The law of unintended consequences in action: increase in incidence of hypokalemia with improved adequacy of dialysis.

In 1996, we raised our peritoneal dialysis (PD) dose to meet new DOQI adequacy targets. Concurrently, we noted an increase in the frequency of K+ levels below 3.5 mEq/L. A continuous quality improvement (CQI) project was initiated to quantify the impact of increasing dialysis dose on the prevalence of hypokalemia in our unit. Measurements of serum K+, blood urea nitrogen (BUN), creatinine, residual renal function, and the number and type of clinical interventions required to maintain eukalemia were abstracted from the charts of 62 patients enrolled in our program for more than 6 months and having more than two adequacy data points. In the seven consecutive 6-month periods from January 1996 to June 1999, dialysis dose progressively increased while median serum K+ decreased, and the percentage of patients requiring either diet counselling or K+ supplementation rose from 9% to 42%. We conclude that the increased clearance of K+ that occurs with increasing dialysis dose may lead to significant hypokalemia in a large proportion of PD patients dialyzed to DOQI adequacy targets. Maintenance of eukalemia in this population often requires increased K+ intake and or oral supplementation. Further studies are needed to ascertain whether the prevalence of hypokalemia is sufficient to warrant routine addition of K+ to PD dialysis solutions.

Lower affinity for substrate for extrarenal synthesis of calcitriol in chronic uremia.

Previous studies from our laboratory have shown that anephric patients have very low, but detectable, levels of 1,25(OH)2D3 (calcitriol) that can be increased to normal by administration of large doses of 25(OH)D3. The report of 1 alpha-hydroxylase activity in pig liver with an affinity for substrate significantly lower than that of the renal enzyme, led us to use the rat as an experimental model to further clarify the need of supraphysiological levels of 25(OH)D3 to correct calcitriol deficiency in chronic uremia. We have measured 1,25(OH)2D3 production by rat liver. Cytosol free liver homogenates (CFH) from normal rats were incubated with 25(OH)D3 and the production of 1,25(OH)2D3 was measured using the thymus radioreceptor assay after solid phase C18 extraction and HPLC purification of the samples. 1,25(OH)2D3 production was linear up to 30 minutes and a CFH protein concentration up to 20 mg. Saturability was attained for a substrate concentration of approximately 60 microM. Ketoconazole, a cytochrome P450 inhibitor, blocked calcitriol production in a dose dependent fashion. Total inhibition of the liver 1 alpha-hydroxylase was achieved with 180 microM ketoconazole. We next compared the kinetics of the 1 alpha-hydroxylases of normal and uremic rat livers. Maximal velocities were not statistically different (139.6 +/- 22.3 pg/mg/min for normals and 217.1 +/- 73.3 pg/mg/min for uremic rats). However, the apparent Km was 35.9 +/- 3.2 microM for uremic animals, significantly higher (P < or = 0.001) than that of normal rats (16.6 +/- 0.7 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of 22-oxacalcitriol on serum calcitriol.

1,25-Dihydroxyvitamin D3 (1,25D) regulates its own levels in circulation by affecting its rates of synthesis and degradation, 22-Oxacalcitriol (OCT), a vitamin D analog with low calcemic activity, decreases circulating PTH levels, one of the regulators of renal 1 alpha-hydroxylase, and stimulates vitamin D degradation in vitro. The purpose of this study was to examine the effects of OCT administration on serum levels of 1,25D. In normal rats, OCT administration (4-200 ng, ip, daily for 5 days) caused a dose-dependent reduction in serum calcitriol levels. At a dose of 200 ng, OCT reduced serum 1,25D from 34.5 +/- 2.7 to 10.9 +/- 0.7 pg/ml (P less than or equal to 0.01) without significant changes in ionized Ca or phosphorus levels. The contribution of the suppression of PTH by OCT to the reduction of serum 1,25D was examined by administering OCT to parathyroidectomized (PTX) rats. Two hundred nanograms of OCT, ip, daily for 5 days significantly reduced serum calcitriol from 29.7 +/- 7.6 to 9.1 +/- 0.5 pg/ml (P less than or equal to 0.01) in rats fed a normal calcium diet. Because OCT increased total calcium (TCa) in this group from 7.4 +/- 0.1 to 9.5 +/- 0.3 mg/dl, similar doses of OCT were given to PTX rats fed a calcium-deficient diet. OCT decreased 1,25D from 58.9 +/- 8.9 to 10.3 +/- 0.4 pg/ml and increased TCa from 4.8 +/- 0.2 to 7.4 +/- 0.1 mg/dl. Comparison of serum 1,25D for identical TCa levels in PTX rats (normal calcium diet controls vs. calcium-deficient diet, OCT-treated) clearly indicates that OCT per se reduced serum 1,25D. Further support for a direct effect of OCT was provided by studies in PTX rats fed a low phosphorus diet. OCT decreased serum 1,25D from 125.8 +/- 15.6 to 10.9 +/- 0.6 pg/ml without significant changes in TCa. To further characterize the mechanisms involved in this effect, similar studies were performed in six normal dogs. Intravenous administration of 0.75 micrograms OCT every other day for 1 week decreased serum calcitriol from 25.4 +/- 3.2 to 12.2 +/- 1.3 pg/ml (P less than or equal to 0.002). Ionized Ca and phosphorus remained unchanged. Despite the short half-life of OCT in the circulation, 1,25D levels returned to basal concentrations 96 h after the last dose of OCT.(ABSTRACT TRUNCATED AT 400 WORDS)