According to the cause of the disease, it can be divided into primary uremia and secondary uremia; according to the severity of the disease, it can be divided into complete uremia and partial uremia; according to the duration of the disease, it can be divided into temporary uremia and permanent uremia. The disease can occur at any age, but is more common in young people, with a male to female ratio of about 2:1.
Disease Overview
Diabetes insipidus is a phenomenon in which the kidneys excrete increased amounts of water due to a deficiency of antidiuretic hormone, one of the posterior pituitary hormones. The cause is impaired reabsorption in the renal tubules. Polyuria means an increase in urine output and is not related to diabetes insipidus.
Pathogenesis
1. Physiology of vasopressin
(a) Synthesis and metabolism of AVP
Vasopressin is synthesized in the neurons of the supraoptic nucleus and paraventricular nucleus of the inferior optic thalamus, and its initial product is prehormone progenitor, which enters the body of the hyperuria consultation ergogenic to form hormone progenitor, which is encapsulated in neurosecretory vesicles. The vesicles flow along the axons of the pituitary bundle to the pituitary gland, and during the flow persuasion active ninepeptides are produced by enzymatic action, namely Arginine Vasopressin (AVP) and a molecular weight (neurophysin) and a glycopeptide consisting of 39 amino acids. All three products are released into the peripheral blood.AVP is secreted by hypothalamic neurons and then travels down the thalamic-pituitary bundle to the terminals where it is stored in the pituitary gland. In recent years, it has been found that AVP fibers are also seen in the lateral band of the median eminence and that AVP can also be secreted into the pituitary portal system, at the base of the third ventricle and in the vasomotor center of the brainstem, among other places.
AVP binds to endothelial cells located in the distal tubules and collecting ducts of the kidney to promote the flow of water from the tubular lumen to the interstitium, helping to maintain a constant osmolarity and volume of body fluids. AVP is present in low concentrations in plasma and has no vasoactive effect, but high concentrations of AVP acting on V1 receptors can cause vasoconstriction. AVP present in axons of the brain may be involved in learning and memory processes, and AVP fibers in the median bulge may be associated with promoting ACTH release.
AVP concentrations in plasma and urine can be measured by immunoassay. In the presence of casual fluid intake, the pituitary gland contains nearly 6 units or 18 mmol (20 μg) of AVP, and peripheral blood AVP concentrations range from 2.3 to 7.4 pmol/L (2.5 to 8 ng/L). Blood AVP concentrations varied with day and night, with the highest levels late at night and early in the morning and the lowest in the afternoon. During normal water administration, healthy people release AVP from the pituitary gland for 24 hours at 23-14pmol (400-1500ng) and excrete AVP from the urine at 23-80pmol (25-90ng). After 24-48 hours of water fasting, the release of AVP increases 3-5 times, and the levels in blood and urine continue to increase. AVP is mainly inactivated in the liver and kidneys, and nearly 7-10% of AVP is excreted from the urine in active form.
(B) Regulation of AVP release
1.Osmolarity receptors
The release of AVP is influenced by a variety of stimuli. Under normal conditions, the release of AVP is mainly due to the regulation of osmolarity receptors in the inferior optic thalamus, and changes in osmolarity stimulate the production and release of AVP. The feedback mechanism of plasma osmolarity changes and AVP release maintains plasma osmolarity in a narrow range. The mean plasma osmolality was 281.7 mOsm/kg?H2O in normal subjects given a 20 ml/kg water load and 287.3/kg?H2O in water-loaded subjects given hypertonic saline.
2. Volume regulation
A decrease in blood volume stimulates tone receptors in the left atrium and pulmonary veins, and stimulates AVP release by reducing the tone inhibitory impulses from pressure receptors to the inferior optic thalamus. In addition, vasodilation due to shouting, uprightness, and warm environment can stimulate this mechanism to restore blood volume. Volume reduction can cause circulating AVP concentrations to reach 10 times the AVP concentration due to hyperosmolarity.
3. Pressure receptors
Hypotension Stimulation of carotid and aortic pressure receptors stimulates AVP release. Hypotension due to blood loss is the most effective stimulus, when plasma AVP concentration increases markedly, and at the same time can lead to vasoconstriction until the blood volume is restored to maintain blood pressure.
4.Neuromodulation
Many neurotransmitters and neuropeptides in the inferior optic thalamus have the function of regulating AVP release. Such as acetylcholine, angiotensin II, histamine, bradykinin, γ-neuropeptide, etc. can stimulate the release of AVP. As age increases, the responsiveness of AVP to increased plasma osmolality increases and plasma AVP concentration increases progressively. These physiological changes may predispose the elderly to increased risk of water retention and hyponatremia.
5.Drug effects
Drugs that stimulate AVP release include nicotine, morphine, vincristine, cyclophosphamide, clofibrate, chlorosulfopropylurea and certain tricyclic antidepressants. Ethanol can produce a diuretic effect by inhibiting pituitary function. Phenytoin sodium and chlorpromazine can inhibit the release of AVP and produce diuretic effect.
(iii) Response of AVP to water fasting and water loading
Water fasting can increase osmolarity to stimulate the release of antidiuretic hormone. The maximum urinary osmolality after water fasting changes with renal medullary osmolality and other intrarenal factors. Plasma osmolality rarely exceeds 292 mOsm/kg?H2O after 18 to 24 hours of water fasting in normal subjects. plasma AVP concentration increases to 14 to 23 pmol/L (15 to 25 ng/L). AVP release can be inhibited by water intake. Plasma osmolality decreased to an average of 281.7 mOsm/kg?H2O after drinking a water load of 20 ml/kg in normal subjects.
(iv) The relationship between AVP release and thirst
Under normal conditions, AVP release and thirst sensation are coordinated, and both are caused by a mild increase in plasma osmolality. When plasma osmolality rises above 292 mOsm/kg?H2O, thirst is gradually evident until urinary concentration reaches the most in limit to stimulate drinking. Thus, under normal conditions, mild hypernatremia caused by water loss enhances thirst and increases fluid intake to restore and maintain normal plasma osmolality. Conversely, when thirst is lost, fluid loss cannot be corrected in time by drinking, and hypernatremia occurs despite the fact that AVP release at this time maximizes urine concentration.
(V) Role of glucocorticoids
Adrenocorticotropic hormone and AVP in the excretion of water has a gi-antagonistic effect. Cortisone can raise the osmotic pressure threshold of AVP release caused by normal infusion of hypertonic saline, glucocorticoid? The body responds abnormally to water load in hyperalgesia. In hyperalgesia, decreased urine release may be due in part to excess circulating AVP, but glucocorticoids can act directly on the renal tubules in AVP deficiency to reduce water permeability and increase free water excretion in AVP deficiency.
(F) Cytological mechanisms of AVP action
The mechanism of AVP action on small renal tubules.
(i) AVP binds to V2 receptors on the tubular cell membrane opposite the lumen.
(ii) Activation of adenylate cyclase by the hormone-receptor complex through guanylate-binding stimulatory protein.
(iii) Increased production of cyclic adenosine monophosphate (cAMP).
(iv) Transfer of c-AMP to the luminal surface cell membrane and activation of membrane protein kinases.
(⑤) Protein kinase leading to phosphorylation of membrane proteins.
(6) Increased permeability of the luminal membrane to water, resulting in increased water reabsorption. Many ions and drugs can affect the action of AVP. Calcium and lithium inhibit the response of adenylate cyclase to AVP and also inhibit cAMP-dependent protein kinases. In contrast, chlorosulfonylurea enhances AVP-induced activation of adenylyl cyclase.
2, Dysfunction at any of the links between AVP production and release leads to pathogenesis.
By comparing the changes in plasma and urine osmolality under normal drinking, water load, and water fasting, central uremia can be categorized into four types.
Type ①: When blood osmolality is significantly elevated during water fasting, while urine osmolality is rarely elevated, there is no release of AVP when hypertonic saline is injected. This type does have AVP deficiency.
Type ②: When urinary osmolality rises suddenly during water fasting, but there is no osmolality threshold when saline is injected. These patients lack an osmolar sensory mechanism and are able to stimulate AVP release only when severe dehydration results in low school volume.
Type (iii): As plasma osmolality rises, urinary osmolality increases slightly and the AVP release threshold rises. These patients have a slow AVP release mechanism, or reduced sensitivity of osmolarity receptors.
Type ④: Both blood and urine osmolality curves shift to the right side of normal. These patients start releasing AVP when plasma osmolality is normal, but the amount released is lower than normal.
Patients with types ② to ④ have a good antidiuretic effect on nausea, nicotine, acetylcholine, chlorosulfonylurea, and antamine, suggesting that synthesis and storage of AVP are present and are released only under appropriate stimulation. In rare cases, patients with types ② to ④ may have asymptomatic hypernatremia with very mild uremia, or even lack a basis for uremia.