A case of nephrocalcinosis

A 42-year-old Caucasian male was initially admitted with generalized weakness, malaise, poor oral intake, and occasional nausea and vomiting for 3 weeks. There was no history of gross hematuria or shortness of breath. Past medical history was notable solely for tobacco use (two packs per day for 20 years). There was no history of hypertension or diabetes and there was no family history of renal disease. The patient took no prescription medications but reported taking antacids as needed and occasional ibuprofen. Physical examination revealed a heart rate of 92 b.p.m., respiratory rate of 12 breaths per min, blood pressure of 108/62 mm Hg, and the absence of edema or cutaneous manifestations. Laboratory evaluation (Table 1) revealed acute kidney injury with a creatinine of 7.2 mg/dl, mild hypokalemia, hypercalcemia, mild hyperphosphatemia, a severe non-anion gap metabolic alkalosis, and a suppressed parathyroid hormone level. The patient reported having not seen a physician for 10 years, and no baseline laboratory values were available for comparison. Urinalysis revealed trace protein and a bland sediment with no red blood cells, white blood cells, or casts. The patient was found to have a urine protein-to-creatinine ratio of 0.37 (mg/mg). Serologic evaluation revealed normal C3 and C4 complement levels and no evidence of a monoclonal spike on serum or urine protein electrophoresis. The following serologies were negative: antinuclear antibody, antineutrophil cytoplasmic antibody, antistreptolysin O, antiglomerular basement membrane antibody, hepatitis B surface antigen, and antihepatitis C antibody. The kidneys measured 9 cm in length by ultrasound, with increased echogenicity but no evidence of obstruction. Two discreet areas of dystrophic calcification were noted within the interpolar region of the renal parenchyma and measured 6 and 3 mm. The patient was admitted and given intravenous normal saline with added potassium for treatment of hypercalcemia and hypokalemia, antiemetics, and a proton pump inhibitor. Over the course of 4 days, the patient's creatinine declined to 4 mg/dl and serum calcium and potassium levels normalized. The patient was discharged. Following discharge, the patient was feeling well and the creatinine declined over 2 weeks to 2.3 mg/dl. Five weeks later, the creatinine was 1.6 mg/dl. Two months after the initial presentation, repeat serum chemistries again revealed acute kidney injury with a creatinine of 5.4 mg/dl. At that time, the patient had a serum sodium of 134 mmol/l, potassium 2.9 mmol/l, chloride 75 mmol/l, CO2 44 mmol/l, calcium 12.8 mg/dl, and phosphorus 6.7 mg/dl. The patient reported no significant new symptoms although he did mention persistent 'heartburn'. On his own, he had discontinued taking the proton pump inhibitor and restarted antacids, without relief of symptoms. Similarly, he reported having to 'drink milk at night' to help the symptoms. Physical examination was unrevealing. Given the unclear etiology of the patient's acute kidney injury, a renal biopsy was performed. The renal biopsy consisted of two cores of renal cortex containing nine glomeruli, one of which was globally sclerotic. Glomeruli appeared normal in size and cellularity with patent capillary lumina and glomerular basement membranes of normal thickness. Proximal tubules displayed degenerative changes characterized by luminal ectasia, cytoplasmic simplification, irregular luminal contours, and prominent nucleoli. The tubular degenerative changes were accompanied by prominent intraluminal, intracellular, and interstitial non-polarizing basophilic calcifications, consistent with calcium phosphate (Figure 1a–b). The calcium phosphate composition of the tubular calcifications was confirmed with the von Kossa stain (Figure 1c). There was mild to moderate tubular atrophy and interstitial fibrosis involving approximately 30% of the cortex sampled. There was patchy, mild interstitial inflammation composed of mainly lymphocytes and associated with rare foci of mild tubulitis. Vessels exhibited mild to moderate arteriosclerosis and arteriolosclerosis with hyalinosis. Immunofluorescence staining for IgG, IgM, IgA, C3, C1q, fibrinogen, albumin, and - and -light chains was negative. Electron microscopy revealed intraluminal, intracellular, and interstitial calcifications. Glomeruli appeared unremarkable, with minimal foot process effacements and no detectable electron-dense deposits. The final diagnosis was an acute and chronic tubulointerstitial nephropathy with prominent tubular and interstitial calcium phosphate deposits, consistent with nephrocalcinosis. Following receipt of the renal biopsy results, the patient was worked up for etiologies of nephrocalcinosis. Upon further questioning, the patient admitted to daily ingestion of 20–30 Rolaids tablets (calcium carbonate 675 mg per tablet, 220 mg elemental calcium per tablet) and at least 1 gallon of milk per day over the past 5–6 years for treatment of reflux symptoms. He stated that he had previously omitted the excessive antacid and milk intake (which total approximately 10 g elemental calcium per day) because he thought it was unrelated to his kidney problem. He also revealed a previous episode of 'heartburn' 1 year prior, at which time he had been admitted elsewhere with a calcium of 13.2 mg/dl and a creatinine of 1.5 mg/dl. There was no history of recent colonoscopy or ingestion of oral sodium phosphate (OSP) solution. The patient was instructed to immediately stop using oral calcium products and markedly reduce milk consumption. Treatment with pantoprazole was restarted and the patient was referred to a gastroenterologist for further evaluation and treatment of symptoms of reflux. Within 1 month, the symptoms of reflux completely abated with proton pump inhibitor administration. The patient discontinued calcium-based antacids, markedly reduced milk intake, and was compliant with a low-calcium diet. At 7 months follow-up, the patient has a creatinine of 1.7 mg/dl. On repeated evaluation, serum calcium and electrolyte levels have remained within the normal range. Nephrocalcinosis due to milk–alkali syndrome (MAS). Nephrocalcinosis is a pattern of renal injury characterized by abundant renal tubular and interstitial deposits of calcium phosphate. The calcium phosphate deposits are associated with varying degrees of acute tubular injury, as well as chronic, irreversible scarring in the form of tubular atrophy and interstitial fibrosis. The finding of nephrocalcinosis on renal biopsy should prompt investigation into conditions associated with hypercalcemia, including hyperparathyroidism, malignancy, and excessive calcium or vitamin D intake. Alternatively, nephrocalcinosis may result from exposure to OSP bowel preparations prior to colonoscopy. The importance of OSP bowel preparations as a cause of nephrocalcinosis is underscored by a 2005 series on 31 cases of nephrocalcinosis from Columbia University, in which more than 80% of patients with this condition had a history of recent exposure to OSP.1 The patient in this report denied exposure to OSP but admitted to significant calcium carbonate ingestion. The clinical history, presentation, and biopsy findings are diagnostic of nephrocalcinosis secondary to MAS. Milk–alkali syndrome was first described in 19232 as a toxic reaction to the Sippy treatment of peptic ulcer disease, which included administration of milk, cream, and a mixture of bicarbonate-containing powders.3 With the advent of antisecretory therapies for peptic ulcer disease, the incidence of MAS declined and was implicated in less than 1% of cases of hypercalcemia by 1985.4 More recently, a resurgence in MAS has been seen. One series reported that 12% of patients presenting with hypercalcemia between 1990 and 1993 were diagnosed with MAS, making it the third most-common cause of hypercalcemia (behind hyperparathyroidism and malignancy).5 Another series examined all 53 cases of MAS reported from 1983 to 2004.6 The mean age was 50.3 years, and more than half of the subjects were female. The source of calcium was calcium carbonate in all of the patients. Interestingly, only 35.2% of patients were reported as having milk or dairy products as a major source of calcium, and only 20.4% were hyperphosphatemic. MAS resulted in permanent renal impairment in 38.8% of patients.6 The cause for the increase in incidence is not entirely clear but likely involves increased consumption of calcium carbonate for prevention or treatment of osteoporosis or dyspepsia. Additional factors may include the increasingly common practice of adding calcium to processed foods (such as juices and cereal) and over-the-counter medications.6 From a pathophysiological standpoint, the two essential ingredients for development of MAS are the ingestion of excess calcium along with an absorbable alkali. The amount of calcium that needs to be consumed to develop the syndrome varies, but in patients with normal renal function, greater than 5 g a day is probably needed. However, in the presence of renal compromise or hyperabsorption of calcium from the gut, the amount may be much less.7 Increased consumption of calcium and alkali causes an initial hypercalcemia and alkalosis. Alkalosis leads to increased tubular reabsorption of calcium. Hypercalcemia directly and indirectly leads to a reduction in glomerular filtration rate by causing renal vasoconstriction and decreasing extracellular volume. Decreased glomerular filtration rate in turn impairs the kidney's ability to excrete calcium, and volume depletion acts as a stimulus for reabsorption of bicarbonate in the proximal tubule. Hypercalcemia also suppresses parathyroid hormone levels, which stimulates bicarbonate reabsorption in the proximal tubule resulting in alkalosis. As such, the simultaneous presence of hypercalcemia and alkalosis leads to a vicious cycle in which each abnormality impairs natural correction of the other.8 A reduction in the ability of the kidneys to excrete excess calcium is central to the maintenance of this disease cycle. More recently, a role for the calcium-sensing receptor has been suggested in the maintenance phase of MAS. Hypercalcemia activates the calcium-sensing receptor in the thick ascending limb of Henle, which allows for some increased calcium excretion, but this excretion is accompanied by natriuresis and diuresis, which exacerbate volume depletion and therefore prevent efficient correction of the alkalosis and hypercalcemia.9 The clinical presentation of MAS classically consists of hypercalcemia, alkalosis, and renal impairment, but presentation varies greatly depending on the severity and duration of exposure. Acute toxemia is often characterized by symptoms including headache, nausea, vomiting, weakness, myalgias, and irritability or apathy. Renal dysfunction occurs early in the disease, and elevations in blood urea nitrogen and creatinine are required for the diagnosis. The urine is often alkaline, but paradoxical aciduria has been reported.10 Hyperphosphatemia is classically seen because milk is rich in phosphate. In the modern era, many cases of MAS result from ingestion of non-phosphate-containing forms of calcium, for instance antacids, which contain calcium carbonate. As such, hypophosphatemia may result from lower phosphate intake and binding of phosphate in the gastric lumen by excess calcium.11 In more chronic cases, the metabolic abnormalities may be essentially asymptomatic, and patients may come to medical attention for unrelated problems with incidental findings (such as soft tissue calcification) that point to the diagnosis of MAS.12 Early stages with acute toxemia are often reversible, but if the disease is chronic and has progressed to nephrocalcinosis, much of the damage may be irreversible. Diagnostic criteria for MAS include hypercalcemia, metabolic alkalosis, a history of excessive consumption of calcium and alkali, and the lack of an alternative etiology for the laboratory abnormalities (for instance, no evidence of hyperparathyroidism). It is important to make the diagnosis of MAS as early as possible to avoid permanent renal damage. Establishing a diagnosis of MAS requires a high index of clinical suspicion coupled with a thorough investigation into medications, dietary supplements, and eating habits of the patient. MAS should be considered in the differential diagnosis for all patients with hypercalcemia and metabolic alkalosis. The two most important diseases in the differential diagnosis of MAS are hyperparathyroidism and hypercalcemia of malignancy. Prompt testing of parathyroid hormone levels is critical. In patients with MAS who receive hydration and diuresis as treatment for hypercalcemia, parathyroid hormone begins to increase within hours of treatment and may transiently exceed normal levels due to rebound hypocalcemia, leading to a misdiagnosis of hyperparathyroidism.6 Rare causes of hypercalcemia should be considered in patients without history suggestive of MAS and without evidence of malignancy or hyperparathyroidism, including sarcoidosis, tuberculosis, vitamin D intoxication, Addison's disease, thyrotoxicosis, and rare familial metabolic disorders.13 The treatment of MAS conventionally consists of discontinuation of excessive calcium and alkali intake along with volume repletion. Once normal volume status is restored, loop diuretics may be used to promote calciuresis. Patients presenting with acute renal failure may require dialysis. Treatment with bisphosphonates has been attempted and has caused significant rebound hypocalcemia in some patients. Importantly, Picolos et al.14 reported in their series of 11 patients with MAS that treatment with bisphosphonates was not found to reduce the median duration of hypercalcemia when compared with traditional therapy. To avoid recurrence of the syndrome, patients must be counseled to avoid calcium supplementation or dyspepsia treatments that include the combination of calcium and absorbable alkali. In addition, excess dietary sources of calcium should be addressed. In summary, MAS is the third most common cause of hypercalcemia in non-end-stage renal disease patients, accounting for 8.8% of cases in a recent series.14 Diagnosis depends on eliciting a history of excessive calcium intake in the context of hypercalcemia and metabolic alkalosis. Prognosis depends on the duration and severity of the exposure and the degree of renal insufficiency, highlighting the importance of prompt diagnosis. Treatment is largely conservative, consisting of cessation of excessive calcium and alkali intake, hydration, and loop diuretics to promote calciuresis.