1Nephrology, Dialysis and Renal Transplantation Unit and 3Electron Microscopy Unit, Pathology Department, St Orsola University Hospital, Bologna, 2Centro E. Grossi Paoletti, Department of Pharmacological Sciences, University of Milano and 4Internal Medicine Department, Genova, Italy
Correspondence and offprint requests to: Giovanni M. Frasca, MD, Nephrology, Dialysis and Renal Transplantation Unit, St Orsola University Hospital, Via Massarenti 9, 40137 Bologna, Italy. Email: frasca{at}orsola-malpighi.med.unibo.it
Keywords: chronic renal failure; focal segmental glomerulosclerosis; genetic diseases; hereditary nephropathies; lecithincholesterol acyltransferase (LCAT) deficiency; nephrotic syndrome
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Introduction |
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To date, 13 affected families have been found in Italy (including the one here described), but the disease may have been underdiagnosed.
We here report on a 33-year-old man investigated for steroid-resistant nephrotic syndrome and progressive deterioration of renal function where clinical, morphological and biochemical data led to the diagnosis of familial LCAT deficiency, confirmed by the identification of two new mutations in the LCAT gene.
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Case |
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In 2001, the patient was admitted to our hospital after a further increase in serum creatinine, which had now risen above 2 mg/dl.
On admission, physical examination showed moderate pedal oedema and normal blood pressure (120/80 mmHg). Corneal greyish opacities were observed.
The family history revealed dyslipidaemia in the father, who had died at the age of 69 of myocardial infarction, and in a brother; a second brother and a sister had no sign of renal disease or lipid abnormalities. The family pedigree is reported in Figure 1.
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Light microscopy showed global sclerosis involving seven out of 11 glomeruli; in the remainder, focal segmental glomerular sclerosis was observed along with mesangial expansion, a mild increase in mesangial cellularity and irregular thickening of the glomerular capillary walls, with vacuolization of the glomerular basement membrane due to intramembranous lipid deposits, resulting in a typical foamy appearance. Diffuse tubular atrophy with thickening of the tubular basement membranes, along with focal interstitial fibrosis and mononuclear cells infiltrates, were also found.
Electron microscopy examination showed lipid deposits with both a vacuolar lucent appearance and electron-dense lamellar structures in the mesangial matrix, in the glomerular and tubular basement membranes, as well as in the Bowman's capsule and endothelial cells.
Genetic analysis showed that the proband was compound heterozygous for two novel mutations, which were designated according to the recommended nomenclature [3]. (i) A deletion of five nucleotides GCCCG (g.977981del, c.141145del) in exon 1. The mutation caused a frameshift after Arg23 with the introduction of 52 novel amino acids and the occurrence of a termination codon at position 76. (ii) A nucleotide transition in exon 5 (g.2439, c.614 G>A), which converted the codon 181 (AGC) for serine into a codon (AAC) for asparagine. The Ser181 residue is one of the components of the catalytic triad, which is conserved in all the animal species examined [4].
The proband's brother carried both mutations; the other brother and the sister were heterozygous for the deletion in exon 1, and the mother was heterozygous for the missense mutation in exon 5.
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Discussion |
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In the case reported here, corneal opacity along with a previous histological diagnosis of focal segmental glomerulosclerosis led us to consider the possibility of an LCAT deficiency. The presence of mild haemolytic anaemia (due to phospholipid abnormalities in the erythrocyte membrane), low HDL cholesterol and a family history of dyslipidaemia supported this hypothesis. The diagnosis was suggested further by the foamy appearance of the glomerular basement membrane on light microscopy examination of silver-stained renal biopsy specimens and by the presence of typical lipid deposits within the glomerular basement membrane and podocytes at electron microscopic examination of renal tissue. The lipid profile and genetic analysis of the patient and his family members definitively confirmed the diagnosis by identifying mutations of the LCAT gene.
It is of interest that the brother (II2) does not show any urinary abnormality although he lacks LCAT activity and carries the same genetic mutations detected in the patient with renal failure. Obviously, we did not carry out a renal biopsy in this subject so we do not know whether some lipid deposition has occurred in his kidney, despite the absence of urinary abnormalities. It has already been observed that clinical manifestations of patients with LCAT gene mutations may vary even among members of the same family carrying identical mutations [5], so it is still unclear whether other factors besides lipid deposition in tissues may affect the clinical picture and, particularly, lead to the development of renal lesions. Immunohistochemical investigations, carried out on renal tissue obtained from LCAT-deficient subjects, has shown that oxidized phosphatidylcholine accumulates in the glomeruli of these patients, as a result of reduced or absent LCAT activity which is also able to remove oxidized lipids [6], and suggested that oxidized phosphatidylcholine may play an important role in inducing renal lesions [2]. More recently, it has been demonstrated that lipoprotein-X, which accumulates in subjects with LCAT deficiency, can stimulate monocyte chemoattractant protein-1 (MCP-1) expression in mesangial cells via nuclear factor-B (NF-
B). This finding suggests that infiltrating monocytes can significantly contribute to renal damage by taking up large amounts of lipoprotein-derived lipids which results in foam cell formation and, on the other hand, by secreting a wide variety of cytokines and growth factors which can lead to development of glomerular sclerosis [7]. Whatever the mechanism(s) superimposed on lipid deposition leading to progressive renal damage, it is important to form a correct diagnosis not only to treat patients appropriately (and avoid useless and potentially dangerous drugs), but also to identify other affected family members and provide genetic counselling.
In conclusion, this case underlines once more the need for a careful physical examination of patients with otherwise unexplained renal disease, focusing attention on whether other organ systems are involved, and may suggest the correct diagnosis. It also stresses the importance of accurate family investigation whenever possible.
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Acknowledgments |
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Conflict of interest statement. None declared.
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References |
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