Etiology
1.Central uremic syndrome
Any condition that leads to impaired synthesis and release of AVP can cause the occurrence of CDI, and its etiology is primary, secondary and genetic.
(1) The primary cause is unknown, accounting for 30%-50% of uremia. Some patients can be found to have significantly reduced or absent cells in the hypothalamic supraoptic and paraventricular nuclei at autopsy.
(2)Secondary
1) Head trauma and hypothalamic-pituitary surgery are common causes of CDI, among which transient CDI after pituitary surgery is the most common. If the surgery causes damage to the pituitary stalk above the median ramus, it can lead to permanent CDI.
2) Tumor uveitis may be the earliest clinical symptom of suprasellar tumor. Primary intracranial tumors are mainly pharyngioma or pineal tumor, while secondary tumors are most commonly intracranial metastases from lung or breast cancer.
3)Granulomatous nodular disease, histiocytosis, sarcoma-like tumors, yellow tumors, etc.
4)Infectious diseases encephalitis, meningitis, tuberculosis, syphilis, etc.
5)Vascular lesions aneurysm, arterial embolism, etc.
6)Autoimmune diseases can cause CDI and the presence of anti-AVP cell antibodies in the serum.
7)Mild uremia can occur in women during late pregnancy and puerperium, which is associated with increased AVP degrading enzymes in the blood.
(3) The heredity can be X-linked recessive, autosomal dominant or autosomal recessive. X-linked recessive inheritance is passed from female, male onset, heterozygous children may have poor urinary concentration power, generally mild symptoms, may not have obvious polyhydramnios, polyuria. Autosomal dominant inheritance can be caused by mutations in the AVP precursor gene or mutations in the AVP carrier protein gene. Autosomal recessive inheritance, often in familial cases, and polyuria in patients since childhood may be due to defects in osmoreceptors.
2.Nephrogenic enuresis
It is caused by the kidney’s unresponsiveness or diminished response to AVP, and there are two kinds of causes: hereditary and secondary.
(1) hereditary 90% of DNI patients are X-linked, of which at least 90% can detect mutations in the AVP receptor type 2 (AVPR2) gene; the remaining 10% of patients are autosomal, and their mutated gene is water channel protein 2 (AQP2), of which 9% are dominant and 1% are recessive.
(2) Secondary
1) Interstitial renal tubular lesions such as chronic pyelonephritis, obstructive uropathy, tubular acidosis, tubular necrosis, amyloidosis, etc.
2)Metabolic diseases such as hypokalemia, hypercalcemia, etc.
3)Drugs such as antibiotics, antifungal drugs, antitumor drugs, antiviral drugs, etc. Among them, lithium carbonate may cause NDI because it makes cellular cAMP production impaired and interferes with renal reabsorption of water.
2.Clinical manifestations
1. Hypotonic polyuria
Polyuria is the most significant symptom in DI patients, and CDI patients generally have a more urgent onset and a clear date. Urine volume exceeds 2500ml/d or 50ml/(kg, d)], and is accompanied by irritable thirst and excessive drinking. Nocturia is significantly increased, and urine volume is usually above 4L/d, and rarely can exceed 10L/d, but up to 40L/d has been reported. urine specific gravity is 1,0001 to 1,0005, and urine osmolality is 50-200mOsm/L, which is significantly lower than plasma osmolality. Chronic polyuria can lead to an increase in bladder volume and therefore a decrease in the number of urinations. If a patient with partial enuresis has mild symptoms and urine volume is 2,4 to 5L/d, if water intake is restricted leading to severe dehydration, urine specific gravity can reach 1,010 to 1,016 and urine osmolality can exceed plasma osmolality by 290 to 600mOsm/L. If the patient’s thirst center is not involved and water intake is not restricted, then generally only sleep is affected and physical weakness is not easily life-threatening. If the patient’s thirst is diminished or disappears, failure to rehydrate in a timely manner can cause severe water loss, markedly elevated plasma osmolality and serum sodium levels, extreme weakness, fever, psychiatric symptoms, and even death. Once the uremia is combined with hypopituitarism, the uremia may be reduced and the symptoms may be reproduced or worsened after glucocorticoid replacement therapy.
Hereditary NDI often starts in infancy, and most have a family history. It is mostly transmitted in females and develops in males. After birth, both polyuria and polydipsia are present. If not detected in time, the disease often dies prematurely due to severe dehydration, hypernatremia and hyperosmolar coma. If survived, there may be slow growth and the symptoms diminish or disappear in adulthood. Due to repeated water loss and hyperosmolarity in infancy, patients may suffer from mental retardation and vascular endothelial damage, and there may be diffuse intracranial and vascular calcification.
2.Clinical manifestations of the primary disease
Patients with secondary uremia also have signs and symptoms of the primary disease. Patients with traumatic CDI may present with transient uremia and triphasic uremia. Triphasic uremia can be divided into acute, intermediate and persistent phases. The acute phase manifests as polyuria, which occurs after the injury and usually lasts 4-5 days, mainly because the injury causes neuronal shock and the inability to release AVP or release biologically inactive precursor substances. The intermediate phase manifests as oliguria and increased urinary osmolality, caused by a sudden increase in circulating AVP due to the overflow of AVP from the degenerating neurons. The persistent phase manifests as persistent polyuria with variable onset and >90% loss of large cell neurons in the supraoptic and paraventricular nuclei of the tract markers or >85% irreversible damage to the pituitary stalk.
Gestational dysuria (GDI) is a group of syndromes with polyuria, hypogravity urine, thirst, polyhydramnios, and electrolyte disturbances that appear in late pregnancy and are mostly transient in nature. Among the various factors causing GDI, the role of vasopressin enzyme secreted by the placenta is the most important, which increases the degradation of AVP. When the balance between the degradation of AVP and the increase of compensatory AVP secretion by the pituitary gland in the body is disturbed, the remaining AVP level cannot maintain sufficient antidiuretic activity, thus causing enuresis. The level of this enzyme decreases rapidly after delivery, and its activity is no longer detectable in plasma after 4 weeks.
3.Check
1.Urinary volume
The urine volume of patients with uremia can reach 4-20L/d, and the specific gravity is often below 1,005, sometimes up to 1,010 in partial uremia.
2.Blood and urine osmolarity
Patients with normal or slightly higher blood osmolality (normal value of blood osmolality is 290-310mOsm/L), urinary osmolality is usually lower than 300mOsm/L (normal value of urinary osmolality is 600-800mOsm/L), and in severe cases, it can be lower than 60-70mOsm/L.
3.Plasma AVP measurement
Plasma AVP (casual drinking) is 2,3-7,4 pmol/L (radioimmunoassay) in normal people, and can be significantly increased after water fasting. In patients with complete CDI, plasma AVP concentration is not measured; in patients with partial CDI, it is below the normal range; in patients with NDI, plasma AVP level is elevated or normal; in patients with psychogenic irritability, it is within the normal range or reduced.
4.Water abstinence-vasopressin test
Compare the changes in urinary osmolality before and after water fasting with those before and after the use of vasopressin.
Method: 6 to 16 hours of water fasting (generally 8 hours of water fasting, depending on the severity of the disease). Weight, blood pressure, plasma osmolality and urine specific gravity were measured before the test, and urine volume, urine specific gravity and urine osmolality were measured every hour thereafter. When the urine osmolality reached a peak, the difference between two consecutive urine osmolality <30mOsm/L, and the urine osmolality no longer increased by continued water fasting, the plasma osmolality was measured, and then 5U of pressin aqueous was injected subcutaneously immediately, and then urine was retained to determine the urine volume and urine osmolality for one to two times.
The results were judged: weight, blood pressure and plasma osmolality did not change much after water fasting in normal people (<295mOsm/L), and urinary osmolality could be greater than 800mOsm/L. After the injection of pressin, urinary osmolality increased by no more than 9%. Those with psychogenic irritable thirst are similar to normal subjects. In complete uremia, the peak plasma osmolality is greater than 300mOsm/L, urinary osmolality is lower than blood osmolality, and urinary osmolality increases by more than 50% after injection of pressor; in partial uremia, the peak plasma osmolality is not higher than 300mOsm/L, urinary osmolality may slightly exceed plasma osmolality, and urinary osmolality increases between 9% and 50% after injection. No reaction. This test should be conducted under close observation. If the patient loses more than 3% to 5% of body weight after water intake, or if there is a significant drop in blood pressure and irritability, the test should be stopped immediately and water should be replenished promptly.
5.Other
Secondary CDI requires measurement of visual acuity, visual field, pterionic saddle photogram, cranial CT or MRI, etc. to clarify the cause. Gene mutation analysis can help to clarify the molecular etiology of hereditary DI.
4.Diagnosis
The disease should be considered in anyone with irritable thirst, polydipsia, polyuria and low specific gravity urine. Blood and urine osmolality measurement and water-fastening-augmentin test can be performed if necessary, which can often clarify the diagnosis of dysuria and help to assess the degree and classification of dysuria.
1.Diagnostic points of CDI
(1) High urine volume, up to 8-10L/d or more;
(2) Hypotonic urine, urine osmolality is lower than plasma osmolality, generally lower than 20mOsm/L; urine specific gravity is low, mostly below 1,005;
(3) Hypernatremia with hypernatremia is often associated with hyperuricemia, suggesting AVP deficiency and elevated blood uric acid due to reduced uric acid clearance;
(4) The application of stimulation tests that excite the release of AVP (e.g., water prohibition test, hypertonic saline test, etc.) does not result in a decrease in urine volume and does not result in a significant increase in urine specific gravity and urine osmolality;
(5) The application of AVP treatment has a significant effect, with a decrease in urine volume and an increase in urine specific gravity and urine osmolality.
2. Diagnostic points of partial CDI
(1) Urine specific gravity reaches 1, 012 to 1, 016 after at least 2 water abstinence;
(2) Urinary osmolality/blood osmolality ratio at peak after water abstinence is greater than 1, but less than 1, 5;
(3) Sensitive to the pressin test.
3. Diagnostic points of NDI
(1) Family history, or history of excess amniotic fluid during pregnancy of the patient’s mother, or history of primary disease that can cause secondary NDI;
(2)Most of them have symptoms after birth, frequent diaper changes, polyhydramnios, slow growth or unexplained fever in infancy, and polyuria, thirst and excessive drinking in children and adulthood;
(3) Reduced urine concentration, significantly increased daily urine volume, specific gravity <1, 010, low urine osmolality, mostly below 300mOsm/L;
(4)The water-suppressant test generally does not show decreased urine volume, increased urine specific gravity and urine osmolality, and urine osmolality/blood osmolality ratio <1. In addition to decreased urine concentration function, other renal functions are also impaired in patients with secondary ndi. < div="">
5.Differential diagnosis
1. Psychogenic irritability
The clinical manifestations are very similar to those of ndi, but AVP is not lacking. The main reason is that mental factors cause irritable thirst and excessive drinking, thus leading to polyuria and low specific gravity urine. These symptoms can fluctuate with mood and are accompanied by other symptoms of neurosis. The water-abstinence-gave test helps to differentiate the two.
2. Diabetes mellitus
There are symptoms of polyuria, irritable thirst, and excessive drinking, but elevated urine specific gravity and urine osmolality, and elevated blood glucose and positive urine glucose are easily distinguished.
3.Chronic kidney disease
Especially renal tubular disease, hypokalemia, hypercalcemia, etc. can affect the renal concentration function and cause symptoms such as polyuria and thirst, but there are corresponding clinical manifestations of the primary disease, and the degree of polyuria is also light.
6.Treatment
1.Replacement therapy
AVP substitution therapy is mainly used for complete CDI. Partial CDI can also be treated with AVP substitution therapy in case of poor efficacy with oral drugs. Alternative agents include: pressin aqueous: the effect is only maintained for 3-6h, must be injected several times a day, long-term application is not convenient. It is mainly used for the treatment of urosepsis after brain injury or neurosurgery. Urosporine stop powder: Lysine pressin is a nasal spray, long-term application can cause chronic rhinitis and affect absorption. Ellagic acid pressin injection: also known as long-acting ureapressin injection once can last 3-5 days, mix well before injection, overdose can cause water toxicity. 1-Deamino-8-dextro-arginine pressin (DDAVP or desmopressin): is a synthetic AVP analogue. DDAVP enhances the anti-diuretic effect, while the vasoconstrictive effect is only 1/400 of AVP, the anti The ratio of anti-diuretic to antihypertensive effect is 4000:1, and the duration of action is 12-24 hours, which is the most ideal anti-diuretic agent at present, and the dosage depends on the condition.
2.Other anti-diuretic drugs
(1) Chlorosulfonylurea This drug can stimulate the pituitary gland to release AVP and enhance the water absorption effect of AVP, which can increase the production of renal tubular cAMP, but it is not effective for NDI. It can cause severe hypoglycemia and also water toxicity, which should be noted.
(2) Hydrochlorothiazide can reduce urine volume by half. The mechanism of action may be due to the increase of sodium excretion in urine, the lack of sodium in the body, the increase of renal proximal tubular reabsorption, and the decrease of original urine reaching the distal tubule, thus the decrease of urine volume. Long-term use may cause potassium deficiency and hyperuricemia, etc. Potassium salt should be appropriately supplemented.
(3) Carbamazepine can stimulate the release of AVP and reduce the urine volume, but the effect is not as good as chlorosulfonylurea.
3.Etiology treatment
For patients with secondary uremia, the primary cause should be treated as much as possible, or based on the above-mentioned drug therapy if it cannot be cured.