RESUMO
BACKGROUND: The oculocerebrorenal syndrome of Lowe gene (OCRL) is located on chromosome Xq25-26 and encodes an inositol polyphosphate-5-phosphatase (OCRL-1). Mutations in this gene cause Lowe syndrome (LS) or type 2 Dent disease, of which low-molecular-weight (LMW) proteinuria is a characteristic feature. Megalin is considered to play an important role in the development of renal tubular proteinuria. Two forms of megalin are excreted into the urine: full-length megalin (C-megalin) and megalin ectodomain (A-megalin). We have explored the role of megalin in the development of LMW proteinuria in patients with OCRL mutations by determining urinary megalin fractions. METHODS: We measured A- and C-megalin in spot urine samples from five male patients with OCRL mutations (median age 9 years), using sandwich enzyme-linked immunosorbent assays, and adjusted the obtained values for excreted creatinine. The results were compared with those of 50 control subjects and one patient with type 1 Dent disease (T1D). RESULTS: All patients demonstrated normal levels of urinary C-megalin. However, patients with OCRL mutations or T1D showed abnormally low levels of urinary A-megalin, with the exception of one 5-year-old boy with LS, who was the youngest patient enrolled in the study. CONCLUSIONS: Decreased excretion of urinary A-megalin in four out of five patients with OCRL mutations suggests that LMW proteinuria may be caused by impaired megalin recycling within the proximal tubular cells. Homologous enzymes, similar to inositol polyphosphate-5-phosphatase B in mice, may help to compensate for defective OCRL-1 function during early childhood.
Assuntos
Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/análise , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Monoéster Fosfórico Hidrolases/genética , Adolescente , Envelhecimento/metabolismo , Criança , Pré-Escolar , Doença de Dent/genética , Doença de Dent/urina , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/química , Masculino , Peso Molecular , Mutação , Síndrome Oculocerebrorrenal/genética , Síndrome Oculocerebrorrenal/urina , Proteinúria/genética , Proteinúria/urina , Microglobulina beta-2/urinaRESUMO
AIM: Optimizing nephron supply to recipient demand is a non-immunologic determinant of renal allograft outcome. Nephron reduction is usually caused by physical donor-recipient mismatch, but its pathologic relevance remains to be determined. METHODS: Thirty-one recipients of living donor renal transplants were divided into three subgroups: those who received transplants from the same gender (n = 6, Group 1) and those who underwent male-to-female (n = 8, Group 2) and female-to-male (n = 17, Group 3) transplants. Renal mass was evaluated by three-dimensional computed tomography (3D-CT) volumetry before and one year after transplantation. Glomerular volume was determined from protocol biopsies obtained one hour and one year after transplantation. RESULTS: Histologically determined glomerular volume in biopsied tissues showed a significant linear correlation with allograft size on 3D-CT volumetry (P < 0.001, r = 0.625). Mismatches in body weight, glomerular volume and kidney volume ratios were significantly greater in female-to-male (Group 3) than in male-to-female (Group 2) transplants (P < 0.001 each). Despite the two groups having nearly equal graft filtration rates one year after transplantation, proteinuria rate was three-fold higher in Group 3 than in Group 2 (P < 0.001). CONCLUSION: These findings suggest that too small graft size, frequent in female-to-male transplants, could cause hypertrophy in both kidneys and glomeruli, thereby affecting allograft function and survival.