B Andreini

Nitric Oxide–Dependent Renal Vasodilatation Is Not Altered in Rat with rHuEpo–Induced Hypertension

Background: Recombinant human erythropoietin (rHuEpo) is the treatment of choice in anemia associated with end–stage renal disease. Its major side effect is hypertension, which occurs in 8–30% of uremic patients. The exact mechanism of rHuEpo–induced hypertension has not been fully elucidated, and several possibilities have been proposed, such as a direct vascular effect of the drug with a shift in the balance of constrictor and relaxing endothelial factors (endothelins and nitric oxide (NO)). Recent papers suggested an enhanced rather than reduced activity of endogenous NO system in rats with normal renal function and rHuEpo–induced hypertension. Our study was designed to verify whether, in spite of enhanced activity of the renal NO system, rHuEpo may affect endothelium–dependent (acetylcholine–induced) and/or endothelium–independent (sodium nitroprusside–induced) vasorelaxation and to evaluate basal NO release by the infusion of NG–nitro–L–arginine methyl ester (L–NAME) in an isolated and perfused rat kidney model. Methods: To investigate this hypothesis, we have determined systemic and renal NO activity in Wistar rats treated with a hypertensive dose of rHuEpo (150 IU/kg b.w. every other day for 2 weeks) by measuring stable NO metabolites (NO2+NO3) in the urine and have also evaluated variations in renal vascular resistance after the injection of Ach, SNP and the infusion of L–NAME. Results: Hematocrit, hemoglobin concentration and arterial blood pressure were significantly increased in the treated group as compared with the controls. Urinary excretion of NO2+NO3 was significantly higher in treated than in the controls (438±66 vs. 294±36 nM/ml/min, p<0.01, respectively). There were no significant differences in the dose–response curves to Ach and SNP between the two groups. The renal vasoconstriction following the infusion of L–NAME was also similar in the two groups. Conclusions: The analysis of our results seems to indicate that the endogenous NO system activity was enhanced in rHuEpo–induced hypertension in rats with normal renal function and a resistance to NO was not developed in renal circulation. Further studies seem to be necessary to better clarify the exact mechanisms underlying the development of rHuEpo–induced hypertension.

Acute Suppression of Parathyroid Activity during Hemofiltration

Hemofiltration (HF) induces a significant reduction in parathormone (PTH). This effect is related not only to the convective removal of PTH molecules but also to the biological suppression of parathyroid glands by plasma-ionized calcium (iCa) increase. The acute inhibitory effect on parathyroid gland activity, ionized calcium mass balance, phosphate kinetics and intact PTH (PTHi) dialytic removal during post-dilution polyamide HF were studied in 31 chronic uremic patients. HF ensures good phosphate removal (from 2.54 +/- 1.19 to 1.27 +/- 0.35 mEq/l; p < 0.01), a positive iCa mass balance (8 +/- 4 mmol/session) with a iCa plasma increase and negligible convective PTHi removal (9 +/- 2 pg/ml). Study of the PTHi profile during HF characterized two different parathyroid responses: 26/31 patients showed a physiological parathyroid gland response to the iCa increase (from 1.17 +/- 0.09 to 1.42 +/- 0.07 mmol/l; p = 0.002) with a significant PTHi decrease (from 123 +/- 111 to 35 +/- 28 pg/ml; p = 0.01) and a maximal PTH inhibition of 88%. In 5 patients, with more severe hyperparathyroidism, in spite of a comparable increase in iCa (from 1.28 +/- 0.12 to 1.46 +/- 0.08 mmol/l; p = 0.02), this physiological calcium-PTHi feedback was lost, revealing an autonomization of the gland (maximal inhibition of 45%). In our experience, study of the PTHi profile during a single HF session may represent a clinical test for the functional exploration of parathyroid glands, suggesting future (medical or surgical) clinical strategy.