Chronic renal failure

Introduction to chronic renal failure Chronic renal failure (CRF) refers to the slow progressive renal dysfunction caused by various kidney diseases, and finally leads to complete loss of uremia and renal function, resulting in a series of clinical symptoms and clinical synthesis of biochemical, endocrine and other metabolic disorders. Sign. From the onset of the primary disease to the onset of renal insufficiency, the interval can range from several years to more than ten years. Chronic renal failure is a serious stage of renal insufficiency. The etiology of chronic renal failure takes the first place in various primary and secondary glomerulonephritis, followed by systemic congenital malformations (such as renal dysplasia, congenital polycystic kidney disease, vesicoureteral reflux, etc.), hereditary diseases (such as hereditary nephritis, renal medullary cystic disease, Fanconi syndrome, etc.). Treatments for chronic renal failure, including medical therapy, dialysis therapy and kidney transplantation, dialysis therapy and kidney transplantation are undoubtedly the best treatment options for patients with end-stage renal failure. Attention should be paid to the conservative treatment of chronic renal failure. basic knowledge The proportion of illness: 0.005% Susceptible people: no specific population Mode of infection: non-infectious Complications: hypertension, anemia, heart failure, pericarditis, cardiomyopathy, renal osteodystrophy, fracture, dementia

Causes of chronic renal failure

Glomerulonephritis (30%):

The etiology of chronic renal failure takes the first place in various primary and secondary glomerulonephritis, followed by systemic congenital malformations (such as renal dysplasia, congenital polycystic kidney disease, vesicoureteral reflux, etc.), hereditary diseases (such as hereditary nephritis, renal medullary cystic disease, Fanconi syndrome, etc.).

Systemic systemic disease (30%):

Renal arteriosclerosis, hypertension, connective tissue disease, etc., in recent years, the primary disease of CRF has changed, CRF caused by renal interstitial tubule damage has gradually received attention, diabetic nephropathy, autoimmune and Connective tissue disease kidney damage, caused by CRF also has an upward trend, secondary factors have been the main cause in Western countries.

Diabetes (20%):

According to the statistics of the United States in recent years, the leading diseases causing chronic renal failure are diabetes, hypertension, and glomerular diseases, which are the third. However, China still uses chronic glomerulonephritis, and the CRF caused by secondary factors is Hypertension, diabetes and lupus nephritis, in addition, CRF caused by hepatitis B associated nephritis is also of concern to domestic and foreign scholars.

Pathogenesis

As for the progress of chronic kidney disease, the pathogenesis of CRF, over the years has been proposed "uremic toxin theory", "complete nephron theory", "correction theory", "glomerular high filtration theory", "lipid metabolism The theory of disorder, "the theory of high-metabolism of the renal tubules", etc., but none of the doctrines can fully explain its pathogenesis. For nearly a decade, with the rapid development of molecular biology and its field of kidney disease The application has deepened people's understanding of the mechanism of CRF. The existing theories have been supplemented and corrected, and new theories have emerged. In particular, the role of various growth factors and vasoactive substances in the progression of CRF has been gradually recognized. Some scholars have also proposed "urinary protein theory", "chronic acidosis theory" and high protein diet, the effect of intrarenal hypoxia on renal function, to understand how glomerular disease causes renal tubules, interstitial damage, renal tubules, The understanding of how interstitial damage aggravates glomerular disease is of great significance.

1, glomerular high filtration theory: In the early 1980s, Brenner et al in 5/6 nephrectomized rats, using micro-puncture studies to confirm the residual renal single renal unit glomerular filtration rate (single nephron GFR, SNGFR Increased (high filtration), increased plasma flow (high perfusion) and increased capillary transmembrane pressure (high pressure) known as the "three high theory" or "glomerular high filtration theory."

The mechanism is mainly caused by the remnant nephron in the small arteries of the small arteries, which is more obvious than the expansion of the small arterioles. It is generally believed that the expansion of the small arteries and the secretion of prostaglandins by the vasodilators are excessive, as well as angiotensin II ( AngII) is not sensitive, and the relatively small expansion of the small arterioles is related to the increased sensitivity of the artery to AngII; in addition, the small arteries of the small arteries have low sensitivity to AngII and local endothelial cell-derived vasodilators (EDRF, It is thought to be mainly related to the increase in NO secretion.

When under high pressure, high perfusion, and high filtration hemodynamics, the glomerulus can be significantly expanded, and then the mesangial cells are pulled, and the mesangial cells are mechanically pulled periodically to make collagen IV, V, I, II, fibronectin (FN) and laminin increased synthesis, extracellular matrix (ECM) increased, glomerular hypertrophy was buffered to some extent and glomerular pressure was alleviated, Increased glomerular compliance, however, a large amount of ECM accumulation, high hemodynamics caused abnormalities in glomerular cell morphology and function, and will cause progressive damage to the glomerulus, eventually developing an irreversible pathological change, ie, small renal The ball hardens.

2. The theory of imbalanced imbalance: In the late 1960s and early 1970s, Bricker et al. proposed a trade-off hypothesis based on a series of clinical and experimental studies on CRF. The accumulation of certain substances in the body is not all due to the reduction of renal clearance, but a balanced adaptation of the body in order to correct the metabolic disorders. The result is a new imbalance, which leads to progressive damage and becomes a CRF patient. One of the important reasons for the progress of the disease.

At CRF, the harm caused by elevated parathyroid hormone (PTH) is the best indication. As CRF decreases, urinary phosphorus excretion decreases, causing hyperphosphatemia, due to an increase in serum calcium and phosphorus products. On the one hand, inorganic salts are deposited in various organs (including the kidneys), and soft tissue calcification occurs; on the other hand, hypocalcemia stimulates the synthesis and secretion of PTH to promote urinary phosphorus excretion and increase blood calcium, but Persistent stimulation of the parathyroid glands can lead to hyperplasia of the parathyroid glands and secondary hyperparathyroidism (SHP), which affects the bones, cardiovascular and hematopoietic systems.

The theory of imbalanced imbalance is of great significance for further explaining the causes of various chronic kidney diseases, and deepening people's understanding of the disorder of calcium and phosphorus metabolism and the pathogenesis of SHP in CRF. It has been highly praised by scholars all over the world. In the past 30 years, this field has been Significant progress has been made in the study, and a new understanding of this doctrine proposed by Bricker et al.

First, the retention of phosphorus is not the initiating factor for SHP. A large number of studies have shown that before the elevation of serum PTH in patients with early renal failure, there is no hyperphosphatemia, and blood phosphorus levels are reduced, only when renal failure is advanced ( When GFR<20ml/min, the patient has phosphorus retention, and hyperphosphatemia not only passes hypocalcemia, but also can promote the secretion of PTH through other routes or directly. In recent years, it has been found that the renal phosphorus load in the renal tubules rises. High, inhibiting the activity of 1-hydroxylase, converting 25-(OH)2D3 to 1,25-(OH)2D3, impairing the inhibition of PTH secretion, and phosphorus may have a direct effect on the parathyroid gland. Because the low-phosphorus diet can reduce the levels of PTH and its precursor PTH mRNA in the absence of changes in serum calcium and 1,25-(OH)2D3 concentrations.

Secondly, hypocalcemia is not the only direct cause of SHP. In fact, serum PTH has increased in patients with early renal failure before hypocalcemia. Supplementation of blood calcium to normal levels does not prevent the development and development of SHP. In addition to hypocalcemia, there are other important factors involved in the formation of SHP.

3, renal tubular high metabolism theory : the study believes that in the progress of chronic renal failure, the renal tubule is not in a passive compensatory adaptation or simply damaged state, but directly involved in the development of continuous decline in renal function, of which, kidney The high metabolism of tubules has been confirmed by animal experiments. When the rats are excised 5/6 kidney, the residual nephron oxygen consumption is 3 times that of normal rats. The mechanism may be multi-faceted, such as possible with residual nephron. Growth factors increased, solute filtration overload increased, lipid peroxidation increased, multiple enzyme activities increased, and Na-H reverse transport hyperthyroidism was associated with increased intracellular Na flux.

High metabolism of renal tubules can cause an increase in the production of oxygen free radicals in the remaining nephron, and the production of free radical scavengers (such as glutathione) is reduced, further causing an increase in lipid peroxidation, which in turn leads to damage to cells and tissues, causing kidneys. The unit was further lost.

In addition, infiltration of interstitial lymphoid-monocytes and release of certain cytokines and growth factors can also cause tubulo-interstitial damage, stimulate interstitial fibroblasts, and accelerate the process of interstitial fibrosis.

4. Proteinuria : In recent years, urinary protein has gradually attracted people's attention in renal tubular-interstitial damage. Clinical and experimental studies have confirmed that urinary protein as an independent factor is directly related to the degree of renal dysfunction.

Clinically, ACEI can not only control hypertension in patients with kidney disease, but also reduce proteinuria, even in patients with normal blood pressure, and delay the decline of renal function, further support the above conclusions, but how urinary protein aggravates renal function damage The mechanism has not yet been truly clarified and can be summarized as follows:

(1) Toxic effect of urinary protein on mesangial cells: Most animal models of progressive renal failure can observe the accumulation of a large number of proteins in the mesangial area, which can promote the proliferation of mesangial cells and increase the production of ECM protein, thus aggravating Glomerular sclerosis, it is particularly noteworthy that lipoprotein plays an important role in this process. Animal experiments have shown that in the proteinuria state, there are a large number of lipoproteins such as Apo B, LDL, VLDL and Apo in the glomerulus. A accumulation, lipoprotein can cause the following series of changes:

1LDL binds to receptors on its mesangial cells, stimulating the expression of proto-oncogenes such as c-fos and c-jun, leading to proliferation of mesangial cells.

2LDL can increase the production of glycoproteins such as FN in ECM proteins and induce an increase in the expression of MCP-1 and PDGF genes.

3LDL can form oxidized LDL in macrophages and mesangial cells. It is now believed that oxidized LDL is more toxic than LDL and can stimulate macrophages to produce a variety of growth factors, cytokines and their ability to stimulate collagen synthesis and mesangial cells. The proliferating medium further promotes glomerular sclerosis, and the administration of antioxidants such as vitamin E and vitamin C can significantly reduce the toxic effects of oxidized LDL.

(2) The direct toxic effect of urinary protein on proximal tubular cells: under normal circumstances, glomerular filtered protein can appear in renal tubule fluid, and then reabsorbed into the blood through the invading function in the proximal tubule, but A large amount of protein exceeds the renal tubular reabsorption capacity, which can cause damage to the renal tubules. Excessive urine protein can increase the load of lysosomes, cause lysosome swelling and rupture, and a large amount of lysosome protease is released into the blood, causing proximal end. Renal tubular damage.

(3) Urine protein can change the biological activity of renal tubular cells: from the embryonic source, the proximal tubules are derived from mesenchymal cells, which are close to the cells of fibroblasts and immune system. Recent studies have shown that urinary protein can regulate renal tubules. Cell function, altering their growth characteristics and phenotype of cytokines and matrix proteins.

Cell culture studies have confirmed that when human renal cortical epithelial cells are exposed to the renal tubular fluid environment, MCP-1 mRNA and protein expression can be increased. MCP-1 is mainly produced by monocytes, and can also be produced by renal tubular epithelial cells. Independent of the tyrosine kinase or protein kinase pathway, it has its own unique signal transduction pathway, ie, with the transcription factor nuclear factor kapa B (NFB), usually, NFB exists in an inactive form. In the cytoplasm, it can be activated by its inhibitory subunit IB protein degradation products. As a result, NFB dimers are translocated into the nucleus and act as transcription factors to stimulate transcription of interferons, cell mediators and cell adhesion factors, including MCP-1.

Proteinuria-mediated renal tubular damage is also associated with integrin expression, a heterodimeric glycoprotein that mediates cell-cell, cell-to-ECM adhesion, and plays an important role in ECM protein synthesis, degradation and redistribution. The role of 31 is normally expressed in human cultured renal tubular cells and localized to v5. Recent studies have shown that when albumin is added to cultured renal tubular cells, a dose-dependent v5 expression can be caused, This albumin needs to carry a lipid molecule to have this effect.

(4) Kidney damage caused by some special proteins: Albumin can cause damage in renal tubule fluid, which is mainly caused by fatty acids contained in it.

When glomerular filtration fluid transferrin flows through the renal tubules, its acidic environment can cause transferrin to release Fe2 ions, which can cause release of lactate dehydrogenase (LDH) and lipid peroxides from renal tubular cells. Dialdehyde, which damages the renal tubules by oxygen free radicals, has also been confirmed that transferrin can up-regulate MCP-1 mRNA expression in proximal tubular cells and aggravate glomerular damage.

Complement is filtered out into the renal tubules and contains a large number of membrane attack complexes C5b-9, which plays a role in progressive glomerular damage. In glomerulonephritis, the level of urinary ammonia is positively correlated with urinary protein levels. A large amount of urinary protein reabsorption occurs, ammonia production increases, ammonia can activate complement through the alternative pathway, producing C5a and C5b-9. C5b-9 can promote the production of cell mediators in glomerular epithelial cells, stimulate collagen synthesis, and cause glomeruli. Progressive hardening.

(5) Effects of urinary protein on glomerular metabolism: In summary, the mechanism of urinary protein in progressive renal injury can be summarized.

5, lipid metabolism disorder theory: progressive renal dysfunction often manifests lipid metabolism disorders, such as plasma triacylglycerol, very low density lipoprotein (VLDL), low density lipoprotein (LDL), increased saturated fatty acids, especially Apolipoprotein (ApoB)-rich lipoproteins are increased, while high-density lipoproteins and unsaturated fatty acids are reduced. In addition to causing arteriosclerosis and accelerating renal dysfunction, lipid metabolism disorders can also promote glomerular sclerosis in a variety of ways. Further leads to a progressive decline in renal function.

6, acidosis, imbalance, theory : the kidney is one of the most important organs of the body to regulate acid-base balance, chronic kidney disease due to a variety of pathway abnormalities, the kidneys have reduced ability to regulate acid load, however, for the entire kidney, part of the health The stored nephron will inevitably accelerate the production of acidic substances through various mechanisms. In a certain period of time, it will maintain a relatively normal acid-base balance, but this will pay a certain price, and even promote the progression of kidney disease. Like the imbalance theory, some scholars also refer to the kidney damage caused by acidosis compensation as Trade-off hypothesis in acidosis. Excessive ammonia production and acidosis can promote kidney disease through various mechanisms. progress.

(1) The growth promoting effect of ammonia: On the one hand, ammonia can increase the effect of AngII on the formation of diacylglycerol (DAG), and ammonia can synergize with various growth factors to stimulate the inositol triphosphate pathway, increase the activity of PKC, and promote protein synthesis. On the other hand, ammonia can inhibit protein degradation.

(2) Complement mechanism: Ammonia can cause tubular-interstitial damage by activating the alternative pathway of complement. For example, the sulphur bond in the C3 molecule in the direct cleavage pathway of ammonia can form amidated C3, which in turn passes C3/C5 convertase. And then cleaved C3, activated C3 can directly react with the amino group on the surface of the mesangium to cause damage; can also produce C5a and C5b-9, C5a as a chemokine to attract various inflammatory cells in the tubule-interstitial accumulation, C5b-9 The cell membrane is then directly lysed as a membrane attack complex.

(3) Increased urinary calcium excretion: three COOHs in the tannic acid molecule can be metabolized to HCO3- to offset a part of the acid load. However, acidosis reduces uric acid levels, while normal tannic acid can be in the urine. It is combined with calcium to form a soluble form, which will inevitably promote the progression of kidney stones and nephrolithiasis and aggravate renal dysfunction.

(4) promote the formation of renal cysts: acidosis can cause low potassium in the cells, the latter promote the formation of renal cysts.

7, protein diet and renal function progression: high protein diet caused or aggravated the progress of renal function mainly in the following aspects:

(1) Hemodynamic mechanism: In the past, it was thought that the increase in trans-glomerular capillary pressure caused by high protein diet was mainly caused by abnormal prostaglandin metabolism and increased vasodilator prostaglandins such as PGE2 and PGI2. Now people are in the experiment. It is found that renal damage caused by hemodynamic disorder caused by high protein diet, such as renal tissue hypertrophy, is unevenly distributed, mainly concentrated in the urine concentrated area such as the outer medulla of the inner layer (IS) and the proximal medullary nephron, further Studies have confirmed that plasma vasopressin (ADH) levels increase about 2 times 2 to 3 hours after a high protein diet, and urine osmotic pressure also increases significantly. Long-term high-protein diet increases plasma ADH levels by about 2 or 6 times, so now It is believed that the hemodynamic damage caused by high protein diet is similar to that of urine concentration. On the one hand, the increase of plasma ADH causes the increase of NaCl reabsorption in the thick segment of medullary collateral (TAL), leading to hypertrophy of TAL and IS segments, and increasing the marrow. The interstitial solute gradient increases the concentration of urine and the free water clearance rate. On the other hand, the TAL segment of NaCl reabsorption increases, the flow of dense plaques decreases, and the local RAS system is inhibited. Inhibition pipe - ball feedback (of TGF), glomerular afferent arteries, increased GFR, glomerular filtration can cause long-term renal hypertrophy.

(2) Non-hemodynamic mechanism: The high-protein diet can also increase proximal tubules: Na/H antiporter activity and ammonia production, and further promote renal hypertrophy.

(3) High-protein diet and RAS: High-protein diet can not only activate the systemic RAS system, but also activate the local RAS system. Many clinical and experimental studies have confirmed plasma renin activity, plasma AngII concentration and renal renin after a high protein diet. mRNA expression significantly increased the renal cortex and renal tubular brush border ACE activity increased significantly. AngII is now considered to be not only a vasoactive substance, but also promotes glomerular hyperfiltration, and is a growth-promoting factor. Ways to promote the progression of kidney disease.

(4) The role of tryptophan metabolites: tryptophan metabolite indoxyl sulfate can also cause or aggravate glomerular sclerosis, under normal conditions tryptophan in the intestinal tract under the action of Escherichia coli Metabolism is sputum, absorbed into the blood in the large intestine, converted to sulphate in the liver, excreted by the kidneys, and when renal insufficiency occurs, sulphuric acid phenol accumulates in the body, not only as a uremic toxin causing a series of uremia In addition to symptomatic symptoms, it also stimulates kidney tissue to produce TGF, TIMP and 1 (IV) type collagen, which promotes renal fibrosis.

(5) The role of arginine and its metabolites: L-arginine can produce dilated blood vessels under the action of endothelial NO synthase (Enos), which has a certain renal protective effect, but the amount produced is relatively small, L - NO produced by arginine under the action of tissue-inducing NO synthase (Inos) has obvious damage in some kidney diseases such as membranous proliferative glomerulonephritis. Recently, some scholars have induced ATS-induced nephritis. In the model, it was found that the membrane cytolysis was inhibited by more than 90% with the NO synthetase inhibitor L-NMMA, and the interstitial mononuclear macrophage infiltration was also significantly reduced. However, in other kidney diseases such as diabetic nephropathy, NO was Significant protection.

8, intrarenal hypoxia and chronic kidney disease progression: the cause of hypoxia in the kidney caused by glomerular damage is mainly secondary to glomerular damage caused by intrarenal hemodynamic disorder, on the one hand, the remaining The glomerulus is often in a hyperfiltration state, and the small arteries and the small arteries of the glomeruli are often compensated for expansion. In addition to the original systemic hypertension, the glomerular capillary network is under pressure to the tubulointerstitial capillaries. Sexual transmission, which causes damage to the capillary endothelial cells after the ball; on the other hand, for proliferative glomerular disease, it can cause glomerular capillary network occlusion, and indirectly affect the tubulointerstitial capillary network.

In addition, due to proteinuria secondary to glomerular damage, renal tubular cells reabsorb urinary protein, which will increase renal interstitial oxygen consumption, thereby aggravating intrarenal hypoxemia.

Hypoxia can induce various damage mediators, vascular endothelial growth factor (VEGF), PDGF, placental growth factor (PGF), TGF-1, interleukin-1, 6, 8 (IL-1, 6, 8) and the like.

9, uremic toxin theory : As early as more than 100 years ago, people have realized that uremia symptoms may be related to the production of "uremic toxins" in the body, and later formed the so-called "uremic toxin theory", when CRF progressively worse, The concentration of about 200 substances in body fluids is higher than normal. Due to the complex symptoms of uremia, involving various aspects of the body, it has not been possible to accumulate one or a group of "toxic" substances in the body to explain all the symptoms of uremia. Traditionally, The uremic toxins are still divided into the following three categories:

(1) Small molecule substances:

Urea is a protein metabolite with a molecular weight of 0,06kD. The neurotoxicity of urea is related to the metabolism of cyanate, which can bind to the N-terminus of the amino acid, alter the cell or enzyme structure and destroy its activity, such as cyanide. The acid salt can cause carbacylation of the neuronal protein, thereby interfering with the integration function of the advanced nerve center.

Creatinine is synthesized in the body, and it is retained in the body during uremia. Generally, the toxicity of low concentration is not great, but when it reaches a certain concentration, creatinine can cause shortening of cell life, and then hemolysis, creatinine can also cause sleepiness, fatigue and other neuromuscular systems. Abnormal function.

Uric acid is a metabolite of bismuth. It is a water-soluble compound. Uric acid mainly causes gout. Recently, uric acid can interfere with the production and metabolism of 1,25-(OH)2D3. In patients with CRF, allopurinol can not only lower blood uric acid level. Moreover, it can increase the level of 1,25-(OH)2D3, and uric acid has a certain relationship with 1,25-(OH)2D3 resistance in patients with CRF.

Terpenoids only produce toxic effects when they reach a certain concentration. Clinically, the concentration of various terpenoids in uremic patients is increased. Among them, methylguanidine is positively charged and easily binds to phospholipids of cell membrane system. Therefore, when methyl hydrazine accumulates in tissues, it can cause damage to various organ systems. It is reported that methyl hydrazine can cause anorexia, nausea, vomiting, diarrhea, peptic ulcer and hemorrhage, itchy skin, anemia, convulsions and disturbance of consciousness, and sugar. Abnormal tolerance can also cause pulmonary edema, pulmonary congestion, alveolar hemorrhage and myocardial degeneration, ventricular block, and cardiac insufficiency.

Guanidinosuccinic acid has a lower toxic effect than methyl hydrazine, but it can inhibit the activity of platelet factor III and promote hemolysis, which may be related to hemorrhage and anemia in uremia.

The phenols include cresol, 4-hydroxybenzoic acid, 4-carboxybenzoic acid, dicarboxylic benzoic acid and phenolic acid, wherein the phenolic acid is an amino acid (phenylamine, tyrosine) which is deaminated and decarboxylated. And oxidative production, is a pseudo-neurotransmitter, mainly causing inhibition of the central nervous system. In addition, high concentrations of phenols can also cause enzymes such as Na-K-ATPase, Mg2-ATPase, and Ca2-ATPase in vivo. inhibition.

Amines include aliphatic amines, aromatic amines and polyamines. Aliphatic amines are derived from creatinine and bile acid metabolites, which can cause myoclonus, flapping tremor and hemolysis, and inhibit the activity of certain enzymes.

The aromatic amine is a metabolite of phenylalanine and tyrosine, which mainly causes brain tissue inhibition.

Polyamines are derived from ornithine and lysine metabolites. High concentrations of polyamines can cause anorexia, nausea, vomiting, proteinuria, and erythropoietin, Na-K-ATPase, Mg2-ATPase. It has an inhibitory effect. It is reported that polyamine substances can also increase the permeability of microcirculation. Therefore, it may be related to uremia pulmonary edema, ascites, and cerebral edema formation.

In addition, certain enzymes in the intestinal tract can also cause an increase in steroids, which may cause certain uremic toxic effects.

(2) Molecular substances: molecular weight 0, 5 ~ 5kD, Bergstrom and other modern biochemical techniques used to measure the presence of a group of substances with molecular weight between small molecules and macromolecules in uremic patients, and certain symptoms of uremia Relatedly, these substances are mainly found in some peptides, mainly causing peripheral neuropathy, uremia encephalopathy, abnormal glucose tolerance, and also have obvious inhibitory effects on cell formation, leukocyte phagocytosis, lymphocyte and fibroblast proliferation, but in recent years, There is more debate.

The Chinese molecular theory helps clinicians to rationally choose blood purification programs. Because human peritoneal membranes have good permeability to medium molecular substances, peritoneal dialysis can be selected for people with high molecular weight.

(3) Macromolecular substances: molecular weight > 5kD, these substances are mainly endocrine hormones such as growth hormone (GH), parathyroid hormone (PTH), adrenocorticotropic hormone (ACTH), glucagon, pepsin and Insulin, etc., in which PTH and insulin act more prominently.

Excessive PTH can cause renal osteodystrophy, aseptic osteonecrosis, metastatic calcification, itchy skin, dialysis dementia, peripheral neuropathy, tubular damage, and inhibition of erythropoietin production and reduce its activity. There is a certain relationship between anemia and anemia. In addition, PTH can inhibit liver lipase activity, down-regulate its mRNA expression and inhibit lipoprotein lipase activity, thereby aggravating uremia lipid metabolism abnormalities.

Hyperinsulinemia can cause erythrocyte membrane Na-K-ATPase, decrease of Mg2-ATPase activity, inhibit renal tubular Na-H exchange, Na-K exchange, and have a certain relationship with uremia and sodium retention, and can also cause fat and Hepatocyte insulin receptor signaling pathway is abnormal, aggravating uremia glucose metabolism disorder.

In addition, there are several low molecular weight proteins such as ribonuclease, 2-microglobulin, lysozyme, 2 glycoprotein, etc., when these substances are elevated in vivo, they may have toxic effects, of which 2-microglobulin causes Systemic amyloidosis is well known.

The CGF has a marked increase in circulating glycosylation products (AGE) in the circulation and tissues, and is involved in many uremic complications, and is therefore considered to be a newly discovered "uremic toxin". AGE is a Maillard reaction. The final product, AGE retention, mainly causes long-term complications of CRF. For example, AGE can increase the collagen in the vascular wall of CRF patients and cause hardening of the arteries. AGE can also modify LDL and impair LDL receptor-mediated clearance mechanism and participate in CRF lipids. In the occurrence of metabolic disorders, AGE can modify 2-MG (2-MG-AGE), which is closely related to CRF amyloidosis. Recent studies have also confirmed that AGE-modified 2-MG can promote the development of uremic bone disease, 2-MG -AGE can increase monocyte chemotaxis, stimulate mononuclear macrophages to secrete IL-1, TNF and IL-6 and other cytokines that promote bone resorption, stimulate joint synovial cells to secrete collagenase and increase connective tissue degradation. It can promote the bone resorption of osteoclasts and inhibit the synthesis of fibroblast collagen.

10, a variety of cell mediators, growth factors and kidney disease progression : cell mediators that promote the progression of kidney disease, growth factors can be divided into the following four categories:

(1) Pro-inflammatory molecules: The initial role of pro-inflammatory molecules is to increase local inflammatory responses, either by activating complement or by stimulating or increasing local lymphocyte and platelet aggregation, for example, many glomerular diseases due to local immune complexes Deposition or formation of activable complement, most of which are derived from the blood circulation, a small part can be synthesized locally, and activated complement components such as C5b-9 can be regarded as a kind of "cell medium" to stimulate glomerular cell proliferation and growth. Factor release, oxygen free radical production and arachidonic acid formation, other cellular mediators such as IL-1, TNF-2 and IFN-2 can upregulate inflammatory responses by increasing lymphocyte chemotaxis, adhesion and release of oxygen free radicals. Damage to the glomerulus.

(2) vasoactive substances: vasoconstrictor substances include AngII, ET-1 and thromboxane. AngII is mainly used for vascular vasoconstriction in renal diseases, which preferentially shrinks glomerular out-of-the-ball arterioles and increases glomerular transjusic capillary pressure. Glomeruli, promote glomerular sclerosis, AngII can also contract the capillary bed after the ball, leading to ischemia, promoting renal tubular-interstitial damage, in addition, AngII can be used as a growth and matrix promoting factor to aggravate glomerular damage. And independent of its hemodynamic effects, ET-1 is another major vasoconstrictor that can cause renal blood perfusion, reduce GFR and RBF, and aggravate the progression of various kidney diseases.

The vasodilators mainly play a role in kidney protection, such as prostaglandins and NO. Studies have shown that the use of non-cortical hormones can aggravate renal insufficiency, while administration of PGE2 can improve renal function and reduce local cell mediators and matrix production in cyclosporine. Renal kidney disease model also confirmed that renal tissue NO can significantly reduce renal tubular-interstitial damage, but NO can also damage glomeruli without relying on its hemodynamic effects, such as NO can stimulate renal tubular mesangial cells to release a variety of cellular mediators. .

(3) Growth factor/matrix-promoting substance: The growth factor/matrix-promoting substance mainly mediates over-repair after renal tissue damage. As mentioned before, once a certain kidney injury occurs, although the progress rate may be different, in the end It is always necessary to develop progressive renal tissue fibrosis and loss of renal function. The root cause is that various growth factors/matrix-promoting substances are activated after various injuries, resulting in excessive repair of renal tissues such as PDGF, bFGF, GH and IGF. -1 and so on can directly stimulate the proliferation of mesangial cells and secrete ECM.

More important is the TGF--mediated effect. TGF- is a multifunctional cellular mediator widely found in fibroblasts, monocytes, platelets, vascular endothelial cells, mesangial cells and kidneys. Tubular epithelial cells are mainly involved in the ECM formation process, as shown in:

1TGF- directly stimulates the formation of various components of ECM such as FN, collagen and proteoglycans, and it is now believed that this regulation occurs mainly at the transcriptional level.

2TGF- can mediate matrix degradation through mediated by matrix proteases. Studies have shown that TGF- can inhibit the activity of plasminogen activator and increase the inhibitor of plasminogen activator-1 (PAI-1). Activity, which in turn increases PAI-1 levels in the matrix, PAI-1 inhibits the synthesis of the plasminogen activator factors uPA and tPA, the latter converts plasminogen to plasmin, and plasmin degrades ECM Many components can activate metalloproteinases (MMPs) and degrade collagen. Therefore, TGF- inhibits matrix degradation mainly by increasing PAI-I activity.

3TGF- also regulates stromal cell integrin receptor expression and promotes cell-matrix adhesion and matrix deposition.

More importantly, TGF- can induce its own production through autocrine action, thereby greatly enhancing its biological activity.

In addition, in addition to the above series of growth factors can promote the accumulation of renal tissue fibers, a large number of studies in recent years have shown that AngII and ET-1 can not only promote glomerular damage as a vasoactive factor, but also act as a matrix promoting substance. Aggravation of renal tissue fibrosis, the so-called non-hemodynamic effect, AngII can affect both ECM synthesis and its degradation, AngII promotes ECM accumulation mainly through TGF-, such as AngII through its target cell ATl Receptor action induces expression of various proto-oncogenes such as c-fos and c-jun, and c-fos and c-jun combine to form AP-1-like transcription factors to promote TGF- gene transcription. In addition, AngII can also be inactive. TGF- is converted into an active form. Of course, part of the action of AngII may be mediated by PDGF stimulation. The inhibition of ECM by AngII is partly through TGF-. In part, AngII itself may promote the synthesis of PAI-1. In addition, AngII also There are many other mechanisms to promote fibrosis after renal tissue injury. For example, AngII stimulates the increase of ammonia production in proximal tubular cells. Ammonia activates complement C5b-9, and AngII can also promote macromolecular substances. Mesangial interstitial, induce renal fibrosis, and finally, AngII can stimulate excessive growth of residual renal mononuclear macrophages and secrete TGF- to promote renal tissue damage. ET-1 is another matrix promoting substance, which can not only Mediating the mitogenic effects of AngII, PDGF, etc., it can also activate a series of intracellular signals such as PLC, PLD, PKC, tyrosine protein, serine/acid kinase, p42, p44 and MAPK, MAPK/ via ETA receptor. ERK kinase increases the expression of c-fos, fra-1 and c-jun, and promotes ECM synthesis. ET-1 also mediates the interaction of mesangial cells with matrix, such as it can induce mesangial expression of TGF-, PDGF. EGF, in addition, ET-1 activates local adhesion kinases and paxillin to mediate cell-matrix adhesion and matrix deposition.

(4) ECM and protease: Although the above mentioned various growth factors and matrix-promoting substances can promote the progressive accumulation of ECM, leading to renal tissue fibrosis, CRF also involves insufficient ECM degradation, under normal conditions, renal tissue intracellular proteins and ECM is in a state of dynamic equilibrium of synthesis and degradation. During glomerular and tubular-interstitial fibrosis, this balance is often broken, that is, protein synthesis is increased, various protease activities are down-regulated, and ECM proteins are degraded. There are three main types of proteases, namely cysteine proteases, matrix metalloproteinases (MMPs) and serine proteases, serine proteases including plasmin, leukocyte elastase and cathepsins. MMPs include: mesenchymal proteases (eg MMP-1, MMP-). 8) and type IV collagenase (such as MMP-2, MMP-9) and stromatolytic enzyme (stromatolysis).

Each protease has its specific substrate, and the plasminogen activator PA/MMP-2 protease system plays a key role in the degradation of ECM. In addition, these proteases also have specific inhibitors such as TIMPs and PAl-1, numerous in vitro studies have shown that a variety of protease activities in the development of a variety of kidney disease decreased, the level of inhibitors increased, the mechanism is partly mediated by TGF-, partly mediated by AngII.

In addition, the increased ECM is now considered to be a "cell mediator" that binds to and retains a variety of growth factors and may also act directly on cells to alter their phenotype.

Chronic renal failure prevention

How to prevent patients with chronic renal failure and delay the progression of chronic renal failure has become a topic of great concern to all countries. At present, level 3 prevention and follow-up measures are proposed.

1. Primary prevention: Also known as early prevention, it is an early onset and timely and effective treatment for existing kidney diseases or the primary causes of CRF, such as chronic nephritis, pyelonephritis, diabetes, and hypertension. Prevent possible chronic renal insufficiency.

2, secondary prevention: that is to prevent chronic renal failure continue to progress and sudden increase, for patients with chronic renal failure, actively correct lipid metabolism disorders, into high-quality low-protein diet, control high blood pressure, avoid aggravating factors, cold and warm, shelter from the wind Cold, avoid exogenous, infection, and pay attention to reasonable diet and rest, in order to effectively prevent the progress of the disease and promote the recovery of the disease.

3, tertiary prevention: is the active treatment of patients with end-stage renal failure, to prevent life-threatening complications, such as hyperkalemia, heart failure, severe metabolic acidosis, etc., in order to prolong the survival of patients, For a developing country with a large population in China, it is necessary to strengthen the early prevention and delay of progression of CRF, pay attention to the development, improvement and promotion of non-dialysis treatment, and dialysis and transplantation therapy should be used when saving lives.

4, follow-up: patients with chronic renal failure must be followed up regularly, the frequency of visits should be determined according to the condition, if there is high blood pressure, heart failure and the speed of deterioration of residual renal function, etc., all patients need to see at least every 3 months Once, you must ask for medical history and physical examination, and do the necessary laboratory tests, such as blood routine, urine routine, blood urea nitrogen, creatinine concentration and electrolytes, serum protein, parathyroid hormone, ferritin, C-reactive protein, etc. According to the condition, the patient is actively treated.

Chronic renal failure complications Complications, hypertension, anemia, heart failure, pericarditis, cardiomyopathy, renal osteodystrophy, fracture, dementia

Often complicated by hypertension, anemia, heart failure, pericarditis, cardiomyopathy, hydropower disorders and acid-base imbalance, renal osteodystrophy, fractures, infections, etc.

In addition to the above systemic complications, long-term dialysis patients with chronic renal failure can also have the following complications:

1. Aluminum poisoning: patients with end-stage renal disease treated by conventional dialysis are prone to aluminum poisoning, leading to chronic renal failure. There are many reasons for aluminum poisoning in regular hemodialysis patients, including: excessive aluminum in dialysate, when in dialysate When the aluminum content is close to 50g/L, the incidence of aluminum-associated bone disease is very high. Therefore, some authors suggest that the aluminum content in the dialysate should be at least 10g/L, preferably less than 5g/L, and the kidney is aluminum-plated. The only way is that aluminum absorbed during chronic renal failure accumulates in the body and causes aluminum poisoning. In patients with end-stage renal disease, the excretion of aluminum is blocked, and the accumulation of aluminum in the body is more important. The content of aluminum in the whole body can be 20 times higher than the normal value. The organs with the most aluminum accumulation are bone, liver and spleen, and the content of aluminum in the bone increases with aluminum. Related to poisoning, can lead to aluminum-related bone disease.

1982

15%25%

1

Maloney()

(>75100µg/L<10µg/L)(150200µg/L)

(DFO)40mg/kg()(44h)>150µg/L>200µg/L

2(DRA)501250%20100%221%750%1390%13100%

(1)

2-(2-microglobulin2-M)A(amyloid A)2-M2-M

2-MI118002-M2-M3mg/kg1500mg/2-M<400600mg/2-M300mg/2-M

DRA8DRA2-M

2-MDRA

2-M2-M2-M

IL-ITNF-2-M

2-M2-M3-(3-deoxyglucose)3-2-M2-M2-M

(2)DRADRA

(CTS)810930%

DRA

8

10%20%MRI

3

(1)

(2)Heinz-6-pH6.5

(3)

6

80%GFP25ml/minGFR10ml/min

1

ARFCRFCRF70%

(1)500mlCRFADHPGE2ADH12%20%CRFGFRGFR10ml/min2000ml/dGFR

CRFGFR

(2)99%50%60%10%20%10%20%1%10500mmol/dCRFCRFGFR

Na -K -ATPNa -K -ATP

CRFCRFANP(urodilatin)PGE2CRF

CRF

(3)99%3000mmol5070mmol50100mmol100%100%

CRF--(RAAS)Na -K -ATPCRFCRF

CRFCRFACEIRAAS

CRFNa -K -ATPNa -K -ATPCRF30%70%

GFR10%50100mmol1g/(kg·d)GRFACEI-10ml/min

(CRF)

(4) CRFPTHPTHPTHPTHPTHD

6070CRF4mmol/L(12mg/dl)45mmol/L(1215mg/dl)

125-(OH)2VD3PTH

PTH

PTHPTHPTH(EPO)

(5) CRFPTH125-(OH)2VD3CRFCRF

CRF

CRFDPTHCRF

(6)GFR30ml/minPTH125-(OH)2VD3

CRF-

GFR30ml/min>1.64mmol/L(4mg/dl)>2.05mmol/L(5mg/dl)

PTHPTHCRF

(7) CRFpH

H Na /H H AH

99%24h810mmolGFR10%7mmol/24hGFR1/101mmol

H Na /CRFH Na /

CRF

99%88%H 1015mmol50%H K

CRFHCO3-K Na -K pH7.407.20pH720

-ATP23-DPGpH<700

2

(1) CRF

CRFGFR25ml/min90%CRF56%

4(glucose transporter 4GluT4)(translocation)

CRF

ET-1

-

CRF

CRF-(TNF-)

CRFPTH125-(OH)2VD3

GFR40%GFR1520ml/min

CRFCRF

(2) CRFCRFCRFIGF-1

CRF(BCKAD)(BCDA)-(ubiquitin-proteasome pathwayUPP),

3

(1)CRFCRF-60%

5%CRF

(2)CRF30%CRF85%2010CRFCRFCRY

CRF

CRF

ACRF80%

BLDLLDL-AGEAGE(RAGE)-1(VCAM-1)LDLA(cyclin A)

CELDLIL-1ET-1/NOTXB2/PGI2

CRF80%3/4l/4CRF

CRF

ACRF

BNa -K -ATPNa -K ATPNa -Ca2

C--(RAAS)5%10%ACEI

DPGE2PGl2RAASCRF

AngPTHPTHCa2 -ATPNa -Ca2 -ATPNa -K -ATPPTHPKCc-fosc-jun125-(OH)2VD3

153%PTHX

CRFCRF()

(3) CRFKussmaul

XCRF

15%20%

PaO2X99mTc-Diphoaphate

CRFCRFCRF23100mm/hCRFXPCR(PPD)

(4) CRF86%

(restless-leg syndrome)45%PTH

(5) CRF

CRF

CRFCRFGPb/aTXA2PGl2()(vWF)CRF-C(tPA)-1(PAI-1)tPA/PAI-1

(6)125-(OH)2VD3PTHC

(7)

(8) CRF13.1%35.7%(PMN)()616()

PMNPMN

PMN650µg/LPMNEPO

PMN125-(OH)2VD3

PMNPMNPMNMac-l(CDllb/CDl8)S-PMNPMNPMN

(GIP-I)PMN(DIPI)(Angiogenin)(ubiquitin)P-PMN

TBCRFCD4 CD8 TCD4 /CD8 TTIL-2TTCR/CD3TPTHLDLPGE2IgGIgMIgABTFc

(9)CRFNa -K -ATP355CRF37.5

Laboratory inspection

1( )( )1.0181.010450mOsm/kgBUNScrCcr-

2CRFCRF80g/L<50g/L(HCO3-K Na Ca Mg2 P3 )<60g/L2mmol/L>1.6mmol/LCO2CPABpH

3(Scr)(BUN)-(Ccr)

4

5IgAIgMIgGC3C4TBCD4 /CD8

6-

Film degree exam

1B<1.5cmCRF

2XXCT()

diagnosis

CRF

1CRFWegner CRFBXMRICTCRF

2CRF

(1)

(2)X

(3)--ARF

(4)CRF

(5)

(6)

(7)

(8)

(9)

(10)

3CRFARFCRFARF

Differential diagnosis

()

1

(1)

(2)

(3)()

(4)

(5)

2

(1)

()

(2)

(3)

3

(1)

(2)

(3)()

(4)

(5)/;

(6)

The material in this site is intended to be of general informational use and is not intended to constitute medical advice, probable diagnosis, or recommended treatments.