a total of 565 cases with diagnoses of igan in native kidneys were retrieved from the renal biopsy registry of the department of pathology , yonsei university health system , between 1999 and 2008 . among these
, 92 cases were diagnosed as igan , subclass ii , according to the haas classification .
the exclusion criteria included ( 1 ) significant glomerular mesangial proliferation of more than three cells in one mesangial area distant from the vascular hilum in 23-m - thick periodic acid 
schiff ( pas)stained sections ; ( 2 ) endocapillary proliferation ; ( 3 ) global glomerulosclerosis or tubular atrophy of 40% or more ; or ( 4 ) insufficient sample size of less than six glomeruli on light microscopy . for comparison , age- and
gender - matched idiopathic fsgs cases from the same period were collected from our renal biopsy registry .
all biopsy samples were examined using light , immunofluorescent , and electron microscopy . for light microscopic examination ,
23-m - thick sections were stained with hematoxylin and eosin , pas , aldehyde fuchsin orange g , and methenamine silver methods .
two to four tissue sections were mounted per glass slide , and two slides were prepared for each stain , resulting in eight slides for each biopsy . for immunofluorescence examination ,
snap - frozen 3-m - thick sections were mounted in optimal cold temperature compound and stained with antibodies against igg , iga , igm , c3 , c4 , c1q , and fibrinogen ( dako cytomation , glostrup , denmark ) . for electron microscopy
, fresh renal tissue was cut at the time of biopsy , and one to three blocks of 1 mm renal tissue were double fixed with glutaraldehyde and osmium tetroxide , routinely processed , and stained with uranyl acetate and lead citrate .
an average of 26.7 consecutive sections ( range , 18 to 32 ) were examined in each case .
the segmental sclerosis was subtyped in each case as classic , perihilar , tip , cellular or collapsing variants and were numbered . in segmental sclerosis , capillary adhesion to bowman s capsule with or without aberrant vessel formation was also counted . to validate aberrant vessels , we followed afferent and efferent arterioles in the vascular poles and confirmed that there were no direct connections between vascular poles and presumed neovessels .
the other histologic parameters that we evaluated were type of glomerular crescent , percentage of global glomerulosclerosis , degree of tubular atrophy , interstitial fibrosis , and interstitial inflammation , and presence of arteriolar hyalinosis and arteriosclerosis .
crescents were defined as extracapillary proliferations of at least two layers that occupied at least 10% of the circumference .
the degrees of tubular atrophy , interstitial fibrosis , interstitial inflammation , and arteriolar hyalinosis were semi - quantitatively scored according to the banff 97 criteria .
patient age , gender , serum creatinine level , hematuria , and proteinuria level at the time of biopsy were obtained from the patient medical records and biopsy requisition forms .
proteinuria was evaluated in 49 fsgs - like igan patients and in 45 idiopathic fsgs patients by 24-hour urine collection or random urine protein to creatinine ratios .
comparisons of the frequencies of segmental sclerosis , tuft adhesion to bowman s capsule , glomerular hyalinosis , and aberrant vessel formation between fsgs - like igan and idiopathic fsgs cases were performed using the mann - whitney u test .
tubulointerstitial and vascular changes were compared using pearson s chi - square test combined with fisher exact test .
a total of 565 cases with diagnoses of igan in native kidneys were retrieved from the renal biopsy registry of the department of pathology , yonsei university health system , between 1999 and 2008 . among these
, 92 cases were diagnosed as igan , subclass ii , according to the haas classification .
the exclusion criteria included ( 1 ) significant glomerular mesangial proliferation of more than three cells in one mesangial area distant from the vascular hilum in 23-m - thick periodic acid 
schiff ( pas)stained sections ; ( 2 ) endocapillary proliferation ; ( 3 ) global glomerulosclerosis or tubular atrophy of 40% or more ; or ( 4 ) insufficient sample size of less than six glomeruli on light microscopy . for comparison , age- and
gender - matched idiopathic fsgs cases from the same period were collected from our renal biopsy registry .
all biopsy samples were examined using light , immunofluorescent , and electron microscopy . for light microscopic examination ,
23-m - thick sections were stained with hematoxylin and eosin , pas , aldehyde fuchsin orange g , and methenamine silver methods .
two to four tissue sections were mounted per glass slide , and two slides were prepared for each stain , resulting in eight slides for each biopsy . for immunofluorescence examination ,
snap - frozen 3-m - thick sections were mounted in optimal cold temperature compound and stained with antibodies against igg , iga , igm , c3 , c4 , c1q , and fibrinogen ( dako cytomation , glostrup , denmark ) . for electron microscopy
, fresh renal tissue was cut at the time of biopsy , and one to three blocks of 1 mm renal tissue were double fixed with glutaraldehyde and osmium tetroxide , routinely processed , and stained with uranyl acetate and lead citrate .
an average of 26.7 consecutive sections ( range , 18 to 32 ) were examined in each case .
the segmental sclerosis was subtyped in each case as classic , perihilar , tip , cellular or collapsing variants and were numbered . in segmental sclerosis , capillary adhesion to bowman
s capsule with or without aberrant vessel formation was also counted . to validate aberrant vessels , we followed afferent and efferent arterioles in the vascular poles and confirmed that there were no direct connections between vascular poles and presumed neovessels .
the other histologic parameters that we evaluated were type of glomerular crescent , percentage of global glomerulosclerosis , degree of tubular atrophy , interstitial fibrosis , and interstitial inflammation , and presence of arteriolar hyalinosis and arteriosclerosis .
crescents were defined as extracapillary proliferations of at least two layers that occupied at least 10% of the circumference .
the degrees of tubular atrophy , interstitial fibrosis , interstitial inflammation , and arteriolar hyalinosis were semi - quantitatively scored according to the banff 97 criteria .
patient age , gender , serum creatinine level , hematuria , and proteinuria level at the time of biopsy were obtained from the patient medical records and biopsy requisition forms .
proteinuria was evaluated in 49 fsgs - like igan patients and in 45 idiopathic fsgs patients by 24-hour urine collection or random urine protein to creatinine ratios .
comparisons of the frequencies of segmental sclerosis , tuft adhesion to bowman s capsule , glomerular hyalinosis , and aberrant vessel formation between fsgs - like igan and idiopathic fsgs cases were performed using the mann - whitney u test .
tubulointerstitial and vascular changes were compared using pearson s chi - square test combined with fisher exact test .
we observed an average of 16.3 glomeruli in each case of fsgs - like igan .
the most common subtype of segmental sclerosis was classic type , followed by tip and perihilar types .
glomerular capillary tuft adhesion to bowman s capsule was observed in 95 glomeruli ( 86.4% of the segmentally sclerosed glomeruli ) in 49 cases . among them , nine cases ( 8.2% of the total segmentally sclerosed glomeruli ) demonstrated capillary - sized blood vessels connecting the segmentally sclerosed tuft and periglomerular interstitium .
these vessels began in the sclerosed tufts , ran perpendicularly through the gap of bowman s capsule , and merged into the capillary networks of the interstitium .
the vessels were surrounded by normal - looking glomerular capillary loops in five glomeruli , but accompanied endocapillary proliferations in four glomeruli ( fig .
segmental sclerosis was observed in 119 out of 746 glomeruli ( 16.0% ) . when segmental sclerosis of igan was compared with that of idiopathic fsgs , the mean percentages of glomeruli with tuft adhesion , aberrant vessel formation , and glomerular crescents were significantly higher in the fsgs - like igan group .
aberrant blood vessels found in fsgs were similar to those seen in igan in morphology but were identified in only one glomerulus ( 0.8% of the segmentally sclerosed glomeruli ) .
the mean percentages of glomerular hyalinosis , the degrees of interstitial fibrosis , tubular atrophy , interstitial inflammation , and arteriolar hyalinosis were not significantly different between the two groups ( table 1 ) .
clinically , hematuria was present in 100% of the fsgs - like igan patients , whereas 51.0% of the idiopathic fsgs patients had hematuria .
proteinuria was more prevalent and severe in idiopathic fsgs : 91.1% of patients had proteinuria and 48.9% were in the nephrotic range , whereas proteinuria was present in 79.9% of fsgs - like igan patients with nephrotic range in 2.0% .
other clinical parameters including mean serum creatinine levels were similar in both groups ( table 2 ) .
we observed an average of 16.3 glomeruli in each case of fsgs - like igan .
the most common subtype of segmental sclerosis was classic type , followed by tip and perihilar types .
glomerular capillary tuft adhesion to bowman s capsule was observed in 95 glomeruli ( 86.4% of the segmentally sclerosed glomeruli ) in 49 cases . among them , nine cases ( 8.2% of the total segmentally sclerosed glomeruli ) demonstrated capillary - sized blood vessels connecting the segmentally sclerosed tuft and periglomerular interstitium .
these vessels began in the sclerosed tufts , ran perpendicularly through the gap of bowman s capsule , and merged into the capillary networks of the interstitium .
the vessels were surrounded by normal - looking glomerular capillary loops in five glomeruli , but accompanied endocapillary proliferations in four glomeruli ( fig .
in age and gender - matched idiopathic fsgs cases , segmental sclerosis was observed in 119 out of 746 glomeruli ( 16.0% ) . when segmental sclerosis of igan was compared with that of idiopathic fsgs , the mean percentages of glomeruli with tuft adhesion , aberrant vessel formation , and glomerular crescents were significantly higher in the fsgs - like igan group .
aberrant blood vessels found in fsgs were similar to those seen in igan in morphology but were identified in only one glomerulus ( 0.8% of the segmentally sclerosed glomeruli ) .
the mean percentages of glomerular hyalinosis , the degrees of interstitial fibrosis , tubular atrophy , interstitial inflammation , and arteriolar hyalinosis were not significantly different between the two groups ( table 1 ) .
clinically , hematuria was present in 100% of the fsgs - like igan patients , whereas 51.0% of the idiopathic fsgs patients had hematuria .
proteinuria was more prevalent and severe in idiopathic fsgs : 91.1% of patients had proteinuria and 48.9% were in the nephrotic range , whereas proteinuria was present in 79.9% of fsgs - like igan patients with nephrotic range in 2.0% .
other clinical parameters including mean serum creatinine levels were similar in both groups ( table 2 ) .
aberrant vessels were more frequently observed in cases of fsgs - like igan than in idiopathic fsgs . otherwise , the morphology of segmental sclerotic glomeruli was indistinguishable in two diseases , and the most common form was the classic type . considering that more than 25 sections were examined , these features were rare and
clinically , our cases were different from those reviewed by haas   but similar to those reviewed by weber et al . .
the frequency of hematuria was higher and that of nephrotic range proteinuria was lower than observed by haas .
however , it has not been resolved whether this entity is a subtype of igan or an overlap of igan and minimal change disease .
likewise , it is possible that the cases of fsgs - like igan described by haas   were subtypes of igan or represented the overlap of igan and minimal change disease / fsgs .
by contrast , consistent hematuria may suggest the involvement of capillary loop injury in fsgs - like igan . extra new vessel formation is rarely reported in animal models or in human diabetic nephropathy .
extraterritorial glomerular capillaries  that connect the glomerular space and periglomerular interstitium are responsible for the development of interstitial fibrosis in a hypertensive rat fsgs model .
the extra vessels were located in the glomerular hilum in human diabetic nephropathy and did not cause rupture of the capillary loops , and most were connected to the second- and third - order branches of the afferent arteriole and drained into the peritubular capillaries . the number of extra vessels ranged from several to more than 10 per glomerulus .
rare extra vessels have been observed in a variety of cases , also localized within the glomerular hilum .
however , the aberrant vessels observed in our study differed from those in diabetic nephropathy in location and numbers . extra vessels similar to our cases can be seen in glomerulonephritis characterizing small vessel vasculitis   such as henoch - schnlein purpura nephritis , antineutrophil cytoplasmic antibody  associated nephritis , and lupus nephritis . in these cases ,
glomerular capillary loop sclerosis and adhesion were grouped together in a proposed oxford classification of igan , mainly to increase reproducibility between observers
. however , not only are they morphologically distinct but they also differ in pathomechanisms .
glomerular capillary loop sclerosis is characterized by capillary loop collapse and accumulation of scleroprotein inside the glomerular capillary basement membrane .
it can be caused by ischemia , toxins , or drugs , but the glomerular basement membrane integrity is essentially preserved .
in contrast , glomerular capillary adhesion to bowman s capsule produces a break in glomerular basement membrane integrity and may develop with or without glomerular capillary rupture .
therefore , adhesions and new vessels in igan might be signs of glomerular capillary injury and rupture .
glomerular capillary loop injury may be triggered by immune deposits along the capillary loops ; however , our cases had localized mesangial deposits without peripheral capillary iga deposits .
glomerular capillary basement membranes may be fragile and likely to break without deposits , since glomerular basement membrane thinning or attenuation is frequent in igan .
mesangial cells have been shown to significantly down regulate vascular endothelial growth factor a mrna and increase inducible nitric oxide synthase mrna when incubated with aberrantly glycosylated iga .
therefore , these molecules may be involved in the evolution of abnormal repair in igan .
it is unclear how aberrant vessels affect glomerular filtration and nearby structures , but they may contribute to interstitial inflammation and fibrosis by directly delivering pathogenic filtrate to the peritubular capillaries and interstitium . in conclusion , aberrant blood vessels were observed in segmentally sclerosed glomerular tufts in fsgs - like igan .
 background : segmental glomerulosclerosis without significant mesangial or endocapillary proliferation is rarely seen in iga nephropathy ( igan ) , which simulates idiopathic focal segmental glomerulosclerosis ( fsgs ) . 
 we recently recognized aberrant blood vessels running through the adhesion sites of sclerosed tufts and bowman s capsule in igan cases with mild glomerular histologic change . 
 methods : to characterize aberrant blood vessels in relation to segmental sclerosis , we retrospectively reviewed the clinical and histologic features of 51 cases of fsgs - like igan and compared them with 51 age and gender - matched idiopathic fsgs cases . 
 results : in fsgs - like igan , aberrant blood vessel formation was observed in 15.7% of cases , 1.0% of the total glomeruli , and 7.3% of the segmentally sclerosed glomeruli , significantly more frequently than in the idiopathic fsgs cases ( p = .009 ) . 
 aberrant blood vessels occasionally accompanied mild cellular proliferation surrounding penetrating neovessels . 
 clinically , all fsgs - like igan cases had hematuria ; however , nephrotic range proteinuria was significantly less frequent than idiopathic fsgs . 
 conclusions : aberrant blood vessels in igan are related to glomerular capillary injury and may indicate abnormal repair processes in igan . 
MATERIALS AND METHODS
Materials
Tissue processing of renal biopsies
Assessment of renal histology
Clinical data
Statistical analysis
RESULTS
Morphologic features of segmental sclerosis in FSGS-like IgAN
Comparison of segmental sclerosis between FSGS-like IgAN and idiopathic FSGS
DISCUSSION