Nephrocalcinosis in adults and children

Hypercalcemic nephropathy, nephrocalcinosis, calcification or calcification of the kidneys is a generalized deposition in the renal tissues of calcium in the form of its insoluble salts (oxalate and phosphate).

Epidemiology

Nephrocalcinosis visualized by microscopy refers to an accidental but rather frequent finding of pathologists, and the clinical statistics of in vivo detection of nephrocalcinosis is 0.1-6%. [1] Nephrocalcinosis has been reported in up to 22% of cases of primary hyperparathyroidism. [2]

According to some reports, the prevalence of nephrocalcinosis in premature infants reaches 15-16%.

In adults, 95-98% of cases are medullary nephrocalcinosis and 2-5% are cortical.

Causes nephrocalcinosis

The main cause of nephrocalcinosis, which occurs in a number of pathologies and is one of their visualized signs, is a violation of calcium metabolism and calcium-phosphorus balance of a systemic nature, leading to the deposition of tissue calcifications (calcifications). In most cases, when these complex processes are disturbed with the participation of various factors, bilateral calcification is noted, that is, nephrocalcinosis of both kidneys develops. [3]

So, the deposition of calcium in the kidney tissue can be due to:

• hypercalcemia  - an increased level of bivalent calcium cations in the blood, which is possible, including with its excessive consumption; [4]
• primary hyperparathyroidism , in which excessive production of parathyroid hormone (parathyroid hormone) leads to bone resorption; [5]
• renal tubular acidosis of the first type, arising from the inability of the kidneys to provide a normal physiological pH level of blood and urine;
• necrosis of the cortical layer of the kidney (cortical necrosis), which can develop in severe infections, pancreatitis, complicated labor, burns, etc.;
• the presence of a congenital anomaly -  medullary spongy kidney ; [6]
• MEN I - type I  multiple endocrine neoplastic syndrome ;
• idiopathic  hypomagnesemia , as well as the excretion of magnesium in diabetes or an increased level of thyroid hormones (thyrotoxicosis);
• destruction (resorption, osteolysis) of bone tissue in osteoporosis, primary tumors or metastases;
• functional insufficiency of the adrenal cortex -  hypoaldosteronism ; [7]

Read also:

• Calcification: what is it?
• Kidney damage in metabolic diseases
• Causes of increased calcium in the blood

Nephrocalcinosis in children can be:

• in cases of premature birth of a child (at a gestational age of less than 34 weeks);
• with  hypercalcemia in newborns ;
• with severe neonatal hyperparathyroidism;
• due to  congenital tubular dysfunction , primarily proximal tubular acidosis and Bartter's syndrome; [8]
• a consequence of  hemolytic uremic syndrome ;
• with  Williams  syndrome or Albright syndrome;
• due to an imbalance of vitamin D and phosphates when artificial feeding a baby; [9], [10]
• in cases of perinatal, infantile or juvenile hypophosphatasia (X-linked disorder of phosphorus metabolism) and autosomal dominant hypophosphatemic rickets;
• due to cystinosis (inability to break down the amino acid L-cysteine) with  Fanconi syndrome ;
• in the presence of hereditary oxalosis (primary hyperoxaluria);
• if there is a hereditary intolerance (malabsorption) of fructose. [11]

Read more in the publication -  Hereditary and metabolic nephropathy in children .

Risk factors

Specialists include the following risk factors for nephrocalcinosis:

• - a history of chronic glomerulonephritis of any etiology,  chronic pyelonephritis , polycystic kidney disease;
• a decrease in bone density - osteoporosis, which may be a consequence of immobilization in patients with prolonged bed rest, dystrophic changes in the elderly, a decrease in the level of sex hormones in women during menopause, an excess of vitamin A in the body, prolonged treatment with systemic corticosteroids or taking medications for heartburn based on aluminum compounds;
• sarcoidosis ;
• malignant neoplasms, plasma cell or  multiple myeloma , lymphoblastic leukemia, etc.;
• hereditary Alport syndrome;
• hypervitaminosis of vitamin D; 
• long-term intake of calcium preparations, thiazide diuretics, laxatives. [12]

Pathogenesis

Calcium is contained in bone tissue, while extra-skeletal Ca accounts for only 1% of this macronutrient in the body. Calcium levels are controlled by the regulatory mechanisms of the gastrointestinal tract, kidneys, and osteogenic cells (osteoclasts).

During the day, the glomeruli of the kidneys are filtered with 250 mmol of Ca ions and approximately 2% of the filtered calcium is excreted in the urine.

In hypercalcemic nephropathy, the pathogenesis of the deposition of calcifications in kidney tissues lies in the violation of the mechanisms of biochemical regulation of the level of calcium and phosphorus, as well as disorders of bone tissue metabolism caused by the parathyroid hormone (PTH), vitamin D, thyroid stimulating hormone calcitonin (affecting the synthesis of PTH), peptide hormone FGF23 is a fibroblast growth factor 23 produced by bone tissue.

So, calcium excretion slows down with an increase in PTH synthesis, and due to a lack of calcitonin, bone resorption increases,

Also, in blood plasma and in extracellular fluids, the level of ionized Ca increases if the content of phosphorus ions is insufficient - due to its increased excretion from the body. And its excretion may be excessive due to impaired renal tubular function or increased production of the hormone FGF23.

In addition, the hyperactivity of the intracellular enzyme 1-α-hydroxylase, which ensures the transformation of vitamin D into calcitriol (1,25-dihydroxyvitamin D3), plays an important role in the increase in the concentration of calcium in the plasma, followed by crystallization and deposition of its salts in the kidneys. Together with a high level of parathyroid hormone, calcitriol stimulates Ca reabsorption in the intestine. [13]

Symptoms nephrocalcinosis

According to nephrologists, the process of kidney calcification itself is asymptomatic, and early or first signs of nephrocalcinosis are absent, except when the effects of causal factors begin to manifest themselves, causing deterioration of renal glomerular filtration and a decrease in its rate.

Symptoms vary by etiology and may include: hypertension; increased urination -  polyuria and frequent urination ; polydipsia (irrepressible thirst).

In cases of medullary nephrocalcinosis, focal calcium deposits can form in the calyx of the kidneys with the formation of urinary calculi, which lead to recurrent urinary tract infections; to abdominal and lumbar pain (up to renal colic); nausea and vomiting; the appearance of blood in the urine (hematuria).

In children of the first year of life, nephrocalcinosis - in addition to urinary disorders and a tendency to infectious inflammation of the urinary tract - inhibits physical and psychomotor development.

Consequences and complications

Among the consequences of nephrocalcinosis, it should be noted the development of focal calcareous dystrophy of the kidneys, leading to acute and  chronic renal failure  with possible intoxication of the body (uremia) with chemical compounds contained in the blood (urea and creatinine). 

A complication is possible in the form of obstructive uropathy, leading to renal edema and hydronephrosis.

Calcification of the apexes of the renal pyramids (papillae) leads to chronic tubulointerstitial nephritis.

Medullary nephrocalcinosis - especially if patients have hyperparathyroidism - is often complicated by urolithiasis, which begins with the deposition of microscopic calcium oxalate crystals in the renal calyx. [14]

Forms

The deposition and accumulation of calcium in nephrocalcinosis can be of three types:

• molecular nephrocalcinosis (or chemical) is an increase in intracellular calcium in the kidneys without the formation of crystals, and it cannot be visualized;
• microscopic nephrocalcinosis, in which crystals of calcium salts can be seen using light microscopy, but they are not visualized on x-ray of the kidneys;
• macroscopic nephrocalcinosis is visible on x-ray and ultrasound.

Deposits can accumulate in the internal medullary interstitium, in the basement membranes and in the bends of Henle's loops, in the cortex and even in the lumen of the tubules. And depending on the localization, nephrocalcinosis is divided into medullary and cortical.

Medullary nephrocalcinosis is characterized by interstitial (intercellular) deposition of calcium oxalate and calcium phosphate in the renal medulla - around the renal pyramids.

If the tissues of the cortical layer of the renal parenchyma are calcified - in the form of one or two strips of deposited Ca salts along the zone of damaged cortical tissues or many small deposits scattered in the renal cortex - then cortical nephrocalcinosis is determined.

Diagnostics nephrocalcinosis

Diagnosis of nephrocalcinosis requires a complete  examination of the kidneys . Pathology is diagnosed, as a rule, by imaging methods, since Ca deposits can only be detected by instrumental diagnostics using:  ultrasound of the kidneys and ureters ; [15] ultrasound dopplerography of the kidneys , CT or MRI.

If the results of radiological methods in the diagnosis of the kidneys are not convincing enough   , a kidney biopsy may be required to confirm nephrocalcinosis  .

Necessary laboratory tests include urine tests: general,  Zimnitsky test ,  total calcium in urine , as well as excretion of phosphate, oxalate, citrate and creatinine. Tests for  total and ionized calcium in the blood , for the content of alkaline phosphase, parathyroid hormone, and calcitonin in the blood plasma.

Given the multifactorial etiology of renal calcification, the range of diagnostic studies can be much wider. For example, cancellous bone CT, X-ray absorptiometry and ultrasound densitometry are performed to detect osteoporosis; more analyzes are required to determine the type I MEN syndrome, etc. [16]

Differential diagnosis

Differential diagnosis is mandatory: with papillary necrosis of the kidney, tuberculosis of the kidney, pneumocystis or mycobacterial extrapulmonary infection in patients with AIDS, etc.

Nephrocalcinosis should not be confused with nephrolithiasis, that is, the formation of kidney stones, although in some patients both pathologies are present at the same time.

Treatment nephrocalcinosis

In the case of nephrocalcinosis, treatment is aimed not only at etiologically related pathology and a decrease in existing symptoms, but also at a decrease in the calcium content in the blood.

Treatment of hypercalcemia requires an increase in fluid intake and hydration with isotonic sodium chloride solution, and calcimimetics are also taken (Tsinacalcet, etc.).

Therapy of macroscopic nephrocalcinosis may include thiazide diuretics and citrate preparations that promote better calcium solubility in urine (potassium citrate, etc.).

If nephrocalcinosis is associated with osteoporosis and increased bone resorption, antiresorptive agents (bone resorption inhibitors) are used - bisphosphonates and other  drugs for the treatment and prevention of osteoporosis .

Phosphate-binding agents (Sevelamer or Renvela) are prescribed to treat hyperphosphatemia. Drug therapy for hypoaldosteronism is carried out with mineralocorticoids (Trimethyl acetate, Florinef, etc.).

Recombinant human parathyroid hormone (Teriparatide) can be administered to patients with chronic hypoparathyroidism.

Nephrocalcinosis, which occurs in the cortical layer of the kidney with its necrosis, requires systemic antibiotic therapy, restoration of water-electrolyte balance in / in the introduction of fluid and hemodialysis.

In order to limit the intake of some macronutrients, a diet is prescribed for nephrocalcinosis, in more detail:

• Diet number 6 and 7 for the kidneys
• Diet number 7
• Kidney Diet

Surgical treatment does not imply the removal of calcium deposits from the kidney tissue: only the formed stones can be removed. Surgical intervention is possible with primary hyperparathyroidism, since by removing the parathyroid gland, it is possible to stop the negative effect of its hormone on the kidneys. [17]

Prevention

Among the measures that can prevent the development of hypercalcemic nephropathy, experts say drinking enough water and reducing the intake of salt and foods containing a lot of calcium and oxalates.

And, of course, timely treatment of diseases that lead to nephrocalcinosis.

Forecast

The etiology of calcium deposition in the kidneys and the nature of complications of this process will determine the prognosis of nephrocalcinosis in each case. Specific causes of nephrocalcinosis, such as Dent's disease, primary hyperoxaluria, and hypomagnesemic hypercalciuric nephrocalcinosis, in the absence of effective treatment, can progress to chronic renal failure,  [18]end-stage renal disease. Radiologically detected nephrocalcinosis is rarely reversible. Pathology rarely progresses, but medicine is not yet able to reduce the degree of calcification.