NDT Advance Access originally published online on April 23, 2007
Nephrology Dialysis Transplantation 2007 22(7):2072-2075; doi:10.1093/ndt/gfm165
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Mesangiolipidosis in Alagille syndrome—Relationship with apolipoprotein A-I
1Division of Nephrology, 2Department of Pathology, 3Division of Gastroenterology and Nutrition, CHU Sainte-Justine, Université de Montréal and 4Division of Nephrology, CHU Sherbrooke, Université de Sherbrooke, Quebec, Canada
Correspondence and offprint requests to: Geneviève Benoit, MD, Division of Nephrology, Department of Pediatrics, CHU Sainte-Justine, 3175 Chemin de la Côte Sainte-Catherine, Montréal, Québec, Canada, H3T 1C5. Email: genevievebenoit{at}yahoo.ca
Keywords: Alagille syndrome; apolipoprotein A-I; lipoprotein-X; mesangiolipidosis
 |
Introduction |
|---|
 Top Introduction Case reportAcknowledgementsReferences |
|---|
Alagille syndrome (AGS) (OMIM #118450) is an inherited multiorgan disorder. Renal mesangiolipidosis was first described in this syndrome in 1982 and is characterized by enlarged glomeruli, secondary to an increase in the mesangial matrix and the presence of cells containing lipid droplets on sections stained with Sudan black [1]. The precise mechanism by which lipids are deposited in the kidneys of AGS patients is unclear. We present a case of mesangiolipidosis associated with apolipoprotein A-I (apoA-I) abnormalities in a child with a known diagnosis of AGS, leading us to consider the role of this lipoprotein in the pathogenesis of mesangial lipid deposition.
|
Case report |
|---|
|
TopIntroductionCase reportAcknowledgementsReferences |
|---|
During the first week of life, the patient presented with conjugated hyperbilirubinaemia and renal dysfunction. Subsequent investigations showed paucity of bile duct on liver biopsy, two small hyperechogenic kidneys, tetralogy of Fallot, dysmorphic facies and butterfly vertebrae. Diagnosis of AGS was confirmed by molecular genetic testing showing a microdeletion in JAG1 within 20p12 by fluorescence in situ hybridization (FISH) technique. During follow-up, the isotopic glomerular filtration rate (GFR), performed at 17 months of age, was 57 cc/min/1.73 m2 (normal GFR for age: 95.7 ± 21.7 cc/min/1.73 m2) and the patient had mild proteinuria up to 1 g/day. Despite treatment with ursodeoxycholic acid, chronic cholestasis and hyperlipidaemia were persistent. At 34 months of age, total bilirubin and conjugated bilirubin were increased to 690 and 420 µmol/l, respectively, while GGT was 105 U/l and INR was 1.02. Non-fasting plasma lipid levels showed an elevated plasma concentration of total cholesterol (8.57, normal 3.20–4.40 mmol/l), triglycerides (2.83, normal 0.4–1.3 mmol/l), Low-density lipoprotein (LDL)-cholesterol (7.16, normal 1.76–3.62 mmol/l) and reduced plasma concentration of High-density lipoprotein (HDL)-cholesterol (0.12, normal 0.93–1.89 mmol/l). Plasma apoA-I level was low (0.25, normal 0.94–1.78 g/l) and apolipoprotein B (apoB) level was elevated (1.83, 0.52–1.09 g/l). Progressively, serum creatinine concentration increased to 1.39 mg/dl (normal 0.26–0.61 mg/dl) and remained consistently high; a kidney biopsy was thus performed.
On renal biopsy, mesangial foam cells, stained with Sudan black on frozen sections, were present (Figure 1A and B). Ultrastructural examination showed clear vacuoles containing osmiophilic lamellated inclusions within the mesangial cell cytoplasm and in the mesangial matrix (Figure 1C and D). In high magnification, mesangial cell cytoplasm contained lipid vacuoles with a mean size of 46 nm (Figure 1E). A standard direct immunofluorescence was negative. An indirect immunofluorescence study was performed with anti-apoA-I antibody (C-18, Goat polyclonal, 1/100, Santa Cruz Biotechnology) and showed positivity in mesangial and tubular cells (Figure 1F). Controls were performed: normal frozen liver biopsy was positive, while normal frozen renal biopsy was negative, as was the patient's frozen renal biopsy without primary antibody.
|
Following the findings on renal biopsy, the lipid profile study was completed after an overnight fast. The chemical characterization of patient lipoproteins [Very low-density lipoprotein (VLDL), Intermediate density lipoprotein (IDL), LDL, HDL2 and HDL3] was abnormal with a greater proportion of free cholesterol and phospholipids (Table 1). Urinary apoA-I was determined using the following technique: urine was concentrated and prepared for western blot. Briefly, apoA-I was immunoprecipitated with specific polyclonal antibodies, visualized on SDS-PAGE and electroblotted onto nitrocellulose membranes concomitantly with the internal apoA-I standard. Urinalysis revealed significant amounts of this lipoprotein (13 ng/ml). Total cholesterol, triglycerides, HDL, LDL or apoB were not detected in the urine sample.
|
Mesangiolipidosis is typically found in AGS, suggesting that this glomerular involvement should be added to the syndrome's characteristic features [2]. However, the precise pathophysiology of lipid deposition in the kidneys of AGS patients has not been fully elucidated.
AGS is frequently associated with cholestasis-induced hyperlipidaemia. In the case presented here, the elevated plasma concentration of total cholesterol, LDL-cholesterol, triglycerides and apolipoprotein B, as well as the low level of HDL-cholesterol were concordant with reported lipid profiles of other patients with AGS [3–5]. The cause of the renal lipid deposition in AGS patients is not likely to be caused solely by hyperlipidaemia, as mesangiolipidosis has not been described in the glomerular basement membrane of patients with minimal change disease, despite their elevated serum lipid levels and lipiduria.
Varying levels of apoA-I concentrations, both elevated and reduced, have been associated with AGS. In the present case, the plasma apoA-I concentration was strikingly lower than values usually reported. This may have been secondary to the significant urinary losses of apoA-I observed in our patient. ApoA-I urinary losses in AGS have not been described previously, and are therefore not well understood. In comparison, in nephrotic syndrome, almost all of the urinary lipoprotein is HDL and its associated apoA-I has been found frequently [6]. However, our patient was not nephrotic and did not present with urinary HDL. Significant apoA-I urinary losses may be explained by a breakdown of the glomerular basement membrane resulting in excessive filtration, or tubular dysfunction preventing its reabsorption. The presence of apoA-I in the tubular cells on indirect immunofluorescence suggests that some apoA-I reabsorption occurred, but the reabsorption threshold could have been surpassed due to increased glomerular filtration. The discovery of cubilin as a tubular renal receptor for apoA-I emphasizes the role of the kidney in the uptake of this lipoprotein [7]. However, this finding does not explain the direct deposition of apoA-I in the renal mesangium.
The glomerular lesions observed in AGS are similar to those observed in familial lecithin-cholesterol acyltransferase (LCAT) deficiency, a rare genetic autosomal recessive disorder leading to progressive glomerulosclerosis. LCAT is a plasma enzyme which catalyses the formation of cholesteryl esters via the hydrolysis and transfer of the sn-2 acyl chain from phosphatidylcholine to cholesterol, a reaction activated by apoA-I. One striking feature of this disease is the presence of lipoprotein-X (Lp-X), an abnormal lipoprotein measuring 30–70 nm in diameter and consisting of phospholipids, free cholesterol, apoA-I and albumin. As affected kidneys of LCAT-deficient patients revealed higher contents of phospholipids and free cholesterol, Lp-X appears to be a good candidate for causing renal lipid accumulation in these patients [8]. Lp-X is also found in cholestatic liver disease, such as AGS [3–5]. In the present case, plasma Lp-X level and LCAT activity were not assessed, but reduced LCAT activity can be expected for two reasons: LCAT function is often decreased in hepatocellular disease and the low plasma apoA-I level may preclude adequate catalysation of the enzymatic reaction. In addition, it is of great interest that the chemical characterization of the patient lipoproteins was abnormal, with a greater proportion of phospholipids and free cholesterol. The significant role of Lp-X in mesangiolipidosis is further evidenced by a rodent study that showed an increase in the lipid contents of kidneys perfused with Lp-X [9]. In the case presented here, the presence of apoA-I in the glomerulus of this young patient with AGS and mesangiolipidosis may indirectly reflect the presence of Lp-X. Moreover, the electron microscopic study in high magnification showed lipid vacuoles with the same size as Lp-X. Both results suggest a major role of Lp-X in the pathophysiology of mesangiolipidosis in AGS.
Further studies are needed to elucidate the mechanisms involved in mesangiolipidosis with emphasis on the role of Lp-X and its associated apoA-I, and to determine preventive and therapeutic interventions aimed at reducing this potential cause of chronic renal failure.
|
Acknowledgements |
|---|
|
TopIntroductionCase reportAcknowledgementsReferences |
|---|
The authors thank the Canadian Institutes of Health Research and Ms Francine Riverin for research and technical support.
Conflict of interest statement. None declared.
|
References |
|---|
|
TopIntroductionCase reportAcknowledgementsReferences |
|---|
- Chung-Park M, Petrelli M, Tavill AS, Hall PW, Henoch MS, Dahms BB. Renal lipidosis associated with arteriohepatic dysplasia (Alagille's syndrome). Clin Nephrol (1982) 18:314–320.[Web of Science][Medline]
- Habib R, Dommergues JP, Gubler MC, et al. Glomerular mesangiolipidosis in Alagille syndrome (arteriohepatic dysplasia). Pediatr Nephrol (1987) 1:455–464.[CrossRef][Web of Science][Medline]
- Gottrand F, Clavey V, Fruchart JC, Farriaux JP. Lipoprotein pattern and plasma lecithin cholesterol acyl transferase activity in children with Alagille syndrome. Atherosclerosis (1995) 115:233–241.[CrossRef][Web of Science][Medline]
- Levy E, Bendayan M, Thibault L, Lambert M, Paradis K. Lipoprotein abnormalities in two children with minimal biliary excretion. J Pediatr Gastroenterol Nutr (1995) 20:432–439.[Web of Science][Medline]
- Davit-Spraul A, Pourci ML, Atger V, et al. Abnormal lipoprotein pattern in patients with Alagille syndrome depends on Icterus severity. Gastroenterology (1996) 111:1023–1032.[CrossRef][Web of Science][Medline]
- Marsh JB. Lipoprotein metabolism in the nephrotic syndrome. Front Biosci (2002) 1:e326–e338.
- Christensen EI, Birn H. Megalin and cubilin: synergistic endocytic receptors in renal proximal tubule. Am J Physiol Renal Physiol (2001) 280:F562–F573.
[Abstract/Free Full Text] - Magil A, Chase W, Frohlich J. Unusual renal biopsy findings in a patient with familial lecithin:cholesterol acyltransferase deficiency. Hum Pathol (1982) 13:283–285.[CrossRef][Web of Science][Medline]
- O K, Ly M, Fang DZ, Frohlich J, Choy PC. Effect of lipoprotein-X on lipid metabolism in rat kidney. Mol Cell Biochem (1997) 173:17–24.[CrossRef][Web of Science][Medline]
Accepted in revised form: 5. 3.07
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||