A Case of Lipoprotein Glomerulopathy with apoE Chicago and apoE (Glu3Lys) Treated with Fenofibrate

Abstract

Lipoprotein glomerulopathy (LPG) is characterized by the accumulation of lipoprotein thrombi within glomerular capillaries. This rare disorder is associated with various types of mutations in the apolipoprotein E gene (apoE). Herein, we present a case of LPG with a combination of apoE Chicago (Arg147Pro) and apoE (Glu3Lys) mutations. A 51-year-old Japanese woman presented with severe (3+) proteinuria. The initial renal biopsy showed glomerular capillary dilation and occlusion with lipid granules, a specific characteristic of LPG. Phenotype, genotype, and apoE DNA sequence analyses detected 2 mutations as described above within the same allele. Although both mutations had already been reported in 1 case of LPG each, this is the first time that the combination of the 2 mutations was identified in the same case. Familial analysis detected the same mutations in the patient's mother. However, she has not suffered LPG thus far. In addition, a re-analysis of the previous LPG case with apoE (Glu3Lys) also identified the apoE Chicago mutation, as was observed in our case. Treatment with fenofibrate and irbesartan was initiated, and urinary protein excretion ceased within 1 year; recurrence was not observed after an additional 2 years of follow-up. A second biopsy after 2 years showed great improvement, with lipoprotein thrombi identified only in 2 of 18 glomeruli.

Keywords: Fenofibrate; Lipoprotein glomerulopathy; Proteinuria; Renal biopsy; apoE (Glu3Lys); apoE Chicago.

Fig. 1.

Light microscopic findings of renal biopsy specimens. The glomeruli were enlarged by distinct dilatation of the capillary lumina, which were filled with thrombus-like substances (a, b). c PAM staining. The thrombus-like substances were stained positive with Oil Red O (d) and for apoE (e). f The thrombus-like substances were absent on the second biopsy.

Fig. 2.

Clinical course. Treatment with fenofibrate and irbesartan was initiated. Two months later, serum triglycerides were within the normal range, and urinary protein excretion was reduced to less than 0.5 g/g Cre. Eight months later, urinary protein excretion ceased and did not recur thereafter.

Fig. 3.

a ApoE phenotype determined by isoelectric focusing polyacrylamide gel electrophoresis (IEF). Lane 1 (E2/2), lane 2 (E3/3, wild-type), and lane 3 (E4/4) are samples; lane 4 (E3/3) is the patient; lane 5 (E4/4) is the mother, lanes 6 and 7 (E3/4) are the 2 brothers; and lane 8 (E2/4) is a re-analysis of a previous patient. b apoE genotype examined by restriction fragment length polymorphism (RFLP). PCR-amplified DNA of apoE, including codons 112 and 158, was digested with HhaI. Lane 1 shows the DNA size marker (100-bp DNA ladder); lane 2 (ε3/3, wild-type), lane 3 (ε2/2), and lane 4 (ε3/4) are samples; lane 5 (ε3/3) is the patient, lanes 6, 7, and 8 (ε3/4) are the mother and the 2 brothers; lane 9 (ε2/3) is a re-analysis of a previous patient. c, d Sequence analysis of PCR-amplified DNA of apoE in the patient. c In exon 3, the normal allele contained the sequence GAG coding for amino acid 3, glutamine. The mutant allele contained the substituted sequence AAG, coding for amino acid 3, lysine. d In exon 4, the normal allele contained the sequence CGG coding for amino 147, arginine. The mutation allele contained the substituted sequence CCG, coding for amino acid 147, proline. e The patient's family tree. Since 3 apoE mutations expressed in the patient's mother were observed in the patient (E-Glu3Lys and E-Chicago [Arg147Pro]) and the 2 brothers (E4 [Cys112Arg]), we confirmed that E-Glu3Lys and E-Chicago were on one allele, and E4 (Cys112Arg) was on the other allele.