How does hypercalcemia cause nephrogenic diabetes insipidus ?<br /><br /><br /><br />Hypercalcemia is a condition in which the calcium level in the blood becomes too high.<br /><br />The symptoms of the hypercalcemia <br /><br />You might not have any symptoms if your hypercalcemia is mild. If it's more serious, your symptoms are related to the parts of your body affected by high blood calcium levels. Examples include:<br /><br />● Kidneys. Excess calcium makes the kidneys work harder to filter it. This can cause serious thirst and frequent urination.<br />● Digestive system. Hypercalcemia can cause stomach upset or pain, vomiting, and constipation.<br />● Bones and muscles. Most often, the extra calcium in the blood is leached from the bones. This weakens the bones. It can cause bone pain and muscle weakness.<br />● Brain. Hypercalcemia can affect how the brain works. That can lead to trouble focusing, confusion, drowsiness and fatigue. It also can cause depression.<br />● Heart. Rarely, serious hypercalcemia can affect the heart. It can cause feelings of a fast-beating, fluttering or pounding heart. It also can cause the heart to beat out of rhythm. It's linked with other heart-related conditions as well.<br /> <br /><br /><br /><br /><br /><br />The causes of the hypercalcemia ، including :<br /><br />● Overactive parathyroid glands : This also is called hyperparathyroidism. It's the most common cause of hypercalcemia. Overactive parathyroid glands make too much parathyroid hormone. The condition can stem from a small tumor that isn't cancer. It also can stem from one or more of the four parathyroid glands becoming larger.<br />● Cancer : Lung cancer, breast cancer and some blood cancers can raise the risk of hypercalcemia. Cancer that spreads to the bones also raises the risk.<br />● Other diseases. Conditions such as tuberculosis and sarcoidosis can raise blood levels of vitamin D. That in turn spurs the digestive tract to absorb more calcium.<br />● Genetic factors : A rare genetic condition called familial hypocalciuric hypercalcemia causes an increase of calcium in the blood. This condition doesn't cause symptoms or complications of hypercalcemia.<br />● Little or no movement : People who have a condition that causes them to spend a lot of time sitting or lying down can get hypercalcemia. Over time, bones that don't bear weight release calcium into the blood.<br />● Serious dehydration : This is a common cause of mild or short-term hypercalcemia. Having less fluid in the blood causes a rise in calcium.<br />● Some medicines. Medicines such as lithium and thiazide diuretics might cause more parathyroid hormone to be released.<br />● Supplements : Taking too much calcium or vitamin D supplements over time can raise calcium levels in the blood.<br /><br /><br />What is nephrogenic diabetes insipidus?<br /><br />Diabetes insipidus: is an uncommon problem that causes the fluids in the body to become out of balance. That prompts the body to make large amounts of urine. It also causes a feeling of being very thirsty even after having something to drink. Diabetes insipidus also is called arginine vasopressin deficiency and arginine vasopressin resistance.<br />What are the different types of diabetes insipidus?<br /><br />There are four types of diabetes insipidus:<br /><br />● Central diabetes insipidus. Damage to the pituitary gland or hypothalamus from surgery, a tumor, a head injury or an illness can cause central diabetes insipidus. That damage affects the production, storage and release of ADH. An inherited disorder may cause this condition too. It also can be the result of an autoimmune reaction that causes the body's immune system to damage the cells that make ADH.<br />● Nephrogenic diabetes insipidus. is a medical disorder that occurs when your kidneys can’t properly balance bodily fluids. Your body fails to respond properly to a natural hormone called antidiuretic hormone (ADH, also called vasopressin). Therefore, it produces too much urine, which can cause rapid, sometimes dangerous dehydration.This happens when there's a problem with the kidneys that makes them unable to properly respond to ADH. That problem may be due to:<br />○ An inherited disorder.<br />○ Certain medicines, including lithium and antiviral medicines such as foscarnet (Foscavir).<br />○ Low levels of potassium in the blood.<br />○ High levels of calcium in the blood.<br />○ A blocked urinary tract or a urinary tract infection.<br />○ A chronic kidney condition.<br />● Gestational diabetes insipidus. This rare form of diabetes insipidus only happens during pregnancy. It develops when an enzyme made by the placenta destroys ADH in a pregnant person.<br />● Primary polydipsia. This condition also is called dipsogenic diabetes insipidus. People who have this disorder constantly feel thirsty and drink lots of fluids. It can be caused by damage to the thirst-regulating mechanism in the hypothalamus. It also has been linked to mental illness, such as schizophrenia.<br /><br />What causes nephrogenic diabetes insipidus?<br /><br />Your kidneys are responsible for filtering blood to remove waste and excess fluid from your body, in the form of urine. ADH (vasopressin) is a hormone that helps your body maintain the balance between fluid intake and urine output.<br />In a healthy person, ADH helps the body understand when to make less urine. For example, when a person sweats a lot or doesn’t drink enough fluids, higher levels of vasopressin tell the kidneys to make less urine. When a person has enough fluid in their body, lower levels of ADH tell the kidneys to make urine.<br /><br />But if your body doesn’t know how to respond properly to vasopressin, then your kidneys make too much urine. This is what happens with nephrogenic diabetes insipidus. You can inherit the condition or develop it at any point during your life.<br /><br />The acquired form is more common and results when something damages your body’s ability to respond to ADH. Examples include conditions that affect your kidneys, such as:<br /><br />● Amyloidosis.<br />● Certain types of cancer.<br />● Chronic kidney disease.<br />● Kidney infection (pyelonephritis).<br />● Polycystic kidney disease.<br />● Medullary sponge kidney<br /><br />Other things that can cause nephrogenic diabetes insipidus include:<br /><br />● Certain medications (for example, lithium).<br />● Low levels of potassium in the blood (hypokalemia).<br />● High levels of calcium in the blood (hypercalcemia).<br />● Sickle cell anemia.<br />● Sjögren’s syndrome.<br />● Urinary tract obstruction<br /><br /><br />The hereditary form involves mutations to the AVPR2 or AQP2 gene. Those genes provide your body with information about how much water to include in urine. The signs and symptoms of hereditary nephrogenic diabetes insipidus usually appear within the first few months of life.<br /><br /><br />What are the symptoms of nephrogenic diabetes insipidus?<br /><br />A person with nephrogenic diabetes insipidus is likely to have the following symptoms:<br /><br />● Symptoms of dehydration such as dry mouth, fatigue and dizziness.<br />● Excessive thirst.<br />● Large amounts of urine output (more than 3 liters a day for adults and 2 liters a day for children).<br /><br />In an infant, signs of nephrogenic diabetes insipidus may include:<br /><br />● Diarrhea.<br />● Failure to thrive and gain weight.<br />● Fever.<br />● Irritability.<br />● Poor appetite.<br />● Seizures.<br />● Vomiting.<br /><br />Mechanism of Hypercalcemic Acquired Nephrogenic Diabetes Insipidus : <br /><br />Chronic hypercalcemia causes downregulation of collecting <br />duct AQP2 expression. This may be due to autophagy of the AQP2 receptor. Additionally, there can be a significant down-regulation of the Na-K-2Cl cotransporter in the medullary thick ascending limb, thereby interfering with the counter current mechanism and this may participate in the development of the urinary concentrating defect .<br /><br /><br /><br /><br /><br /><br /><br /><br /> <br /><br />Discussion:<br /><br />There have been seven different types of aquaporins identified in the kidneys. The Aquaporin-2 subtype (AQP2) has been shown to be the primary target for vasopressin regulation of collecting duct water permeability. Vasopressin is released from the posterior pituitary gland . It finds to the vasopressin-type 2 receptor on the basolateral membrane of the collecting duct. This causes production of aquaporins, which insert into the luminal/apical membrane. These <br />allow water reabsorption and concentration of the urine.<br /><br /><br />Management:<br /> Hydration, antibiotics, intravenous pamidronate for rapid control of hypercalcemia, parathyroidectomy, surgical removal of the large kidney stones, a low-protein and low-sodium diet, and initiation of treatment with a thiazide diuretic.<br /><br />جامعة المستقبل الجامعة الاولى في العراق<br />قسم تقنيات المختبرات الطبية الاول في التصنيف الوطني العراقي