Nephrogenic diabetes insipidus

　　First, etiology

　　Renal diabetes insipidus is caused by congenital genetic factor abnormalities and acquired factors, i.e., acquired factors. Common secondary causes include:

　　1. Abnormal diet, excessive water intake, insufficient sodium intake, and insufficient protein intake.

　　2. Chronic renal failure, reduced concentrating function.

　　3. Electrolyte imbalance, hypokalemia, and hypercalcemia.

　　4. Diuresis after the relief of urinary tract obstruction.

　　5. Diuretic phase of acute renal failure.

　　6. Paroxysmal hypertension.

　　7. Systemic diseases such as sickle cell anemia, Sjögren's syndrome, amyloidosis, Fanconi syndrome, sarcoidosis (nodular sclerosis), renal tubular acidosis, and light chain nephropathy, etc.

　　8. Lithium, demeclocycline (demethyl tetracycline), colchicine, vinblastine, methoxyflurane, anesthetics, tosulfamide, chlorpropamide, amphotericin B, gentamicin, furosemide, ethacrynic acid, osmotic diuretics, angiographic agents, cyclophosphamide, etc.

　　Second, pathogenesis

　　Renal diabetes insipidus is characterized by resistance of the distal tubule and collecting duct epithelium to the action of ADH (antidiuretic hormone), resulting in diabetes insipidus symptoms, while the plasma ADH level is higher than normal. Injection of ADH does not increase the level of urine cAMP, hence it is believed that the key lies in the inability of the renal tubules to produce cAMP under the action of ADH. Hereditary renal diabetes insipidus is an X-linked dominant inheritance, and if the abnormal X chromosome is transmitted by the father, the son is healthy and the daughter is sick, XYxx → XxXxxYxY; if transmitted by the mother, both the son and the daughter can be affected, XxxY → XxXYxxxY. Male patients are more severe than female patients, as male patients do not have a normal X chromosome, while female patients, although they have one abnormal X chromosome, also have one normal X chromosome that can counteract the abnormal chromosome. Hereditary renal diabetes insipidus is caused by chromosomal abnormalities, which lead to the insensitivity of the distal renal tubules and collecting ducts to antidiuretic hormone, resulting in insufficient cAMP production within the renal tubular epithelial cells (or insufficient receptors, competitive inhibition and decreased affinity of other substances with receptors), or the action of cAMP on the luminal side of the cell membrane, causing dysfunction in the water permeability function. Currently, people are able to reveal the molecular mechanism of renal diabetes insipidus at the genetic level, and it is believed to be caused by a defect in the V2 receptor (V2R) on the peritubular membrane of the renal collecting duct or a defect in the water channel of the renal tubular cells (a type of membrane glycoprotein selectively permeable to water). Secondary cases are caused by the primary disease destroying the hypertonic state of the renal medulla, leading to dysfunction in the renal tubular concentrating urine, but still having a certain response to antidiuretic hormone.

　　1. Bladder distension, ureteral dilation, renal pelvis hydronephrosis, and chronic renal insufficiency. The cause of the above diseases is due to the long course of the disease and the excessive urine causing stasis.

　　2. Hyperosmotic dehydration and electrolyte imbalance, such as hypokalemia or hypernatremia.

　　3. Growth and intellectual development disorders.

　　1. Polyuria and polydipsia:This is an outstanding clinical manifestation of the disease. Congenital NDI may have polyuria and polydipsia symptoms at birth, and may even manifest as polyhydramnios before birth.

　　2. Hypotonic urine:The urine specific gravity is usually continuously lower than 1.005, or the urine osmolality is lower than 200 mOsm/(kg·H2O). With solute diuresis, it can only reach the degree of 280-300 mOsm/(kg·H2O) equivalent to plasma osmolality.

　　3. Hyperosmotic dehydration and insufficient blood volume:Due to the inability of infants and young children to express thirst, it is easy to occur hyperosmotic dehydration and insufficient blood volume, which can lead to central nervous system symptoms and infantile intellectual development disorders. Severe dehydration can lead to death. When dehydration is caused by factors other than CDI and NDI, the urine should be concentrated. Therefore, if infants have dilute urine accompanied by dehydration, it should be vigilant for the possibility of this disease. Adult patients may also develop severe hyperosmotic dehydration due to inappropriate water restriction or accompanied by osmoreceptor central disorder.

　　4. Growth and development delay:Seen in congenital NDI.

　　5. Intellectual disability and psychological abnormalities:It is generally believed that intellectual retardation is one of the main complications of congenital NDI. Less than half of the patients have varying degrees of low IQ, attention deficit, and psychological disorders, and the IQ of most patients can be at a normal level.

　　6. Urinary tract obstruction:Patients with this disease may have urinary tract obstruction due to long-term large urine flow, and even without urinary tract obstruction can also occur hydronephrosis. Long-term hydronephrosis can induce or worsen chronic renal failure.

　　7. Brain tissue calcification:This disease is often accompanied by intracranial calcification, the incidence of which increases with the extension of the course of the disease, and is related to the control of polyuria and polydipsia symptoms, which can cause seizures.

　　8. Hyperprostaglandin E syndrome:The excretion of urinary prostaglandin E is significantly increased, and it occurs in both congenital and acquired cases. Controlling this phenomenon can alleviate the clinical manifestations of NDI.

　　9. Manifestations of the primary disease:Acquired NDI has clinical manifestations of underlying diseases and corresponding renal pathological changes. Some patients have mild symptoms and are incomplete NDI. Drug-induced NDI is not only seen in patients with long-term lithium salt use, but also mainly seen in critically ill patients in the ICU, who receive a variety of drug treatments, especially antibiotics and antitumor drugs.

　　10. Genetic cases:About 90% occur in males, usually onset soon after birth, and the latest onset is at the age of 10. The main symptoms are polyuria (low specific gravity urine), polydipsia, polyphagia, growth and development disorders, etc. Newborns or severe patients often have symptoms such as fever, convulsions, hypernatremia, and other clinical symptoms due to dehydration. With the increase of age, the symptoms can gradually subside. Long-term dehydration, extracellular fluid interstitial state, damage to brain cells, can cause intellectual disability.

　　11. Secondary cases:Initially, the symptoms of the primary disease are manifested, followed by polyuria, thirst, dehydration, and blood concentration, and corresponding symptoms and signs. Laboratory tests may show hypernatremia, hyperchloremia, and decreased urine osmolality (below 200 mmol/L).

　　Aggressive treatment of the primary disease, symptomatic treatment of complications, early diagnosis and treatment for severe symptoms to prevent acute dehydration-induced electrolyte imbalance. The focus of this disease is the prevention of secondary NDI, as a considerable part of it is iatrogenic, and clinical attention should be paid. Avoid long-term mental stress, as long-term mental stress (such as fear, sadness, anxiety, or nervousness) can cause functional disorders of the cerebral cortex, leading to endocrine disorders, increasing the secretion of antidiuretic hormone, increasing urine output, and exacerbating the symptoms of thirst and polyuria. Avoid high-protein, high-fat, spicy, and high-sodium foods and smoking and alcohol, as these can increase plasma osmolality, thereby exciting the thirst center of the brain; and they are also easy to produce heat, dry up the Yin, and exacerbate the symptoms of thirst and polyuria. Avoid drinking tea and coffee, as tea and coffee contain caffeine and theophylline, which can excite the central nervous system, enhance myocardial contraction, dilate renal and peripheral blood vessels, and have diuretic effects, increasing urine output and exacerbating the condition.

　　1. Urine test:Daily urine output is significantly increased, accompanied by decreased urine specific gravity (1.001～1.005), urine osmolality is usually between 150～180 mmol/L, and the vasopressin test shows no reaction (partial reaction may occur in 'incomplete presentation' cases).

　　2. Blood tests:Due to the concentration of blood, the increase of plasma osmolality, the extracellular fluid presents a hyperosmotic state. When the plasma osmolality is greater than 280 mOsm/L, hemoglobin and hematocrit increase, blood sodium and chloride increase, blood sodium is greater than 150 mmol/L, and late urea nitrogen and creatinine can increase.

　　Exogenous vasopressin injection is ineffective, the level of cAMP in urine does not increase, the hypertonic saline test shows no reaction, and the water deprivation test can be used to distinguish between primary, psychiatric, and renal diabetes insipidus.

　　Routine imaging and B-ultrasound examinations can detect excessive amniotic fluid at birth, renal pelvis obstruction, ureteral obstruction, bladder dilation, etc. Brain CT examination can detect calcification of brain tissue, and EEG examination can detect abnormal waves or epilepsy-like discharges.

　　1. General Rehabilitation Therapy

　　1. Eliminate the cause of the disease

　　Especially for secondary diabetes insipidus: this condition can be cured, for those caused by tumors, radiotherapy or surgery should be performed, and appropriate anti-infection treatment should be adopted for those caused by infection. It is important to provide adequate water intake to prevent dehydration and potassium loss, and to limit sodium in diet, avoid drinking tea and coffee, and avoid fatigue and emotional fluctuations.

　　2. TCM Classification and Treatment Methods with Chinese Herbs

　　1. Deficiency of both Qi and Yin

　　Excessive drinking and urination, fatigue, spontaneous sweating, shortness of breath, exacerbation upon exertion, dry mouth and tongue, restlessness and feverishness of the five heart regions, constipation, soreness and softness of the loins, pale red tongue with bluish hue, teeth marks on the tongue edges, thin white coating with little saliva, and a thin, weak pulse.

　　[Therapeutic Method] Invigorate Qi and Nourish Yin.

　　[Prescription] Modified Liuwei Dihuang Pill: 25 grams of raw rehmannia, 16 grams of fructus corni, 25 grams of山药, 12 grams of poria, 12 grams of alisma, 12 grams of atractylodes, 25 grams of scutellaria, 35 grams of astragalus, 16 grams of codonopsis, 12 grams of rhizoma atractylodis macrocephalae.

　　2. Yin and Yang Deficiency

　　Polyuria and polydipsia, turbid like grease, fatigue and spontaneous sweating, cold limbs, ashy face, soreness in the loins and knees, dry earlobes, edema and decreased urine output, or diarrhea in the early morning, premature ejaculation, pale tongue, white fur, deep and rapid pulse.

　　[Therapeutic Method] Warm Yang and Nourish Yin.

　　[Prescription] Modified Jinkui Shenqi Pill: 12 grams of prepared aconite (decocted first), 4 grams of cinnamon, 25 grams of prepared rehmannia, 12 grams of fructus corni, 25 grams of山药, 25 grams of poria, 12 grams of peony, 12 grams of alisma, 35 grams of astragalus, 16 grams of trichosanthes, 1s grams of fructus alpiniae oxyphyllae, 16 grams of cryptotympana.

　　First, treatment

　　The basic principle is to replenish water to maintain water balance, reduce the intake of solutes such as sugar and salt. Pay attention to improve the patient's mental and nutritional status.

　　1. Provide a large amount of fluid to prevent dehydration. For acute dehydration, intravenous fluid replacement (using 5% glucose solution) should be considered. If the patient's plasma is in a hyperosmotic state, low-tonicity fluid should be considered for infusion.

　　2. Limit the intake of solutes, such as low-salt, low-protein diet, the intake of sodium chloride should be controlled at 0.5-1.0g per day to reduce the need for water.

　　3. Sodium-reducing diuretics, such as hydrochlorothiazide (双氢克尿塞) 25-50mg per dose, three times a day orally, can reduce urine output by 50%. The mechanism may be that it stimulates the reabsorption of sodium by the proximal tubules by affecting the production of negative sodium balance in the distal renal tubules, making the fluid flowing through the medullary loop and distal renal tubules hypotonic. Therefore, sodium intake should be limited when using this drug.

　　4. Indomethacin (消炎痛) especially when used in combination with hydrochlorothiazide (双氢克尿塞), can significantly reduce urine output, commonly used at a dose of 25mg, three times a day. Indomethacin is a non-steroidal anti-inflammatory drug (NSAIDs), and it can be used to treat NDI patients with high prostaglandin E syndrome. After the use of NSAIDs, patients can prevent the production of prostaglandins and improve clinical symptoms. Clinical studies have found that the combination of NSAIDs with thiazide diuretics is more effective. It can even be used as emergency medication. The safety of NSAIDs in the treatment of NDI is higher than that in other kidney diseases. This may be related to the fact that patients often have a high prostaglandin E syndrome. Some studies have found that the effect of hydrochlorothiazide in reducing urine output in NDI is further enhanced when NSAIDs are added, and it has no significant effect on glomerular filtration rate and renal blood flow. However, patients have less tolerance to the combination of hydrochlorothiazide-indomethacin than to hydrochlorothiazide-amiloride therapy. NSAIDs have good therapeutic effects on congenital NDI both in utero and extrauterine. Smith et al. reported that they first used indomethacin to treat polyhydramnios and achieved good results. After the fetus was born, an accurate diagnosis of NDI was made, and the continued use of indomethacin still had significant effects.

　　5. Symptomatic treatment, if concurrent with hypokalemia and other electrolyte deficiencies, potassium salts or the corresponding electrolytes can be supplemented.

　　6. Secondary cases should be treated for the primary disease according to the cause, and symptomatic treatment can also be given to those with severe polyuria.

　　Recent research has proven that under a moderate salt-restricted diet [Na1.2mmol/(kg·d)], the combination of potassium-sparing diureticamiloride (urea derivative) 20mg/(1.73m2·d) and hydrochlorothiazide (dihydrochlorothiazide) 2mg/(kg·d) in the treatment of renal diabetes insipidus for more than one year is effective. There are no complications of hypokalemia due to combined treatment, so potassium supplementation is not needed. It is superior to the therapy of hydrochlorothiazide plus indomethacin in reducing urine volume and increasing urine osmolality. It is known that the combination of amiloride and hydrochlorothiazide (dihydrochlorothiazide) can offset the potassium loss that occurs as a complication of long-term use of hydrochlorothiazide (dihydrochlorothiazide). It can play a synergistic antidiuretic effect.

　　7. ADH preparations may have a certain therapeutic effect on some NDI patients and those with CDI. Jonat et al. reported a case of a congenital NDI patient with intractable enuresis. After using thiazide diuretics and dietary treatment to reduce urine output by 2/3, and without improvement in enuresis, 1-deamino-8-d-arginine vasopressin was administered to relieve the symptoms.

　　II. Prognosis

　　Congenital cases are lifelong diseases, and the intellectual and growth and development disorders of patients are irreversible. Symptoms can be alleviated after adulthood. Early diagnosis and treatment have a good prognosis. However, hyperosmolar dehydration can be life-threatening, and 5% to 10% of patients may die of dehydration in infancy.