The Case |[mid]| The eyes have it!
Kidney International(2009)
摘要
A 33-year-old man, who denied chronic renal disease, was referred to us for evaluation of proteinuria. After a 3-week upper-respiratory infection, he reported to his physician, who observed a hemoglobin count of 9.5 g/dl, a serum albumin level of 2.3 g/dl, and proteinuria of 1.8 g per 24 h. The referring physician suspected IgA (immunoglobulin A) nephropathy. At our referral center, the initial physical evaluation showed a normal blood pressure and a normal physical examination, with the exception of the patient's eyes (Figure 1). The laboratory reported normal electrolytes, an estimated glomerular filtration rate of 114 ml/min, no abnormal antibodies, normal complement levels, and a transferrin saturation of 30% with a ferritin level of 822 g/l. The urinary sediment disclosed dysmorphic erythrocytes consistent with glomerulonephritis. The serum lipid values showed a total cholesterol level of 153 mg/dl, a high-density lipoprotein cholesterol (HDL) level of 11 mg/dl, an LDL (low-density lipoprotein) cholesterol level of 3 mg/dl, and triglycerides at 544 mg/dl. What is the clinical diagnosis? The patient reported that one of his brothers also had abnormal eyes, as did his father (Figure 2a).1 A kidney biopsy showed focal segmental glomerulosclerosis (Figure 2b). Electron microscopy detected lipid deposits with both vacuolar lucent appearance and electron-dense lamellar structures within the mesangial matrix and glomerular basement membrane (Figure 2c). The finding of 'Fish Eyes' and low HDL levels, along with renal biopsy findings suggested LCAT deficiency. LCAT gene sequencing in our patient revealed two hitherto undescribed mutations in LCAT, namely a deletion on one allele resulting in a stop codon (193delG in exon 2) and a point mutation on the other (602T>A, exon 5).2 LCAT, also known as phosphatidylcholine-sterol O-acyltransferase, is an enzyme that converts free cholesterol into cholesteryl ester, which is a more hydrophobic form of cholesterol (Figure 2d).3 This product is then sequestered into the core of a lipoprotein particle, eventually making the newly synthesized HDL spherical and forcing the reaction to become unidirectional as the particles are removed from the surface. The enzyme is bound to HDL and LDL in the blood plasma. The disease has two forms, familial LCAT deficiency, in which there is complete LCAT deficiency, and 'fish eye' disease, in which there is a partial deficiency. Both are autosomal recessive disorders caused by mutations of the LCAT gene on chromosome 16q22.4 LCAT knockout mice have partly helped our understanding of the pathogenesis of this disease.5 Knockout mice had low-HDL and non-HDL cholesterol levels. Some of these mice accumulated lipoprotein X, a lamellar particle of 30–70 nm in diameter, with a high phospholipid (66%) and unesterified cholesterol (22%) content. Proteinuria and renal lesions were detected only in mice that accumulated lipoprotein X in their kidneys. Glomeruli of the affected animals showed glomerulosclerosis with increased amounts of extracellular matrix in the mesangium and occasional macrophages, similar to that seen in our patient's biopsy. These data suggest an etiological role for lipoprotein X in the development of glomerulosclerosis, although the exact mechanism is unknown. In addition, lipoprotein X may cause pseudohyponatremia, which our patient did not have.6 Eye lesions were not present in the LCAT-deficient mice.
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关键词
kidney, renal, nephrology, dialysis, hypertension, urology, transplantation, diabetes, clinico-pathological, KI, nature journals, nature publishing group, International Society of Nephrology, ISN
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