A rare case of lipoprotein glomerulopathy in a white man: an emerging entity in Asia, rare in the white population.
Abstract: * Lipoprotein glomerulopathy is a rare entity that predominantly affects the Asian population, mainly the Japanese and Chinese. Lipoprotein glomerulopathy is clinically characterized by proteinuria and progression to renal failure and is caused by glomerular lipoprotein thrombi formation in association with increased levels of serum apolipoprotein E. The disease has a male predominance and can affect virtually any age group. We describe the third reported case, to our knowledge, of lipoprotein glomerulopathy to affect a white patient.

(Arch Pathol Lab Med. 2010;134:279-282)
Article Type: Clinical report
Subject: Kidney diseases (Development and progression)
Kidney diseases (Risk factors)
Kidney diseases (Diagnosis)
Blood lipoproteins (Physiological aspects)
Lipoproteins (Physiological aspects)
Proteolipids (Physiological aspects)
Authors: Boumendjel, Redouane
Papari, Mona
Gonzalez, Miguel
Pub Date: 02/01/2010
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2010 College of American Pathologists ISSN: 1543-2165
Issue: Date: Feb, 2010 Source Volume: 134 Source Issue: 2
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 230245850
Full Text: Lipoprotein glomerulopathy is a rare disease caused by glomerular lipoprotein thrombi formation in association with increased levels of serum apolipoprotein E. This entity has been described mostly in the Japanese population and other individuals of Asian descent but can also occur in other populations. (1,2) The disease has a male predominance and can affect virtually any age group. At the initial presentation, patients have steroid-resistant nephrotic syndrome, hypertension, and, rarely, microscopic hematuria, which is followed by the gradual deterioration of renal function and progression to renal failure. Approximately 50% of patients will also have type III hyperlipoproteinemia (increased total cholesterol, plasma triglycerides, very low density lipoprotein, and intermediate density lipoprotein). The characteristic microscopic features of lipoprotein glomerulopathy are glomerular enlargement with marked, diffuse, microaneurysmal dilatation of the capillary lumina by amorphous lipoprotein thrombi, which stain positively with lipid-soluble dyes (Oil red O, Sudan III). On electron microscopy, the glomerular capillary lumina appear distended and occluded by large granular or vacuolated lipid thrombi.


A 31-year-old white man presented to his primary care physician with a chief complaint of bilateral leg swelling and was found to have high blood pressure and proteinuria. He was referred to a nephrologist at Advocate Lutheran General Hospital for investigation of his proteinuria. His past medical history was unremarkable. His family history was significant for polycystic kidney disease affecting his maternal grandmother, mother, and maternal uncles.

On physical examination, the patient was hypertensive and had bilateral, lower extremity edema. The rest of the physical examination was unremarkable.

The patient's laboratory results showed the following: hypoalbuminemia (1.7 g/dL; reference range, 3.5-5 g/dL), hypoproteinemia (4.5 g/dL; reference range, 6-8.2 g/dL), proteinuria (24hour urine protein, 9800 mg/d, reference range, 0-255 mg/d; random urine protein, 2124 mg/dL, reference range, 0-20 mg/ dL), high serum creatinine level (2.3 mg/dL; reference range, 0.71.3 mg/dL), and a lipid profile that showed a high total serum cholesterol level (221 mg/dL; reference range, 100-200 mg/dL), high low-density lipoprotein fraction (143 mg/dL; reference range, 0-130 mg/dL), high triglycerides (224 mg/dL; reference range, <150 mg/dL), and low high-density lipoprotein fraction (33 mg/dL; reference range, >39 mg/dL).

The patient was treated with olmesartan and furosemide and underwent a computed tomography-guided, left kidney biopsy.


The renal biopsy showed focal glomerular sclerosis. The remaining glomeruli were notable for distortion of the glomerular architecture by pseudoaneurysmally dilated capillary lumina containing thrombi of bubbly material that stained weakly with hematoxylin-eosin (Figure 1), periodic acid-Schiff (Figure 2), and trichrome. The thrombus material stained strongly with Oil red O for neutral lipids on frozen sections (Figure 3), consistent with lipid material. In addition to the thrombi, the glomerular capillaries showed segmental areas of scarring, adhesion, and hyalinosis. In the most severely involved areas, there were double contours of the capillary walls, and even the well-preserved areas showed some mottling with the Jones silver stain (Figure 4). In general, the glomerular cellularity was slightly increased in the segmental mesangial areas, and some of the glomerular capillaries contained foamy macrophages. Of 39 glomeruli, 10 (26%) showed global sclerosis. There was widespread interstitial fibrosis, tubular atrophy, and scattered lymphoplasmacytic infiltrates occupying more than 50% of the cortex. The small arteries and arterioles were unremarkable.

Ultrastructural examination revealed podocytes with a well-preserved anatomy, with only focal effacement (<20%). The glomerular basement membranes showed focal, large, subendothelial, electron-dense deposits and cellular interposition. Many of the glomerular capillaries were occluded by amorphous thrombi. The mesangial areas were expanded by matrix material and cell processes and contained some scattered electron-dense deposits. The adjacent arteriole appeared normal (Figures 5 and 6).


Immunofluorescence demonstrated 1+ to 2+ granular staining for C3d and C1q in a diffuse, peripheral, and segmental pattern; 1+ staining for immunoglobulin (Ig) M in a similar pattern and distribution; 1+ linear, peripheral staining for IgA; traces of fibrinogen; and absent staining for IgG. These immunofluorescence findings and the electron-dense deposits were attributed to scarring and glomerular injury.

Apolipoprotein E (apoE) genotyping was performed by serial invasive signal amplification reaction using genomic DNA. The patient was found to be homozygous for the apoE alleles of the wild-type E3/E3 (Athena Diagnostics, Worcester, Massachusetts).

The current status of the patient is unknown to us because he was lost to follow-up.


This is the first case, to our knowledge, of lipoprotein glomerulopathy in a white patient in the United States; 2 previous cases involved a 28-year-old, American-born, Chinese man and a 32-year-old, Mexican man. (3,4) To our knowledge, this is the third case of lipoprotein glomerulopathy in a white patient worldwide; the other 2 confirmed cases were 2 French patients. (1,2)

Lipoprotein glomerulopathy was first described by Saito et al (5) in 1989 in a case of lipoprotein storage in the glomerular capillaries of a patient with dyslipidemia similar to type III hyperlipoproteinemia. Worldwide, more than 50 cases have been reported, and most have occurred in patients of Japanese and Chinese descent. (6) Although, the disease may affect both sexes, it is more common in young men. Rare cases have been reported to occur in children of Japanese origin.

A hereditary component for the lipoprotein glomerulopathy has been considered previously because of the familial occurrence of the cases, the recurrence of the disease in the transplanted kidneys, and the correlation with the elevated levels of apoE. (7)

Apolipoprotein E is a glycoprotein that has 3 isoforms: E2, E3, and E4, which are encoded by 3 alleles at a single gene locus on chromosome 19. Most of the population worldwide has the wide-type E3 allele. Among patients with lipoprotein glomerulopathy, the most common isoform is apoE2. Further sequencing of the APOE gene demonstrated various mutations, such as apoE Sendai, which was found in multiple Japanese patients and showed an autosomal-recessive mode of transmission. (5,8) Other mutations are Apo Kyoto, also described in Japanese patients and the deletion ApoE Tokyo/Maebashi. (9,10) Apolipoprotein E Chicago has recently been described in a patient homozygous for the apoE alleles of the wild-type E3/E3. (9) Most authors suggest that the end result of these mutations is excessive binding of the apoE to the low-density lipoprotein receptors, leading to development of the glomerulopathy. The mechanism is not entirely clear and not fully known, but in animal models, the disease was induced by introduction of apoE Sendai to mice that were initially deficient in apoE. (11)

However, there are family members of patients affected by the disease that have the same mutations but no evidence of glomerulopathy, leading to the conclusion that other factors are probably involved in the pathogenesis of this disease.

The clinical presentation is significant for proteinuria, often in the nephrotic range, and blood pressure elevation in most patients. Hematuria is observed only in rare cases. Most patients have a slow deterioration in renal function but progress toward renal insufficiency and end-stage renal disease. As mentioned previously, these patients have an abnormal lipid profile similar to type III hyperlipoproteinemia, with elevated cholesterol and triglycerides, the presence of [beta]-very-low-density lipoprotein, which is associated with elevated levels of apoE, but without systemic manifestations, such as cutaneous xanthomas, atherosclerosis, and corneal arcus. (12)

Histologically, the glomerular capillaries are distended by lipoprotein thrombi, which have a vacuolated and laminated structure and are lightly positive for periodic acidSchiff. On frozen sections, the thrombi stain positive with Oil Red O and Sudan III stains.

In time, the glomeruli show segmental sclerosis and hyalinosis followed by global sclerosis. There are tubular and interstitial changes present in most cases, but these occur secondary to the glomerular changes.

Electron microscopy of the thrombi ultrastructure shows lamellation of the granular or vacuolated lipid material of which they are comprised and also demonstrates the presence of the lipid material between the glomerular basement membrane and the endothelial cells.

Immunofluorescence examination for Ig and its complement is usually negative in the glomeruli, but the thrombi will stain positively for apoB, apoE, and pre-p lipoprotein.

At the present time, there is no specific treatment for the disease because the nephrotic syndrome is resistant to steroids and immunosuppresants. Recently, patients who received therapy with lipid-lowering drugs and lipid apheresis have shown improvement of their lipid profiles and also stabilization of their renal functions.8 Lipoprotein glomerulopathy has been shown to recur in renal allografts.2

In summary, we presented a rare case in a white man of lipoprotein glomerulopathy that showed characteristic clinical and pathologic features of this condition.

We thank Melvin Schwartz, MD (Rush University Medical Center, Chicago, Illinois), for his invaluable contribution to this case.



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(8.) Oikawa S, Matsunaga A, Saito T, et al. Apolipoprotein E Sendai (arginine 145 [right arrow] proline): a new variant associated with lipoprotein glomerulopathy. JAm Soc Nephrol. 1997;8(5):820-823.

(9.) Matsunaga A, Sasaki J, Komatsu T, et al. A novel apolipoprotein E mutation, E2 (Arg25Cys), in lipoprotein glomerulopathy. Kidney Int. 1999;56(2):421- 427.

(10.) Konishi K, Saruta T, Kuramochi S, et al. Association of a novel 3-amino acid deletion mutation of apolipoprotein E (Apo E Tokyo) with lipoprotein glomerulopathy. Nephron. 1999;83(3):214-218.

(11.) Ishigaki Y, Oikawa S, Suzuki T, et al. Virus-mediated transduction of apolipoprotein E (ApoE)-Sendai develops lipoprotein glomerulopathy in ApoE-deficient mice. JBiol Chem. 2000;275(40):1269-1273.

(12.) Jennette JC, Olson J, Schwartz M, et al. Heptinstalls Pathology of the Kidney. 6th ed. Philadelphia, PA: Wolters-Kluwer/Lippincott Williams and Wilkins; 2006:1203-1205.

Redouane Boumendjel, MD; Mona Papari, MD; Miguel Gonzalez, MD

Accepted for publication April 2, 2009.

From the Department of Pathology, University of Illinois, Chicago (Drs Boumendjel and Papari); and the Department of Pathology, Advocate Lutheran General Hospital, Park Ridge, Illinois (Dr Gonzalez).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Redouane Boumendjel, MD, Department of Pathology, University of Illinois, 835 S Wood St, Chicago, IL 60612 (e-mail: rboumendjel@sbcglobal.net).
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