Pediatric nephrogenic diabetes insipidus

　　Detailed introduction of the causes of pediatric nephrogenic diabetes insipidus?

　　First, etiology

　　1. Hereditary, belonging to sex-linked recessive inheritance, the majority are male.

　　2. Secondary nephrogenic diabetes insipidus can occur in various chronic kidney diseases (such as hypokalemic nephropathy, interstitial nephritis, chronic pyelonephritis) and drug-induced kidney damage, etc.

　　Second, pathogenesis

　　1. Hereditary nephrogenic diabetes insipidus:The distal renal tubules and collecting ducts are insensitive to ADH, or it may be due to insufficient cAMP produced in the renal tubular epithelial cells or cAMP acting on the luminal side of the cell membrane, resulting in water permeability dysfunction. The onset of the disease is related to two gene mutations:

　　(1) Mutation of the vasopressin type-2 receptor (V2R) gene: One type is a mutation in the V2R gene (sex-linked recessive inheritance), located on the X chromosome q27-28. More than 60 types of variations have been found. After mutation, the V2R cannot bind to ADH, and the adenylate cyclase cannot be activated (post-receptor information transmission disorder), and 90% of congenital NDI patients are related to this gene mutation.

　　(2) Aquaporin-2 (AQP2) gene mutation: Another cause is AQP2 gene mutation, which is autosomal dominant or recessive inheritance. The coding gene is located on chromosome 12q13. AQP2 is regulated by ADH in two ways: first, ADH stimulates the translocation of the AQP2-containing cytoplasmic vesicles to the apical membrane of principal cells, followed by the long-lasting effect of ADH, which increases the expression of AQP2 in the collecting ducts. 10% of congenital NDI is related to AQP2 gene mutation.

　　2. Secondary nephrogenic diabetes insipidus:This is because the primary disease has destroyed the hypertonic state of the renal medulla, causing dysfunction of the renal tubular concentrating function.

　　In addition to its clinical manifestations, pediatric nephrogenic diabetes insipidus can also cause other diseases. The disease can complicate with hyperosmotic dehydration, convulsions, growth and development disorders, intellectual disability, urinary tract obstruction, and chronic renal failure, among other conditions.

　　The specific clinical manifestations of pediatric nephrogenic diabetes insipidus include the following:

　　1. Polyuria and polydipsia

　　This is an outstanding clinical manifestation of the disease. About 90% of genetic cases occur in males, and it can manifest as polyhydramnios before birth. It can present with polyuria and polydipsia at birth, and usually develops within a short time after birth to 10 years of age. The main symptoms are polyuria (low specific gravity urine), polydipsia, polydysuria, and growth and development disorders. In severe cases, patients may exhibit symptoms such as high fever, convulsions, dehydration, hypernatremia, and other clinical manifestations and corresponding signs. As age increases, symptoms can gradually subside. Secondary cases first present the symptoms of the primary disease, and then polyuria, polydipsia, dehydration, and blood concentration appear as corresponding symptoms and signs. Laboratory tests may show hypernatremia, hyperchloremia, and other conditions.

　　2. Hypotonic urine

　　Urine specific gravity often remains below 1.005, or urine osmolality below 200 mOsm/(kg·H2O). Administration of solute diuretics can only reach a level of 280-300 mOsm/(kg·H2O) equivalent to plasma osmolality.

　　3. Hyperosmotic dehydration

　　Insufficient blood volume can easily occur due to infants' inability to express thirst, leading to hyperosmotic dehydration and insufficient blood volume. This can cause central nervous system symptoms and developmental disorders in infants' intellectual development, such as death due to severe dehydration. When dehydration is caused by factors other than CDI and NDI, the urine should be concentrated. Therefore, if infants have dilute urine along with dehydration, it should be vigilant of the possibility of the disease. Adult patients may also experience severe hyperosmotic dehydration due to inappropriate water restriction or accompanied by osmoreceptor central disorder.

　　4. Growth and development delay

　　It is seen in congenital NDI.

　　5. Intellectual disability and psychological abnormalities

　　It is generally believed that intellectual disability is one of the main complications of congenital NDI. Hoekstra et al. conducted a study on 17 patients, showing that more than half of the patients' IQ can reach normal levels, and less than half of the patients have varying degrees of intellectual disability, attention deficit, and psychological disorders.

　　6, Urinary Tract Hydronephrosis

　　Patients with this disease may develop urinary tract obstruction due to a large urine flow for a long time, even without urinary tract obstruction. Long-term urinary tract obstruction can induce or exacerbate chronic renal failure. Zender et al. reported a case of an adult NDI patient with bilateral hydronephrosis, ureteral hydronephrosis, bladder dilation, and chronic renal failure, who developed left ureteral rupture after a minor injury.

　　7, Brain Tissue Calcification

　　This disease is often accompanied by intracranial calcification, the incidence of which increases with the duration of the disease, and is related to the control of polyuria and polydipsia symptoms. It can cause seizures.

　　8, Hyperprostaglandin E Syndrome (Hyperprostaglandin E Syndrome)

　　Significant increase in the excretion of prostaglandin E2, which occurs in both congenital and acquired cases. Controlling this phenomenon can alleviate the clinical manifestations of NDI.

　　9, Manifestation of the Primary Disease

　　Acquired NDI has clinical manifestations of underlying diseases and corresponding renal pathological changes. Some patients have mild symptoms, which are incomplete NDI. Drug-induced NDI is seen in patients with long-term lithium salt use, as well as in critically ill patients in the ICU, mainly due to multiple drug treatments, especially antibiotics and antitumor drugs.

　　10, Pathological Changes

　　This disease has no significant pathological changes. Adult patients can find some ultra-microscopic changes. Ishii reported a case of a 58-year-old congenital NDI, in which renal biopsy found that the mitochondrial of the collecting tubular epithelial cells became smaller and rounder, and the brush border decreased.

　　The focus is on the prevention of secondary NDI, as a considerable part of it is iatrogenic, and clinical caution is required. For the prevention of CDI, it should be referred to other congenital defects. To reduce the incidence of this disease, prevention should start from pre-pregnancy and贯穿 to prenatal periods, strengthen genetic counseling work, and pre-marital physical examination plays a positive role in preventing birth defects. The size of the role depends on the items and content of the examination, mainly including serological tests (such as hepatitis B virus, syphilis spirochete, HIV), reproductive system examination (such as cervical inflammation screening), general physical examination (such as blood pressure, electrocardiogram), and inquiry of the family history of disease.

　　Personal medical history, family history, etc., pregnant women should try to avoid harmful factors, including staying away from smoke, alcohol, drugs, radiation, pesticides, noise, volatile harmful gases, and toxic and harmful heavy metals. During the prenatal health care process of pregnancy, systematic screening for birth defects is required, including regular ultrasound examinations, serological screening, and when necessary, chromosomal testing. If abnormal results occur, it is necessary to determine whether to terminate the pregnancy; the safety of the fetus in the uterus; whether there are sequelae after birth, whether they can be treated, and how the prognosis is, etc., and to take practical and feasible diagnostic and treatment measures.

　　Clinical diagnosis and examination can be made using blood and urine in children with nephrogenic diabetes insipidus.

　　1. The onset of this disease is related to two gene mutations

　　First, mutation of the arginine vasopressin 2-type receptor gene (X-linked recessive inheritance), located on the X chromosome q27-28, more than 60 variants have been found; second, mutation of the aquaporin-2 gene, which is autosomal dominant or recessive inheritance, and the coding gene is located on chromosome 12q13.

　　2. Urine tests

　　Urine specific gravity below 1.005, urine osmolality below 200 mOsm/(kg·H2O), administration of solute diuretics can only reach 280-300 mOsm/(kg·H2O).

　　3. Blood tests

　　There may be hypernatremia, hyperchloremia, and other conditions. Blood sodium > 150 mmol/L, late NPN and creatinine may increase, B-ultrasound, imaging, and other examinations can find polyhydramnios, renal积水, ureteral hydronephrosis, bladder dilation, etc. Brain X-ray examination, CT examination can find calcification of brain tissue, and EEG may show abnormal waves or seizure-like discharges.

　　Patients with pediatric nephrogenic diabetes insipidus should eat light and easy-to-digest foods, eat more vegetables and fruits, reasonably match the diet, and pay attention to adequate nutrition. Avoid spicy, greasy, and cold foods. In addition, patients also need to pay attention to avoid spicy, greasy, and cold foods.

　　The specific treatment methods for pediatric nephrogenic diabetes insipidus are as follows:

　　First, treatment

　　1. Ensure intake and adequate nutrition:At any time, it is necessary to maintain sufficient fluid volume. Maintaining sufficient water load is more important for infants and children patients and patients with defective ADH receptor centers.

　　2. Symptomatic therapy:Including fluid replacement, reducing solute intake, and intravenous infusion (such as glucose solution, hypotonic sodium-containing solution, etc.) should be given to those with difficulty in taking oral medication. Limiting sodium intake is beneficial to alleviate polyuria and polydipsia symptoms.

　　3. Drug therapy:

　　(1) Diuretics: Hydrochlorothiazide, amiloride, and triamterene have been proven effective in the treatment of NDI through clinical practice. Hydrochlorothiazide acts on the ascending limb of the loop of Henle, inhibiting the reabsorption of sodium chloride and increasing the excretion of potassium; amiloride and triamterene act on the distal tubules and cortical collecting ducts, inhibiting the reabsorption of sodium chloride while having a potassium retention effect. The action sites of the two types of drugs are different, and they have a synergistic or additive diuretic effect. Therefore, in clinical practice, hydrochlorothiazide is often combined with amiloride or triamterene when treating NDI. The mechanism of diuretics in the treatment of NDI is unknown, and it may be that such drugs cause diuresis, reducing extracellular volume, leading to increased reabsorption of sodium chloride and water in the proximal tubules, thereby reducing the amount of sodium chloride and water reaching the distal renal units. If sodium intake is also restricted at the same time, the efficacy will be more significant. Ishii reported a case of an adult patient.

　　(2) Non-steroidal anti-inflammatory drugs (NSAIDs): Patients with NDI accompanied by high prostaglandin E syndrome are the basis for using NSAIDs to treat NDI. Hohler et al. reported that after using NSAIDs, this type of patient can not only prevent the production of prostaglandins but also improve clinical symptoms. Several points to note:

　　①The combined use of NSAIDs and thiazide diuretics has a better therapeutic effect: Hochberg et al. reported a group of 9 patients with AQP2 gene mutation NDI, who were first given desmopressin (desmopressin) 5-100mg. Eight patients were given a low-sodium diet and thiazide diuretics a few days later, and ibuprofen was added after 4-11 weeks. The study results showed that the baseline urine PGE2 and 6-keto-PGF-1α were significantly higher than those in the normal control group. Desmopressin could not increase the urine osmolality of patients with this disease, and the urine osmolality remained at 60-70mOsm/(kg·H2O). Sodium restriction combined with thiazide diuretics could reduce urine output by 30%, and the plasma osmolality decreased by an average of 15mOsm/(kg·H2O), and the urine osmolality increased by 80-96mOsm/(kg·H2O). After the addition of ibuprofen, urine output decreased by 38%, and the plasma osmolality decreased by an average of 22mOsm/(kg·H2O), and the urine osmolality increased by an average of 146mOsm/(kg·H2O).

　　②For some NDI patients, the efficacy of NSAIDs may be better than that of diuretics, and they can even be used as emergency medication. Lam et al. reported a case of NDI caused by lithium salts, where fasting for 48 hours induced severe hyperosmotic dehydration and coma, with urine output reaching 24L/d. Large amounts of fluid replacement could not correct the hyperosmotic state. Administration of 1-deamino-8-dextro-streptamine vasopressin, thiazide diuretics, and amiloride could not reduce urine output. After administration of 150mg indomethacin, urine output was immediately reduced by half, followed by the normalization of urine output and serum sodium concentration. Serum creatinine increased from 135moL/L to 173mol/L. When the dose was reduced to 75mg/d, serum creatinine decreased to 152mool/L, and urine output stabilized at 2L/d.

　　③The safety of NSAIDs in the treatment of NDI is higher than that in other kidney diseases: This may be related to the concurrent presence of high prostaglandin E syndrome. Before 1997, a total of 22 cases of NDI (16 congenital, 6 caused by lithium salts) were reported in the literature, all of whom could reduce urine output by one-third within a few hours after using NSAIDs. A few patients may cause mild renal function impairment, and the renal function of most patients (except one case) improved after reducing the dose of NSAIDs. Some studies have found that the effect of hydrochlorothiazide on reducing urine output and lithium clearance 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 combined use of hydrochlorothiazide-indomethacin than to hydrochlorothiazide-amiloride therapy.

　　④NSAIDs treatment for congenital NDI shows good efficacy both intrauterine and extrauterine: Smith et al. reported that they first used indomethacin to treat polyhydramnios and achieved good efficacy. After the fetus was born, an explicit diagnosis of NDI was made, and the continued use of indomethacin still had significant efficacy.

　　(3) Prostaglandin Synthesis Inhibitors: Such as indomethacin (消炎痛), aspirin, etc., which can reduce urine output and increase urine osmolality.

　　(4) Carbamazepine: Czako et al. conducted research on CDI and NDI patients using carbamazepine. They found that carbamazepine was effective for CDI patients but ineffective for NDI patients, thus considering that the action of carbamazepine is similar to that of ADH. However, Brooks et al. reported that in patients with mania induced NDI by lithium, the addition of carbamazepine can control polyuria and polydipsia.

　　(5) ADH preparations: For some NDI patients and those with concurrent CDI, ADH preparations may have certain efficacy. Jonat et al. reported a case of a congenital NDI patient with intractable enuresis. In a case where the enuresis did not improve despite the reduction of urine output by 2/3 with thiazide diuretics and dietary treatment, the enuresis was relieved after administration of 1-deamino-8-dextroarginine vasopressin.

　　4. Treatment of the causeSome acquired NDI can be corrected by removing the cause. For those caused by long-term use of lithium salts, stopping medication can only improve NDI partially, and some may persist for a long time, so early prevention and dynamic observation are extremely important. Regularly measuring serum lithium salt concentration and 24-hour urine output is important. The harmfulness of NDI caused by lithium salts is not only that it is easy to cause dehydration, but also that it can increase the toxicity of the drug. Secondary NDI caused by other reasons can often be reversed by removing the cause in time. Buridi et al. reported a case of an adult patient who developed hypokalemia, nephrotic kidney disease, and NDI due to excessive consumption of soft drinks. After stopping the consumption of soft drinks, limiting sodium, supplementing potassium, and using a small amount of thiazide diuretics, the patient was completely recovered. Ellis et al. reported a case of a patient with primary hyperparathyroidism complicated with NDI, whose renal concentrating function was immediately restored after surgical resection of the parathyroid gland.

　　Second, Prognosis

　　Intellectual and growth and development disorders are irreversible. Congenital ones are lifelong diseases, and symptoms may alleviate after adulthood. Hyperosmolar dehydration can be life-threatening to children. Lithium salts can cause NDI, which can last for a long time after stopping medication. Stone reported a case 8 years after stopping medication, and Thompson et al. reported a case 10 years after stopping medication, still with polyuria and polydipsia.