement levels (80%); how- ever, decreased levels occur more frequently in patients with eryo- slobulinemia, The liver enzyme els and liver function tests may be normal at disease onset, although the serologic findings are typically posi- tive" Patients with hepatitis 6 and glomerulonephritis typically have positive findings for hepatitis Bsurface antigen and antibodies to hepatitis B core, and negative find= {ngs for antibodies to hepatitis B sur- face antigen in serum.” Among this group, the incidence of sys- temic involvement (ie, polyarteri- (©2001 American Medical Association. Al rights reserved, Downloaded From: on 0192/2018Table 3. Complement Levels and Kidney Deposits to Distinguish idiopathic Membranoprolferative Glomerulonephritis (MPGN) and Poststreptacoccal Glomerulonephrits (GN)* ostsroptosoeet om Tnmunotonesanee 196,62 C3 predominates Che 198,03 jor) ton dense Subendothal mesangial Dans BM deposits kaye. ‘Subendotl msangal deposits ‘ten kod BM subethall (humps). a Levee tute Posies ow Levee cute Loe for2-4 then noma co Nos oF dices mal Nm Ala ow nama ‘ater path). Paoantibodie CONE CaN NL cave caer Antisrptoccal anodes EH sd SS Se Na SE a ce me ec A eC a a a ar a rc oa So eT een ea eet ee me Ce ee aay et el hr ae oe oe oe ae oe ae erat steclsnn ha 'trieea shee: tis) varies widely by geography; from ney. Occasionally ANCA may be most all patients with idiopathic, as high as 84% im cities with in-_foundin patients with lupusnephri-—_patici-immune glomerulonepheitis creased drug use, to amuch lower is, although its significance is une have ANCA, however, 75% ofthis incidence in rural areas. Patients clear. group express pANCA.» In the elini- with glomerulonephritis associ- cal setting of RPGN, these assays are aed withabscessypically havenor- Serologic Evaluation, Use of the especially useful, with high positive ‘mal complement levels (unless there Kidney Biopsy in Clinical and negative predictive values fs endocarditis), and the ste of in- Practice, Referral to a (©0026). However, they have much {ction is usually apparent from the Nephrologist lower predictive vals in ther lini Ihistory and results of physical ex- cal setings (eg, hematuria oF none amination." The clinical presentation provides nephrotic-range proteinuria with nor- clues, but serologic testing facilic mal serum creatinine levels) and the Primary Renal Diseases. The clini- tates rapid diagnosis, especially in ulllity of ANCA vs other iniracell- cal presentation of IgA nephropa- patients without systemic symp-_larantigens i less clear. thy varies considerably (eg, asymp- toms. We recommend initially ob- Pathologie evaluation also is tomatichematuria, RPGN. nephrotic taining C3and C#levels.along with useful for rapid diagnosis, for dis- syndrome). Most often i Is idio- determination ofserum ANCA, anti~ _tinguishing primary renal diseases, puhie, although liver diseases the DNA, and anti-GBM antibody lev- and for determining disease seve most frequent association." Re- els (Table 2). The perinuclear ity." In most eases, systemic di nal biopsy is requited for definitive (pANCA)and eytoplasmic (@ANCA) eases associated with glomerulone- diagnosis paliernsofstainingfor ANCA should phritis are apparent from the clinical Rapidly progressive glomeru- be determined. These serologic presentation, and serologic testing lonephritis may be associated with _evalviations are especially impor- confirms the diagnosis. In some i= any formf glomerulonephrits,in- tant in patients with RPGN and stances, however theserologefind- chiding those associated with low should be determined immediately ingsare not diagnostic or not readily complement levels. Most patients, in this situation. The results may available, and histologie examina- hhowever, present without systemic obviate the need for immediate tion of the kidney is required. Al- symptoms and with normal levels Kidney biopsy. and theserologicre- though the pathologic findings are (95% have normal complement sults should dictate initial ther-__notalways diagnostic, they help to levels) The majority of patients apy.”*” Determination of hepatitis narrow the differential diagnosis with idiopathic RPGN are ANCA Serologies and evaluation of eryo- ‘The pathologie findings also are positive Less commonly 10%-20%), globulin Levels also should be pet helpfulin determining the degece of patients have ant-GBM disease (eg, formed. disease activity (eg, the level of in- linear GBM deposits and crescentic Patients with Wegener grant flammation of the extent of fibro- glomerulonephrits); occasionally lomatesisiypicallyhaveserumANCA sis), and this taformation may help {G%-10%), patients will have posi (B0%-95%), and the most common guide therapy Live findings for ANCA and antic pattern is ANCA, with antigente Renal biopsy may be espe- GBM antibodies" Thelattergroup Specificity for proteinase 3. Most of cally important for patients with 4s more likely to have vasculitis inthe restof the ANCA are directed at RPGN, where prompt diagnosis and organsotherthan thelungsandkid- myeloperoxidase (pANCA).”” Ale treatment are essential. For ex- (seputep) RGTNTEN HEDVOLIOL FE ar WW ARCHNTERNMED COM (©2001 American Medical Association. Al rights reserved, Downloaded From: on 0192/2018ample, ina patient with RPGN (cre centic glomerulonephriis) for whom serologic findings are not rapidly available, theabsence of immunede- posits (le, pauci-immune glomeru- onephritis) on evaluation of biopsy fs consistent only with vasculitis oF Wegener granulomatosis; anti-GBM disease (ie, linear immune deposits) and the major immune deposit-med- fated diseases are excluded by that finding. In this regard, ifsystemic vas calitis Is suspected, angiography or biopsy of other affected organs pro- vides a more specific diagnosis.” As ‘mentioned previously, the extent of disease activity in this situation is also useful in guiding therapy. Pathologic evaluation is also particularly helpful in diagnosing glo- ‘merulonephritis in patients with un- explained, acute renal failure, when the diagnosis is uncertain from the clinical findings. For example, in pa- tuents with progressive renal failure without significant urinary oF sys- temic symptoms, the pathologic find {ngs may be very helpful in confirm ing oF excluding a diagnosis. The results derived from the biopsy are also very useful in patients with slowly progressive renal failure due to glomerulardisease, where itis dil ficult to determine the level of dis- cease activity (eg, the extent of Nbro- sis and irreversible disease) from the clinical presentation alone.” For ex- ample, in some instances it may be difficult to distinguish disease sctiv- ity Ge, exacerbation amenable to fur ther immunosuppression) from pro- gressive bros, unassociated with a dlisease flare. Treatment in the latter situation would not be specific to the underlying disease, but it would in- clude control of systemic hyperten- sion (preferably by use of an angio- tensin-converting enzyme inhibitor) and hyperlipidemia. Nevertheless, the clinician must beaware of limitations of the use and {interpretation of the kidney biopsy results. Ifthe kidneys are small (eg, <9 em in length for a 70-kg pa tient), the risk associated with bi- opsy (ie, major bleeding requiring Wanslusion and other interven- tion) is increased, and the probabil- ity of obtaining clinically useful, di ‘agnostic information is substantially reduced.” In this setting, severeand. irreversible glomerulosclerosis and (aepniyTeD) ARGTINTERN MEDIVOL a] TAN ana WHWAR Interstitial fibrosis will be present, ‘whatever the underlying cause of the primary renal disease, and diagnos- lic interpretation will be limited. tervention is greatly reduced.” In situations where the patient is asymptomatic (eg, RBC and RBC ‘ass present on urinalysis, without systemic findings) and the GFR is normal, the physician should ob- serve the serum creatinine level closely over time, while proceeding ‘with the evaluation. We emphasize that in cases ofisolated hematuria (ie, ‘without casts or proteinuria), the source of bleeding from other sites ‘within the urinary tract (eg, blad- der, prostate, or ureters), should be explored by means of visualization of the kidney and the collecting sys- tem (ie, cystoscopy and intravenous pyelogram and/or computed tomo- ‘graphic scan). Depending on the re sults, renal biopsy may be per~ formed to confirin oF elucidate the diagnosis of glomerulonephritis and to determine the level of disease ac- Livity. Sometimes, lack of abnormal Lindings on histologic evaluation is helpful in excluding a renal cause of the bleeding. The urgency for referral toa ne phrologist for further consider- ‘ion and renal biopsy depends on the GFR. For example, in situa- lions where there are isolated uri- nary abnormalities, history and physical examination are unteveal- ing, and serum creatinine level is normal and stable (ie, <88 4 pmol/L. [1.0 mg/dL] in a 70-kg man), pro- ceed with the serologic workup ‘while closely monitoring renal func tion, belore consultation, consider- ation of biopsy, and treatment. How- ever, if the GPR is abnormal or rapidly deteriorating, or i there are systemic symptoms, immediate con- sultation (ic, that day) is advisable for clinical decisions regarding treal- ment, biopsy, need for dialysis, ete NEPHROTIC SYNDROME Nephrotic-range proteinuria in adults is defined as urinary excre- lion of more than 3.5 g protein per 1.73 m’ in 24 hours, Although an ar- bitrary definition, persistent pro- teinuria at or above this level ust- ally leads to hypoalbuminemia, resuling in edema, Furthermore, we hhave known for more than 20 years ‘that patients with urinary protein ex cretion rates of less than 2 g/d have 1 better prognosis.© The clinical complex referred to as nephrotic syndrome results from heavy pro- teinuria and includes edema, bypo- alburninemia, hyperlipidemia, and lipiduria. Many factors influence the onset and severity of edema, includ {ng the degree and duration of pro- teinuria, the serum albumin lev. the patient’s underlying renal dis cease (ie, sodium retentive state and, renal function), dietary sodium in- take, accompanying cardiovascular and liver function, ete. The pres- fence oF severity of nephrotic syt drome does not predict the under lying pathological disturbance, and the syndrome can be due to a pri- ‘mary renal orasystemic disease. The incidence of diseases associated with, the nephrotic syndrome varies mark- edly with age, thus providing im- portant diagnostic information. | ‘most children and adults, the ii tial manifestation of disease is pe- ripheral edema. The elderly (aged. >05 years) may be misdiagnosed with congestive heat failure. Many patients are asymptomatic Systemic Diseases Initial diagnostic evaluation in- cludes consideration of systemic di ceases and drugs; the most common associations are listed in Table 4. Diabetes mellitus is the most com- ‘mon cause of nephroticsyndrome in adults in the United States.*" Ap- proximately one tied of patients with, juvenile-onset (type 1) diabetes melli- ‘us develop nephrotic syndrome, pr dictably leading to renal falureand. recent evidence indicates that there fs genetic suscepubility tothe devel- opment of nephropathy.*" In pa- tents with type 1 diabetes mellitus in whom nephropathy develops, the natural history ofthe disease is fairly predictable and has diagnostic ut ity. Asymptomatic microalbumin- uria, the initial manifestation, oc- curs 5 0 10 years into the illness; overt proteinuria (0.5-3.0 g/d) 0c ceurs 13 to 20 years alter disease on- set, and nephrotic-range protein- ria (>3.5 g/d) developsa few years (©2001 American Medical Association. Al rights reserved, Downloaded From: on 0192/2018Table 4, Major Causes of Nephotic Syndrome Primary renal dseses Martrane nephropathy (A) (3%) Feoal lomrdostleai (FSGS) (2%) gh nephropathy (lg) (1%) Minimal change ese (MCD) (15%) Miranoproleaiveglomerulonephrtis (MPGN) 25%) Oar 6, porate lomerlngphis) (5-7) ‘Systemic diseases" Datetes -Amylioss Stam pus erythematosus Dysprotinanias Mutipa myeloma Inmunctctodintary glomerlonepitis pit chin-depostion disease Heavy chain- deposition disease Inectone Human immunodstieny virus disease (6) Hepat B (uN) patti (MPG) Sypis (aN) Neda (aN) Satosomise (MN) Tuberelss (yl) Leprosy tt) Malignant ope Sold adenocarcinomas, ong, rss, clon (Mt) Hodakinymphoma (MCD) (ther malar neoplasms Drugs or oxins ‘Nonstaria n-infmmatory dogs (MCD) ald a) Piclaine (MN) Probnec (A) Merciry (Mt) Capp Ober Proedampsia Chron allegra Bes tng erin inatenus, F868) Heroin (sn poppers” aoc) \escourteral tox FSS) = Lesions tat see primary olomeuar diseases are ndeatedn parentheses: Table modified with permission rom Koenig ar Baton" thereafter. The period between onset of microalbuminuria and renal failure can be extended by rigorous control ‘ofblood glucose leveland blood pres- sue, use of angiotensin-converting enzyme inhibitors, and, perhaps, e- striction of dietary proteinand reduc ‘don of hyperlipidemia." Neverthe- less, progression toend-stage renal fail- ure Is fairly predictable within a few yeatsalter the onset of nephroticsyn- drome.” In patients with type 2 dia- betes mellitus, the prevalence and expression of diabetic nephropathy are more variable, as the nephropathy {s often complicated by hypertensive and atherosclerotic disease in older patients.” (aepnuy ED) ARGHINTERN MEDIVOL GIANT Diabetic retinopathy i use marker of diabetic nephropathy in pac tients with nephrotic syndrome, es- pecially im patients with type 1 dia- betes (290% of patients with nephropathy have reuinopatly) mie ‘rovascular disease inthe retina is in- dlicative of diabetic nephropathy and usually precedes it" Fluorescein at lography is necessary to adequately evaluate the retinal microvascula- ture, and it should be performed in patients with diabetes and protein- tria when the diagnosis is nce tain. Nevertheless, retinopathy is less predictable in patents with ype 2di- fase and proteinuria (approximately 50%-80% will have diabetic le- sions), and those without retinopa- thy are more likely to have nondis- betic glomerular disease. We reserve renal biopsy for diabetic patients with, nephrotic syndrome with atypical history, examination results, orclini- cal course for diabetic nephropathy (eg, early-onset renal failure, rapid progression of renal failure, lack of evidence of microvascular disease clsewhere, of evidence of avert glo- ‘merulonephritis) Nephrotic syndrome in pa- ‘dents with lupus nephritis is most of ten indicative of a severe prolifers- live of inflammatory lesion.2°* However, some patients develop non- inflammatory, membranous, lupus lesions and present with a normal GERand heavy proteinuria, Acute re nal failure for another reason (eg, use of nonsteroidal anti-inflammatory drugs or interstitial nephritis) ina pa- ent with membranous lupus ne- phropathy may confuse the situs- tion.” As discussed previously, loss of autoantibodies inthe urine can te sult in negative serologic findings and delay diagnosis. However, de- pressed serum complement levels ‘or/and other clinical features of sys- temic lupus should raise suspicion of this disorder, Pathological evalua- tion of the kidney is necessary for determination of disease activity and the extent of fibrosis, Less common- ly, nephrotic syndrome has been as- sociated with other rheumatologic diseases'?= (Table 4). Amyloidosis and the dysprotein- cemias should he considered in pa tients older than 40 years, although ‘most patientsare older than 50 years. Eighty percent of patients with amy- loidosts have proteinutia, and the n phrotic syndrome oceurs inabout one third.” Amyloidosis may be idio- pathic orassociated with multiple my- cloma, long-standing rheumatoid ar thrti, or chronic infections, although. the latter are much less common in recent decades." Most patients with, amyloidasisin the United States have immunoglobulin light chain-asso- ciated disease.” Accompanying sys temic symptoms (eg, fatigue or ‘weight loss) and/or cardiac involve- ‘mentare common, although other or sgans may be allected. A monoclonal spike is found in the serum or urine by electrophoresis in more than 80% of proteinutic individuals and more (©2001 American Medical Association. Al rights reserved, Downloaded From: on 0192/2018than 90% of patients with nephrotic syndrome; approximately 20% of these paticnts will have free light chains." The yield of abdominal {at-pad biopsy ts approximately 75% Jn this group, and the procedure should be performed in paticnts older than 40 years with unex- plained proteinuria.” Skin, gingi- Wal, and rectal biopsy Findings are less sensitive, unless there is overt clinical involvement.” Results of bone marrow examination may dem- onstrate evidence of monoclonal e- Other related disorders, nelud- ing tmmunotactoid and/or fibril lary glomerulopathy and heavy chain-deposition disease, may pre- sentasnephrotie syndrome (with or without progressive renal failure) These entities are dificult to diag nose on elnical rounds alone, and renal biopsy is requited for disgno- sis." The size, shape, and nature of the immune deposits and miero- Iibrils distinguish these entities from amyloid deposits and each other: Recognition aftheassociaion of nephrotie syndrome with infections hhas been rekindled with the epi- demic of acquired immunodeli- ciency syndrome (AIDS). Pa- tients With AIDS may present with a variety of nephrologte syndromes CFable 5). The varied clinical pre~ scntations and pathologie entities ob- served in these patients likely reflect diferencesin pathogenesis and host response to vital infection. Renal in- volvement may occural any sage of infection, although the entity oe- cursmore commonly in patients wath cslablished AIDS. The pathologic ab- ‘Table 5. Human immunodetcieney Virus Glomerulopathies” eval abnormaites cinial Fetes F505 (clapsng mare common) Prosiura Nephi syndrome Progressive eal insuteiency HusrTerTMA, Progressive eal insuteiency Micreangpathic amo anaria Trombocytopeia Sjtomic ivohment (og ceil neva yee) longs ‘cut glrarlnephiis Prodominany IgA andar gS deposits Membranous Ph ‘Associate wih hepatitis 8, hati C Syphis sescn Postinlectous gomerdonophiis, associated vith Btn ar ter atone F868 indeates focal semen lomerdosclerost HUS bem uemie syndrome TTB ‘trombote thamboeytopet pura: THA, tronbotc mioangograpty I mmundgiobuln; MPG, !nemvanoproltatneglomesuonepnits: and APSGH.glamenionepits afer steptococalinecn, Gla presenttan may be complete by arugnduced disease o. leated creatine ee! Secondary to ethoprinsulmethoazae on oer aepr atx) andr te pesence of fubutnesl seas cling acute tubular necrsis). proteinuria should raisesuspicionof _edemaand heavy proteinuria.” The the diagnosis." Less common forms cause of these entities is uncertain, of glomerulopathies associated with although circumstantial evidence of HIV include IgA deposition, micro- an immune-mediated pathogenesis angiopathy, and acute renal [ail- exists in most instances. The terms ture Regarding the later, renal bi- used to eategorize these patients re- ‘opsymay benecessary todistinguish fer tothe typical pathologie descrip- theeause ofaculerenal{ailureinthese on of the light microscopy find- individuals. Otherinfectionsassoci- ings of kidney tissue (Table 4) atedwith thenephroticsyndromeate Accordingly, histologic evaluation of jiven in Table 4." kidney biopsy specimens is re- ‘A variety of neoplasms and quired to make a definitive diagno- drugs have been linked to the ne- sis, These lesions ustally are indis- phrotic syndrome; the more com- _nguishable from those of patients mon pathologic associationsare in-_with systemic diseases. Infact, kid- dicatedin Table4""" In mostcases, ney biopsy specimens [rom pa- the neoplasm is obvious from the tients with systemic diseases fre- history and results of physical and quently are categorized as having laboratory examinations, although “disease like” the idiopathic varie- oceasionally the nephrotic syn- ties (ie, membranous-like or mini- 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 glomerulosclerosts.®° most common drugsassociated with on of the abnormality using re- Amore severe form, termed collaps-__the nephrotic syndrome, probably sults of kidney biopsy has utility in ing glomerulopathy,morecommonin the result of their widespread use. classifying the disease and in pre- patients whoarescropositiveforhu- With drug-induced disease, deter” _dicting outcome and response to ‘man immunodeficiency virus (HIV), mining causality may bedifficult,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." Ithasbeen postulated that ation of use of the offending agent. syndrome HIV infection of renal cells (eg, me- sangial or epithelial) contributes 10 Primary Glomerular Diseases Because of these considerations, our fibrosis and the more rapid progees- recommendations for the initial sion torenal failure observedin these Idiopathic nephrotic syndromes the workup of adults with nephrotic patients." Urinary protein excre- term used to describe nonsystemic syndrome are outlined in Table 6. tion can exceed 20 g/l 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 ton. Patients typically present with diagnostic evaluation and subse- (nEPRINTED) XRCHINTERN MEDIVOL eT, JAN DOT WWW ARCHINTERSOIED COM (©2001 American Medical Association. Al rights reserved, Downloaded From: on 0192/2018biopsy findings also provide prog- nostic information, thereby influ encing therapeutic decisions.” Thus, History wwe recommend renal biopsy when Fay story and history of rug seo toxin exposure hedingnosisleunceruinr knowl, Physical xaination It patient >60 y, usual ecammendations for age, including stool examination ‘edge of the severity of disease will Tabl atlon of Nephrotie Syndrome in Adults* Uhamocet esting 3) influence therapy. Nevertheless, if sto examinations negate, perform fable sigmoidoscopy the probability of a specific disease tol saminabon is pst, prfrm stands seinen! at workin for group of diseases is high, the risk Laboratory ting of complication due to biopsy is, ‘Compl taod cl count meseurement of setumeresnin, los, enzymes, tte igh wed the sake ot ahersty a dehydrogenase, allaine phosphatase and lure pd pote, and chest ay eae cca pear reasonable (eg, short course of uoresoin agasapy (for diabetes melts) high-dose oral steroids), then em- ‘Artin anibdis (er sytem lupus exythaatoss) pirical therapy without biopsy Consider malignant neoplasms, e, amy o ih chin disease or myeloma Should be strongly considered Em- Nether patient >$0y orl eatin aes suspicion peta pirical use of steroids in children Sot po cpa an With minimal-change disease ls in pain scope good example ofthis approach, Aantal pel pay ‘As noted inthe discussion of consis ein slomerulonephrits, pathological Pate a pat B, mas moder vi slog ing Erliaton of te kidncy also has ul- iyindefining the dsease subtype and fant determining the severity of dlsease Tedstguch nay mera exse e y Ferg unsspcn cnn Goer Ste The results of renal biopsy are also cz ami) ‘ery helpful when atemplingtosor Toddrane dae sey but the poten contribution of2 or tore diseases. In this regard, iis ei orp ete, pai fr ae case eae 6 2 oth seevctinees teat to dcterene whether acuity of the underlying Table 7 her Consideration inthe Diagnosis dlsease of aupetimpestion of ane of Glomerular Diseases” other primary disease the case of ia in ner or ample nephrove sjdtone ape “ipl na ats ce tiene with wellcontrolled diabetes Family tory, males savy atta hs hy or other ale airs develop hematuria Bt trl are ee ee ee ee Paee cree eg eae ee festations of microvascular disease “ype ealagen abner oped assembly of 3) (2) anda) alan Patani wh have wdegone vanslartaton ay eto rit-lomarurbaseert should raise suspicion of another imembrance (ype 3] colgen) cause. The pathological results of ten are very helpful in the seting of rapidly progressive renal failure in an Ce V-seropostive patient; this clini- ‘Auoenbodes tonto of en Wilebran fate clang protease HIV seropositive patient this cl Fant cal presentation should evoke a di- Dancy of von Ween fable prtast agnostic workup for other causes of slomerular disease Homo uremic syndrome! Thvombotethomtoeytopnic purpura RENAL DISORDERS THAT See MASQUERADE AS ACUTE GLOMERULONEPHRITIS AND/OR NEPHROTIC. eat tubular necraie SYNDROME Insta episod induced) teroomboli renal disease Patients with the diseases listed in Table 7 may present with signifi- cant hematuria, RBC casts, and/or ne «Previous istry of severe yertension rbyperesie retnopthy. system atures (rash ats) orassocdted complications lading to dsemnated avascular coagulate, Ss) may ‘be help in distinguishing from glomerlonephitis. phrotic-range proteinuria, thus mim- fcking acute glomerulonephritis oF quently refer the patient to a ne- mal, the patient most likely has nephrotic syndrome. These condi- phrologist to assist with manage-idiopathienephroticsyndrome. The ons should be considered in pa- ment. Further evaluation (and results of the kidney biopsy distin- tients without an obvious disease as- therapy) should bedriven by there-_guish among primary renal dis- sociation. Theclinical history, results sults of the initial studies. I'he 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- (nepRINTED) XRCHINTERN MEDIVOL oT, AN DOT WWW ARCHNTERSOIED COM (©2001 American Medical Association. Al rights reserved, Downloaded From: on 0192/2018nga differential diagnosis, Renal bi opsy, however, often is necessary 10 make a precise diagnosis. CONCLUSIONS arly recognition and prompt diag- nosis of glomerular disease are es- sential, because delay in therapy may result in irreversible loss of renal function. The clinical presentation (eg, nephritis vs nephrosis, normal vsabnormal GFR, orsystemie symp- toms or lack thereo!) provides clues to the underlying cause. Serologic evaluations and repeated measure- ment of serum creatinine levels should be performed in all patients for diagnosis, 1o determine disease severity and monitor disease pro- gression, Renal biopsy'should be per formed when either rapid diagno- sis is essential, the presence of smuliple diseases contributing to the clinical picture confounds diagno- sis, and/or the level of disease activ- ity requires pathological determina ion, Collectively, this diagnostic approach provides rapid evalua- tion en route to specific therapy Accepted for publication July 20, 2000. This work was supported by _grant DK45191 from the George M. OfBrien Kidney and Urological Re- search Center, Public Health Service ‘awards DK 33694 and AI27915; the DCI RED FUND, the Lupus Founda tion of Philadelphia and the Philadel- phia Chapter of the American Heart Association, Philadelphia, Pa, We thank Ajay Singh, MD, for careful review of the manuscript and constructive criticisms. Corresponding author and re- prints: Michael P. Madaio, MD, Uni- versity of Pennsylvania Medical Cen- ter, Renal Electrolyte and Hypertension Division, 700 Clinical Research Bldg, 415 Curie Blvd, Philadelphia, PA 19104-6144 (e-mail: Madaio® mail ‘med.upennedu). SSS 1. anc BM, Hoste Ty, Hume DH Malu lartasisotpetsruat gamer ogi. WE ‘e978 208 22688, 2. hadron ,Poinua. n renbeg Ao Primer on Kay Disease. rand, a: Re ei Paes Ie 19084246, 8. ane ison Gabba, aptly (aepnuy TED) ARGHINTERN MEDIVOL ISIN OT a 2 a a fet lomarinjuy. Meson, Causa WG, es. mmunologe Renal Diseases Pi Sofa, Pa: Uppnent avn ubshars 107 2-280. Cuser WS Median larry. JA Ste Mei 100011828 oon aodpasure'syconsNepholapy Forum), Kia lot 109530 75178 Rotnson RR. sot pron gyno ‘spain e180 1895-408 Fed LG. ae WR are LM, Joseph 8, Hams ‘wri aneertdedialandsurgesppan, Padar ahaa Am 157 AC 91-210, Kahin CE. Hamat In: Greenbrg A 0 Pima Kay Diseases, anda Fa: Aa dae Pes ng 0063641 Kasih 2S. 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An J Key is ‘aoe (Aga Apa 8, Ral pata of hanan inanodtnz vis incton Semi etal {est8a0621 Sruggeman LA Osan, Mang, Quaggn SE Cotman TM, Reiman PE. Mephrapthy man inmuneetiengy vist wane mice Is dst rend range expression. Ci est 1o7-00a4.02, 49, Haring JT CP: clapsing glomerdopaty Hole Merl 00681617. 40, Ales CE, Catan Seopa nf lamerar ig. i In. 1986.30 465-4. (Cours WG, Aer CE Memtaraus eprops thy Maan ES, Couser Ws. Immuno ap Renal Dasa: Pisépia Ppa vn Pabishas 197 02-1065. 2. Kasha CE, Mich AF Apr syarome Ki ay In 0665014451058. 6, Flan Rae Sorehaer Mk Lami B.A (©2001 American Medical Association. Al rights reserved, on 0102/2018 red decane ven Werden Ingprotasen pater wih froma hombo- ‘ype pupa Bod 126 2030246, Furano, Gabon le ear ‘ac-lnrgpetsintvombat voor peicpupuaardtadiewenesjtone Ng ea 106,30 57-128