Hypercalcemic nephropathy

　　1. Etiology

　　Common causes of hypercalcemia include hyperparathyroidism, including primary and secondary hyperparathyroidism, acute and chronic renal failure, post-renal transplantation, malabsorptive osteomalacia; hyperthyroidism or hypothyroidism, adrenal cortical insufficiency, pheochromocytoma; malignant tumors; excessive calcium intake; vitamin D, A intoxication; increased sensitivity to vitamin D, such as sudden infant hypercalcemia, granulomatosis, sarcoidosis, tuberculosis, histoplasmosis, coccidioidomycosis; other acromegaly, gigantism, widespread peritonitis, and so on.

　　1. Primary Hyperparathyroidism Primary hyperparathyroidism (abbreviated as primary hyperparathyroidism) is the most common cause of hypercalcemia, accounting for about 50% of all cases of hypercalcemia.Approximately 250 per million patients with primary hyperparathyroidism occur annually. Although it can occur at any age, it is most common in the elderly and women.

　　85% of patients have a single benign adenoma in one parathyroid gland, while the other patients have hyperplasia in all four parathyroid glands. It is extremely rare for a gland to develop a cancer. The biochemical characteristics of primary hyperparathyroidism patients are elevated PTH, 1.25(OH)2D3, and the resulting effects. PTH stimulates osteoclast resorption, reduces urinary calcium excretion, and causes hypercalcemia. PTH increases urinary phosphorus and bicarbonate excretion, causing hyperchloremic acidosis and increasing urinary cAMP excretion. Many patients have elevated blood alkaline phosphatase levels.

　　Many patients with primary hyperparathyroidism are discovered during routine laboratory tests, and most patients have no symptoms. Patients with symptoms are mostly diagnosed with recurrent renal calculi caused by hypercalciuria; patients occasionally have subperiosteal resorption and diffuse osteopenia of the skull; some patients experience muscle weakness caused by type II muscular atrophy; acute pancreatitis may occur occasionally.

　　Primary hyperparathyroidism can also manifest as one of the multiple endocrine neoplasia syndromes. Type I of this syndrome includes hyperparathyroidism, pituitary adenomas secreting prolactin or growth hormone, and islet cell tumors secreting insulin or gastrin-releasing hormone. Type II includes hyperparathyroidism, medullary thyroid cancer, and pheochromocytoma. Both types are autosomal dominant inherited.

　　2. Hypercalcemia caused by malignant tumors is the second most common cause of hypercalcemia.Hypercalcemia in patients with malignant tumors may be related to most stress symptoms, such as nausea, vomiting, and confusion. It is recommended to use intensive measures to lower blood calcium levels to improve symptoms.

　　Some tumors are more likely to cause hypercalcemia. The most common are lung squamous cell carcinoma and breast cancer. Breast cancer patients only commonly have hypercalcemia when the tumor has widely metastasized to the bone. Other tumors include myeloma, T-cell lymphoma, squamous cell carcinoma of the head and neck, renal cell and ovarian cell carcinoma. Tumors that less commonly cause hypercalcemia include lung adenocarcinoma, gastric, colorectal, and female reproductive tumor cancers.

　　3. Thyrotoxicosis The past survey results showed an incidence rate of 10% to 20%, and the possibility is higher after measuring ionized calcium.It is usually moderate hypercalcemia, asymptomatic. Some patients may have hyperparathyroidism at the same time. In patients with thyrotoxicosis, blood phosphorus levels usually increase, while in patients with hyperparathyroidism, blood phosphorus levels decrease. After treatment for thyrotoxicosis, hypercalcemia will return to normal.

　　4. Lack of exercise is common in adolescents with rapid bone remodeling and complete inactivity, such as paraplegia, quadriplegia, and bedridden patients after fractures.Hypercalciuria is more common than hypercalcemia. Hypercalcemia can last for several months. Intravenous administration, intensive treatment, bisphosphonates, glucocorticoids, or CT are beneficial.

　　5. Sarcoidosis and other granulomatous diseases Hypercalcemia occasionally occurs in sarcoidosis, tuberculosis, histoplasmosis, coccidioidomycosis, candidiasis, and beryllium poisoning.Among them, sarcoidosis is the most common. Hypercalcemia is often moderate, below 120mg/L. Hypercalciuria is more common. Renal calcification and soft tissue calcification often occur. The etiology is related to the production of 1,25(OH)2D3 by granulomatous tissue. Sarcoid macrophages and granuloma cells can convert 25(OH)D3 into 1,25(OH)2D3. Disseminated giant cell virus infection caused by acquired immunodeficiency syndrome (AIDS) can also cause hypercalcemia, which is related to granulomatous lesions. Treatment can include fluid expansion, calcium restriction, and, if necessary, corticosteroids.

　　6. Vitamin D toxicity can cause hypercalcemia and hypercalciuria.Like hypercalcemia caused by sarcoidosis, patients may present with hyperphosphatemia, renal dysfunction, renal calcification, and soft tissue calcification. Hypercalcemia caused by vitamin D lasts longer than that caused by its active metabolites, and can last for several months. Therefore, if hypercalcemia is severe, vitamin D toxicity requires corticosteroid treatment. Increased sensitivity to vitamin D: sudden infantile hypercalcemia, granulomatosis, sarcoidosis, tuberculosis, histoplasmosis, coccidioidomycosis.

　　7. Vitamin A toxicity Vitamin A rarely causes hypercalcemia.Commonly seen in vitamin abusers. Vitamin A toxicity can cause vertebral ligament calcification, osteophyte formation, and osteoporosis. Removal of vitamin A and the use of corticosteroids can effectively treat hypercalcemia.

　　8. Medications

　　(1) Thiazide diuretics: occasionally cause moderate hypercalcemia. Serum calcium is almost always below 110mg/L. However, the effects of thiazide diuretics can be additive to primary hyperparathyroidism or hypercalcemia due to other causes.

　　(2) Lithium: accounting for 5% of hypercalcemia caused by medication, the mechanism is unknown. An inappropriately high level of PTH suggests a change in the calcium set point that inhibits PTH secretion. Stopping lithium treatment can restore blood calcium levels.

　　9. Milk-alkali syndrome is caused by hypercalcemia due to the excessive use of non-absorbable calcium antacids with milk.It often accompanies alkalosis and renal injury. Since such antacid drugs are not commonly used, this syndrome has become rare. Treatment is to remove the cause, strong fluid expansion, and, if necessary, use CT and corticosteroids.

　　10. Familial hypouricemic hypercalcemia is characterized clinically by hypercalcemia with hypophosphatemia, reduced renal excretion of calcium and magnesium.It must be recognized that these patients are insensitive to parathyroidectomy. This disease is an autosomal dominant inheritance. iPTH is within the normal range. Most patients do not require treatment.

　　11. Addison's disease rarely causes hypercalcemia.In these patients, hypercalcemia may be related to fluid loss or reduced cortisol production.

　　12. Paget's disease is rare.If there is hypercalcemia, it often coexists with primary hyperparathyroidism.

　　13. Renal Failure:Most patients with renal failure have hypocalcemia. Hypercalcemia itself can cause renal failure, especially in patients with sarcoidosis, milk-alkali syndrome, vitamin D intoxication, or myeloma. Hypercalcemia caused by acute renal failure appears during the polyuria phase, and most patients have rhabdomyolysis, the cause is unknown. Hypercalcemia occasionally occurs in patients with chronic renal failure, which is related to secondary hyperparathyroidism or aluminum intoxication. Aluminum intoxication often accompanies low turnover-type osteomalacia. It is characterized by no significant increase in iPTH and low alkaline phosphatase.

　　2. Pathogenesis

　　The main effect of hypercalcemia on the kidneys is to decrease renal blood flow and glomerular filtration rate, which may be caused by the release of catecholamines, leading to vasoconstriction of the glomerular vessels; since calcium can reduce the permeability of the renal tubules to water, inhibit the Na-K pump in the medullary loop, and reduce the reabsorption of Na, the osmotic pressure in the medullary high osmotic area decreases, calcium can reduce the sensitivity of the distal tubules to antidiuretic hormone, thereby affecting water reabsorption, and also reducing the kidney's concentrating function; in addition, calcium salts can deposit in the kidneys and cause interstitial nephritis. The pathophysiological changes of this disease are:

　　1. Impaired Water Reabsorption:During hypercalcemia, the renal tubular epithelial cell membrane becomes more compact, reducing the permeability of the distal tubules to water, and reducing water reabsorption. At the same time, the activity of the Na-K-ATPase in the medullary loop is inhibited, reducing the reabsorption of Na, decreasing the osmotic pressure in the medullary high osmotic area, and reducing water reabsorption.

　　2. Acid-Base Imbalance:Hypercalcemia caused by hyperparathyroidism often leads to metabolic acidosis, while hypercalcemia without increased parathyroid hormone often causes metabolic alkalosis. Hypercalcemia can cause damage to the distal tubules, reducing the secretion of H and ammonia production, which can lead to metabolic acidosis. Hypercalcemia can also stimulate the secretion of gastric acid and bone resorption, releasing alkaline substances into the extracellular fluid, and at the same time promoting the reabsorption of bicarbonate, thus causing metabolic alkalosis.

　　3. Azotemia and renal insufficiency:Hypercalcemia directly causes the constriction of renal microvessels or increases the release of catecholamines, leading to a decrease in renal blood flow and the appearance of azotemia. Long-term hypercalcemia nephropathy may lead to chronic renal failure due to renal parenchymal damage.

　　4. Hypertension:The mechanism of hypertension in this disease may be related to the change of neuromuscular excitability caused by hypercalcemia, which leads to the contraction of vascular smooth muscle or the increase of the release of vasoconstrictive substances.

　　The treatment with antidiuretic hormone is ineffective in this disease, and complications such as nephrogenic diabetes insipidus may occur. In patients with a long course of disease, aminoaciduria, renal glucosuria, proteinuria, renal calcification, urinary tract stones often occur, and pyelonephritis often occurs. In the late stage, GFR decreases, azotemia, and uremia appear. The special signs of general manifestations are chronic conjunctivitis, corneal calcification rings (ring-shaped keratitis). It can be accompanied by atrophy of the lingual muscles, decreased sense of smell, hoarseness, difficulty in swallowing, ataxia. Hypercalcemia can stimulate the secretion of gastric glands and cause ulcer disease, which can lead to gastric hemorrhage and perforation. A hypercalcemic crisis may occur when the blood calcium concentration increases rapidly and exceeds 3.7 mmol/L.

　　1. Early manifestations:Polyuria, nocturia, thirst, decreased urine specific gravity and osmolality, even nephrogenic diabetes insipidus, treatment with antidiuretic hormone is ineffective. In patients with a long course of disease, aminoaciduria, renal glucosuria, proteinuria, renal calcification, urinary tract stones often occur, and pyelonephritis often occurs. In the late stage, GFR decreases, azotemia, and uremia appear.

　　2. General manifestations:Including symptoms such as dehydration, hypokalemia, hyponatremia, hypomagnesemia, tubular acidosis, pruritus, chronic conjunctivitis, corneal calcification rings (ring-shaped keratitis) are special signs of hypercalcemia. It can be accompanied by atrophy of the lingual muscles, decreased sense of smell, hoarseness, difficulty in swallowing, ataxia. Hypercalcemia can stimulate the secretion of gastric glands and cause ulcer disease, which can lead to gastric hemorrhage and perforation. This disease can cause multiple stones, peptic ulcers, pancreatitis, and other symptoms if it is caused by increased secretion of parathyroid hormone.

　　When the blood calcium concentration increases rapidly and exceeds 3.7 mmol/L, hypercalcemic crisis may occur, with a mortality rate of up to 60%, patients may experience severe polyuria, dehydration, a rapid increase in blood pressure, a rapid deterioration in renal function, headaches, nausea, vomiting, abdominal colic, convulsions, drowsiness, delirium, rigidity, coma, ventricular tachycardia, or ventricular fibrillation.

　　3. Laboratory examination:Hypercalcemia, hypophosphatemia, hyperchloremia, increased BUN and serum creatinine, decreased creatinine clearance, increased urinary calcium (hypercalciuria), more than 0.1 mmol/ (kg·24h), males more than 7.49 mmol/24h, females more than 6.24 mmol/24h, proteinuria is mostly mild, mainly low molecular weight proteinuria, and sometimes red blood cells, white blood cells, cellular casts, and occasionally calcium casts can be seen.

　　4. Imaging examination:Kidney stones or renal calcification can be detected.

　　According to the clinical manifestations and findings from laboratory examinations such as increased blood calcium concentration, increased urinary calcium (hypercalcemia), and sometimes the presence of red blood cells, white blood cells, cell casts, and occasionally calcium casts in the urine, as well as clinical features of renal dysfunction such as polyuria, nocturia, aminoaciduria, renal glycosuria, proteinuria, renal calcification, urinary tract stones, often complicated with pyelonephritis, and in the late stage, GFR decline, azotemia, and uremia; or the presence of systemic special signs such as chronic conjunctivitis, calcified corneal rings (corneal ring disease); as well as lingual atrophy, decreased sense of smell, hoarseness, difficulty swallowing, ataxia, gastric hemorrhage and perforation; and when blood calcium concentration increases rapidly, a hypercalcemic crisis occurs, the patient shows severe polyuria, dehydration, a sudden increase in blood pressure, acute deterioration of renal function, and symptoms such as headache, nausea, vomiting, abdominal colic, convulsions, somnolence, delirium, rigidity, coma, ventricular tachycardia, or ventricular fibrillation; at this time, the disease can generally be diagnosed. Patients with renal failure may find it difficult to diagnose due to the decrease in blood calcium levels.

　　The principle is to treat the primary disease and rapidly control hypercalcemia. Peritoneal dialysis and hemodialysis can be used for patients with hypercalcemic crisis and renal failure. Paying attention to controlling infection and preventing complications can effectively prevent the progression of the disease.

　　1. Blood test:Hypercalcemia, hypophosphatemia, hyperchloremia, hypokalemia, hyponatremia, hypomagnesemia, tubular acidosis, and increased BUN and serum creatinine can be found. The creatinine clearance rate is reduced, and the level of serum alkaline phosphatase is increased, and the serum PTH level is increased.

　　2. Urinalysis:Increased urinary calcium (hypercalcemia), higher than 0.1 mmol/(kg·24h), with men higher than 7.49 mmol/24h and women higher than 6.24 mmol/24h. Proteinuria is usually mild, mainly low molecular weight proteinuria, and sometimes red blood cells, white blood cells, cell casts, and occasionally calcium casts can be seen.

　　3. Imaging examination:Kidney stones or renal calcification can be detected. The pathological changes in the acute phase of this disease are mainly in the medulla. After a short period of sustained hypercalcemia, there is a rapid swelling, degeneration, necrosis, and shedding of the epithelial cells of the distal tubules and collecting ducts. The basement membrane of the tubular epithelial cells calcifies and necrotic tissue blocks the renal tubules. The mechanism of occurrence is the abnormal increase in calcium concentration inside and inside the mitochondria, leading to calcification of the tubular basement membrane and structural damage, which causes adjacent interstitial inflammation, infiltration, and proliferation. The shedding of necrotic cells leads to tubular atrophy, obstruction, secondary expansion, and pressure injury to the proximal tubular segments. The calcification of the necrotic and damaged areas causes characteristic renal calcification visible on radiological examination. In patients with a long course of disease, the glomeruli are also affected, showing glomerular calcification and glomerular hyalinosis with periglomerular fibrosis. The deposition of calcium in the glomerular capillaries and interstitial vessels is related to the progressive damage of the kidney. In the chronic phase, the typical changes of chronic tubulointerstitial nephritis can be seen, including tubular atrophy, interstitial fibrosis, and infiltration of mononuclear cells. The formation of kidney stones and the obstructive nephropathy caused by them further exacerbate the tubulointerstitial damage. The above characteristic changes can be seen in renal biopsy.

　　I. Dietary therapy for hypercalcemia nephropathy

　　1. Astragalus and Malva verticillata fish soup

　　Main ingredients: one fish (about 800g), 30g of raw Astragalus, 25g of Malva verticillata seeds, 9g of raw ginseng, 30g of yam, a little salt, and a little monosodium glutamate.

　　Preparation method: cut the raw ginseng into slices, wash the Malva verticillata seeds and wrap them in gauze; put the cleaned fish, Astragalus, and yam in a pot, then add the raw ginseng and Malva verticillata seeds, add an appropriate amount of water, bring to a boil over medium heat, then reduce to a steady heat and simmer for one and a half hours; add a little salt and monosodium glutamate to mix well and then remove from heat.

　　Method of consumption: as a side dish, eat meat and drink soup, consume in two servings.

　　2. Yam and Euryale ferox soup

　　Main ingredients: 25g of yam, 25g of Euryale ferox, 15g of mung bean, 20g of lotus seed, and an appropriate amount of sugar.

　　Preparation method: put the prepared dried yam, Euryale ferox, mung bean, and lotus seed together in a pot; add an appropriate amount of water, bring to a boil over high heat, then reduce to low heat and simmer for 60 minutes, then add sugar to taste and it is ready to eat.

　　II. What is good for the body in hypercalcemia nephropathy

　　1. Eat light and easy-to-digest foods.

　　2. Eat fresh vegetables and a moderate amount of fruit.

　　3. Drink water appropriately.

　　III. What foods should be avoided in hypercalcemia nephropathy

　　1. Avoid seafood, beef, mutton, spicy刺激性 foods, alcohol, and all heat-producing foods such as five-spice powder, coffee, coriander, etc.

　　2. Avoid all tonics, tonics, and easy-to-heat-up foods such as chili, lichee, chocolate, etc.

　　I. Treatment

　　The treatment of hypercalcemia should be aimed at the cause, and for hypercalcemia caused by malignant tumors, the blood calcium level must be directly reduced. The treatment method depends on the cause, but is influenced by other factors, especially renal function. For those with increased intestinal calcium absorption, calcium intake should be limited, and if unsuccessful, corticosteroids can be used. Most patients can limit calcium intake to about 400mg per day. For patients with pseudosarcoma, this concentration is sufficient to maintain normal blood calcium levels. If it cannot be corrected, corticosteroids are extremely effective. Corticosteroids act directly on intestinal epithelium, inhibiting calcium absorption and interfering with vitamin D metabolism. Initially, 40mg of prednisone per day is administered, then the dose is reduced to the lowest amount that can maintain normal blood calcium levels. Corticosteroids may take 7 to 10 days to produce beneficial effects. If steroids are ineffective, chloroquine or ketoconazole (Ketoconazole) can be used. Patients should consume as much sodium as possible, with at least 150mmol of sodium per day. While consuming more sodium, diuretics such as furosemide should be used (note not to use thiazide diuretics). The use of furosemide can increase calcium excretion by utilizing the linear function relationship between urine calcium and urine sodium clearance rates. Calcium disodium edetate (EDTA) can chelate calcium and increase the excretion of calcium in urine. Drinking plenty of water, at least 3000ml per day, or correcting dehydration by expanding fluid volume, combined with diuretics, to increase urine output to more than 100ml/h, 2000ml/d, to promote calcium excretion.

　　For primary hyperparathyroidism, surgical resection is the best treatment. For patients who are contraindicated for surgery, there is currently no better method. For some asymptomatic patients with primary hyperparathyroidism, the difference in outcomes between surgery and no surgery is not significant. If the patient can be followed up, especially for those who are asymptomatic and have blood calcium levels below 110mg/L, not performing active surgery is reasonable. For patients with symptoms and higher blood calcium levels, surgical treatment is needed. For post-menopausal women, estrogen replacement therapy has been proven to be effective, but the mechanism of action is unclear. Commonly used estrogens include diethylstilbestrol and ethinyl estradiol (dienestrol). For patients who are contraindicated to estrogen, they can take a salt containing 3g of elemental phosphorus, 3 times a day or 4 times a day. Oral phosphorus can reduce blood calcium levels and reduce the occurrence of kidney stones. However, PTH levels may increase, and occasionally it can cause麻烦的 diarrhea, soft tissue calcification. Patients with renal impairment cannot use it. After correcting hypercalcemia, blood pressure can return to normal. Early renal impairment can gradually recover after correcting hypercalcemia, but for those with long-standing disease and severe renal parenchymal damage, renal failure may still exist after correcting hypercalcemia. Itching caused by hyperparathyroidism can disappear after subtotal parathyroidectomy.

　　It is important to recognize the hazards of hypercalcemia in malignant tumors. Since it can cause stress symptoms and signs, appropriate treatment is easy to reverse. There is controversy regarding whether to treat patients who are asymptomatic and have blood calcium levels below 130mg/L. Due to the progressive nature of hypercalcemia caused by tumors, active treatment may be beneficial. Indomethacin (anti-inflammatory) and aspirin can be used for patients with tumors that excrete increased prostaglandin PG-E2. Mitomycin (autocrystalline) and mitoxantrone can be used for malignant tumors or those that are ineffective with other therapies.

　　Emergency treatment for hypercalcemia caused by malignant tumors:If the patient has symptoms and the blood calcium level is higher than 130mg/L, emergency treatment is required. These patients need to be infused with normal saline, and 3 to 5 liters need to be administered daily. Even if the blood volume is normal, the infusion of normal saline will increase urinary calcium excretion. Furosemide 20 to 40mg may be needed to prevent excessive fluid overload.

　　Osteoclast bone resorption increases almost always in patients with hypercalcemia due to tumors, and to maintain normal blood calcium levels, it is necessary to administer osteoclast resorption inhibiting drugs to the patients. For patients with normal renal function, intravenous infusion of pamidronate disodium (dicarbonate phosphate) preparation at a dose of 30mg, the infusion time should be longer than 4 hours; subcutaneous administration of calcitonin (CT) at a dose of 200 units every 6 hours. For patients with renal impairment, avoid using pamidronate disodium (dicarbonate phosphate), and use calcitonin (CT) at a dose of 200 units every 12 hours. Alternatively, calcitonin (CT) can be used in combination with corticosteroids, at a dose of 200 units every 6 hours; or add calcitonin (CT) to half-methyl hydrogenated hydrocortisone, infused intravenously at a dose of 100mg every 6 hours. Calcitonin (CT) produces an effective effect within 12 hours.

　　2. Chronic management of hypercalcemia caused by tumors:If blood calcium is below 130mg/L and there are no symptoms, there is no need for emergency treatment. However, as hypercalcemia is progressive, it may worsen within a few days, and all patients need active treatment. The ideal drug can effectively reduce blood calcium, is oral, and has no side effects. Because most of these patients will have widespread metastasis in the next 6 months, the goal of treatment should be to alleviate symptoms.

　　(1) Pamidronate disodium (bisphosphonate): It is the most effective drug. It can inhibit osteoclastic resorption, reduce blood calcium, alleviate pain, and increase bone resorption. Now there are only Etidronate (sodium hydroxyethanediphosphonate) and Pamidronate, the latter is more effective and less likely to cause bone mineralization damage. Take a phosphate mixture of 20 to 60ml, 3 times a day, and those with renal insufficiency should not exceed 60ml/day. The formula is: anhydrous disodium hydrogen phosphate (Na2HPO4) 3.66g, dihydrate sodium dihydrogen phosphate (NaH2PO4·2H2O) 1g, orange syrup in appropriate amount, add water to 60ml. Calcitonin can inhibit osteoclastic resorption, and has a synergistic effect with phosphates. It can be used by those with normal renal function and blood phosphorus below 37mg/L.

　　(2) Glucocorticoids: Effective in 30% of tumor-related hypercalcemia, most effective for tumors in the blood system. Glucocorticoids are difficult to work on hypercalcemia caused by solid tumors.

　　(3) Mithramycin (Plicamycin): Inhibits RNA-dependent DNA synthesis, can reduce blood calcium to a satisfactory level in 80% of patients with this type. However, it has direct nephrotoxic effects, causing abnormalities in liver and coagulation function. It must be intravenously injected 25μg/kg daily. After the patient takes this drug, normal blood calcium can be maintained for 5 to 14 days.

　　(4) Gallium nitride: Very effectively inhibits osteoclastic resorption, non-toxic. It must be continuously intravenously injected for more than 5 days. There may be nephrotoxic effects in patients with fluid loss and chronic renal failure.

　　II. Prognosis

　　After active treatment of the primary disease, including the removal of parathyroid tumors or other malignant tumors, stopping the use of vitamin D, calcium preparations, and thiazide diuretics to control hypercalcemia, the condition can be alleviated. The prognosis of the disease depends on the degree and nature of the primary disease.