PREECLAMPSIA-ECLAMPSIA: CALCIO URINARIO COMO MARCADOR DE PREDICCIÓN *

The authors explore the hypothesis that tumor necrosis factor-alpha (TNF-alpha) and possibly other inflammatory cytokines are overproduced by the placenta in response to local ischemia/hypoxia contributing to increased plasma levels, and subsequent endothelial activation and dysfunction in the pregnancy disorder, preeclampsia. It is widely held that inadequate trophoblast invasion and physiologic remodeling of spiral arteries initiate placental ischemia/hypoxia in preeclampsia. Furthermore, focal areas of placental hypoxia have been implicated in the production of "toxic" factor(s) by the placenta, which circulate and cause maternal disease. Placental trophoblast cells and fetoplacental macrophages normally produce TNF-alpha and interleukin-1 (IL-1), which are capable of producing endothelial cell activation and dysfunction. Hypoxia has recently been reported to increase TNF-alpha and IL-1 production by term villous explants from the human placenta. Placental cells also express erythropoietin (EPO), which is the prototype molecule for transcriptional regulation by hypoxia in mammals. Interestingly, TNF-alpha and IL-1 have DNA sequence homologous or nearly homologous to the hypoxia-responsive enhancer element of the EPO gene, thus providing a potential, but as of yet, untested molecular link between placental hypoxia and stimulation of cytokine production. Inflammatory cytokines overproduced by the placenta in response to hypoxia may then lead to increased plasma levels and endothelial activation and dysfunction in preeclampsia. The purpose of this short review is to critically evaluate the hypothesis that placental cytokines contribute to the pathogenesis of preeclampsia. Of note, the etiology of the disease presumably related to deficient trophoblast invasion is beyond the scope of this work.

We previously reported that preeclampsia is associated with hypocalciuria (N Engl J Med 1987; 316:715). The purpose of this study was to determine whether alterations in calcium regulatory hormones are present in preeclampsia and, if so, whether they are responsible for hypocalciuria. Thirty-two pregnant women were studied in the second and third trimesters of pregnancy (11 women with preeclampsia, nine with chronic hypertension, and 12 normotensive women). 1,25-Dihydroxyvitamin D, C-terminal parathyroid hormone, ionized calcium, and urinary calcium excretion were measured. 1,25-Dihydroxyvitamin D was significantly lower in the women with preeclampsia in the third trimester when the disease developed (37.8 +/- 15 pg/ml) than in women with chronic hypertension (75 +/- 15 pg/ml, p less than 0.05) and normal women (65 +/- 10 pg/ml, p less than 0.05). Parathyroid hormone was higher, but not significantly, in those with preeclampsia. Ionized calcium was not significantly different among the three groups. Urinary calcium excretion was abnormally low for pregnancy (less than 50 mg/24 hr) in all but one women with preeclampsia. We conclude that 1,25-dihydroxyvitamin D is reduced in preeclampsia and may lead to hypocalciuria by causing decreased intestinal absorption of calcium, stimulation of parathyroid hormone, and increased distal renal tubular resorption of calcium. The cause of reduced 1,25-dihydroxyvitamin D in preeclampsia is unknown and may be due to either diminished renal or placental production of the hormone.

We studied 40 women in the third trimester of pregnancy to determine whether alterations in serum calcium levels or in urinary calcium excretion would distinguish patients with preeclampsia from normal pregnant women or women with other forms of gestational hypertension. Our population included 10 normal pregnant women, 5 pregnant women with transient hypertension, 6 with chronic hypertension, 7 with chronic hypertension and superimposed preeclampsia, and 12 with preeclampsia. The serum levels of ionized calcium, phosphate, and 1,25-dihydroxyvitamin D were not different among the various groups. In contrast, the mean (+/- SD) 24-hour urinary calcium excretion in the patients with preeclampsia or hypertension with superimposed preeclampsia was significantly lower (42 +/- 29 and 78 +/- 49 mg) than that in normal pregnant women (313 +/- 140 mg per 24 hours), women with transient hypertension (248 +/- 139 mg per 24 hours), or women with chronic hypertension (223 +/- 41 mg per 24 hours) (P less than 0.0001). The hypocalciuria in the women with preeclampsia was associated with a decreased fractional excretion of calcium. Although the mean creatinine clearance was reduced in the women with preeclampsia, the range of values overlapped with those in the other groups. In contrast, we observed little or no overlap with respect to calcium excretion. We conclude that preeclampsia is associated with hypocalciuria due to increased tubular reabsorption of calcium. Measurement of calcium excretion may be useful in distinguishing preeclampsia from other forms of gestational hypertension.