an incidence between 3% and 5.7% has been reported in retrospective studies ( 1 , 2 ) , and both acute tubular necrosis ( atn ) and acute tubulointerstitial nephritis ( atin ) have been reported ( 1 , 3 ) . hemophagocytic syndrome , a very rare complication of hav infection , is characterized by abnormal activation of macrophages with subsequent hemophagocytosis , splenomegaly , fever , and cytopenia ( 4 ) ; hemophagocytic syndrome can also be complicated by multiple organ failure . our patient developed dialysis - dependent acute kidney injury ( aki ) secondary to hav infection and progressively showed features of virus - associated hemophagocytic syndrome ( vahs ) , which was successfully treated by steroids . we suggest a possible link between atin that was characterized by macrophage and t cell infiltration and development of vahs caused by hav infection . a 48-yr - old man was transferred to our hospital with the diagnosis of aki due to hav infection requiring dialysis on june 4 , 2009 . the initial laboratory examination revealed the presence of igm anti - hav antibody , aspartate transaminase 1212 ( 5 - 45 ) iu / l , alanine transaminase 2,462 ( 10 - 40 ) iu / l , total bilirubin 7.8 ( 0.3 - 1.4 ) mg / dl , direct bilirubin 6.2 ( 0 - 0.4 ) mg / dl , gamma - glutamyl transpeptidase 102 ( 0 - 39 ) iu / l , hemoglobin 14.4 ( 13.1 - 17.2 ) g / dl , white blood cell count 14,700 ( 4,500 - 11,000)/l , and platelet count 163,000 ( 150,000 - 400,000)/l . the blood urea nitrogen ( bun ) and creatinine were 43.6 ( 7 - 20 ) and 9.3 ( 0.7 - 1.3 ) mg / dl , respectively , and hemodialysis was started . he developed fever on day 4 before transfer and vancomycin was administered for possible catheter - related bacteremia . upon presentation to our hospital , he was markedly jaundiced , and complained of weakness , fever , and rash . the vital signs were as follows : blood pressure , 200/100 mmhg ; pulse rate , 108 beats / min ; respiratory rate , 24/min ; and body temperature , 38.1. there were no palpable lymph nodes . the bun and creatinine levels rose to 85 and 15.2 mg / dl , respectively , and the total bilirubin level progressively increased to 21.8 mg / dl , with a normal prothrombin time . viral markers , including ebstein - barr virus ( ebv ) and cytomegalovirus , were negative ; hav was positive . urinalysis showed dark - colored urine with 2 + bilirubin , a trace of blood , and 1 + proteinuria . a chest roentgenogram initially showed pulmonary congestion with a bilateral pleural effusion that was improved by furosemide . on the 3rd hospital day , a kidney biopsy was performed and showed a diffusely edematous interstitium with infiltration of inflammatory cells and severely damaged tubules , findings which were compatible with atin . an immunohistochemical study identified the infiltrating cells as predominantly cd3 t cells and cd68 activated macrophages ( fig . the glomeruli were relatively well - preserved . on the 8th hospital day , consolidation in both upper lobes developed . all microbiological culture studies were negative and no endobronchial lesions were detected . despite catheter exchange and empirical antibiotics , a high fever , consolidation , and rash persisted . with hemodialysis and supportive care , liver and kidney dysfunction gradually improved , while anemia worsened and leucopenia and thrombocytopenia developed ; the hemoglobin was 7.4 g / dl ( hematocrit , 22.2% ) , the absolute neutrophil count was 130/l , and the platelet count was 141,000/l . the ferritin level was 2678 ( 17 - 390 ) ng / ml , the triglycerides were 493 ( 55 - 327 ) mg / dl , and the fibrinogen was 557 ( 225 - 457 ) mg / dl . vahs was highly suspected and steroids were added to the treatment regimen . upon steroid treatment , the fever , rash , and bilateral consolidation rapidly subsided . hemodialysis was stopped after 13 dialysis sessions and renal function remained stable with a serum creatinine level of 1.7 mg / dl . hav infection is generally self - limiting , but it can cause serious morbidity , such as aki and occasional mortality ( 3 ) . although not frequently reported , hav infection is also associated with hematologic complications , including vahs ( 5 ) . hps is characterized by impaired function of nk and cytotoxic t cells , resulting in uncontrolled and ineffective immune activation , and leading to cellular damage as well as proliferation of benign macrophages with hemophagocytosis ( 6 , 7 ) . ebv is the most common triggering agent and herpes infection is responsible for > 50% of secondary vahs cases ( 8) . hav is known to be associated with vahs , but only 14 cases have been reported ( 4 , 9 ) . the following diagnostic guidelines for vahs were first proposed in 1991 by the histiocyte society and updated in 2004 ( 10 ) : 1 ) fever , 2 ) splenomegaly , 3 ) cytopenia ( 2 of 3 lineages ) , 4 ) hypertriglyceridemia ( 265 mg / dl ) and/or hypofibrinogenemia ( 150 mg / dl ) , 5 ) hemophagocytosis in the bone marrow , spleen , or lymph nodes , without evidence of malignancy , 6 ) low or absent nk cell cytotoxicity , 7 ) hyperferritinemia ( 500 ng / ml ) , and 8) elevated soluble cd 25 ( il-2r chain 2,400 iu / ml ) . fever and splenomegaly are main clinical features and jaundice , hepatomegaly , lymphadenopathy , rash , and lung infiltration are also common ( 7 ) . our patient met 6 of the 8 criteria ( fever , splenomegaly , cytopenia , hypertriglyceridemia , hemophagocytosis in bm , and hyperferritinemia ) . the diagnosis of vahs was delayed until the development of marked cytopenia in the current case . on kidney biopsy , interstitial mononuclear cells were identified to be mostly t lymphocytes and macrophages . although an occasional association of hav with atn or atin has been reported , the precise pathogenic mechanisms are unknown , partly due to the rarity of kidney biopsies or immunohistochemical studies . ( 8) suggested that the possible mechanism of aki in hps was direct toxicity of pro - inflammatory cytokines ( il-6 and tnf- ) on kidney tubular cells . in our case of pathologically - confirmed atin due to hav infection in which the hospital course was complicated by hps , we observed massive kidney infiltration of activated macrophages and t cells . the role of macrophages or t cells in an animal model of aki is well - known and is thought to contribute to renal dysfunction . however , whether the kidney infiltration in this case was specific to atin caused by hav or was secondary to concurrent vahs is unknown . the number of interstitial cd68 macrophages or cd3 t cells in the current case was much higher than those of other kidney biopsy specimens from patients with hav complicated by aki ( data not shown ) . therefore , massive interstitial infiltration of macrophages and t cells in the kidney is likely to be associated with hps . even though there are no randomized controlled trials addressing the treatment modalities for this rare hps , patients are often started on corticosteroids with or without intravenous gamma - globulin , as well as supportive care and treatment for the underlying infection . in addition , cytotoxic drugs , such as etoposide and cyclosporine , have been used and recent reports support the safety of g - csf in patients with severe neutropenia . g - csf and steroids were administered to our patient and clinical features , such as cytopenia , fever , rash , and pulmonary infiltrates , recovered rapidly . herein we have reported a case of atin secondary to hav infection characterized by kidney infiltration of activated macrophages and t cells in which the clinical course was complicated by vahs , suggesting a possible link between macrophage- and t cell - predominant atin and vahs caused by hav infection . in addition , when unusual symptoms , such as persistent fever and cytopenia , develop in patients with hav infection , concurrent hps should be considered .
hepatitis a virus ( hav ) infection is generally a self - limited disease , but the infection in adults can be serious , to be often complicated by acute kidney injury ( aki ) and rarely by virus - associated hemophagocytic syndrome ( vahs ) . 
 our patient , a 48-yr - old man , was diagnosed with hav infection complicated by dialysis - dependent aki . 
 his kidney biopsy showed acute tubulointerstitial nephritis with massive infiltration of activated macrophages and t cells , and he progressively demonstrated features of vahs . with hemodialysis and steroid treatment , 
 he was successfully recovered .