hritis (APSGN) are 2 common causes of ac-uired renal disease in the pediatric population.imultaneous development of these disorderslinically and/or histologically is rare, but haseen reported in the literature.1-5 The nature ofhe interaction between these 2 disease processess unclear, as are potential predisposing factors.
e present the case of a 5-year-old boy with theimultaneous occurrence of both disorders anduggest a possible pathogenic risk factor.
CASE REPORT
A 5-year-old boy with a history of mild reactive airwayisease presented to a local emergency department with a0-day history of an upper respiratory tract infection, an-rexia, vomiting, decreased energy, and headache. Thereas no history of diarrhea. Oliguria and dark urine devel-ped 3 days before admission. On initial evaluation, he wasound to be hypertensive, anemic, and thrombocytopenicnd was transferred to our institution for further evaluationnd management. Vital signs showed a blood pressure of60/120 mm Hg. Physical examination was remarkable forallor, abdominal and lower-extremity petechiae, and mildacial edema. His father had died of a myocardial infarctiont 46 years of age. There was no family history of renalisease or thrombosis.Initial laboratory evaluation showed the following values:
ic antibody, and anti–glomerular basement antibodies werell negative. Coagulation studies showed normal prothrom-in time, partial thromboplastin time, fibrinogen level, andhrombin time and an elevated d-dimer at 7.9 �g/mL (nor-al, �0.5 �g/mL). Urine showed 2� blood, 3� protein, and
ctive sediment with erythrocyte, renal tubular, leukocyte,yaline, and granular casts present. A renal ultrasound showednlarged echogenic kidneys with a normal Doppler evalua-ion. He underwent hemodialysis on admission, receivedacked red blood cell transfusions, and, subsequently, a
enal biopsy was performed.
merican Journal of Kidney Diseases, Vol 47, No 2 (February), 20
ular glomeruli. The majority had global endocapillary pro-iferation with exudative infiltrates that obscured capillaryumens; cellular crescents occupied Bowman space in ap-roximately 40% (Fig 1). Others had moderate mesangialypercellularity associated with focal mesangiolysis, ectaticlood-filled capillary lumens, occasional fragmented eryth-ocytes, and few fibrin thrombi, either in peripheral capillar-es or, uncommonly, at the hilum. Rare necrotic lobules wereoted. Occasional glomeruli possessed features of bothrocesses. There was mild edema without significant fibrosisnd patchy lymphoplasmacytic infiltrates in the interstitium.any tubules were filled with erythrocytes or protein casts
nd lined by mildly vacuolated and attenuated epithelium.Immunofluorescence staining on frozen sections showed
oarse granules along the peripheral capillary loop positiveor immunoglobulin G (1�) and C3 (4�) that also stronglytained the mesangium. Granular immunoglobulin M (1�)taining of the mesangium was noted. Fibrinogen was presentn Bowman space associated with crescents, but not readilyetected in the glomerulus. There was no staining withntibodies directed toward immunoglobulin A, C1q, or C4.
Electron microscopic analysis showed occasional glomer-lar hump-like subepithelial electron-dense deposits pluscattered small subendothelial deposits (Fig 2). Capillaryumens were narrowed by subendothelial flocculent materialnd markedly swollen endothelial cells. Foot processes ofisceral podocytes were diffusely effaced. The mesangiumas hypercellular, and mesangial interposition was focal.athological findings were interpreted as postinfectious glo-erulonephritis with thrombotic microangiopathy.
ollow-UpThe patient received pulse methylprednisolone therapy
or 3 days, followed by a slow taper of oral prednisoneosage for approximately 8 weeks. He required intermittentemodialysis therapy and antihypertensive medications for
University of Washington and Children’s Hospital andegional Medical Center, Seattle, WA.Received June 2, 2005; accepted in revised form July 22,
005.Originally published online as doi:10.1053/j.ajkd.2005.07.052
n December 28, 2005.Address reprint requests to David Simon, MD, 4800 Sand
weeks. Lactate dehydrogenase levels normalized within 3onths. C3 and C4 levels returned to normal 5 weeks after
resentation, with levels of 133 and 25 mg/dL (1.33 and 0.25/L), respectively. Because of the known association be-ween low serum C3 levels and factor H deficiency in aelect subset of patients with atypical (diarrhea-negative)US,6 the patient’s factor H level was measured and found
o be normal. The patient’s strong family history of earlyyocardial infarction combined with the unusual presence
f microangiopathy in a biopsy specimen obtained from aatient with APSGN led to a suspicion that he may have annderlying hypercoagulable state. Evaluation of several co-gulation proteins was performed. These studies showed aeterozygous factor V Leiden mutation and factor VIIIctivity level elevated at 158% (normal, 50% to 150%). Heever had an episode of clinically overt thrombosis. Seven-een months after presentation, his creatinine level is 1g/dL (88 �mol/L), and he still requires amlodipine, labe-
Fig 1. (A) A hypercellular glomerulus has endocapobular configuration and often obscures peripheraapillaries in this moderately hypercellular glomerulurteriole (arrowhead). Fragmented erythrocytes are evi400). (C, D) Some glomeruli showed features of micro
left and lower) have neutrophilic infiltrates and anuadrants have congested capillaries and focal mesariginal magnification �400.)
alol, and enalapril for blood pressure control. s
DISCUSSION
This patient presented with several classiclinical features of APSGN, including an anteced-nt upper respiratory tract infection, gross hema-uria, oliguria, and hypertension. He lackedloody diarrhea associated with typical HUS, butad several laboratory findings indicative ofhrombotic microangiopathy, including microan-iopathic hemolytic anemia and thrombocytope-ia. Although this is an unusual presentation,imilar cases have been published previouslyTable 1). A unifying pathogenetic mechanism isnknown, although 1 hypothetical paradigm ishat thrombotic microangiopathy occurs as a
roliferation and an exudative infiltrate that imparts alaries (trichrome; original magnification �400). (B)distended with blood. Fibrin fills the lumen of a hilarrrows) (hematoxylin and eosin; original magnificationathy and APSGN. The markedly hypercellular lobules
nt cellular crescent (arrows), whereas the oppositesis (hematoxylin and eosin, Jones methamine silver;
illary pl capils aredent (aangiopadjace
econdary manifestation of endothelial injury
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SUBEPITHELIAL HUMPS AND MICROTHROMBI 367
nduced by severe hypertension caused byPSGN.2,3,5
The family history of early myocardial infarc-ion in this case led to further investigations forenetic risk factors associated with hypercoagu-ability. The finding of a heterozygous factor Veiden mutation is unique among reported pa-
ients with simultaneous APSGN and HUS, al-hough these data were not reported for the otheratients. Could this mutation be an unrecognizedisk factor for the development of thromboticicroangiopathy in a patient with APSGN? We
re aware of only 1 other report in the literaturef a patient with atypical HUS and a factor V
Fig 2. Electron microscopic findings. There is difndothelial cells that narrow the lumen. Occasionalarrowheads). Large subepithelial humps are focally pr
Recent work identified the nephritis-associ-ted plasmin receptor (NAPlr) as a dominantephritogenic antigen in patients with APSGN.8
his antigen, which is identical to glyceraldehyde--phosphate dehydrogenase of group A strepto-occus, has been postulated to stabilize plasminctivity and trigger an enzymatic cascade involv-ng the activation of metalloproteinases and sub-equent damage to the glomerular basement mem-rane (GBM) and podocytes in patients withPSGN9 (Fig 3). Diagnostic renal biopsies usu-
lly are restricted to patients with atypical mani-
odocyte foot-process fusion and markedly swollensubendothelial electron-dense deposits are presentnt (arrow).
fuse p
estations of APSGN because the clinical presen-
Table 1. Clinical Characteristics of Previous Case Reports
Features Current ReportDe Chadarevian
et al1 Laube et al2 Laube et al2 Tan et al3 Medani et al4Proesmans
et al5
Age (y) 5 5.5 12 6 10 13 14Sex M M M F F M MInitial findings
NOTE. To convert serum creatinine in mg/dL to �mol/L, multiply by 88.4; albumin and hemoglobin in g/dL to g/L, multiply by 10; C3 and C4 in mg/dL to g/L, multiply by 0.01.Abbreviations: ND, not done; RBC, red blood cell; WBC, white blood cell; HPF, high-power field; ASOT, anti-streptolysin O titer.
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SUBEPITHELIAL HUMPS AND MICROTHROMBI 369
ation, positive streptococcal serological studyesults, and time-limited hypocomplementemiaake it possible to presumptively diagnosePSGN in most patients. Fibrinogen depositionas been observed along the endothelial aspectf the GBM in 60% of renal biopsies performeduring the acute phase of APSGN.8 Recent worky Oda et al9 identified intraglomerular plasminctivity in the kidneys of patients with APSGN,ut not in normal control kidneys. Although thislasmin activity may promote protease-depen-ent damage to the glomerular capillary wall,oth directly and indirectly through activation ofatent metalloproteinases, plasmin activity alsoay enhance the recovery process through itsbrinolytic activity. Release of fibrin into Bow-an space is thought to recruit macrophages and
ontribute to the formation of crescents, as ob-erved in 40% of our patient’s glomeruli. It islausible that his factor V Leiden mutation led toore aggressive fibrin deposition within the glo-erular capillaries in response to subendothelial
mmune complex deposition and/or hypertension-nduced endothelial damage. Although large sub-pithelial immune deposit “humps” are consid-
Fig 3. Proposed pathogenetic paradigm. The NAPlrte to podocyte and GBM damage by concentrating plahe NAPlr antigen deposits on the subendothelial asplong the glomerular capillary wall and prevent the abrinolytic activity. In the presence of a hypercoagulabmicroangiopathic process.
red a hallmark feature of APSGN, subendothelial m
eposits often are detected when renal biopsiesre performed during the early phase of theisease.This patient had atypical HUS. Although sev-
ral predisposing factors have been implicated inhe pathogenesis of atypical HUS, most geneti-ally determined factors involve abnormalities inhe complement cascade, especially low levels ofactor H. Although factor H level was normal inhis patient, we cannot rule out the possibility ofn anti–factor H antibody leading to depressedactor H activity, which has been detected in 3atients with atypical HUS.10 Although this pa-ient’s glomerular C3 deposits were impressive,his is an expected finding in patients with uncom-licated APSGN. NAPlr itself is known to acti-ate the alternative complement cascade in vitro.8
Because the risk for thrombosis is increased 5-o 10-fold in a patient with heterozygous factor Veiden mutation,11 it is possible that his natu-
ally enhanced propensity for thrombosis couldave triggered a unique interaction not usuallyeen in patients with APSGN who have a normallotting cascade. It is tempting to speculate thatn patients with typical APSGN, localized plas-
n deposited in the subepithelial location may contrib-nd collagenase activity in the area. Conversely, whenthe GBM, it may serve to enhance protease activity
lation of fibrin strands caused by enhanced plasmine, local plasmin activity may be inadequate to prevent
antigesmin aect of
ccumu
in activity trapped within the subendothelial
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SIMON, FINN, AND EDDY370
pace by the NAPlr antigen efficiently degradesmall fibrin strands before microangiopathic in-ury can develop (Fig 1). When fibrin depositions more aggressive, as in the case of factor Veiden mutations, local plasmin activity may beverwhelmed and thrombotic microangiopathynsues. Whether similar prothrombotic risk fac-ors may have accounted for the simultaneousccurrence of APSGN and HUS in the otheratients is unknown.Factor VIII levels also were transiently el-
vated in this patient during his acute illness.edani et al4 reported an elevated factor VIII
evel in their patient and postulated that thislevation could be a marker of severe endothelialnjury that initiated platelet aggregation and eryth-ocyte fragmentation. Based on the current case,t seems reasonable to suggest that when a pa-ient develops renal disease with features of bothPSGN and HUS, a workup for evidence of annderlying hypercoagulable state should be con-idered, including evaluation for factor V Leidenutation, prothrombin mutation, and antiphos-
holipid antibodies, as well as abnormal levels ofrotein C, protein S, and antithrombin III.In summary, recent studies showed that
PSGN is characterized by the deposition ofAPlr along the glomerular capillary wall ande novo generation of intraglomerular plasminctivity. Although such activity may have a rolen the pathogenesis of glomerular injury in pa-ients with APSGN, the associated features ofxtensive glomerular fibrin deposition and throm-otic microangiopathy in our patient in the facef factor V Leiden mutation suggests a poten-ially protective role for the NAPlr-plasmin inter-ction by preventing fibrin accumulation in thelomerular microcirculation and subsequent in-
ury caused by thrombotic microangiopathy. This a
athogenetic paradigm remains hypothetical un-il further studies are performed in the uniqueetting of patients who develop HUS in associa-ion with APSGN.
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