Nephrocalcinosis Clinical Presentation

The underlying etiology primarily determines the presentation of nephrocalcinosis, although in many cases, the condition remains asymptomatic and is identified only as a radiologic abnormality. Potential clinical features include the following:

• Clinical features of hypercalcemia

  • Relative vasopressin resistance with decreased renal concentrating ability and increased free water diuresis (nephrogenic diabetes insipidus), manifesting as polyuria and polydipsia.
  • Other defects, such as renal glycosuria, reduced glucose tubular maximal, aminoaciduria, and nonglomerular proteinuria have occasionally been reported.
  • Reversible hypertension occurs in approximately 50% of patients, due to increased peripheral vasoconstriction.
  • Hypercalcemia is also a well-established cause of renal failure, due to direct renal vasoconstriction and to volume depletion induced by excessive diuresis. This usually is reversible, with normal renal function returning as the hypercalcemia is corrected with volume replacement. However, irreversible failure can occur with long-standing hypercalcemia and is always associated with calcium crystal deposition.
• Clinical features of microscopic nephrocalcinosis

  • A few studies describe the effects of nephrocalcinosis on renal function in rats.^[9] Various investigators have observed reduced concentration capacity, increased blood urea nitrogen (BUN), and prolongation of a single nephron transit time in a distal tubule,^[10] although no detailed studies of glomerular filtration or renal tubular function exist in these models.
  • Occasionally, rats with the pelvic type of nephrocalcinosis may develop acute pyelonephritis or calculous ureteral obstruction with renal failure.
  • However, nephrocalcinosis in rats is a poor model for humans because of the high incidence of spontaneous glomerulosclerosis in laboratory rats, the different distribution of calcium in the kidney, and the absence of a rat model for many of the diseases that cause human nephrocalcinosis.
• Clinical features of macroscopic nephrocalcinosis

  • A wide range of abnormalities can occur with medullary nephrocalcinosis. Calcium nodules may rupture through the papillary epithelium into the calyceal system to become urinary stones and elicit the clinical presentations of renal colic, hematuria, passage of urinary stones, or urinary tract infection. However, macroscopic nephrocalcinosis should not be considered synonymous with urinary stones, because nephrocalcinosis usually implies a more profound metabolic derangement.
  • Polyuria and polydipsia may be prominent because of the excess of free water diuresis with reduced renal concentrating ability.
  • Hypertension is relatively less common, probably reflecting a reduced ability to conserve sodium.
  • Proteinuria may be observed, although it is in the nonnephrotic range and usually is less than 500 mg per day.
  • In Dent disease, loss of low – molecular weight proteins may exceed 2 grams per day. Hypercalciuria, nephrolithiasis, and nephrocalcinosis are some additional presenting features.
  • Microscopic pyuria is frequently found and represents a chronic inflammatory response to medullary calcification.
  • Distal tubular dysfunction is common with a mild salt-losing defect; this defect may become obvious only with profound decrease of per os intake (anorexia) or when another source salt-water loss emerges, such us diarrhea or vomiting.
  • Proximal tubular dysfunction is unusual, except for tubular proteinuria and the aminoaciduria of Dent disease.
  • Medullary nephrocalcinosis of any etiology can cause secondary distal tubular acidosis related to distal tubular calcium deposition and chronic inflammation in the medulla.
  • Patients may present with renal failure or with features of their underlying disease.

The physical findings are nonspecific and reflect the underlying disorders responsible for nephrocalcinosis.

• Primary hyperparathyroidism is the single most common cause of nephrocalcinosis in adults. While nephrocalcinosis is a relatively rare complication (5%), primary hyperparathryroidism is relatively common, especially in the elderly. Nephrocalcinosis itself is related more to the duration than to the intensity of hypercalcemia. The classic clinical findings are sometimes referred to as "(abdominal) groans, stones, and bones." This common phrase is a reminder that patients may present with kidney stones, bone pain, osteoporosis, and pathologic fractures, all of which can result in abdominal discomfort. Rarely, hyperparathyroidism can be associated with multiple endocrine neoplasia type 1 (MEN1).
• Distal RTA is the second most common cause of medullary nephrocalcinosis. The familial form and the secondary form (autoimmune-associated anti-K/H channel antibody) have a high incidence.^[11] The contributing mechanisms to nephrocalcinosis in distal RTA are hypercalcemia, hypercalciuria, metabolic acidosis, and reduced excretion of citrate in the presence of increased urinary pH. Because medullary nephrocalcinosis can itself be a cause of distal RTA, separating out the initial insult can be difficult. Renal function is fairly well maintained.
• Other causes of nephrocalcinosis are hypervitaminosis-D states^[12] resulting from excessive treatment of hypoparathyroidism, self-administration of vitamins, and the presence of a granulomatous disease, such as sarcoidosis.^[13] In granulomatous disorders, there is an increased conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol in the granuloma, resulting in an unregulated production of bioactive vitamin D with resultant excessive intestinal absorption of calcium and phosphorus. In addition, cytokines (IL-2) released in these disorders cause dysregulation of calcium homeostasis and activation of osteoclasts, resulting in subacute and chronic hypercalcemia.
• Any other cause of hypercalcemia, particularly when associated with hypercalciuria, can be a contributor to nephrocalcinosis. Etiologies include milk-alkali syndrome (due to excess ingestion of antacids, in the modern era with CaCO ₃ supplements), hyperparathyroidism, and malignant disease (due to bone involvement and humoral factors, including cytokines and parathyroid hormone – related peptide). Idiopathic hypercalciuria,^[14] a common metabolic disease, also is known to cause nephrocalcinosis.
• Nephrocalcinosis and renal failure are increasingly being recognized as common complications of phosphate supplementation, particularly in the elderly.^{[15, 16, 17, 18, 19]} Other possible risk factors are preexisting renal failure, high blood pressure, and the treatment of high blood pressure (with angiotensin-converting enzyme [ACE] inhibitors or angiotensin-receptor blockers). Phosphate supplements may contribute to renal calcifications in children with hypophosphatemic rickets. In vitro studies have shown that an increased urinary concentration of phosphate can result in intratubular crystallization with altered solubility.
• Medullary sponge kidney is a common cause of medullary calcification, with calcium lying in dilated collecting ducts rather than in the renal substance. These ectatic outpouchings are believed to be areas of urinary stasis possessing the ideal milieu for the formation of these calcifying complexes. The calcium deposits are larger and more sharply defined than they are in metabolic disease, and they are uneven in distribution.^[8] Associated hemihypertrophy of the body may exist. Unlike the severe renal damage with minimal calcification associated with hypercalcemic states, nephrocalcinosis associated with distal RTA and medullary sponge kidney usually is gross, and renal function is relatively well preserved.
• Renal papillary necrosis associated with analgesic nephropathy is identified as calcified papillae rather than as a speckled pattern.
• Other associations with nephrocalcinosis include rapidly progressive osteoporosis due to immobilization, menopause, aging, or steroids.
• Primary (familial) hyperoxaluria, or secondary hyperoxaluria due to increased intake of oxalates, enhanced absorption due to intestinal disease, or ingestion of ethylene glycol or methoxyflurane can induce medullary calcification.^{[20, 21]} Primary hyperoxaluria and ethylene glycol intoxication is also associated with diffuse calcium-oxalate depositions in many other organs, including the eye and the heart.
• Chronic hypokalemic states, such as Bartter syndrome, primary hyperaldosteronism, Liddle syndrome, and 11-beta hydroxylase deficiency, are associated with reduced urine citrate excretion and tubular epithelial damage, leading to calcium precipitations.
• Autosomal dominant hypophosphatemic rickets and X-linked hypophosphatemic conditions^[22] have been associated abnormal phosphate wastage and nephrocalcinosis due to elevated levels of phosphatonins (fibroblast growth factor 23; secreted frizzled-related protein 4).^{[4, 5]} Nephrocalcinosis is very common (~80% on ultrasonography) and may be associated with phosphate supplementation for the condition.
• Dent disease and familial magnesium-losing nephropathy are rare inherited diseases causing medullary calcification.

  • Dent disease arises from a defect in a gene on the short arm of the X chromosome that codes for the renal chloride channel in the proximal tubule (CLC-5). This disease is referred to by several other names in the international literature, including X-linked recessive hypophosphatemic rickets (Italy), X-linked recessive nephrolithiasis, and idiopathic low-molecular weight proteinuria with hypercalciuria and nephrocalcinosis (Japan). Mutations in the OCRL-1 gene — normally associated with Lowe's syndrome — have been described in cases of clinical Dent disease, expanding the potential for genetic diversity.^[23]
  • Inherited forms of magnesium-losing nephropathy have been described.^[24] Familial hypomagnesemia hypocalciuric nephrocalcinosis (FHHNC) is an autosomal recessive disease associated with cation loss through a defect in renal tight junctions protein (paracellin-1) involved in paracellular transport.^{[25, 26]}
• Associated malignancies are not typical in nephrocalcinosis, because patients seldom survive long enough with hypercalcemia to develop them; one possible exception is the parathyroid carcinoma.
• Familial benign hypercalcemia and hyperthyroidism are not associated with renal calcification.
• Premature, sick infants have been observed to develop diffuse nephrocalcinosis (about 2/3 among infants born < 1500 g), typically when exposed to diuretic therapy or prolonged O ₂ therapy. There is no clearly effective therapy.^[27] While these lesions may improve later on,^[28] the natural history of this phenomenon is not well understood.^[29]
• There has been a growing awareness of the diffusely increased calcifications in patients with advanced renal failure and end-stage renal disease.^[30] In the uremic environment, the presence of large, pharmacologic dose vitamin-D analogs and calcium-based phosphorus binders appear to accelerate the process. It appears that the presence of extraskeletal calcifications is more closely correlated with calcium x phosphorus product (sometimes referred to as the "double product") and total-body calcium overload then with the presence of serum hypercalcemia. Calcifications are not limited to the kidneys but involve multiple organs, including the heart, vascular beds, parenchymal organs, skin, and subcutaneous tissues.