After an initial phase (Fig. 3A) during which 12-hour urine collections were obtained while the patient was cycled on and off TPN, calcium in the TPN solution was reduced to 5 mmol/24 hours (before, 15 mmol/24 hours; Fig. 3B). In a third step, chlorothiazide(Diuril) was administered in an increasing dosage, divided into two short infusions administered before and after nighttime TPN. Titration was stopped, and a final dosage was considered to be established when marked reduction of hypercalciuria was reached without the appearance of such side effects as hypokalemia or diuresis. After this dosage (25 mg/kg body weight) was established, calcium in TPN-solution was increased to original concentrations. For the duration of the trial, 12-hour urine was collected during both the on- and off-TPN phases. The samples were measured for calcium and creatinine. Blood was drawn every day and analyzed for potassium, sodium, chloride, calcium, and phosphorous. Levels of 1,25-dihydroxycholecalciferol, parathyroid hormone, and alkaline phosphatase were measured weekly. Bone density was measured using lumbar spine dual-energy x-ray absorptiometry before and 6 months after initiation of administration of the drug.
During the initial phase, calcium excretion was increased by 4 times during on-TPN periods and 1.5 times during off-TPN periods (Table 3A). In two out of four measurements, calcium balance was negative (Fig. 4A). Reduced phase (Fig. 3B) decreased to the two-fold of the upper normal level during on-TPN phases and a high normal level during the off-TPN phase. Calcium balance was even more negative in this phase. During the chlorothiazide titration phase, calcium excretion dropped to a level within the normal range in on-TPN and off-TPN phases. After increasing calcium in the TPN solution to original levels, calcium excretion increased to values of 7.1 mmol/12 hours and 4 mmol/12 hours in on- and off-TPN periods, respectively. Tubular reabsorption rate for phosphate increased to normal values.
At day 11, when the highest dosage of chlorothiazide was administered, serum potassium dropped to 2.5 mmol/l without causing clinical symptoms. The dosage was reduced. No other side effects were observed. The final dosage of chlorothiazide was 18 mg/kg body weight, divided into two doses that were administered before and after the nightly TPN cycle.
Measurement of bone mineral density (DXA, Hologic, Waltham, MA, U.S.A.) of lumbar spine (L1-L4) revealed a rise from 0.562 g/cm2 (i.e., -3.45 SD for this age and gender) to 0.606 g/cm2 (-2.88 SD) 6 months later.
In many studies, investigators have examined potential causes of hypercalciuria in patients receiving TPN, but the exact pathomechanism and its prevention still remains unclear. Amino acid infusion(15), protein intake (16), and concentrated infusions of D-glucose (17) as nutritional factors have been discussed. Urinary calcium excretion increases during cyclic infusion and decreases during continuous infusion(18). The amount of calcium excreted is positively correlated with the duration of TPN. In rats receiving TPN, with nearly entirely resected small bowel, Chu et al. (19) recorded an increase in calcium excreted compared with that in a control group that was also fed parenterally, but in which the intestine was transected and anastomosed without resection. Peak excretion occurred 3 to 4 days after resection and returned thereafter to a slightly elevated level. In their work, Chu et al. noted a lower incidence of hypercalciuria in rats with longer duration of TPN than in control subjects that had received TPN for a shorter time.
Hypercalciuria is associated with the appearance of metabolic bone disease. This complication of long-term TPN (10-14) is associated with osteopenia, in severe form, with destruction of the joints and pathologic fractures. Bone pain and orthopedic disabilities are observed. The histologic picture is assumed to depend on the age of the patient, producing osteomalacia in adults and rickets in growing children (20,21). Premature infants are at higher risk for developing hypercalciuria (22-24). Aluminum has also been determined to be a cause of metabolic bone disease (25,26). This leaves the question of whether hypercalciuria and metabolic bone disease are different phenomena of one entity or distinct complications appearing independently from each other. It is uncertain whether the elevated aluminum level in our patient has significance, because we have no earlier values with which to make comparison. Furthermore, his bone disease progresses, although TPN solutions have been almost aluminum free since 1993, when clinicians became aware of this problem.
The parenteral infusion of calcium and phosphorous is an important nutritional factor. Increased calcium concentrations in TPN solutions are recommended (27,28), and the Ca:P ratio should not be less than 1:1 for premature infants (29,30). During the past 10 years, vitamin D, especially in its active form 1,25-dihydroxycholecalciferol has been identified as a key factor. Its physiologic action is to improve intestinal calcium uptake and to promote bone remodelling by activation of osteoclasts (31-33). It is presumed that in patients receiving TPN, the intestinal action of vitamin D is not needed and the bone action of vitamin D is not desired. This may be the reason some investigators report improvement of metabolic bone disease after withdrawal of vitamin D from the TPN solution. However, there are still no controlled studies, and following official guidelines, our patient receives vitamin D (200 IU/ 24 hours).
Persistent or intermittent high concentrations of calcium in the tubular system and a surplus of matrix-forming agents (e.g., oxalate) and the reduction of crystal-forming inhibitors (e.g., citrate), together with low pH are the main factors in the development of nephrolithiasis and nephrocalcinosis (28). Compared with the incidence of nephrocalcinosis in otherwise healthy patients with hypercalciuria, we found only one report in the literature an older child receiving TPN with nephrocalcinosis (34), whereas it is not unusual to see it in preterm infants receiving TPN (24,27,34). Probably other factors, including furosemide therapy, prematurity, and bronchopulmonary dysplasia, play a role in this special group of patients.
The reduced tubular reabsorption rate for phosphate in our patient is considered to be secondary to hypercalciuria, because it normalized with reduction of urinary calcium excretion. The patient exhibited many known problems of patients receiving long-term TPN (metabolic bone disease, hypercalciuria, reduced growth rate, elevated aluminum levels). It is presumed that with persistent severe hypercalciuria and negative calcium balance, nephrocalcinosis is almost unavoidable. We do not assume that his reduced kidney function is only caused by nephrocalcinosis, because it has been shown that patients receiving long-term TPN have reduced kidney function, although the exact cause remains unclear (35,36).
Thiazide diuretics were successfully used in different forms of hypercalciuria, but the main indications are still idiopathic hypercalciuria and stone prophylaxis (9,37). The supposed mechanism of action is the inhibition of sodium reabsorption and the stimulation of calcium reabsorption in the renal distal convoluted tubules. Thiazide diuretics probably block chloride entry in tubule cells through the apical membrane. Subsequent hyperpolarization stimulates calcium entry by the apical membrane (38). Because of the short bowel syndrome, we used chlorothiazide, the only available thiazide that can be used intravenously. To our knowledge, this is the first time the drug has been used in such a patient. The results show marked reduction of hypercalciuria, especially during TPN infusion, but it is reduced without TPN as well. In contrast, a simple reduction of calcium in the TPN solution showed no decrease in hypercalciuria.
Our objective was to reduce hypercalciuria, to prevent the further deterioration of renal function in this patient. Even though the degree of nephrocalcinosis is low, creatinine clearance is already reduced so that further damage will promote renal insufficiency. Therefore we think that in this patient, chlorothiazide provides a possible method for preventing a rapid progression to endstage renal disease.
Nevertheless, the effect of chlorothiazide on bone mass is remarkable in this short period of 6 months. Although it is not the drug of choice for osteoporosis, its positive effect on bone mass in adults is well documented(39,40,41). The accuracy of dual-energy x-ray absorptiometry, especially is growing children, is controversial(42,43). Taken together, a negative calcium balance is an indicator for decreasing bone density. Therefore, the gain of bone mass itself is a success, regardless of absolute values. However, it is important to see whether the drug actually has a positive long-term effect on metabolic bone disease.
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