Introduction:
Calcium regulates various body functions like muscle contraction, secretory mechanisms, and neuronal excitation. Serum calcium concentrations are regulated by parathyroid hormone activity, which induces bone resorption and renal calcium excretion. Less than 1% of body calcium is in extracellular space and maintains calcium homeostasis. The association between hypercalcemia and renal function has yet to be studied adequately. This article discusses available data on the link between kidney function and hypercalcemia.
What Is Hypercalcemia?
It is a condition where calcium levels within the serum are above normal, with reduced urine excretion or enhanced bone deposition. Serum calcium levels are maintained by the interplay of three hormones: parathyroid hormone, calcitriol, and calcitonin. Excess calcium levels in the body can weaken bones, produce kidney stones, and interfere with heart and brain function. Kidney injury depends on the severity of hypercalcemia.
A serum calcium level exceeding 10.5 mg/dL (milligram per deciliter) is known as hypercalcemia. Hypercalcemia can be mild, severe, temporary, or chronic.
What Are the Causes of Hypercalcemia?
Some of the causes of hypercalcemia are:
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Overactive parathyroid glands account for 60 % of hypercalcemia cases.
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Hypercalcemia occurs in 30 % of cancer patients, leading to the worst prognosis. Lung, breast cancer, multiple myeloma, renal cell carcinoma, leukemia (blood cancer), lymphoma (lymphatic cancer), and recovery phase of rhabdomyolysis (breakdown of skeletal muscle) are associated with hypercalcemia.
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Medical disorders like sarcoidosis, tuberculosis, and other granulomatous diseases.
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Medications like Thiazide diuretics and Hydrochlorothiazide could cause hypercalcemia.
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Excess intake of calcium and vitamin D supplements.
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Excess bone resorption.
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Renal calcium retention.
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Excessive intestinal calcium absorption.
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Milk-alkali syndrome.
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Immobilization.
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Renal transplant or dialysis.
What Are the Symptoms of Hypercalcemia?
Regardless of the underlying cause, the clinical symptoms of hypercalcemia remain the same. Dehydration, fatigue, weakness, nausea, anorexia (eating disorder), vomiting, abdominal pain, bone pain, polyuria, and mental confusion are some presenting symptoms.
Hypercalcemia also reduces glomerular filtration rate, increases sodium excretion, and depletes total body water, causing increased bicarbonate absorption and metabolic alkalosis. Metabolic alkalosis increases calcium reabsorption in the distal nephron, increasing hypercalcemia.
What Are the Renal Effects of Hypercalcemia?
Excess calcium in the body causes kidneys to function harder to filter, leading to excess thirst and frequent urination. Renal inefficiency due to hypercalcemia is caused by prerenal involvement, direct alterations to intravascular tone, and glomerular permeability. Excess calcium ions act on arteriolar smooth muscles, inducing direct vasoconstriction. Therefore, increasing renal vascular resistance with reduced renal blood flow. As a consequence, the following hypercalcemia effects develop:
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Arteriolar vasoconstriction.
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Reduction in glomerular ultrafiltration coefficient.
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The decline in tubular sodium reabsorption.
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Nephrogenic diabetic insipidus.
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Prerenal azotemia (kidneys fail to filter blood adequately).
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Acute tubular necrosis (death of tubular epithelial cells).
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Nephrolithiasis (kidney stone).
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Nephrocalcinosis (chronic kidney stone).
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Tubulointerstitial fibrosis.
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Acute kidney injury.
What Is the Association Between Hypercalcemia and Renal Function?
Most patients with acute renal failure are hypocalcemic. However, the presence of co-morbidities along with hypercalcemia could cause acute renal failure.
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Hypercalcemia is common in multiple myeloma patients. Multiple myeloma patients with renal insufficiency have poor prognosis. In patients with myeloma, excessive bone resorption releases a large quantity of calcium, resulting in hypercalcemia. Renal damage is likely in patients with light chain and IgD myeloma (Immunoglobulin D). Chemotherapy could improve patient survivability in multiple myeloma and decrease serum calcium levels. However, severe renal insufficiency increases the risk of early death in multiple myeloma patients.
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Primary hyperparathyroidism is a common cause of hypercalcemia. In some patients, there is a decline in glomerular filtration, leading to acute renal failure. However, it is reversed with the normalization of blood calcium levels.
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Individuals with milk-alkali syndrome present with unexplained hypercalcemia, renal impairment, and suppressed parathyroid hormone plasma levels caused by self-medication with antacid preparation containing alkali and calcium.
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Vitamin D toxicity causes hypercalcemia due to bone reabsorption and suppressed parathyroid hormone levels. The condition is managed with bisphosphonate therapy. Highly potent bisphosphonate zoledronate used for treating hypercalcemia caused by malignancy can lead to renal failure and toxic acute tubular necrosis. Discontinuation of vitamin D treatment can reverse hypercalcemia and alterations to renal function.
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Sarcoidosis causes various kidney impairments, including disordered calcium metabolism, nephrocalcinosis, nephrolithiasis, granulomatous interstitial nephritis, and glomerulonephritis. In 15 % of patients, hypercalcemia develops, further worsening tubular and glomerular function. Macrophages within sarcoid granuloma activate vitamin D to form excess calcitriol, which causes hyperglycemia. Glucocorticoids treat severe hypercalcemia, block calcitriol, and inhibit macrophages. Acute renal failure symptoms improved with reducing serum calcium levels after glucocorticoid therapy.
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Leprosy is a granulomatous disease that is associated with hypercalcemia. Suppression of parathyroid hormone and abnormal calcitriol levels could lead to hyperglycemia. Renal functions improved after treatment with calcitonin and leprosy.
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Patients with acute renal failure and rhabdomyolysis become hypercalcemic during the diuretic phase. Elevation of the serum level of calcitriol plays a role in developing hypercalcemia.
How Is Hypercalcemia in Renal Patients Treated?
Individuals with acute hypercalcemia have significant body volume depletion, nausea, vomiting, and polyuria caused by the effects of excess calcium on the kidney.
Hydration with isotonic saline can regulate the water deficit and help reduce serum calcium levels. Furosemide is frequently used with sodium chloride infusions to treat hypercalcemia. It is administered to block calcium reabsorption and promote their elimination. However, this mechanism is not safe for patients with advanced renal failure. Such patients are recommended calcium-free hemodialysis (blood purifying process).
Calcitonin administration is the preferred therapy for acute hypercalcemia. It inhibits osteoclast bone resorption and promotes urinary calcium excretion. Calcitonin acts rapidly and reduces serum calcium levels within 12 to 24 hours. Since the agent is not potent, combination calcitonin therapy with etidronate or pamidronate reduces serum calcium levels rapidly. Pamidronate and Bisphosphonate zoledronate are associated with nephrotic-range proteinuria (protein in urine).
Mithramycin could treat hypercalcemia, but the reduction in serum calcium levels is not sustained. The drug induces several side effects and is currently used for unusual cases. Bisphosphonates have replaced Mithramycin for hypercalcemia therapy. Zoledronate could cause acute tubular necrosis. Therefore, zoledronate is not recommended in patients with creatinine clearance of less than 30 mL/min (milliliter per minute).
Kidney function and protein excretion must be monitored in patients receiving prolonged therapy.
Conclusion:
Hypercalcemia is common among patients with hypoparathyroidism and cancer patients. Hypercalcemia most often exhibits renal effects when associated with other co-morbid disorders. Kidney stones, glomerulosclerosis, renal tubular injury, and kidney damage are noticeable. Mild kidney damage can be reversed by administering treatment to regulate serum calcium levels. However, severe kidney damage requires calcium-free hemodialysis.
