Lipoprotein glomerulonephritis

　　1. Etiology of the disease

　　Genetic studies have shown that this disease is inherited in an autosomal recessive manner.

　　2. Pathogenesis

　　The pathogenesis of lipoprotein glomerulopathy has not been fully elucidated, and most believe it is related to abnormal lipid metabolism. It is now known that abnormal lipid metabolism can promote glomerular injury; while glomerular lesions can also affect lipid metabolism. Many systemic diseases (including rare diseases such as Fabry disease, Niemann-Pick, and Gaucher disease) can increase the deposition of lipids in the kidney, and it is quite common that renal lipid deposition is secondary to nephrotic syndrome, with hyperlipidemia being a characteristic manifestation. Because nephrotic syndrome is treated effectively, plasma lipids normalize, and in this case, hyperlipidemia is a consequence of kidney disease.

　　The main pathway of lipoprotein metabolism is the metabolic pathway of its receptors. Apolipoprotein is the signal and marker for the receptor to recognize lipoprotein, among which apoE is one of the most important components of apolipoproteins. ApoE can bind to chylomicron remnant receptors as well as low-density lipoprotein receptors, making apoE an important factor affecting blood lipid levels. Current research has found that different gene expression types of apoE have different receptor binding activities, so these apoE isomers with different receptor activities may affect the metabolism of blood lipids. For example, in organisms with the E4/4 gene expression type, the receptor binding activity of apoE is significantly enhanced, the clearance speed of chylomicron remnants is accelerated, and blood lipid levels are reduced; the gene expression type of apoE in familial type III hyperlipoproteinemia is pure apoE2/2, and this apoE isomer has a defect in the ability to bind to lipoprotein receptors, resulting in lipoprotein metabolism disorders and elevated plasma lipid levels. The gene expression type of this disease is mainly heterozygous apoE2/2, so it is believed that this isomer also has a defect in the ability to bind to lipoprotein receptors, leading to elevated plasma lipoprotein levels. This disease has many similarities with familial type III hyperlipidemia: total cholesterol, triglycerides, and apoE levels are all elevated, electrophoresis shows broadening of the pre-β lipoprotein band, and there are manifestations of nephrotic syndrome. However, the latter has a tendency to early-onset atherosclerosis, often appears xanthoma, is prone to intermittent claudication, and has hyperuricemia, etc. These clinical manifestations do not appear in lipoprotein glomerulopathy, indicating differences. Through the study of apoE gene expression types, it is speculated that heterozygotes with E2 may have a tendency to develop lipoprotein glomerulopathy.

　　Some scholars have found through the amino acid analysis of apoE isomers that the primary structures of these isomers are different, thus speculating that whether due to the replacement of amino acids, it affects the structure of apolipoprotein and even the structure of lipoprotein, making it easy to deposit in the glomerulus and directly cause damage to the glomerulus. For example, some people have found that apoE3 contains 1 cysteine, apoE4 does not contain cysteine, and apoE2 contains 2 cysteines but is 1 arginine less than apoE3. It is due to the exchange of cysteine/arginine that reflects the differences in charge between them. The glomerular basement membrane always carries a negative charge predominantly, so it is speculated that apoE2 is more likely to bind to the basement membrane and is not easy to be cleared from the capillaries, leading to the occurrence of the disease.

　　Oikawa et al. also found that the apoE isomers of 3 patients with lipoprotein glomerulopathy are particularly special, with arginine at position 145 replaced by proline. This isomer is named after the place name (Sendai), called apoE Sendai or apoESendai. Since the nitrogen atom in the proline structure is in a rigid pentagonal ring, there is no hydrogen on the nitrogen atom of the peptide bond, so it is impossible to form a hydrogen bond. It is generally believed that wherever there is a proline residue in the peptide chain, the direction of the peptide chain changes, and it cannot form an alpha-helix, so proline is the 'killer' of alpha-helix. In apoESendai, due to the destruction of the helical structure of apoE protein by proline, the protein structure is deformed as a whole or locally, further concentrated and deposited in the glomerulus, causing glomerular lesions.

　　As can be seen from the above, the research hotspots in the pathogenesis of lipoprotein glomerulopathy mainly focus on the relationship between the gene expression of apoE and lipoprotein metabolism, as well as the pathogenic effect of the change in the primary amino acid structure of apoE isomers leading to the structural deformation of globulins. While Watanabe et al. proposed the in situ pathogenesis of lipoprotein nephropathy. Saito et al. also found through electron microscopy that the deposition of lipoproteins initially occurs in the glomerular mesangium, and excessive lipoprotein substances can protrude into the glomerular capillary lumen, forming lipoprotein thrombi. The components of lipoprotein thrombi depend on the composition and content of various lipids in patients. AnHangYang et al. believe that the gene expression pattern is not very important in the pathogenesis of lipoprotein glomerulopathy, and the change in the local environment of the capillaries may be more important in the occurrence of the disease. They have found that the treatment of the disease with the antioxidant probucol (Probucol, butylphenol) is effective, so it is speculated that the deposition of lipoproteins may be related to the abnormal local environment of the glomerular capillaries and the previous oxidative state. The exact pathogenesis of lipoprotein glomerulopathy still needs further in-depth study.

　　Complicated with varying degrees of hyperlipidemia and slowly progressive renal failure. This disease can also be complicated with IGA nephropathy, lupus nephritis, and membranous nephropathy.

　　1, IGA nephropathy:A group of glomerular diseases characterized by mesangial proliferation and significant diffuse IgA deposition. Their clinical manifestations are diverse, with hematuria being the most common, which can be accompanied by varying degrees of proteinuria, hypertension, and kidney function impairment.

　　2, Lupus nephritis:Lupus nephritis refers to a disease in which systemic lupus erythematosus is associated with immunological damage of different pathological types in both kidneys, accompanied by obvious clinical manifestations of kidney damage.

　　3, Membranous nephropathy:Also known as membranous glomerulonephritis, the pathological feature is the deposition of immune complexes beneath the epithelial cells of the glomerular basement membrane with diffuse thickening of the basement membrane. Clinically, it is mainly manifested as nephrotic syndrome (NS) or asymptomatic proteinuria.

　　Lipoprotein glomerulopathy mainly affects the kidneys, and the glomerular damage is the main feature. All patients have proteinuria, some of which gradually progress to nephrotic-range proteinuria, and a few cases are accompanied by microscopic hematuria. Although the plasma cholesterol, triglycerides, and VLDL of patients with this disease increase, there are usually no extrarenal manifestations. Lipoproteins do not form emboli outside the kidney. Most patients show resistance to hormone treatment and slowly progress to renal failure.

　　This disease is a genetic disorder, and there are currently no effective preventive measures to prevent its occurrence. For patients with clear diagnosis, it is necessary to actively lower blood lipids and treat symptoms, such as using ACE inhibitors for antihypertensive drugs, which can reduce urine protein while controlling blood pressure and reducing kidney damage. Patients with hyperlipidemia need to actively use statins to control blood lipid levels, avoid exacerbating kidney vascular injury, and can control the progression of the disease, prevent the occurrence of renal failure.

　　1, Urine examination

　　All patients have varying degrees of proteinuria, ranging from 1g to 3g/24h, with microscopic hematuria.

　　2, Blood examination

　　All patients have varying degrees of hyperlipidemia. Saito et al. have compared the hyperlipidemia in patients with lipoprotein glomerulopathy and primary nephrotic syndrome and found that the plasma triglyceride levels in patients with lipoprotein glomerulopathy seem to increase significantly compared to their total cholesterol levels; they further analyzed and found that the cholesterol is mainly elevated in very low density lipoprotein and intermediate density lipoprotein, which is extremely similar to familial type III hyperlipoproteinemia. The most characteristic finding in laboratory tests is that all cases show a significant increase in plasma apolipoprotein E levels (103-388 mg/L), and the gene expression type detection of apoE shows that the gene expression type containing E2 is dominant.

　　3, Light microscopy

　　Under light microscopy, the characteristic lesions show highly expanded glomerular capillary lumens, filled with abundant pale-staining reticular substances. The capillaries exhibit balloon-like changes, and some refer to this as capillary angiomatous dilatation. Special stains, including PAS, PASM, and MASSON, are all negative. Sudan III and oil red O stains show a large number of positive lipid droplet-like substances within the expanded capillary lumens, and scattered small lipid droplets can also be seen in the surrounding renal tubular cells. The glomerular mesangial cells and matrix often show mild hyperplasia and can also present with mesangial dissolution, separation of the mesangium from the basement membrane, and double-barreled insertion of the mesangium. The glomerular basement membrane generally does not show thickening or spike formation. The renal tubular interstitium usually shows no significant changes, nor are there any signs of lipid abnormal deposition such as foamy cells. No abnormal proteinemia is seen in the renal vessels. Repeated renal biopsies have found that with the progression of the disease, lipid protein embolism-like substances in the capillary lumens gradually decrease, and the mesangial cells and matrix show marked hyperplasia, accompanied by segmental mesangial insertion and sclerosis. Lipoprotein thrombotic-like substances are gradually replaced by hyperplastic mesangium. The renal tubular interstitium often shows corresponding tubular atrophy, interstitial lymphocyte and mononuclear cell infiltration, and fibrous tissue hyperplasia.

　　4. Electron microscopy

　　It is characterized by明显 expanded capillaries, filled with a large number of particles of different sizes and electron densities. These particles can be arranged in streak-like patterns, similar to fingerprint structures. There are also cavity-filling substances in the form of unequal-sized vacuoles, often arranged in clusters or layers. Red blood cells and endothelial cells in the lumen are compressed between lipoprotein thrombotic substances and capillary walls.

　　In the early stage, the mesangial area only shows mild hyperplasia. As the disease progresses, the mesangial area becomes significantly wider, with mesangial cells and mesangial matrix hyperplasia. Sometimes mesangial insertion and mesangial dissolution may occur. The glomerular basement membrane is not thickened, and there is no dense matter deposition.

　　5. Immunofluorescence

　　Routine immunofluorescence staining such as IgG, IgA, IgM, C1q, Fg staining shows no characteristic changes. Monoclonal antibody staining for lipoproteins and apolipoproteins reveals the deposition of β-lipoprotein and apoE in the glomerular capillary lumen. In addition, there are also scattered fine granular deposits of apolipoproteins in the mesangial area, and α-lipoprotein staining is negative.

　　This disease can also be complicated with IgA nephropathy, lupus nephritis, membranous nephropathy, etc. At this time, immunofluorescence, light microscopy, and electron microscopy all show characteristic changes, which are of great value in diagnosis.

　　1. Energy:Sufficient energy can improve the utilization of protein, with a nitrogen-to-energy ratio of 1:200 being appropriate, and energy supply at 35kcal/(kg.d).

　　2. Protein:Due to the large loss of protein, traditional nutritional therapy advocates for a high-protein diet [1.5-2.0g/(kg.d)]. However, clinical practice has proven that when the energy supply is 35kcal/d and the protein supply is 0.8-1.0g/(kg.d), the synthesis rate of albumin approaches normal, protein degradation decreases, hypoproteinemia is improved, blood lipids decrease, and a positive nitrogen balance can be achieved. If the energy supply remains unchanged and the protein supply is >1.2g/(kg.d), the protein synthesis rate decreases, albumin degradation increases further, hypoproteinemia is not corrected, and urinary protein increases instead. This is because a high-protein diet can cause glomerular hyperfiltration and promote glomerulosclerosis. A high-protein diet can activate the renin-angiotensin system within the renal tissue, leading to increased blood pressure, increased blood lipids, and further deterioration of renal function.

　　3. Carbohydrates:Should account for 60% of total energy.

　　4. Fats:With concurrent hyperlipidemia and hypoproteinemia, it should be first corrected to hypoproteinemia; fats should account for ≤30% of total energy, limit cholesterol and saturated fatty acid intake, and increase intake of unsaturated and monounsaturated fatty acids.

　　5. Water:For those with significant edema, water intake should be restricted. Water intake = urine output from the previous day + 500-800ml.

　　6. Sodium:Generally controlled at 3-5g/d, those with significant edema should adjust according to blood total protein and sodium levels.

　　7. Potassium:Supplement potassium preparations and potassium-rich foods in a timely manner based on blood potassium levels.

　　8. Select foods rich in vitamin C and vitamin B in moderation.

　　9. Increasing dietary fiber can assist in lowering blood ammonia and alleviating acidosis.

　　1. Treatment

　　There is currently no satisfactory treatment for lipoprotein glomerulonephritis. Traditional treatment plans for nephrotic syndrome, such as hormones, immunosuppressants, and anticoagulants, have no significant efficacy and may even worsen kidney lesions. Current treatment trials show that lipid-lowering drugs such as probucol can effectively improve hyperlipidemia, but the effect on reducing proteinuria excretion is uncertain. Plasma exchange is also one of the recommended methods, and research suggests that this method can alleviate hyperlipidemia and proteinuria, but repeated renal biopsies have confirmed that plasma exchange cannot improve the progressive deterioration of glomerular lesions, so its efficacy is still uncertain. Even if renal transplantation surgery is performed, the transplanted kidney can still develop lipoprotein glomerulonephritis.

　　2. Prognosis

　　As the discovery of this disease has only been around 10 years, it is currently difficult to determine its natural course and prognosis. From the current data, the prognosis seems to be poor, with 8 of the reported 26 cases progressing to end-stage renal failure, 6 showing no significant change, and 4 showing signs of remission.