Nephrotic Syndrome Caused by Immune-Mediated Acquired LCAT Deficiency

Abstract

Lecithin-cholesterol acyltransferase (LCAT) is an enzyme involved in maintaining cholesterol homeostasis. In familial LCAT deficiency (FLD), abnormal lipid deposition causes renal injury and nephrotic syndrome, frequently progressing to ESRD. Here, we describe a 63-year-old Japanese woman with no family history of renal disease who presented with nephrotic syndrome. The laboratory data revealed an extremely low level of serum HDL and undetectable serum LCAT activity. Renal biopsy showed glomerular lipid deposition with prominent accumulation of foam cells, similar to the histologic findings of FLD. In addition, she had subepithelial electron-dense deposits compatible with membranous nephropathy, which are not typical of FLD. A mixing test and coimmunoprecipitation study demonstrated the presence of an inhibitory anti-LCAT antibody in the patient's serum. Immunohistochemistry and immunofluorescence detected LCAT along parts of the glomerular capillary walls, suggesting that LCAT was an antigen responsible for the membranous nephropathy. Treatment with steroids resulted in complete remission of the nephrotic syndrome, normalization of serum LCAT activity and HDL level, and disappearance of foam cell accumulation in renal tissue. In summary, inhibitory anti-LCAT antibody can lead to glomerular lesions similar to those observed in FLD.

Novel Missense LCAT Gene Mutation Associated with an Atypical Phenotype of Familial LCAT Deficiency in Two Portuguese Brothers

“…However, as it is quite unlikely that the striking glomerular foam cell infiltrate characteristic of FLD was overlooked on the original LM examination, we hypothesize that in patients with residual LCAT activity and kidney involvement, the major histopathological feature might be a membranous nephropathy. This is in line with the report of a patient presenting with nephrotic syndrome caused by immune-mediated acquired LCAT deficiency (Takahashi et al 2013), whose baseline kidney biopsy exhibited glomerular lesions similar to those of FLD, together with changes of membranous nephropathy. A follow-up kidney biopsy, obtained 5 months after the initiation of steroids and clinical improvement with serum LCAT activity normalization, showed a marked reduction in the glomerular foam cells, and improvement of the mesangial lesions, but persistence of diffuse GBM thickening.…”

Foam cells and the pathogenesis of kidney disease

“…Dissolution of the normally compact mesangial matrix (“mesangiolysis”) frequently is present in conjunction with glomerular foam cell accumulation, but whether these processes are mechanistically linked remains unknown. Rare glomerular diseases in humans characterized by foam cell accumulation include immune-mediated acquired lecithincholesterol acyltransferase deficiency [3] and a glomerulopathy associated with a homozygous mutation of apolipoprotein E (apolipoprotein E2) [4]. Foam cells commonly populate the interstitium in nephrotic states and in Alport syndrome, and at least one study has suggested that these cells contribute to progressive tubulointerstitial injury and are associated with a higher prevalence of concurrent FSGS regardless of primary disease etiology [5].…”

Current Status of Familial LCAT Deficiency in Japan

“…There have been reports of patients exhibiting marked reduction in plasma HDL-C and renal dysfunction, similar to those in genetic LCAT deficiency, but are due to the presence of autoantibodies against LCAT protein 51,52) . Immunemediated LCAT deficiency is sometimes found through a gradual decrease in HDL-C.…”