Nephrocalcinosis (Nephrocalcinoses)

Nephrocalcinosis refers to abnormal deposition of calcium, oxalate crystals and phosphate on the kidney. Accumulation of these compounds can impair normal kidney function and lead to chronic kidney disease. Causes include any metabolic or intrinsic factors and illnesses interfering with normal calcium metabolism. Diagnosis is confirmed through radiographic and laboratory tests and treatment depends on the underlying cause.

Nephrocalcinosis stems from this process: biochemical.

Presentation

The initial stages of nephrocalcinosis are asymptomatic, and patients may not report any complaints. When the disease is established, however, symptoms may appear, including polyuria, nocturia, hematuria, dysuria, and urinary incontinence [10]. Other symptoms, such as back pain or flank pain, either unilateral or bilateral, may appear, as well as nausea, vomiting, generalized edema and altered mental status (drowsiness, lethargy or altered consciousness) [11]. Other symptoms may accompany this condition, depending on the cause, and are related to elevated levels of serum calcium.

Workup

In order to establish the diagnosis of nephrocalcinosis, and its underlying cause, a detailed workup is necessary, and includes:

  • Patient history and physical examination - before obtaining blood samples for testing, it is imperative to obtain a good patient history and perform a thorough physical examination. Vital information may be obtained from the patient, which can guide the physician towards the diagnosis.
  • Biochemical analysis - electrolyte levels including serum levels of calcium, phosphate, sodium, potassium and magnesium, as well as urine levels of calcium, sodium and uric acid, should be measured. Additionally, the hormonal status should be evaluated, primarily focusing on the thyroid and parathyroid glands (TSH, free T3, T4, PTH)
  • Radiography - An abdominal ultrasound (US) may be performed to obtain a view of the kidneys. An abdominal Computerized Tomography (CT) scan may be useful as well, to gain an insight into the surrounding structures.

Treatment

Treatment of nephrocalcinosis is targeted at the underlying cause. Rarely is elevated serum calcium treated solely separately, without identifying the cause. Treatment principles range from supportive and symptomatic therapy to surgical procedures.

Correction of elevated calcium levels in the serum can be achieved by oral intake of phosphates (for mild imbalance), by intravenous infusion of saline combined with furosemide (severe imbalance), and administration of Ca-lowering drugs, such as bisphosphonates. As a last resort, hemodialysis is indicated if Ca levels are very high (> 18 mg/dl) and other options are not effective. Corticosteroids may be useful in reducing serum calcium levels, as they reduce vitamin D activity and slightly decrease intestinal calcium absorption. Correction of other electrolytes, including magnesium and potassium, is sometimes necessary, in order to restore normal serum values.

Apart from correcting hypercalcemia with medication, treatment of the underlying cause is imperative in order to permanently resolve nephrocalcinosis. For the correction of possible hyperparathyroidism, drugs such as cinacalcet may be used. In more aggressive forms of hyperparathyroidism, surgical removal may be indicated. If the presence of tumors of the skeletal system is confirmed, appropriate therapeutic measures must be implemented, whether it is surgery, chemotherapy or radiation therapy.

Prognosis

The prognosis depends on the etiology of nephrocalcinosis. In general, the prognosis is good if the underlying cause is recognized early and treated properly, with minimal or no residual damage to the kidneys. However, if nephrocalcinosis, and its underlying cause goes unrecognized and untreated (or if there is no cure for the diagnosis), renal failure may develop, which then has limited options for recovery.

Etiology

Disorders that interfere with calcium metabolism and lead to renal calcification are numerous [3] [4]:

Because of the nature of the disease, nephrocalcinosis usually occurs bilaterally.

It is important to distinguish nephrocalcinosis from nephrolithiasis (formation of kidney stones). The majority of Ca oxalate stones develop from the abnormally deposited Ca in the interstitium, which makes nephrocalcinosis one of the initial steps in the development of kidney stones.

Epidemiology

Nephrocalcinosis is found in the majority of patients with kidney stones and in up to 100% of patients with calcium phosphate stones [6]. Given the fact that 1/1000 adults in the USA is hospitalized annually because of renal calculi [7], and that up to 12% of men and 5% of women develop a urinary calculus by age 70, it can be concluded that nephrocalcinosis is common among patients with kidney stones. This disorder can be observed in any individual regardless of age and gender, but adults, as well as those who have predisposing conditions which lead to hypercalcemia and hypercalciuria, are patients who most frequently develop the condition.

Sex distribution
Age distribution

Pathophysiology

The physiological mechanism of calcium and phosphate homeostasis is quite complex, but under normal circumstances, the kidneys play a vital role in the regulation of serum calcium levels. The tubular system has a role of absorbing and secreting calcium, phosphate and oxalate, among many other substances, under the influence of parathyroid hormone (PTH), vitamin D and calcitonin.

Normally, tiny depositions of calcium are formed in the kidney intersititum, but they break loose and travel along with urine. However, when hypercalcemia occurs, it poses a threat to the kidneys and the tubular system. Among other mechanisms which regulate serum calcium concentrations, the kidneys compensate by increasing the excretion of Ca ions, resulting in hypercalciuria. However, increased levels of Ca in urine lead to its accumulation along the renal system and calcification of the renal interstitium can frequently occur, leading to nephrocalcinosis. 

Elevated serum Ca has several effects on the kidneys. Renal vasoconstriction is induced by elevated serum calcium, which reduces the glomerular filtration rate (GFR) and overall kidney function. In addition, hypercalcemia interferes with effects of vassopressin, or antidiuretic hormone (ADH), presumably through calcium-sensing receptors or through medullary synthesis of prostaglandins [8]. All of these factors contribute to an overall decrease of kidney function, which may lead to chronic kidney disease and even renal failure.

Because of the straining of the kidneys in the attempt to regulate serum levels of Ca, other metabolic disturbances may occur. In the case of hyperparathyroidism, hydrogen ion excretion is reduced, leading to tubular acidosis. Also, sodium and magnesium excretion is increased, leading to hyponatremia and hypomagnesemia [9], which initiates other forms of compensation for sodium loss, mainly through ADH.

All of these alterations have a negative effect on the kidneys and the tubular system. If nephrocalcinosis is not resolved, it leads to a chronic state and numerous consequences may arise, the most detrimental being life-threatening and irreversible kidney failure.

Prevention

Prevention of nephrocalcinosis primarily focuses on identifying the signs and symptoms of the disease in its early stages, although the disease may initially have an asymptomatic course. However, regular check-ups should include serum electrolyte levels, especially for patients with nephrolithiasis and other diseases of the kidney, because progressed stages of kidney failure are practically impossible to treat. Identifying the cause early is the key to preventing nephrocalcinosis from causing chronic kidney disease.

Summary

Nephrocalcinosis is a disease characterized by abnormal deposition of calcium (mainly in the forms of calcium-phosphate and calcium-oxalate) in the kidney interstitium, which can result in impaired kidney function [1]. It is caused by numerous conditions which interfere with the normal metabolism of calcium, including autoimmune, metabolic and congenital diseases, but also infections, certain drugs and chronic diseases of the kidney. Under physiological conditions, calcium deposits grow in the interstitium of the kidney and spontaneously break loose, excreted with urine. Conditions that lead to higher concentrations of calcium and other salts, result in calcifications of the surrounding structures and decreased functional capacity of the kidney, thus rendering patients prone to nephrolithiasis and, potentially, kidney failure [2]. Workup involves the detection of the underlying cause of abnormal calcium deposition and includes radiographic, biochemical and microbiological investigations. Treatment is directed at the underlying cause and prognosis depends on the cause of this condition. Nephrocalcinosis may lead to chronic kidney disease and renal failure if not treated early.

Patient Information

Nephrocalcinosis refers to the abnormal accumulation of calcium and its salts in the kidneys. Normally, the kidneys constantly excrete some amounts of calcium, which sometimes "sticks" onto the system of the kidney and under normal circumstances breaks loose and travels into the urinary bladder, where it is then excreted. However, when calcium levels are higher in the blood (and consequently in urine) than usual, larger amounts of calcium can be deposited and can impair normal kidney function.

This condition can occur as a result of various causes, including hyperparathyroidism, renal tuberculosis, chronic kidney disease, tumors of the skeletal system, but also due to inherited conditions, such as Alport syndrome and any other condition that disturbs the normal metabolism and distribution of calcium in the body.

Nephrocalcinosis usually occurs in adults, but also in younger patients who have familial conditions which impair the metabolism of calcium. Symptoms may be absent in the initial stages of the disease, but later on, symptoms such as increased urine volume, urinary incontinence, frequent and painful urination, a need to urinate at night and blood in the urine may be observed and reported by patients. Additional symptoms such as back pain or flank pain may also be reported.

The diagnosis of nephrocalcinosis is achieved through patient history and physical examination and evaluation of serum electrolyte levels, mainly calcium, phosphate, other electrolytes and uric acid, to confirm the presence of elevated calcium in the blood, as well as other electrolyte disturbances. Assessment of renal function, as well as hormone levels, especially of the thyroid and parathyroid glands, may be useful in determining the cause. The prognosis of this disorder depends on a timely diagnosis and its early identification, since it may lead to chronic kidney disease and cause potentially debilitating and life-threatening kidney failure, if left untreated.

Treatment of nephrocalcinosis depends on the underlying cause, since calcium-correcting and adjunctive therapy may only temporarily resolve the symptoms. Prevention is the key, because when it is diagnosed early, minimal or no damage to the kidneys may occur, while latter stages of the disease may cause severe complaints and greatly impair the quality of life.

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References

  1. Asplin JR, Mandel NS, Coe FL. Evidence of calcium phosphate supersaturation in the loop of Henle. Am J Physiol. 1996; 270(4 Pt 2):F604.
  2. Markowitz GS, Nasr SH, Klein P, et al. Renal failure due to acute nephrocalcinosis following oral sodium phosphate bowel cleansing. Hum Pathol. 2004; 35(6):675. 
  3. Schepens D, Verswijvel G, Kuypers D, et al; Images in Nephrology. Renal cortical nephrocalcinosis. Nephrol Dial Transplant. 2000; Jul 15(7):1080-2.
  4. Hoppe B, Langman CB. A United States survey on diagnosis, treatment, and outcome of primary hyperoxaluria. Pediatr Nephrol. 2003;Oct 18(10):986-91.
  5. Leumann E, Hoppe B. The primary hyperoxalurias. J Am Soc Nephrol. 2001; Sep; 12(9):1986-93.
  6. Sayer JA, Carr G, Simmons NL. Nephrocalcinosis: molecular insights into calcium precipitation within the kidney. Clin Sci (Lond). 2004; 106(6):549.
  7. Porter RS, Kaplan JL. The Merck Manual of Diagnosis and Therapy. 19th Edition, Whitehouse Station, NJ; 2011. Merck & CO., Inc;
  8. Sands JM, Naruse M, Baum M, et al. Apical extracellular calcium/polyvalent cation-sensing receptor regulates vasopressin-elicited water permeability in rat kidney inner medullary collecting duct. J Clin Invest. 1997;Mar 15; 99(6):1399-405.
  9. Jonsson KB, Zahradnik R, Larsson T, et al. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. N Engl J Med. 2003;Apr 24; 348(17):1656-63.
  10. Ammenti A, Pelizzoni A, Cecconi M, et al; Nephrocalcinosis in children: a retrospective multi-centre study. Acta Paediatr. 2009; Oct 98(10):1628-31.
  11. Adams ND, Rowe JC. Nephrocalcinosis. Clin Perinatol. 1992; Mar 19(1):179-95.

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