Chronic renal failure(CRF). It affects various systems and organs, causing a variety of clinical manifestations. However, before 80% of the renal units are lost, or before GFP decreases to 25ml/min, there may be no symptoms or only very few biochemical changes. In chronic progressive diseases such as polycystic kidney disease, even if GFR is below 10ml/min, there may be no symptoms, which is due to the enormous adaptive capacity of the remaining renal units.
The late stage of chronic renal failure mainly causes the following various clinical lesions:
I.D. Disturbance of water, electrolyte, and acid-base balance
The basic function of the kidneys is to regulate water, electrolyte, and acid-base balance. When renal function is impaired, due to its dysfunctions in excretion or metabolism, it will inevitably cause varying degrees of water, electrolyte, and acid-base imbalance. However, unlike ARF, CRF, during its long course, due to various compensatory mechanisms of the body, these metabolic disorders sometimes do not seem very obvious. In fact, in mild to moderate CRF, the kidneys that have lost part of their function can still completely excrete various exogenous intake and substances or waste produced within the body. When normal renal function is lost by about 70%, there will generally only be partial disturbances in water, electrolyte, and acid-base balance. Only when renal function further declines, and there is an excessive intake or production of water, electrolytes, acidic or alkaline substances, will there be obvious clinical manifestations.
1. Water metabolism:The kidneys regulate the body's balance through their concentration and dilution functions. Normally, even if the daily water intake is less than 500ml, the kidneys will maintain the body's water balance through their concentration function. The concentration function of the kidneys depends on the integrity of its medullary anatomy and the transport function of substances. CRF, especially when the interstitial tubules are replaced by many fibrous tissues, due to the disordered spatial structure of the Henle loop and the distal tubule, the collecting duct and its corresponding straight blood vessels, or various active transport dysfunction, leads to a decrease in the sensitivity of the whole kidney or the collecting duct itself to ADH. As a result, the solute gradient in the renal medulla cannot be maintained, the urine concentration function decreases. In addition, to maintain normal renal blood flow and solute transport, the remaining renal units secrete excessive prostaglandins, especially PGE2, to counteract ADH, which will also damage the kidney's concentration function, causing obstacles in the reabsorption of water. The kidney's dilution function is achieved by excreting an excessive amount of free water. Normally, 12% to 20% of the renal filtrate is excreted in the form of free water. In mild CRF, due to the remaining renal units retaining their solute reabsorption function while the water reabsorption function decreases, the ratio of free water excretion to GFR is maintained, resulting in no difficulty in water excretion. Only when GFR decreases to 10ml/min, the total free water excretion is less than 2000ml/d, and with other factors such as insufficient blood volume causing a decrease in GFR and reducing the flow of the distal renal tubule solution, water retention will occur. Therefore, it is urgent to limit intake to prevent excessive water intake and water intoxication.
In chronic renal failure (CRF), both water retention and dehydration can occur, along with dilutional dysfunction of urine. Indiscriminate excessive water intake and the large-scale atrophy of renal units in the late stage of the disease can lead to the occurrence of water retention; while the latter can occur especially when the urine concentration function is severely decreased, leading to dehydration, which is manifested clinically as polyuria and nocturia. Nocturia is because the solutes such as dietary intake and metabolic products in the body cannot be completely excreted during the day and must be excreted at night. Of course, when patients have other acute diseases or mental disorders that cause a decrease in water intake or increased water demand, such as fever, insensible water loss, and vomiting or diarrhea, it can also cause dehydration, leading to insufficient blood volume, decreased glomerular filtration rate, further deterioration of renal function, which in turn promotes more water loss, aggravating uremia, forming a vicious cycle. However, if overhydration occurs too quickly, it can also lead to water retention.
2, Sodium metabolism:The kidney maintains fluid balance not only in its regulation of water balance but also in its regulation of sodium balance and blood volume stability. Since sodium is mainly distributed in the extracellular fluid, it affects the extracellular volume and the distribution of water between the cells and extracellular fluid. Therefore, sodium balance plays a very important role in the whole process. Under normal dietary salt load and cardiovascular system stability, about 99% of sodium in the glomerular filtrate is reabsorbed into the blood by the renal tubules, of which 50% to 60% occurs in the proximal tubules, 10% to 20% in the loop of Henle, and 10% to 20% in the distal renal unit, but the mechanisms are different. The sodium excreted outside the body accounts for less than 1% of the glomerular filtrate. The sodium balance varies with the dietary sodium load. Under normal dietary sodium load of 10 to 500 mmol/d, the normal kidney can maintain sodium balance. In the case of chronic renal failure (CRF), the sensitivity of kidney regulation of sodium balance decreases, directly leading to changes in extracellular volume. Although some patients may experience salt loss due to different primary diseases, CRF is mainly manifested as sodium retention, the fundamental cause of which lies in the decrease in glomerular filtration rate (GFR) leading to decreased sodium filtration.
With the destruction of renal units, the glomerular filtration of sodium decreases, resulting in temporary increase of extracellular fluid volume due to increased sodium levels, thus increasing cardiovascular load. The increased cardiac output promotes compensatory increase in the filtration of sodium salts.
With sodium retention, the body can produce various adaptive natriuretic substances, inhibit the activity of Na-K-ATPase on the basolateral membrane of renal tubular epithelial cells, inhibit sodium reabsorption, such as digoxin-like natriuretic factor, atrial natriuretic peptide, etc., among which the digoxin-like natriuretic factor can block the Na-K-ATPase in cells of various tissues throughout the body.
Insufficient aldosterone production or decreased aldosterone response in the renal tubules during CRF can also promote natriuresis. During CRF, many vasoactive substances increase in level and have natriuretic effects on the kidneys, such as the ANP-derived kidney-derived urodilatin (urodilatin) acting on the renal medulla to inhibit sodium reabsorption; prostaglandins, especially PGE2, can not only increase glomerular capillary blood flow to promote sodium filtration but also directly inhibit renal tubular sodium reabsorption; other vasoactive substances such as kininase are also involved in the adaptive changes of sodium retention during CRF.
In clinical practice, the various manifestations caused by abnormal sodium metabolism during CRF are mainly attributed to these adaptive processes in the early stage. For example, with the increase of sodium and fluid inside the cells, the cells are prone to depolarization, which may especially cause neuromuscular dysfunction, such as muscle spasms and muscle weakness. An increase in natriuretic substances can also lead to cell dysfunction, such as the cardiotonic-like substances in the circulation can cause an increase in cellular calcium, leading to hypertension. Therefore, with the progression of renal function, it is necessary to strictly control dietary intake to reduce these adaptive processes. However, due to the decreased sensitivity of renal lesions to the regulation of excessive or insufficient sodium intake, dietary sodium intake must be cautious. A sudden increase in sodium load can cause excessive volume, leading to hypertension and congestive heart failure; conversely, a sudden decrease in sodium intake, especially when the kidney has produced adaptive processes, can cause sodium deficiency.
3. Potassium balance:Potassium is the second largest cation in the body, 99% distributed within the cells, accounting for about 3000 mmol, while extracellularly it contains only 50-70 mmol. The potassium content in normal diet is about 50-100 mmol, and after absorption into the body, it mainly enters the cells. The balance of potassium in the body depends on an excessive amount of potassium flowing from inside the cells to outside, and then excreted by various excretory organs. The kidney is the main organ for excreting potassium in the body, but almost 100% of the potassium filtered out by the glomerulus is reabsorbed before the Henle loop. The potassium in the urine comes from the secretion of the distal tubules. In addition, under normal circumstances, when potassium load is administered, the potassium excretion fraction of the kidney can reach more than 100%. With the decline in renal function, as long as various adaptive functions are normal, the excretion fraction will also increase significantly. Therefore, potassium retention only occurs in severe renal insufficiency or sudden oliguria.
The adaptive changes in the kidney during CRF first initiate the renin-angiotensin-aldosterone system (RAAS) to act on the distal tubules to promote potassium excretion. With the decrease in potassium excretion, the intrinsic characteristics of renal tubular epithelial cells change, such as the increased activity of Na-K-ATPase promoting potassium excretion, the cause is related to hyperkalemia and aldosterone. Other body fluid factors, such as dopamine, can directly act on the distal tubules to promote potassium excretion without depending on aldosterone, and the mechanism is not yet clear. During CRF, many non-adaptive changes will also promote potassium excretion, such as the increased osmotic load of the surviving renal units can increase the flow of the filtrate in the distal renal units and increase potassium excretion; chronic metabolic acidosis, especially when combined with excessive loss of bicarbonate in the proximal tubules during CRF, can lead to decreased potassium reabsorption.
Some patients with CRF may exhibit refractory hyperkalemia in clinical practice, even if renal damage is not too severe, which is known as potassium secretion disorder. These patients often have insufficient or decreased activity of mineralocorticoid production, adrenal insensitivity to renin stimulation, such as primary or secondary adrenal insufficiency in CRF, and iatrogenic factors such as the use of non-steroidal anti-inflammatory drugs, ACEIs, and heparin that inhibit RAAS at different levels. Some patients may clinically present with hyperkalemia accompanied by mild type IV renal tubular acidosis. Other conditions such as early diabetic nephropathy with insufficient blood insulin levels not only reduce potassium excretion but also alter potassium intracellular and extracellular redistribution, promoting hyperkalemia. Potassium secretion disorder can also occur when the level of mineralocorticoids in the blood is normal or slightly elevated, which often occurs in obstructive nephropathy, interstitial nephritis, lupus nephritis, sickle cell disease, amyloidosis, renal transplant rejection, and hereditary tubular dysfunction. In these patients, the potassium excretion fraction does not increase due to adaptive changes as renal insufficiency progresses, indicating an inherent defect in tubular function. Other factors such as potassium-sparing diuretics and some antibiotics such as trimethoprim can also cause refractory hyperkalemia, which should be paid attention to.
In addition to the adaptive changes in the kidneys that increase potassium excretion during CRF, many extrarenal adaptive changes can also promote potassium excretion, mainly in the intestinal mucosa, especially the colon mucosa, which can exist Na-K-ATPase like renal tubular epithelial cells and respond to aldosterone. High potassium itself can also directly stimulate Na-K-ATPase. In severe CRF, intestinal potassium excretion can increase by 30% to 70%.
Although potassium excretion by the kidneys decreases as renal function deteriorates, various adaptive changes are sufficient to maintain potassium balance in the body, unless renal function suddenly worsens or dietary potassium intake increases dramatically, the risk of hyperkalemia is still relatively low. In fact, if the GFR is above 10%, the daily potassium excretion by the kidneys can still reach 50-100 mmol. At this time, general dietary control, such as a moderate low-protein and low-potassium diet of 1g/(kg·d), can maintain potassium balance in the body. However, in the presence of high catabolism such as fever, infection, hemolysis, gastrointestinal bleeding, tissue damage, hematoma, burn, and surgery, as well as pre-renal GRF decline such as insufficient blood volume or congestive heart failure, the use of various drugs that can reduce potassium excretion such as potassium-sparing diuretics, ACEIs, β-adrenergic blockers, heparin, non-steroidal anti-inflammatory drugs, and methyldopa, even if renal damage is not too severe, can also cause hyperkalemia. Of course, if renal function is severely reduced below 10ml/min, hyperkalemia can also occur even in the absence of the above causes.
Some patients with chronic renal failure (CRF) may also have low blood potassium levels, mainly due to insufficient intake, excessive use of diuretics, and in some cases, patients with distal renal tubular acidosis may also have low blood potassium levels. However, when severe renal failure is accompanied by hypokalemia, although potassium supplementation is necessary, it must be done with great caution to prevent sudden hyperkalemia.
4, Phosphorus Metabolism:Early in CRF, PTH levels can rise. PTH can inhibit the reabsorption of phosphorus in the renal tubules and promote the release of bone calcium and intestinal reabsorption to alleviate hypocalcemia. However, as renal function progresses, this effect is no longer compensatory. For example, the gradually increasing phosphorus levels can directly inhibit the effect of PTH, thereby reducing the adaptive changes of PTH. Phosphorus can inhibit the bone calcium release effect of PTH, interfere with intestinal reabsorption, and cause the re-deposition of calcium salts in the bone. Phosphorus can also inhibit the hydroxylation of vitamin D in the renal tissue.
In clinical practice, the series of manifestations caused by phosphorus metabolism disorder is mainly due to hyperphosphatemia and secondary hyperparathyroidism. Hyperphosphatemia itself can induce metastatic calcification and tissue damage. Metastatic calcification in the skin and subcutaneous tissue presents as itching, corneal calcification causes keratoma, subconjunctival calcification presents as acute irritative symptoms and 'sick eye', periarticular calcification leads to tendinitis and arthritis, calcification of the vascular wall can cause permanent ischemia. Other calcifications such as those in the heart, lungs, and brain can cause cardiac conduction disorders, mitral stenosis, restrictive and fibrotic lung disease, and 'organic brain disease'. Renal tissue calcification can cause renal damage and become one of the pathogenesis mechanisms of kidney disease. Other rare metastatic calcifications present as soft tissue necrosis, tumor calcinosis disease, etc. When the calcium-phosphorus product exceeds 60-70, the risk of metastatic calcification significantly increases. However, even in CRF, blood calcium levels can be well regulated. Therefore, it is mainly determined by phosphorus levels. It is generally considered that when blood phosphorus levels exceed 4 mmol/L (12 mg/dl), it indicates an increased phosphorus burden in the body. When it exceeds 4-5 mmol/L (12-15 mg/dl), the risk of metastatic calcification significantly increases.
Secondary hyperparathyroidism mainly causes osteodystrophy, clinically presenting as proximal myopathy, soft tissue calcification, and bone disease. Bone disease mainly includes the following series of manifestations:
(1) Osteomalacia: Characterized by incomplete bone mineralization, the formation of various osteoid, and its pathogenesis is low calcium, high phosphorus, decreased activity of 1,25-(OH)2VD3, increased PTH, and other factors such as acidosis, uremic toxins, aluminum poisoning, and malnutrition.
(2) Fibrous Osteitis: Primarily caused by PTH, characterized by increased osteoclast activity, bone salt dissolution, and presenting as a spongy disease, with trabecular formation in cancellous bone.
(3) Fibrous Osteitis: The most characteristic lesion of secondary hyperparathyroidism, mainly involving subperiosteal bone resorption, which can occur in the hands, long bones, clavicle, and skull. Clinically, it presents as bone disease, arthritis, or periarthritis, weakness of proximal muscles, and growth and development delay in children. Biochemical examination shows increased alkaline phosphatase and abnormal calcium-phosphorus metabolism to varying degrees, significantly elevated PTH levels, inactive carboxyl-terminal fragments and active amino-terminal fragments in urine, and the symptoms and signs can be alleviated to some extent after subtotal parathyroidectomy. In addition, the elevated PTH levels are also related to uremic encephalopathy, decreased recognition function, and anemia. It is reported that PTH can inhibit the production of erythropoietin (EPO).
5, Calcium metabolism:In CRF, the main manifestation is hypocalcemia, with a very complex mechanism, such as phosphorus retention, PTH action, toxic effects of uremic toxins, decreased renal volume, and insufficient or decreased activity of 1,25-(OH)2VD3. The main manifestation of calcium metabolism disorder in CRF is hypocalcemia, but the body can still undergo various adaptive changes to maintain blood calcium levels temporarily. For example, decreased calcium filtration by the kidneys in the early stage of CRF can play a certain adaptive role, but it can gradually weaken as renal function decreases.
Clinically, hypocalcemia can increase neuromuscular irritability, which is a common cause of cramps and other symptoms in CRF patients. However, due to the high solubility of calcium in acidic solutions, although the overall blood calcium level may be low during acidosis, the level of free calcium is still normal, and hypocalcemia symptoms may not appear. However, once acidosis is corrected quickly, these symptoms may reappear, and sufficient attention should be paid to them in clinical practice.
In some cases of CRF, hypercalcemia may also occur, which is mostly a major factor in the progression of certain kidney diseases, such as multiple myeloma, primary hyperparathyroidism, vitamin D intoxication, ectopic production of PTH by tumor tissue, milk-alkali syndrome, myxoid sarcoma, and others. Other factors such as long-term bed rest in CRF patients and aluminum intoxication can also cause hypercalcemia.
6, Magnesium metabolism:It is mainly hypermagnesemia caused by reduced glomerular filtration, but before GFR decreases to 30ml/min, various adaptive changes inside and outside the kidney can temporarily maintain magnesium balance. The main adaptive changes inside the kidney are to reduce tubular magnesium reabsorption and increase the magnesium excretion fraction. In addition to the increased magnesium burden directly inhibiting tubular magnesium reabsorption, other factors such as osmotic diuresis, acidosis, decreased PTH responsiveness, and calcitonin can also inhibit magnesium reabsorption. The main adaptive changes outside the kidney are a decrease in intestinal reabsorption, mainly related to the decreased activity of 1,25-(OH)2VD3 and uremic toxins. Other factors such as increased blood magnesium levels and increased magnesium uptake by bone tissue and cells also have a certain buffering effect.
In some cases of CRF, magnesium deficiency may also occur, mainly seen in tubulointerstitial diseases of the kidney, especially in nephrotoxicity caused by cisplatin, aminoglycoside antibiotics, and pentamidine. Recent studies have also found that long-term alcohol consumption can lead to excessive reversible tubular magnesium loss.
When GFR is below 30ml/min, various adaptive changes are insufficient to counteract the retention of magnesium in the body. Especially when consuming a diet rich in magnesium, hypermagnesemia may occur, but there are usually no obvious clinical symptoms. When the serum magnesium concentration is greater than 1.64mmol/L (4mg/dl), it can cause drowsiness, speech disorders, and decreased appetite; when it is greater than 2.05mmol/L (5mg/dl), it can significantly suppress neuromuscular function, leading to drowsiness, decreased blood pressure, weakened tendon reflexes, and muscle weakness. As the serum magnesium concentration further increases, bradycardia, atrioventricular conduction or ventricular conduction blockage may occur, and in severe cases, it can lead to sudden cardiac arrest.
In addition, magnesium has a certain influence on calcium balance and bone metabolism. High levels of magnesium can directly inhibit the reabsorption of the renal tubules, leading to increased urinary calcium. However, high levels of magnesium can also inhibit the secretion and responsiveness of PTH, thereby lowering blood calcium. Some researchers have reported that magnesium deficiency can inhibit PTH secretion, so the effect of magnesium on calcium is not yet definitive. The main effect of magnesium on bones is to interfere with their normal mineralization process, which is related to malnutrition of bone in CRF.
7. Metabolic acidosis:In the early stage of CRF, acidosis in the body is not significant, mainly maintained by a series of extrarenal and intrarenal compensatory changes to maintain the pH value of body fluids. Intrarenal compensatory changes include:
(1) Partial compensatory increase in H+ excretion by the remaining renal units: This can occur in the proximal renal tubules, the ascending limb of the loop of Henle, and the cortical collecting ducts. The former mainly increases the activity of the luminal Na/H antiport protein, while the latter increases the number of A-type intercalated cells that regulate H+ secretion by increasing the excretion of H+.
(2) Increased production of ammonia by the remaining renal units.
(3) Decreased excretion of citrate: Under normal circumstances, it can be freely filtered by the glomeruli, with 99% reabsorbed in the proximal renal tubules, containing 8-10 mmol in the urine per 24 hours. When the glomerular filtration rate (GFR) decreases to 10%, the excretion rate of citrate in the urine decreases only slightly, approximately 7 mmol/24h. When the GFR decreases to 1/10 of normal, the excretion of citrate in the urine can decrease proportionally to about 1 mmol. However, the concentration of citrate in the blood does not significantly increase, indicating that most of the retained citrate can be metabolized and increase the alkaline reserve in the body.
(5) Increased reabsorption of citrate in the renal tubules: Citrate in the renal tubules is reabsorbed in the form of H-citrate and is regulated by the Na/citrate co-transport protein. During CRF, the increased activity of the remaining renal units' Na/H and Na/citrate co-transport proteins is beneficial for the reabsorption of citrate; the reabsorbed citrate can be used to synthesize bicarbonate.
(6) In some cases of chronic renal failure (CRF), the increased level of aldosterone in the blood can directly or indirectly affect the acidification function of the distal tubules and the production of ammonia through the excretion of potassium.
Extrarenal compensation primarily involves intracellular and extracellular protein buffering during acute acid load, while chronic acid load mobilizes alkaline reserves in the body, mainly the skeletal system. Bones are the largest alkaline reserve in the body, storing about 99% of calcium and 88% of carbonates. Research shows that when H+ ions accumulate in the body beyond 10-15 mmol, approximately 50% of the bone alkaline reserve needs to be mobilized. This is related to both usual biochemical reactions and bone resorption. During acidosis, the activity of osteoblasts decreases, while that of osteoclasts increases. Finally, extrarenal compensation includes increased intracellular H+ flow during acidosis, which has a certain effect on acute acid load, but at the cost of increasing the concentration of K+ ions in the cells.
Clinically, due to the above series of adaptive changes in CRF, acidosis is often not severe, and the concentration of HCO3- is maintained. However, this is at the cost of an increase in a series of compensatory functions of the body. Acute acidosis, the main harm is cardiovascular and central nervous system dysfunction, which can produce lethal ventricular arrhythmias, decreased myocardial contractility, and decreased responsiveness to catecholamines. The occurrence of arrhythmias is mainly related to the increase in extracellular K+ caused by acidosis. Of course, the inhibitory effect of acidosis on the Na-K pump of myocardial cell membranes is also one of the causes. Although the adrenal medulla releases adrenaline, which has a positive inotropic effect on the heart during acidosis, severe acidosis can block the effect of adrenaline on the heart, leading to decreased myocardial contractility. Generally speaking, when the pH is between 7.40 and 7.20, the two opposite effects are almost equal, and the change in myocardial contractility is not significant. When the pH is less than 7.20, myocardial contractility decreases due to the blockade of the effect of adrenaline.
During acidosis, the responsiveness of the vascular system to catecholamines is low, mainly evident in precapillary sphincters, while the changes in small veins are not significant. Peripherally, blood vessels dilate, blood pressure slightly decreases, and the central nervous system is mainly functionally inhibited. In severe cases, it can lead to drowsiness, coma, which is related to the increase in γ-aminobutyric acid levels in brain tissue caused by acidosis, the weakening of oxidative phosphorylation process, and insufficient ATP supply. In the respiratory system, acidosis mainly causes respiratory reserve deficiency, manifested by deepening and acceleration of respiration. In addition, acidosis can shift the oxygen dissociation curve of tissues to the left, and reduce tissue oxygen supply, which is due to the suppression of 2,3-DPG production in red blood cells by acidosis. When severe acidosis occurs, such as pH
IIGlucose, fat, protein, and amino acid metabolism disorders
1. Glucose metabolism disorder:The mechanism of CRF's disorder in glucose metabolism is multifaceted, involving almost every aspect of glucose metabolism, but mainly includes: insulin resistance; increased liver glucose output; abnormal insulin secretion; decreased clearance rate of insulin by the kidney.
Insulin resistance, that is, the decrease in insulin sensitivity, can occur in the early stage of CRF, before GFR decreases to 25ml/min, mainly occurs in peripheral tissues, especially muscle tissues, because muscles almost metabolize more than 90% of the body's glucose load. The glucose clamp test shows that the glucose utilization rate of muscle tissue in CRF decreases by more than 56%, and the main mechanisms include:
(1) Decreased peripheral tissue vasodilatory effect of insulin to glucose, and insulin transport obstacle to peripheral tissue.
(2) Abnormal translocation of insulin-stimulated glucose transporter 4 (glucosetransporter 4, GluT4) from intracellular to cell surface due to post-receptor signaling pathway disorder of insulin.
(3) The activity of key enzymes involved in intracellular glucose metabolism regulated by insulin decreases, leading to abnormal aerobic or anaerobic glucose metabolism and decreased glycogen synthesis, such as pyruvate dehydrogenase, phosphoenolpyruvate carboxykinase, and glycogen synthase, all of which show significant decreases in activity during CRF.
(4) There are many substances in the blood that can antagonize insulin activity, such as free fatty acids, growth hormone, glucagon, ET-1, and uremic toxins such as pseudouridine.
(5) High-protein diet and anemia can both lead to decreased insulin sensitivity. With the administration of low-protein diet plus alpha-keto acids and the correction of anemia, insulin sensitivity also improves.
(6) Acidosis is a common abnormality in CRF, which can lead to decreased insulin sensitivity, and the mechanism is not yet clear.
(7) During CRF, various cytokines increase, especially tumor necrosis factor-alpha (TNF-α), which can inhibit the action of insulin in many tissues.
The increased liver glucose output is mainly manifested as increased gluconeogenesis in CRF. Abnormal secretory mechanism of the islets of Langerhans to glucose stimulation is mainly reflected in two aspects: on the one hand, beta cells of the islets can increase insulin secretion to overcome peripheral tissue resistance to insulin, which can make the glucose tolerance test normal; on the other hand, beta cells of the islets become less sensitive to glucose stimulation, leading to reduced insulin secretion. The main reason is that the increased blood PTH level due to secondary hyperparathyroidism and the decreased activity of 1,25-(OH)2VD3 lead to increased calcium levels in the beta cells of the islets, which inhibits insulin secretion.
With the decline in renal function, the renal clearance rate of insulin also decreases. When GFR decreases to less than 40%, tubular cells around the kidney can increase insulin uptake and degradation to maintain blood insulin levels. However, when GFR decreases to 15-20 ml/min, it will eventually lead to a decrease in insulin clearance.
In addition, spontaneous hypoglycemia can also occur during CRF. Diabetic patients may have a decreased demand for insulin, mainly seen in cases where peripheral tissue resistance to insulin is not significant, while renal clearance of insulin has significantly decreased. Of course, during CRF, long-term insufficient intake and severe malnutrition can also lead to hypoglycemia.
2. Disorders of protein and amino acid metabolism:CRF patients often show protein, amino acid synthesis, increased catabolism and negative nitrogen balance. If not corrected in time, in children, it can lead to delayed growth and development, while in adults, it manifests as protein malnutrition, which seriously affects the patient's recovery, wound healing, and increases the risk of infection, and is an important factor in increasing the incidence and mortality of CRF patients. In addition to anorexia and long-term low-protein diet that can cause protein metabolism disorders, the inherent pathophysiological changes in the pathogenesis of CRF are also important factors in causing or aggravating protein metabolism disorders, mainly including metabolic acidosis, insulin resistance, secondary hyperparathyroidism, increased corticosteroid levels, uremic toxins and IGF-1 resistance, and some cytokines, etc.
Metabolic acidosis can accompany the entire process of CRF. On one hand, it can increase the activity of branched-chain amino acid ketoglutarate dehydrogenase (BCKAD), promote the decomposition of branched-chain amino acids (BCAA), and on the other hand, it can activate various enzyme systems that promote protein degradation, especially the ubiquitin-protein degradation pathway (ubiquitin-proteasome pathway, UPP), further promoting the increase in protein degradation.
Three, Dysfunction of various systems
1, Digestive system:Symptoms of the digestive system are the earliest and most prominent manifestations of CRF, often acting as a diagnostic clue for CRF. Early manifestations include anorexia, a feeling of fullness in the gastrointestinal tract after eating, with the progression of renal function, especially during uremia, symptoms such as nausea, vomiting, diarrhea may occur. In severe cases, it can lead to water, electrolyte, and acid-base balance disorders, aggravating the symptoms of uremia, forming a vicious cycle. Stomatitis and oral mucosal ulcers are also not uncommon during uremia, and patients may have halitosis, an ammonia-like smell, and the parotid glands are often swollen. The esophageal mucosa may have focal hemorrhage, and most patients may also have symptoms of gastric or duodenal ulcers, with an incidence of ulcer disease confirmed by endoscopy reaching more than 60%, and gastritis and duodenitis are also very common. Symptoms are often confused with ulcers.
In addition, upper gastrointestinal bleeding is very common in uremic patients, which can cause hematemesis, black stools, and in severe cases, massive bleeding accounting for about 5% of the total deaths of uremia. The cause is related to superficial mucosal lesions of the gastrointestinal tract, peptic ulcers, underdevelopment of gastric and duodenal blood vessels. In CRF, platelet dysfunction, vascular wall sclerosis, and abnormal coagulation mechanism will also cause and worsen the tendency of upper gastrointestinal bleeding to some extent.
2, Cardiovascular system:Cardiovascular diseases are common complications of CRF and also the leading cause of death during the progression to uremia. Moreover, with the popularization and development of renal replacement therapy, the incidence has decreased. A study group shows that 30% of CRF patients may have symptoms of heart failure, but echocardiographic examination confirms that almost more than 85% of patients have changes in cardiac structure. Another study shows that the mortality rate of cardiovascular disease in uremic dialysis patients is 20 times higher than that of the general population, and the mortality rate of cerebrovascular disease is more than 10 times higher. Cardiovascular complications of CRF include atherosclerosis, hypertension, cardiomyopathy, pericarditis, and heart failure. The main cause is metabolic abnormalities in the development process of CRF itself, plus complications of renal replacement therapy and underlying cardiovascular system diseases that caused CRY.
(1) Atherosclerosis: Atherosclerosis is one of the important manifestations of cardiovascular system abnormalities in CRF patients, and it is positively correlated with the high incidence of coronary heart disease and cerebrovascular accidents.
The causes of the occurrence of atherosclerosis in CRF include:
A, Mechanical factors: The main factors include hypertension and changes in shear force. Hypertension occurs in up to 80% of CRF patients, which can increase vascular wall tension, promote the migration of macrophages to the vascular endothelium, and directly activate pressure-dependent ion channels. It can also cause vascular ischemia and hemorrhage.
B. Metabolic and humoral factors: including disorders of lipid and sugar metabolism, hyperhomocysteinemia, and smoking, etc. Disordered lipid metabolism can not only promote atherosclerosis but also be modified lipoproteins such as oxidized, carbamylated, and non-enzymatically glycosylated lipoproteins, especially oxidized LDL, non-enzymatically glycosylated late products such as oxidized LDL-AGE, which not only have the effect of lipoproteins but can also bind to AGE receptors (RAGE) on vascular endothelial cells to induce the expression of vascular adhesion factor-1 (VCAM-1), promoting the aggregation of monocytes in the vascular endothelium. Hyperglycemia and hyperinsulinemia, in addition to causing disorders of lipid metabolism, can also cause damage by producing oxygen free radicals through non-enzymatic glycosylation and autoxidation. Hyperhomocysteinemia is related to folate deficiency, which can promote the autoxidation of LDL, thrombosis within the blood vessels, and can also increase the expression of cyclin A (cyclin A) in vascular endothelial cells, stimulating the proliferation of vascular endothelial cells.
C. Other factors promoting atherosclerosis: such as calcium and phosphorus metabolism disorders, which can not only cause calcification of atherosclerotic plaques but also induce calcification of the aortic valve. Vitamin E deficiency can promote the autoxidation of LDL, increase the adhesion and aggregation of platelets and monocytes in the vascular endothelium, and inhibit the production of oxygen free radicals and IL-1β by monocytes, as well as the proliferation of vascular smooth muscle cells. The imbalance of vasoconstrictive substances and vasodilatory substances produced by vascular endothelial cells and platelets, such as ET-1/NO, TXB2/PGI2, can also promote the occurrence of atherosclerosis.
The result of atherosclerosis can cause remodeling of arterial structure, including diffuse expansion, hypertrophy, and stiffness of large, medium, and small arteries. On the other hand, it can cause changes in cardiac structure and insufficient myocardial blood supply, such as hypertrophy of the left ventricle and a decrease in myocardial blood flow under the endocardium.
(2) Hypertension: The incidence of hypertension in CRF patients reaches 80%, and almost all patients who require renal replacement therapy have hypertension. Three-quarters of the patients can control hypertension by adopting a low-sodium diet and dialysis to remove excess extracellular fluid from the body. Another one-fourth of the patients have an increase in blood pressure after dialysis to remove excess sodium and water from the body. In addition, hypertension in CRF patients has its inherent characteristics, such as the loss of the physiological trend of nocturnal blood pressure decrease, and some may be simple systolic hypertension.
The pathogenesis of CRF hypertension mainly includes:
A. Imbalance of sodium balance leads to water and sodium retention, an increase in total extracellular fluid volume, which increases cardiac output, followed by an increase in peripheral resistance, which is the primary factor of CRF hypertension. By controlling water and sodium intake, diuresis, and dialysis, improvement is expected.
B. The increase of endogenous digitalis-like factors is a compensatory response of the body to sodium retention, which can inhibit the activity of Na-K-ATPase in renal tubular epithelial cells, reduce renal sodium reabsorption. However, this substance also inhibits the activity of Na-KATPase in vascular smooth muscle cells, leading to an increase in intracellular sodium levels, inhibiting Na-Ca2+ exchange, a decrease in calcium efflux from intracellular, an increase in calcium levels in vascular smooth muscle cells, resulting in increased tension in vascular smooth muscle and increased sensitivity of vascular smooth muscle cells to vasoconstrictive substances.
C. Disruption of the renin-angiotensin-aldosterone system (RAAS), accounting for only 5% to 10% of renal failure patients, can control blood pressure with the use of ACE inhibitors or bilateral nephrectomy.
D. The reduction of antihypertensive substances secreted by the kidney, such as PGE2, PGI2, kinins, and renal medullary antihypertensive lipids, not only dilates blood vessels and promotes natriuresis and diuresis but also counteracts the RAAS. Long-term hypertension not only promotes atherosclerosis and damages the heart but is also an important factor in cerebrovascular accidents in CRF patients.
(3) Cardiomyopathy: Also known as uremic cardiomyopathy, it refers to specific myocardial dysfunction caused by uremic toxins. Pathologically, the characteristic change is interstitial myocardial fibrosis. The causes include uremic toxins, lipid metabolism disorders, and deficiency of carnitine, local Ang II action, and dialysis-related amyloidosis. In recent years, PTH in uremic toxins has been considered an important factor in uremic cardiomyopathy. PTH not only causes metastatic calcification within the myocardium but also inhibits the activity of myocardial cell membrane Ca2-ATPase, Na-Ca2-ATPase, and Na-K-ATPase, promoting an increase in cellular calcium load. Studies have also found that PTH can cause left ventricular hypertrophy, which may be related to increased cellular calcium or activation of PKC, inducing the expression of proto-oncogenes such as c-fos, c-jun, etc. The removal of the parathyroid gland, 1,25-(OH)2VD3, and calcium channel blockers can alleviate uremic cardiomyopathy. Clinically, the most prominent manifestation of uremic cardiomyopathy is left ventricular hypertrophy and decreased left ventricular diastolic function, including congestive heart failure, arrhythmias, and ischemic heart disease.
(4) Pericarditis: The incidence of pericarditis is about 15.3%, which can be divided into uremic pericarditis and dialysis-related pericarditis. The former mainly occurs before or at the beginning of dialysis, caused by metabolic abnormalities of uremia itself, including uremic toxins, electrolyte and water metabolism disorders, secondary hyperparathyroidism, infection, and others; the latter may be related to insufficient dialysis, leading to the accumulation of body fluids and certain toxins, especially middle molecular substances and PTH, etc. Other factors include cell or viral infection during dialysis, heparin administration, and low platelet function. Pathologically, both types of pericarditis show similar features, both being fibrinous pericarditis with exudation and hemorrhage, which can develop into encapsulated fibrosis, subacute or chronic constrictive pericarditis. Patients often have chest pain, which worsens in the supine position and during deep breathing. Fever is more common in dialysis-related pericarditis.粗糙的心包摩擦音或扪及摩擦感 may be heard in the precordial area, and signs of varying degrees of pericardial effusion may be present. Severe cases may develop cardiac tamponade, which is more common in dialysis-related pericarditis and is often related to heparin overdose, commonly leading to death due to acute circulatory failure. Patients may also have varying degrees of atrial arrhythmias, and electrocardiogram and X-ray examination may show characteristic changes. Sudden decrease in blood pressure or hypotension during dialysis is an extremely important diagnostic clue. Uremic pericarditis responds well to intensified dialysis treatment, and for those with poor dialysis response, infection, inflammation, and immune factors should be considered. For dialysis-related pericarditis, it is necessary to change the dialysis treatment plan, such as hemodialysis filtration and peritoneal dialysis, etc.
(5) Heart failure: It occurs during the development of CRF and is an important cause of death in CRF patients. Heart failure is often manifested as palpitations, shortness of breath, orthopnea, distension of the jugular veins, enlargement of the liver and edema. In severe cases, acute pulmonary edema may occur. Hemodialysis treatment is often effective, but positive inotropic drugs such as digitalis often have poor response and are prone to accumulate and cause poisoning in the body. Drugs to improve pre- and post-load of the heart, such as dopamine, sodium nitroprusside, and phenylephrine (Regitine), can sometimes have a relieving effect on symptoms.
3. Respiratory system:In the early stage of CRF, a decrease in lung volume, restrictive ventilation disorders, and a decrease in oxygen diffusion capacity often occur. When accompanied by metabolic acidosis, shortness of breath may occur, even Kussmaul breathing. When entering the uremic stage, uremic lung, uremic pleurisy, and pulmonary calcification may occur, and the incidence of pulmonary infection increases significantly.
Uremic lung refers to the butterfly-shaped shadow centered on the hilum and radiating to both sides on the chest X-ray in uremia. Pathologically, it is mainly characterized by pulmonary edema, with the formation of hyaline membranes rich in fibrin on the alveoli. This is mainly due to excessive body fluids, hypoproteinemia, congestive heart failure, and retention of uremic toxins during CRF, especially some uremic toxins can significantly increase the permeability of pulmonary capillaries. It is generally more common in the late stage of uremia and is often manifested clinically as cough, blood-tinged sputum, and dyspnea.
The incidence of uremic pleurisy can reach 15% to 20%, and severe cases can present with pleural effusion, which can be exudative or hemorrhagic, and can occur unilaterally or bilaterally simultaneously. It can be caused by multiple factors, such as uremic toxins increasing the permeability of pleural capillaries, congestive heart failure leading to pleural effusion, platelet dysfunction causing bleeding in the pleural cavity, and heparin used during hemodialysis causing coagulation disorder, etc.
Pulmonary calcification is the manifestation of metastatic calcification caused by secondary hyperparathyroidism in the lungs, which has attracted increasing attention in recent years. Pathologically, there is calcification in the alveolar septum, hardening of the lung tissue, increased weight, widening of the alveolar septum leading to fibrosis, and calcification can also be seen in the bronchial wall and small artery wall, leading to reduced diffusion capacity of the lungs, ventilation disorders, and decreased lung volume. Clinically, it is mainly manifested as dry cough, shortness of breath, decreased PaO2 and arterial oxygen content in blood gas analysis, and the degree of decrease is linearly related to the extent or severity of lung calcification. Simple chest X-ray often cannot clearly show metastatic calcification, but it can also present as diffuse infiltration, which is often confused with pulmonary edema and infection. If 99mTc-Diphosphate scan is performed, it can help in differential diagnosis.
CRF is often accompanied by decreased immune function, along with anemia, malnutrition, metabolic acidosis, and other factors that impair the body's defense mechanism, leading to various infections in CRF patients, especially in those with diabetes, collagen disease, advanced age, and hormone use. It is particularly worth noting that in recent years, the incidence of tuberculosis in CRF patients has increased compared to the general population, often accompanied by extrapulmonary tuberculosis such as lymph nodes, liver, bones, and hematic disseminated granulomatous pulmonary tuberculosis. If not treated in time, it may lead to death. Two to three months after dialysis in the late stage of renal failure is a favorable period for tuberculosis. Recurrence of old tuberculosis is also common. Clinically, there may be a lack of typical tuberculosis symptoms, such as high fever, weight loss, anorexia, and other symptoms that do not respond to general antibiotics. The peripheral blood white blood cell count may increase, and the erythrocyte sedimentation rate may reach more than 100mm/h. When CRF is complicated with tuberculosis, there may be no typical tuberculosis signs on the X-ray chest film, and the detection rate of sputum smear or culture is also not high. Due to low immune function, the tuberculin skin test often shows false-negative results, making it difficult to diagnose clinically. According to reports by Chinese scholars, the use of sputum tuberculosis PCR examination and determination of blood tuberculin purified protein derivative (PPD) can significantly improve the diagnostic rate.
4. Nervous system:Abnormalities in the nervous system of chronic renal failure (CRF) can be divided into central nervous system lesions and peripheral nervous system lesions, with an incidence rate of up to 86% during the uremic stage.
In the early stage, central nervous system abnormalities often manifest as functional inhibition, such as apathy, fatigue, and decreased memory. When the condition worsens, there may be disorders of memory, judgment, orientation, and calculation ability, and there may also be euphoria or depression, delusions, and hallucinations. There may be flapping tremors, and it may eventually develop into somnolence and coma. Pathological changes include cerebral parenchymal hemorrhage, edema, or pinpoint hemorrhage, gliosis, or hyperplasia, and electroencephalography often shows significant abnormalities with an increase in slow waves.
Peripheral neuropathy commonly presents with lower limb pain, burning pain, and hyperesthesia, which disappear after exercise, hence patients often move their legs, now known as restless legs syndrome (RLS), with an incidence of 45%. Further development may lead to limb weakness, unsteady gait, decreased deep tendon reflexes, and eventually motor disorders. Some patients may also have autonomic nervous system dysfunction, leading to orthostatic hypotension, sweating disorders, neurogenic bladder, and premature ejaculation. Pathologically, it often manifests as demyelination of nerve fibers, and the cause is related to excessive guanidinoacetic acid or PTH in the blood of uremia, which inhibits the intracellular transketolase of nerve cells. Recently, there is evidence that a decrease in calcium content in nerve fibers may reduce excessive conduction of nerve fibers.
5. Blood system:Abnormalities in the blood system of CRF can manifest as anemia, hemorrhagic tendency, and thrombotic tendency.
Anemia can occur in all CRF patients, but the primary disease varies in degree. Anemia caused by polycystic kidney disease, hypertension, and renal sclerosis is relatively mild. Anemia caused by bilateral nephrectomy, accompanied by nephrotic syndrome, and obvious hyperparathyroidism is relatively severe.
The symptoms of anemia in clinical practice depend on the degree and speed of anemia. Generally, it is mainly a series of manifestations caused by excessive compensation leading to a hyperdynamic state, such as increased heart rate, increased cardiac output and stroke volume, increased myocardial preload and contractility. In the long term, it can lead to myocardial thickening and vascular dilation. Laboratory examination is often normal red blood cell normal pigment anemia, and the reticulocyte count can be slightly reduced. Sometimes, a few irregular red blood cells can be seen in the peripheral blood. Treatment of anemia should not be corrected too quickly because the body has been in a state of anemia for a long time, and various intracellular enzymes adapt to anaerobic metabolism. Rapid correction of anemia will not make the body immediately switch from anaerobic metabolism to aerobic metabolism, but will cause many adverse effects.
Hemorrhagic tendency is a common complication in CRF patients, generally mild bleeding, mainly manifested as subcutaneous ecchymosis, purpura, epistaxis, and gingival bleeding. In severe cases, it can also lead to hemorrhagic pericarditis, retroperitoneal hemorrhage, gastrointestinal hemorrhage, and even intracranial hemorrhage. Hemorrhage after surgical operations or trauma is more common. The mechanism of hemorrhage in CRF patients is not fully understood, and it mainly involves platelet dysfunction, such as decreased activity of platelet factor III, impaired activity of platelet membrane glycoprotein GPⅡb/Ⅱa complex, lack of platelet storage, and reduced production of TXA2, which may be related to decreased activity of cyclooxygenase. In addition, abnormal blood vessel walls, such as insufficient production of PGI2, decreased activity of the vascular (pseudo) hemophilia factor (vWF), and abnormal coagulation mechanism, such as increased concentration of antiphospholipid antibodies and lupus anticoagulant, can also promote hemorrhage. However, CRF patients also have a tendency to form thrombi, manifested as easy blockage of arteriovenous fistulas and external fistulas in dialysis patients, which is related to hypercoagulable state of platelet function in some patients. Other factors such as decreased activity of antithrombin III and protein C, and insufficient fibrinolysis can also promote thrombosis. Studies have shown that some dialysis patients have decreased activity of tissue-type plasminogen activator (tPA) in the circulation while the activity of plasminogen activator inhibitor-1 (PAI-1) increases. The tPA/PAI-1 system is the most important substance in the process of fibrinolysis.
6, Musculoskeletal System:Advanced uremia often has myopathy, manifested as severe muscle weakness, mainly affecting the proximal muscles, with difficulties in lifting arms or standing, gull-like gait, and other symptoms. Electrophysiological findings show a decrease in the resting potential of muscle cells and a shortening of the action potential duration, which is related to changes in intracellular ion concentrations. The main reasons include insufficient 1,25-(OH)2VD3, increased PTH levels, excessive aluminum load, and malnutrition. Patients may have symptoms such as bone pain, spontaneous fractures, arthritis, periarthritis, and tendon rupture. Children often have delayed growth and development and symptoms of scurvy. Adults may also develop spondylolisthesis or kyphosis of the spine, and renal osteodystrophy is very common. In addition to calcium-phosphorus metabolism disorders, secondary hyperparathyroidism is the main factor, and it is also related to excessive aluminum load and chronic metabolic acidosis.
7, Skin Changes:Uremic patients may have pale or yellowish-brown complexion due to anemia. This change in skin color was once believed to be due to increased urobilinogen, but it has now been proven to be mainly caused by melanin, becoming a unique facial feature of uremic patients. Secondary hyperparathyroidism can cause skin itching, ulcers, and necrosis of soft tissues. Uremic itching is also related to the formation of urea crystals on the skin due to high concentrations of urea.
8, Immune System:CRF patients are accompanied by infection, and severe infection accounts for 13.1％～35.7％ of the mortality rate of uremia, indicating abnormal immune function and low defense mechanism of the body. In addition to the dysfunction of white blood cells, especially polymorphonuclear leukocytes (PMNs), there are also functional defects in lymphocytes and monocytes. This is reflected in the prolonged survival of skin grafts in uremic patients, decreased delayed hypersensitivity, low antibody production after vaccination with various vaccines (such as hepatitis B, influenza, Streptococcus pneumoniae, etc.), a tuberculosis infection rate up to 6-16 times higher than that of the normal population, and a significant increase in the opportunity for viral infections (such as hepatitis B, cytomegalovirus infection, etc.). Moreover, once infected, the body is difficult to clear the infection, and it can present as a carrier of the virus.
PMNs are the most important substances for the body's defense against bacterial infections. They can kill bacteria by adhering, digesting, oxidative burst, and releasing various proteases. Most studies show that PMNs have a decrease in chemotaxis, phagocytosis, and bactericidal function. The reasons include:
(1) Excessive iron load can significantly inhibit the phagocytic function of PMNs. When the serum iron level exceeds 650μg/L, even if the transferrin saturation decreases, it can still significantly inhibit the bactericidal and oxidative burst ability of PMNs, which can be improved with EPO treatment.
(2) Increased intracellular calcium, secondary hyperparathyroidism, and certain dialysis membranes can inhibit the phagocytic and glycolytic ability of PMNs. Administration of 1,25-(OH)2VD3 and calcium channel blockers is expected to improve the condition.
(3) Malnutrition.
(4) The use of biologically incompatible membranes during dialysis can activate complement, leading to the accumulation of PMN in the lungs, causing low PMNemia. On the other hand, the activated PMN can highly express adhesion molecules Mac-1 (CD11b/CD18), increasing its adhesion to alveolar epithelial cells, but low expression of S-selectin. As a result, the adhesion function of PMN to vascular endothelium is reduced, and the adhesion of PMN to vascular endothelium is the first step of its杀菌 activity. In addition, the persistent activation of PMN will also reduce its phagocytic function.
(5) Uremic toxins, recently there have been reports that granulocyte inhibitory protein I, II (GIP-I, II), a large amount of immunoglobulin light chains, PMN cell granule inhibitory protein (DIPI), angiogenin, ubiquitin, and P-cresol in the uremic circulation can inhibit PMN function.
Lymphocytes mainly mediate immune responses in the body. Cell-mediated immunity is mediated by T cells, while humoral immunity is mainly mediated by B cells. During CRF, the count of circulating lymphocytes is often reduced, but CD4 and CD8 T cells as well as the CD4/CD8 ratio are still normal. The dysfunction of T cells is mainly manifested in the defect of T cells' proliferative response to antigen stimulation, a decrease in the production of IL-2 and interferon, and also manifested in the down-regulation of the T cell receptor TCR/CD3 complex. T cell dysfunction is often related to uremic toxins such as PTH, guanidine derivatives, especially methylguanidine, LDL, PGE2, and increased iron load. Although the levels of plasma IgG, IgM, and IgA are still normal during uremia, the antibody response of B cells to T cell stimulation is significantly reduced, mainly related to hyperparathyroidism, excessive iron load, increased soluble antigens and Fc receptors in the circulation.
9. Endocrine system:In addition to the dysfunction of endocrine hormones produced by the kidneys, sex hormones are often disordered, and sexual function is often impaired. Female patients may experience amenorrhea and infertility; male patients often have impotence, decreased sperm production or reduced vitality, and the levels of plasma testosterone, estrogen, and progesterone are often reduced. Lactation hormone and luteinizing hormone are often increased. Thyroid function may be low, leading to a decrease in basal metabolic rate. In addition, CRF patients often have紊乱 in body temperature regulation, which is related to the decrease in Na-K-ATPase activity of the central nervous system. Patients may show a normal body temperature curve dropping to 35.5℃, so if the body temperature of CRF patients is above 37.5℃, it indicates the presence of serious infection, which requires active treatment.
