nephrotic syndrome ( ns ) is a minimal - change disease ( mcd ) in about 90% of children younger than 10 years and in about 5070% of older children .
occasionally , however , ns is induced by self - limited renal diseases , such as infection - related glomerulonephritis ( irgn ) .
irgn is usually characterized by hematuria , proteinuria , edema , and often by hypertension and a mild degree of acute renal injury .
when these characteristic findings are not present , misdiagnosis may be made without histological study . here , we report a rare case of ns due to irgn without hematuria and hypertension .
a 14-year - old boy was referred to our hospital because of a 5-day history of low - grade fever , nausea , weight gain and recent leg edema .
he had been in his usual health until approximately 1 week before admission and had no symptoms suggestive of upper respiratory or skin infection .
six months before admission , his urinalysis on school examination was normal . on admission ,
his blood pressure was 118/66 mm hg , his pulse 66/min , and his temperature 36.7c .
he weighed 63 kg and had experienced 7 kg of weight gain in the preceding week .
the hematocrit was 41.6% , hemoglobin concentration 15.1 g / dl , platelet count 248,000/mm , and leukocyte count 8,860/mm .
the serum urea nitrogen level was 10.1 mg / dl , the creatinine level 1.03 mg / dl , uric acid 4.5 mg / dl , total cholesterol 199 mg / dl , total protein 5.2 g / dl , and albumin 2.4 g / dl .
the c - reactive protein level was 0.22 mg / dl , igg 985 mg / dl ( normal range : 8701,700 ) , iga 134 mg / dl ( 80140 ) , and igm 116 mg / dl ( 34220 ) .
the total complement level was 27.0 iu / l ( 3045 ) , c3 91 mg / dl ( 80140 ) , c4 9.5 mg / dl ( 1130 ) , and c1q < 1.5 g / ml . antistreptolysin o was 164 iu / l ( < 166 ) .
hepatitis b virus surface antigen , hepatitis c virus antibody , human immunodeficiency virus antibody , antinuclear antibody , anti - neutrophil cytoplasmic antibodies , and cryoglobulin were all negative .
renal ultrasound and computed tomography showed normal kidneys . on the 2nd hospital day , kidney biopsy was performed to investigate the cause of ns .
the patient 's renal biopsy showed mild endocapillary hypercellularity , mainly of mononuclear cells , with several neutrophilic leukocytes ( fig .
mitotic figures and several apoptotic changes of the tubular epithelial cells were observed ( fig .
mild cellular infiltrations around blood vessels , which were not clear enough to be conclusively diagnosed as vasculitis , were observed , but arteriosclerosis was not found . by immunofluorescent study , prominent fine granular igg ( 2 + ) and weakly positive c3 (
1 + ) deposits were found along the capillary walls and in the mesangium ( fig .
2 ) , but iga , igm , c4 , and c1q deposits were very modest in the same pattern .
electron - microscopically , many relatively small subepithelial hump - like electron - dense deposits were observed . a few subendothelial , intramembranous and mesangial deposits were also observed ( fig .
electron - microscopic findings were roughly compatible with the early phase of post - streptococcal acute glomerulonephritis ( psagn ) . from the clinical and histopathological findings , the diagnosis of ns due to infection - related endocapillary proliferative glomerulonephritis ( engn ) was made , and we observed the patient with just rest and dietary cure . on the 11th hospital day , serum complement levels and renal function returned to normal : the total complement level was 43 iu / ml , c3 134 mg / dl , c4 20.9 mg / dl , and the serum creatinine level was 0.71 mg / dl .
on the 14th hospital day , his edema subsided and his proteinuria decreased to 1.0 g / day . on the 20th hospital day , he was discharged without any subjective symptoms . to find the causative organism of his renal lesion
the levels of antibodies to the following pathogens were measured : parvovirus b19 ( b19 ) , herpes simplex virus , varicella zoster virus , parainfluenza virus , coxsackievirus a and b , cytomegalovirus , measles virus , rubella virus , mumps virus , and epstein - barr virus , as well as fecal adenovirus antigen , which has been reported as the other responsible organism of post - infectious glomerulonephritis ( pign ) .
nasal swabs for influenza type a and b , and serum antibody to mycoplasma and legionella were negative .
we investigated his serum using human parechovirus and enterovirus polymerase chain reaction primer sets , which could detect human parechovirus and enterovirus ( including poliovirus , coxsackievirus a and b , echovirus , and rhinovirus ) .
immunofluorescence staining of the renal biopsy tissues with anti - b19 , anti - antigen nephritis - associated plasmin receptor antibody and anti - streptococcal pyrogenic exotoxin b were all negative . from the above findings
on the 2nd hospital day , kidney biopsy was performed to investigate the cause of ns .
the patient 's renal biopsy showed mild endocapillary hypercellularity , mainly of mononuclear cells , with several neutrophilic leukocytes ( fig .
mitotic figures and several apoptotic changes of the tubular epithelial cells were observed ( fig .
mild cellular infiltrations around blood vessels , which were not clear enough to be conclusively diagnosed as vasculitis , were observed , but arteriosclerosis was not found . by immunofluorescent study ,
prominent fine granular igg ( 2 + ) and weakly positive c3 ( 1 + ) deposits were found along the capillary walls and in the mesangium ( fig .
2 ) , but iga , igm , c4 , and c1q deposits were very modest in the same pattern .
electron - microscopically , many relatively small subepithelial hump - like electron - dense deposits were observed .
electron - microscopic findings were roughly compatible with the early phase of post - streptococcal acute glomerulonephritis ( psagn ) .
from the clinical and histopathological findings , the diagnosis of ns due to infection - related endocapillary proliferative glomerulonephritis ( engn ) was made , and we observed the patient with just rest and dietary cure . on the 11th hospital day , serum complement levels and renal function returned to normal : the total complement level was 43 iu / ml , c3 134 mg / dl , c4 20.9 mg / dl , and the serum creatinine level was 0.71 mg / dl .
on the 14th hospital day , his edema subsided and his proteinuria decreased to 1.0 g / day . on the 20th hospital day
, he was discharged without any subjective symptoms . to find the causative organism of his renal lesion
the levels of antibodies to the following pathogens were measured : parvovirus b19 ( b19 ) , herpes simplex virus , varicella zoster virus , parainfluenza virus , coxsackievirus a and b , cytomegalovirus , measles virus , rubella virus , mumps virus , and epstein - barr virus , as well as fecal adenovirus antigen , which has been reported as the other responsible organism of post - infectious glomerulonephritis ( pign ) .
nasal swabs for influenza type a and b , and serum antibody to mycoplasma and legionella were negative .
we investigated his serum using human parechovirus and enterovirus polymerase chain reaction primer sets , which could detect human parechovirus and enterovirus ( including poliovirus , coxsackievirus a and b , echovirus , and rhinovirus ) .
immunofluorescence staining of the renal biopsy tissues with anti - b19 , anti - antigen nephritis - associated plasmin receptor antibody and anti - streptococcal pyrogenic exotoxin b were all negative . from the above findings
based on the abrupt onset of nephrotic - range proteinuria , mild hypocomplementemia , its benign clinical course , and renal pathological findings , our patient was diagnosed as having ns due to irgn .
the diagnostic criteria for irgn are : ( 1 ) clinical or laboratory evidence of infection preceding or at the onset of glomerulonephritis ; ( 2 ) depressed serum complement ; ( 3 ) endocapillary proliferation and exudative glomerulonephritis ; ( 4 ) c3-dominant or co - dominant glomerular immunofluorescence staining , and ( 5 ) hump - shaped subepithelial deposits on electron microscopy .
at least three of the above criteria were required for the diagnosis of irgn , and our patient almost fulfilled the criteria .
although histological findings of the present case showed diffuse engn , the clinical characteristic findings of irgn , such as hematuria , obvious low serum complement level and hypertension , were not recognized .
we could not detect the causative organism of his irgn from the laboratory and renal histopathological findings .
the nomenclature for glomerulonephritis associated with infections has become confusing . in a recent study ,
glassock et al .   proposed a nomenclature for glomerulonephritis associated with infections , which were classified into two , pign and irgn .
our patient exhibited some clinical findings , such as fever , weight gain and leg edema , simultaneously , and there was no latent period .
such a clinical course suggested that our patient had irgn , which was directly related to the infection itself , but without any evidence of an ongoing infection .
another possibility must be considered , i.e. , that the causative agent could directly damage the kidney tissue , followed by immunocomplex - type glomerulonephritis , as suggested in parvovirus b19 irgn .
, engn is reported to be recognized in only 0.5% of primary glomerular disease except iga nephropathy .
in addition , ns due to psagn is uncommon , occurring in approximately 0.4% of patients .
psagn is the major disease among glomerulonephritis associated with infections , and the most typical histopathological finding is engn . in the case of psagn ,
sudden onset of edema together with gross hematuria and hypertension is a common finding and correlates with volume expansion due to sodium and fluid retention .
alternative complementary pathways are activated in psagn ; more than 90% of patients with psagn have low levels of total complement and c3 , and normal or mildly depressed c4 levels .
our patient exhibited abrupt onset of edema , normal anti - antistreptolysin o titer , hypoalbuminemia and high - selectivity proteinuria , but no hematuria or hypertension .
our patient was a 14-year - old nephrotic boy with mild renal dysfunction and mild hypocomplementemia .
these abnormalities were minor ; however , renal biopsy was performed to determine the accurate treatment plan . from the renal histopathological findings
however , without renal histopathological examination , our patient could have been diagnosed with corticosteroid - sensitive ns .
glomerulonephritis associated with infection is commonly triggered by streptococci , although many other organisms , including bacterial , viral , parasitic , rickettsial and fungal infections , can also cause the condition [ 8 , 9 ] . in spite of the detailed examinations
acute glomerulonephritis associated with several viral infections , such as b19 , hepatitis a virus , measles , yellow fever and epstein - barr virus , was reported [ 8 , 9 ] . in such cases ,
extrarenal specific symptoms associated with viruses ( such as rash , liver injuries , lymph adenopathy , and arthralgia ) were present .
however , our patient showed no extrarenal findings . recently , various renal findings associated with b19 infection have been reported .
acute nephritic syndrome with hypocomplementemia often following a prodrome of fever , rash , and arthritis is common , and nephrotic - range proteinuria is seen as well . using renal histology , immune complex - mediated acute engn
hypercellularity composed of mainly mononuclear cells and a few neutrophils , mesangiolytic changes , and mitosis of endothelial cell were observed .
such findings resemble those of irgn following b19 infection , although from the laboratory and renal immunohistopathological findings , b19 infections were not probable . using frozen serum , we examined human parechovirus , which could cause injury of endothelial cells   as well as b19 ; however , its preceding infection was not proven .
recently , several cases of iga - dominant acute pign were reported . in our patient ,
the immunofluorescence pattern was obviously igg dominant , and it was different from iga - dominant pign .
we speculate that another unrecognized pathogen , perhaps a virus , could cause ns due to irgn .
therefore , it may not be completely denied that cases who have self - limited renal diseases received corticosteroid therapy .
corticosteroids have well - recognized and potentially serious adverse effects such as poor growth , obesity , hypertension , diabetes mellitus , osteoporosis and behavioral disturbances , especially in childhood .
as shown here , in childhood , ns could be induced by irgn , and clinical and laboratory findings may resemble those of mcd .
when an acute nephrotic child shows atypical clinical or laboratory findings , such as very transient hypocomplementemia , acute renal injury , and so on , irgn should be considered as the differential diagnosis .
 nephrotic syndrome without hematuria due to infection - related glomerulonephritis is uncommon . 
 the present report describes a case of nephrotic syndrome due to infection - related glomerulonephritis without hematuria and hypertension in an older child . 
 a 14-year - old boy was referred to our hospital because of a 5-day history of fever , nausea , weight gain and recent leg edema without hypertension . 
 laboratory data showed nephrotic - range proteinuria , hypoalbuminemia , mild hypocomplementemia and acute renal injury without hematuria . 
 although , due to the clinical presentation , minimal - change nephrotic syndrome was mostly suspected , a renal biopsy showed endocapillary hypercellularity mainly of mononuclear cells with segmental mesangiolytic changes . 
 fine granular igg and c3 deposits were noted by an immunofluorescent study ; many relatively small electron - dense deposits were observed electron - microscopically . 
 these findings led to the diagnosis of nephrotic syndrome due to infection - related endocapillary proliferative glomerulonephritis , although the causative organism of his nephritis was not detected . 
 he recovered with rest and dietary cure . 
 when we examine an acute nephrotic child , infection - related glomerulonephritis should be considered as the differential diagnosis to avoid unnecessary use of corticosteroids . 
Introduction
Case Report
Renal Biopsy
Clinical Course
Discussion
Statement of Ethics
Disclosure Statement