Malignant small artery kidney in elderly primary malignant hypertension

　　One, Etiology

　　Malignant arteriolosclerosis is caused by rapid progressive or malignant hypertension. At this time, the main arterial lesions are fibrinoid necrosis of the arterial wall and thickening of the adventitia.

　　1. Fibrinoid necrosis

　　This lesion is considered a characteristic lesion of malignant hypertension, which can occur in arcuate arteries, interlobular arteries, and glomerular arterioles, and can extend from the glomerular arterioles to the glomerular capillary loops.

　　The occurrence of fibrinoid necrosis is related to severe hypertension itself, and some people have found that diastolic pressure needs to be as high as about 150 mmHg to cause necrosis of the arteriolar wall, and higher necrosis is even more severe; it is also related to many abnormal vascular active substances at this time, including overactivation of renin-angiotensin-aldosterone system (RAS), increased vasopressin activity, decreased prostacyclin, and decreased kinin levels, etc.; in addition, the occurrence of fibrinoid necrosis may also be related to local coagulation caused by vascular endothelial injury, and increased intracellular calcium content and other factors.

　　2. Thickenning of the adventitia

　　Similar to benign arteriolosclerosis, it mainly invades the walls of interlobular arteries and arcuate arteries. The pathogenesis is the same as that of benign arteriolosclerosis.

　　Two, Pathogenesis

　　The size of the kidney can be normal (if it is secondary hypertension caused by chronic renal parenchymal disease, the kidneys can shrink). The renal surface may have pinpoint hemorrhages like flea bites. Under the microscope, there are two characteristic pathological changes:

　　1.纤维素样坏死 of the glomerular arterioles;

　　2. Intercalated artery proliferative endarteritis, which is considered a pathological feature of malignant arteriolosclerosis, is characterized by granular fibrinoid deposits in the middle layer of the arteriolar wall, which can also be deposited in the endothelium. Hematoxylin-eosin staining shows bright pink, Masson staining shows deep red. Tissue chemistry and immunofluorescence techniques confirm the presence of fibrin; the muscle fibers in the middle layer are no longer present, the nuclei disappear or are only left in fragments; red blood cells or fragments seep into the arteriolar valves, causing pinpoint hemorrhages on the renal surface; due to wall thickening and intravascular fibrin thrombosis, the lumen becomes narrowed; sometimes polymorphonuclear leukocytes and monocytes also seep into the vascular wall, manifesting as necrotizing arteritis.

　　Malignant hypertension causes damage to blood vessels, manifesting as systemic progressive vascular disease, with kidney involvement occurring relatively late (this is known as malignant arteriolosclerosis). The clinical manifestations can range from minimal proteinuria without renal function damage to severe renal failure, the latter sometimes even indistinguishable from terminal primary renal parenchymal disease.

　　The onset is usually very acute (often able to remember the specific date), the most common symptoms are headache, blurred vision, and weight loss, followed by dyspnea, fatigue, discomfort, nausea, vomiting, upper abdominal pain, polyuria, increased nocturia, and gross hematuria. The headache symptoms are not specific, but severe hypertension accompanied by newly onset headache or turning into persistent should be seriously considered as possible to turn malignant; 76% of the first-time patients have visual symptoms, 90% will eventually occur. The most common is blurred vision and decline, 14% sudden blindness, may have blind spots, diplopia, and hemianopia. Weight loss is another early symptom, the cause (at least partially) is due to the natural diuresis and blood volume decrease at the beginning of the malignant state (see above), and often occurs before anorexia and uremia. Blood pressure significantly increased, diastolic pressure is generally over 16.0～17.3kPa (120～130mmHg), due to the considerable overlap between the blood pressure values of benign hypertension and malignant hypertension, there is no specific critical blood pressure level for malignant hypertension, for example, those with normal blood pressure, if the diastolic pressure suddenly rises to 13.3～14.7kPa (100～110mmHg), it may be malignant; conversely, there are also primary hypertension with very high diastolic pressure and lasting for many years, which has never entered the malignant state.

　　The damage to the vessels by malignant hypertension is manifested as systemic progressive vascular disease, affecting the kidneys relatively late (this is malignant small artery renal sclerosis), and its clinical manifestations can range from minor proteinuria without renal function damage to severe renal failure, the latter of which sometimes cannot be distinguished from the terminal primary renal parenchymal disease. It can be roughly divided into 4 types:

　　1. Subacute progression (within a few weeks to several months), until the end-stage renal failure (death within one year), seen in cases without adequate treatment;

　　2. Only temporary renal function damage, seen in those who can effectively control blood pressure from the early stage of onset;

　　3. When malignant hypertension is found, there are already hypertensive retinopathy (see below), severe hypertension, and renal failure;

　　4. Oliguria-type acute renal failure.

　　1. Severe hypertension

　　The纤维素样坏死和增生性动脉内膜炎 in this disease are directly caused by the mechanical stress on the vascular wall due to severe hypertension. The malignant condition of hypertension, although caused by various etiologies, all have severe hypertension. If the blood pressure can be effectively controlled, the malignant condition can be reversed. From the sympathetic nerve resection in patients with severe hypertension and simultaneous renal biopsy, it was found that general diastolic pressure reached about 20kPa (150mmHg) before the occurrence of small artery necrosis, and if it is higher, the necrosis is more serious. In patients with unilateral renal artery stenosis, secondary malignant hypertension occurs, and renal artery necrosis only occurs in the contralateral kidney, not in the stenotic side. Animal experiments have clearly shown that severe hypertension can cause pathological changes similar to human malignant small artery renal sclerosis.

　　2. Vascular toxicity

　　The main doubts about the pressure theory are that there is a lot of overlap between the blood pressure of the two groups of patients with benign and malignant hypertension, and even some patients may have persistent severe hypertension for a long time but do not enter the malignant state. Therefore, some scholars have proposed that the sudden transformation from a benign hypertension with few symptoms to a malignant hypertension with obvious symptoms and multi-system damage may involve many other factors in addition to hypertension, and vascular toxicity is one of them.

　　3. Renin-angiotensin

　　The activation of the renin-angiotensin (RA) system is often associated with the activation of the RA system in malignant hypertension. Some patients have elevated plasma RA levels, and it is also often found that there is glomerular apparatus hyperplasia, adrenal cortical spherical zone hyperplasia and nodularization.

　　4. Vasopressin

　　Mohring et al. also found that the plasma arginine vasopressin (AVP) level in animals with bilateral renal artery stenosis and malignant hypertension is also increased (three times that of animals with benign hypertension, and four times that of normal controls), and some patients may be sensitive to AVP or AVP may enhance the body's pressor response to angiotensin II or catecholamines, or even AVP may have a direct toxic effect on the constricted vessel, thereby promoting the formation of malignant hypertension.

　　5. Local coagulation

　　Vascular endothelial damage in hypertension can cause local intravascular coagulation, thereby aggravating the condition; in animal models, microangiopathic hemolytic anemia can occur; for this reason, some scholars have proposed that coagulation abnormalities may be another reason for the transition from benign hypertension to malignant hypertension.

　　Decrease in prostacyclin (PGI2) synthesis

　　Smokers and women taking oral contraceptives are prone to malignant hypertension, because smoking and contraceptives can damage the vascular endothelium and affect the synthesis of PGI2. According to measurements, the level of 6-keto-prostaglandin F1a (6-keto-PGF1a), a stable metabolite of PGI2, is reduced in the blood of these two groups of people, and increasing the synthesis of PGI2 may be a method to reduce vascular damage in hypertension.

　　Increase in intracellular calcium content

　　Excess intracellular calcium may be an important factor in the development of malignant hypertension. Feeding high-salt diets to Dahl salt-sensitive rats can cause an explosive hypertension with renal necrotizing vascular lesions. If calcium antagonists such as nifedipine (nifedipine) are given to inhibit calcium influx, this condition can be prevented, and nisodipine and nitrndipine also have similar effects, while captopril has no such effect.

　　8. Low potassium diet

　　Tobian believes that the distinctive low potassium dietary habits of South Americans may be a cause of susceptibility to malignant hypertension and can at least partially explain why they are prone to renal failure after hypertension. If potassium intake is supplemented in Dahl salt-sensitive rats with high-salt diet, although blood pressure does not decrease, it can prevent intimal thickening of interlobular arteries. High potassium diet can also prevent intimal thickening of mesenteric and intracerebral small arteries in stroke-prone spontaneously hypertensive rats (SHR-SP).

　　9. Immune mechanism

　　Gudbrandsson et al. observed the immune indicators of 20 patients who recovered from malignant hypertension and found that compared with the normal control group of the corresponding age and gender, their T lymphocyte response to human arterial antigens increased. Regardless of whether this response is primary or secondary to vascular damage, it may worsen vascular wall damage. Forsberg et al. observed 32 patients with malignant hypertension with uremia, and compared them with healthy blood donors and those with glomerulonephritis (without malignant hypertension) confirmed by renal biopsy. The incidence of HLA-BW35 and CW4 antigens was significantly higher, and the authors speculated that these HLA antigens may be associated with vascular damage of malignant hypertension through some unknown pathways.

　　1. Laboratory examination

　　There is generally no abnormality in blood routine, red blood cells, and hemoglobin, but in the case of rapidly progressive hypertension, there may be intravascular hemolytic anemia with negative Coombs test, accompanied by increased blood viscosity and a tendency to form thrombotic complications (including cerebral infarction) and left ventricular hypertrophy.

　　2. Urinalysis

　　In the early stage, the urine routine is normal. When the renal concentrating function is damaged, the urine specific gravity gradually decreases, and there may be a small amount of proteinuria, red blood cells, and occasionally casts. With the progression of renal lesions, the amount of proteinuria increases. In patients with benign renal sclerosis, if the 24-hour urine protein is above 1g, it indicates poor prognosis. The number of red blood cells and casts may also increase, and the casts are mainly transparent and granular.

　　3. Renal function

　　The renal function is usually estimated by blood urea nitrogen and creatinine. In the early stage, there is no abnormality in the examination. When the renal parenchyma is damaged to a certain extent, it can start to increase. When the creatinine level in adults is greater than 5mg/dl, and in the elderly and pregnant women is greater than 1.2mg/dl, it indicates renal damage.

　　4. Phenol red excretion test

　　Urea clearance rate, endogenous creatinine clearance rate, and other indicators may be lower than normal.

　　Factors to be considered in food therapy, such as the acceleration of intravascular fat deposition, are prone to cause atherosclerosis, leading to increased blood pressure.

　　1. Eat more low-fat, high-quality protein foods, which have a positive effect on increasing vascular elasticity and preventing the occurrence of complications of malignant hypertension. Eating more high-quality protein foods such as beans, fish, and poultry can help improve the permeability of the blood vessels in malignant hypertension patients. Malignant hypertension patients should not exceed 50g of fat intake per day.

　　2. Eat more green vegetables and fruits, carotenoids, fiber, and other nutrients, which can improve myocardial function and blood circulation, help excrete excess cholesterol and fat in the body.

　　3. Eat more calcium-rich foods, which also have antihypertensive effects. Malignant hypertension patients should eat more milk, beans, seafood, green vegetables, and other foods rich in calcium.

　　4. Eat more coarse grains and tubers as staple foods, such as corn, oatmeal, buckwheat, and millet. These coarse grains contain abundant dietary fiber, which can promote peristalsis and excrete excess cholesterol.

　　5. Eat regularly, eat less and more meals, eat to about 70-80% of fullness, reduce the burden on the gastrointestinal tract, maintain weight, and it is beneficial to control blood pressure. Malignant hypertension patients should eat less and more meals, eat at regular times and in fixed amounts, and develop good habits.

　　6. Eat a light diet, and salt also has an antihypertensive effect. Malignant hypertension patients should eat less salt.

　　7. Stay away from foods that excite the nervous system, such as coffee and strong tea, which stimulate nervous excitement. These drinks can cause blood pressure to rise.

　　1. Treatment

　　1. The principles and methods of antihypertensive treatment

　　Malignant hypertension must be rapidly reduced to prevent serious complications such as hypertensive encephalopathy, cerebral hemorrhage, acute pulmonary edema, and acute renal failure.

　　In cases of hypertensive encephalopathy, intracranial hemorrhage, acute pulmonary edema, acute myocardial infarction, acute renal function decline, acute pancreatitis, rapid vision loss, gastrointestinal bleeding, mesenteric arteritis-induced acute abdominal pain, and difficulty taking oral medications due to vomiting, intravenous emergency administration should be given first, commonly using sodium nitroprusside, diazoxide, hydralazine (hydralazine), and labetalol (labetalol), among which sodium nitroprusside is the first choice. For safety, the initial decrease in blood pressure is generally 20% or reduced to 21.3-22.7/13.3-14.7 kPa (160-170/100-110 mmHg), and then, under the monitoring of the patient's brain and myocardial hypoperfusion, the diastolic pressure should be gradually reduced to 12 kPa (90 mmHg) within 12-36 hours.

　　Once the condition is stable, oral antihypertensive drugs should be added, and after the oral drugs take effect and the dosage is adjusted, intravenous administration should be completely withdrawn. When oral drugs are started, small artery dilators such as hydralazine (hydralazine), nifedipine (nifedipine), or minoxidil (long-acting antihypertensive) should be used. Since vascular dilation can reflexively activate the adrenergic system, leading to tachycardia, increased cardiac output, and reduced antihypertensive effect, adrenergic β-receptor blocking drugs such as propranolol (propranolol) and atenolol (amylxanthine) should be used concurrently. Some vasodilators can also cause sodium and water retention, and diuretics should be added in the long-term treatment.

　　2. Blood volume status and the use of diuretics

　　Patients with malignant hypertension can develop pulmonary edema even without excessive systemic salt load. Due to increased systemic vascular resistance (SVR), the left ventricle is forced to work excessively, causing a decrease in its compliance and resulting in increased left ventricular end-diastolic pressure (LVEDP) and the formation of pulmonary edema. This means that even if the left ventricular end-diastolic volume (LVEDV) is close to normal, the LVEDP can still increase. Vasodilators can reduce SVR and improve left ventricular compliance, resulting in a decrease in LVEDP and improved pulmonary congestion. Therefore, the focus of treatment for malignant hypertension complicated by pulmonary edema should be to reduce the afterload on the heart rather than to diurese excessively. If there is no obvious fluid overload at the start of treatment, diuretics should not be used, but they should be added later during long-term oral administration of vasodilators (due to the strong sodium and water retention side effects) as it is difficult to control blood pressure effectively without them.

　　3. Treatment for renal insufficiency

　　Regardless of the degree of renal function impairment, patients with malignant hypertension should have their blood pressure strictly controlled to prevent further damage to renal function. In cases of renal insufficiency (especially when glomerular filtration rate is below 20 ml/min), controlling blood pressure occasionally can lead to oliguric acute renal failure, but this should not be a contraindication to antihypertensive treatment. Controlling blood pressure can protect the function of vital organs (heart and brain), and even if the patient has entered the terminal stage of renal disease due to malignant arteriolosclerosis, strictly controlling blood pressure may still be possible to restore renal function.

　　If uremia has developed, in addition to making efforts to control hypertension, dialysis therapy should also be added to correct uremia and fluid retention. It is difficult to satisfactorily control blood pressure with dialysis alone, and antihypertensive drugs must be added. Clinical evidence shows that the combined use of minoxidil (Long-press) and propranolol (Propranolol) is effective.

　　4. Optimal treatment plan

　　In the case of acute hypertension, it is necessary to lower blood pressure rapidly, and intravenous administration is appropriate to allow for timely changes in the dose of the drug used.

　　(1) Sodium nitroprusside: Directly dilates arteries and veins, causing a rapid decrease in blood pressure. It is initially administered intravenously at a rate of 10 μg/min, and blood pressure should be closely monitored. The dose can be increased by 5 μg/min every 5 to 10 minutes. The antihypertensive effect of sodium nitroprusside is rapid, and its action disappears within 3 to 5 minutes after the infusion is stopped. The drug solution is light-sensitive and must be freshly prepared before each use; the infusion bottle should be wrapped in aluminum foil or black cloth. Sodium nitroprusside metabolizes in the body to produce cyanide, and中毒 may occur with high doses or prolonged use.

　　(2) Nitroglycerin: mainly dilates veins, and also dilates arteries at higher doses. Intravenous infusion can quickly lower blood pressure, starting with a dose of 5-10μg/min, and then increasing by 5-10μg/min every 5-10 minutes to 20-50μg/min. The effect disappears several minutes after discontinuation. Side effects include tachycardia, facial redness, headache, nausea, etc.

　　(3) Nicardipine: a dihydropyridine class calcium channel blocker, used for emergency treatment of hypertension with an intravenous infusion starting dose of 0.5μg/(kg·min), closely observing the accumulation and gradually increasing the dose, which can be up to 6μg/(kg·min). Side effects include tachycardia, facial congestion and redness, nausea, etc.

　　(4) Urapidil: an α1 receptor antagonist, used for hypertensive crisis with an intravenous injection dose of 10-50mg (usually 25mg). If the blood pressure does not decrease significantly, the injection can be repeated, and then 50-100mg is administered in 100ml of fluid for intravenous infusion to maintain, with a speed of 0.4-2mg/min, which can be adjusted according to the accumulation.

　　5. Rehabilitation Treatment

　　The rehabilitation treatment for hypertension and renal sclerosis patients mainly includes physical rehabilitation,配合心理康复，such as reducing the occurrence of anxiety, depression, and promoting psychological adjustment. Health education related to patients and their families is conducted, and individual psychological counseling and guidance are provided. This includes health education for patients and their families on physical rehabilitation, mainly endurance exercise training, including low-intensity stretching activities, soft gymnastics, etc., which may cause slight muscle pain but should avoid fatigue.

　　In addition, physical therapy and traditional therapy can also be applied, such as microwave therapy can improve renal blood supply, ultrasonic therapy can soften atherosclerotic plaques and improve blood circulation. Traditional therapies such as qigong can reduce the influence of various risk factors of hypertension and can eliminate the tension state of the cerebral cortex. Choices can be made from static qigong, Tai Chi Chuan, etc., massage can promote blood circulation and enhance the inhibitory process of the cerebral cortex.

　　II. Prognosis

　　Although the mortality rate of malignant hypertension patients is extremely high, timely treatment and appropriate measures can still result in good prognosis for some patients when blood pressure is controlled quickly, and renal function damage can also be restored to varying degrees.