according to the world health organization 's classification of glomerular diseases , both thrombotic microangiopathy ( tma )   and fibrillary glomerulonephritis ( fgn )   consist of glomerular lesions , the former in the context of a vascular disease and the latter in the setting of a metabolic disease .
anti - glomerular basement membrane ( gbm ) antibody glomerulonephritis is considered to be a glomerular nephritis of a systemic disease . here ,
we report an anti - gbm antibody - positive patient with fgn associated with tma .
our patient was a 54-year - old male who presented with anuria , fever , and lower - leg edema .
on june 3 , 2012 , the patient visited the urology department of a local community hospital with macroscopic hematuria and dysuria .
he was diagnosed with acute prostatitis and began treatment with levofloxacin hydrate , loxoprofen sodium hydrate , and cernitin pollen extract . however
, his condition did not improve , and he subsequently developed lower extremity numbness , bilateral flank pain , and diarrhea , followed by anuria .
on june 11 , he visited another hospital in his community and was eventually transferred to our hospital on june 13 for inpatient treatment of possible acute kidney injury . physical examination on admission revealed the following : height 175 cm ; body weight 80 kg ; systolic and diastolic blood pressure values 179 and 102 mm hg , respectively ; pulse 98 beats / min ( regular ) , and body temperature 37.9c .
g / l ) , blood ( + + + ) , pyuria , and a fractional sodium excretion rate of 20.3% .
hematological analyses of peripheral blood yielded a white blood cell count of 9.61  10 cells / l ( neutrophils 85.0% , lymphocytes 8.5% ) , a red blood cell count of 3.44  10 cells / l , a hemoglobin level of 100
g / l , the presence of fragmented red blood cells , and a platelet count of 90  10 cells / l .
g / l , the prothrombin time was 45.6 s , and the fibrinogen level was 4.1
serum biochemistry tests yielded a blood urea nitrogen level of 58.1 mmol / l and a creatinine level of 2,044 mol / l , suggesting significant renal impairment .
iu / l , and the haptoglobin level was below 1.2 mol / l . the patient had hypoproteinemia , as evidenced by a total serum protein level of 58
serum samples were negative for anti - nuclear antibodies as well as myeloperoxidase- and proteinase 3-specific antineutrophil cytoplasmic autoantibodies , although anti - gbm antibody levels were high at 230 elisa units .
the patient reported a history of cervical disc herniation diagnosed at the age of 52 years .
he had no noteworthy family history and was not taking any medications on a regular basis at the time of admission to our hospital .
changes in platelet counts , lactate dehydrogenase levels , and mean blood pressure over time during the 119-day hospital stay are schematically represented in figure 1 , along with major therapeutic interventions . computed tomography ( ct ) imaging conducted on admission indicated renal atrophy and ascites , but no collapse of the inferior vena cava .
these findings negated the possibility of prerenal and postrenal failure and suggested an acute aggravation of chronic kidney disease rather than a typical acute kidney injury .
since the patient had not undergone regular medical checkups , it was not clear whether proteinuria had existed in the past . during the early hospitalization period , we administered -globulin , diuretics , and hemodialysis , under the assumption that the patient had either sepsis- or drug - induced acute kidney injury .
peripheral blood smears revealed the presence of fragmented red blood cells ( hospital day 2 ) , suggesting hemolytic uremic syndrome ( hus ) resulting from food poisoning caused by escherichia coli o-157:h7 or other pathogenic strains .
however , the patient had no diarrhea and was negative for intestinal pathogens and verotoxins .
epistaxis developed on hospital day 4 , platelet counts and hemoglobin levels decreased to 29  10 cells / l and 55
g / l , respectively , and the lactate dehydrogenase level rose to 1,253 iu / l .
the patient 's anemia was unresponsive to erythropoiesis - stimulating therapy , and frequent blood transfusions were required ( i.e. , a total of 16 units of irradiated red cell concentrates ) .
the patient was diagnosed with tma [ thrombotic thrombocytopenic purpura ( ttp ) or hus ] based on the following findings : thrombocytopenia , hemolytic anemia evidenced by anemic signs and elevated lactate dehydrogenase levels , signs of renal impairment , fever , bleeding episodes ( i.e. , epistaxis ) , neuropsychiatric manifestations ( i.e. , headache ) , direct and indirect coombs test results , and haptoglobin levels below 1.2
assays conducted several days later indicated an adamts13 activity of 31.6% ( reference range 70 - 120% ) , and adamts13 inhibitors were negative .
these findings led us to administer plasma exchange therapy with a total of 30 units of fresh frozen plasma , starting on hospital day 8 . on hospital day 15 , steroid pulse therapy ( 3 methylprednisolone doses of 1,000 mg / day ) was initiated to lower the elevated anti - gbm antibody level . following the completion of this 3-day course ,
the patient was given oral prednisolone at a starting dose of 50 mg / day , which was gradually tapered and discontinued .
after this , platelet counts rose to 197  10 cells / l , and kidney biopsy was conducted on hospital day 22 ( fig .
seventeen glomeruli examined by optic microscopy all showed destructive patterns with characteristic architecture ranging from atypical proliferative changes to global sclerosis .
renal arterioles , both afferent and efferent , showed extensive endothelial cell edema and swelling , indicative of glomeruloid changes .
electron microscopy showed that the loss of glomerular structure observed under optic microscopy was the result of an extensive and dense extracellular deposition of fibrillar components , which were larger in diameter than amyloid fibers and aggregated to form large bundles .
immunofluorescence analysis for immunoglobulin g and third component ( c3 ) deposits was not carried out because of glomerular collapse .
available findings supported the diagnosis of fgn involving severe glomerular destruction . on hospital day 29 , a second course of steroid pulse therapy was started due to significantly decreased platelet counts . on hospital day 46 , the mean blood pressure values started to increase gradually . although the target body weight was lowered and arotinolol hydrochloride and methyldopa hydrate were added to nifedipine and candesartan cilexetil , these measures did not achieve successful blood pressure control . on hospital day 56 , the patient had a mild seizure .
t2-weighted fluid - attenuated inversion recovery ( flair ) magnetic resonance scans of the bilateral cerebellum , occipital lobe , and parietal lobe showed multiple high - intensity areas , suggesting a diagnosis of reversible posterior leukoencephalopathy syndrome ( fig .
carvedilol , nifedipine , and nitroglycerin infusion , hypertension persisted , and the patient 's headache continued . on hospital day 61 , generalized convulsions recurred , and head ct images showed multiple hemorrhagic lesions in the right temporal , right parietal , and right frontal lobes ( fig .
blood pressure levels gradually decreased with the increase in platelet counts , starting around hospital day 65 . on hospital day 72 , the patient started rehabilitation exercises .
fgn and immunotactoid glomerulonephritis are characterized by electron - dense deposits of fibrillary structures in the glomerular extracellular matrix . for both conditions , optical microscopy of renal biopsies
fgn is characterized by randomly oriented nonbranching fibrils with a mean diameter of 15 - 25 nm , a size comparatively larger than that of amyloid fibrils ( 8 - 10 nm ) . in our case , although immunofluorescence analysis of immunoglobulin g and c3 was not conducted because of glomerular collapse , the diagnosis of fgn was established based on the negative congo red staining and electron microscopy findings .
the term tma designates pathological conditions characterized by microangiopathic hemolytic anemia , thrombocytopenia resulting from peripheral destruction of platelets , and organ damage due to platelet thrombi ( notably , renal impairment ) .
the differential diagnoses include disseminated intravascular coagulation syndrome , idiopathic thrombocytopenic purpura , heparin - induced thrombocytopenia , paroxysmal nocturnal hemoglobinuria , and systemic lupus erythematosus .
analyses of adamts13 activity and adamts13 inhibitors and further investigation suggested that idiopathic ttp or hus , autoimmune diseases or malignant tumors were highly probable diagnoses . considering that adamts13 activity and observed clinical signs did not meet the diagnostic criteria for atypical hus , we judged that atypical ttp was more likely than atypical hus .
they are present at high levels in patients with anti - gbm nephritis and goodpasture 's syndrome , a condition often culminating in rapidly progressive glomerulonephritis .
the likelihood of goodpasture 's syndrome was rejected in our case because the patient did not present with any pulmonary disorders .
while admitting the possibility that high levels of anti - gbm antibodies had a complicating impact on tma or fgn , we considered it unlikely that anti - gbm nephritis was the primary cause given the renal biopsy findings . with all of the above taken into consideration , we concluded that the patient had fgn associated with tma and high levels of anti - gbm antibodies .
our literature search identified a patient with fgn who was diagnosed as having anti - gbm glomerulonephritis based on immunofluorescence microscopy findings .
this patient was found to be negative for circulating anti - gbm antibodies 1 week after the start of treatment .
this example illustrates the possibility that the anti - gbm antibody status could shift from positive to negative over time in patients with anti - gbm nephritis , suggesting that anti - gbm antibodies may have aggravated the fgn in our patient . a literature search conducted in 2011 identified 11 reported cases of tma patients positive for anti - gbm antibodies .
due to tma - induced glomerular collapse , we did not attempt to diagnose anti - gbm nephritis via immunofluoroscopy examination of immunoglobulin g or c3 depositions .
the fact that our patient was positive for anti - gbm antibodies may suggest that he had anti - gbm nephritis .
deficiency of factor h induces uncontrolled activation of the alternative pathway and c3 consumption , resulting in endothelial injury .
research suggests that factor h mutations confer a predisposition to the development of hus , and factor h deficiency has been reported in anecdotal cases of fgn   and membranoproliferative glomerulonephritis type ii .
these findings suggest that decreased levels of factor h contributed to the co - occurrence of fgn and tma . however , the direct relation of fgn and tma through factor h was not accepted because the factor h was within normal levels in our case
. there may be a relationship between fgn and tma through anti - gbm antibody in our case .
reversible posterior leukoencephalopathy syndrome ( rpls ) is characterized by neurologic conditions resulting from hypertensive cerebral edema . to the best of our knowledge ,
6 cases of antineutrophil cytoplasmic autoantibody - negative anti - gbm disease with central nervous system involvement have been reported in the literature .
it is likely that rpls was caused by hypertension , which developed from the combination of anti - gbm antibody- and tma - induced vasculitis , judging from uncontrolled rises in blood pressure and the onset of numbness and seizures .
our medical opinion was supported by a retrospective analysis of 46 acute ttp patients by burrus et al . , which showed that renal function was the only variable highly associated with the occurrence of rpls on brain magnetic resonance imaging in acute ttp patients .
plasma exchange therapy can effectively improve atypical ttp through the following mechanisms : elimination of ultralarge von willebrand factor multimers ; supplementation of normal - size von willebrand factor multimers , which play an important role in blood coagulation ; removal of proinflammatory cytokines from the circulation ; elimination of adamts13 inhibitors , and supplementation with adamts13 .
a previous study reported a case of fgn in which repeat plasma exchange therapy resulted in remission of refractory nephrotic syndrome .
these previous findings suggest that plasma exchange therapy contributed to improving both tma and fgn in our case .
 we present the first report of a case of fibrillary glomerulonephritis ( fgn ) associated with thrombotic microangiopathy ( tma ) and anti - glomerular basement membrane antibody ( anti - gbm antibody ) . 
 a 54-year - old man was admitted to our hospital for high fever and anuria . on the first hospital day 
 , we initiated hemodialysis for renal dysfunction . 
 laboratory data revealed normocytic - normochromic anemia with schistocytes in the peripheral smear , thrombocytopenia , increased serum lactate dehydrogenase , decreased serum haptoglobin , and negative results for both direct and indirect coombs tests . 
 based on these results , we diagnosed tma . 
 assays conducted several days later indicated a disintegrin - like and metalloprotease with a thrombospondin motif 13 ( adamts13 ) activity of 31.6% , and adamts13 inhibitors were negative . 
 we started plasma exchange using fresh frozen plasma and steroid pulse therapy . 
 anti - gbm antibody was found to be positive . 
 renal biopsy showed fgn . 
 blood pressure rose on the 46th hospital day , and mild convulsions developed . based on magnetic resonance imaging of the head 
 , the patient was diagnosed with reversible posterior leukoencephalopathy syndrome . 
 hypertension persisted despite administration of multiple antihypertensive agents , and the patient experienced a sudden generalized seizure . computed tomography of the head showed multiple cerebral hemorrhages . 
 however , his blood pressure subsequently decreased and the platelet count increased . 
 tma remitted following 36 plasma exchange sessions , but renal function was not restored , and maintenance hemodialysis was continued . 
 the patient was discharged on the 119th day of hospitalization . in conclusion , it was shown that tma , fgn and anti - gbm antibody were closely related . 