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Low dialysate to blood flow rate ratios are a unique characteristic of continuous arteriovenous hemodiafiltration (CAVHDF) that should allow complete saturation of dialysis fluid with small-molecular-weight blood solutes. The aim of the investigation was to evaluate the performance of different hemofilters in CAVHDF. In 10 critically ill patients with acute renal failure, the efficiency of four hollow-fiber hemofilters, polyamide 0.6 m(2), polyacrylonitrile (PAN) 0.3 and 0.6 m(2), acrylonitrile sodium methallylsulfonate (AN69HF) 0.6 m(2), has been evaluated. For comparison, dialysate flow rates (Q(di)) were standardized to 16.6 and 25 ml/min. Samples for urea nitrogen were obtained from the arterial blood line (C(bi)) and from the dialysate exit port (C(do)) within 24-hour running time. Outflowing dialysate (Q(do)) was also measured at the same time. Blood flow (Q(b)) was calculated by the bubble transit time technique. Diffusive and total urea clearances were determined. AN69HF and PAN hemofilters provided higher clearances than the polyamide hemofilter. Despite the smaller surface area, PAN 0.3 m(2) had a total urea clearance comparable to that of PAN 0.6 m(2) and AN69HF at Q(di) = 16.6 ml/min. While at Q(di) = 16.6 ml/min equilibrium between blood and dialysate (C(do)/C(bi) congruent with 1) occurred with the AN69HF and PAN hemofilters, at Q(di) = 25 ml/min the equilibrium was obtained only with the AN69HF hemofilter. In conclusion, almost complete urea saturation of dialysis fluid has not been obtained with all hemofilters tested here. In our experience, membrane characteristics play an important role in determining diffusive efficiency in CAVHDF., (Copyright 2000 S. Karger AG, Basel)

Na+/Ca2+ exchange contributes to the control of cytosolic free Ca2+ levels ([Ca2+]i) in resting and activated cultured human mesangial cells. We have previously shown that activation of phospholipase C by vasoconstrictors enhances Ca2+ influx upon extracellular Na+ withdrawal. This effect is not mediated by concurrent activation of protein kinase (PK) C, since it occurs even after PKC inhibition, and phorbol esters actually blunt both basal and stimulated Na+/Ca2+ exchange. We now studied the effects of PKA and PKG activation by adenylate/guanylate cyclase stimuli or by permeant analogues of cyclic nucleotides in monolayer cultures loaded with the fluorescent Ca(2+)-sensitive probe, fura-2. The exchanger was inhibited by the stable prostaglandin I2 analogue, iloprost, which is transduced by cAMP (peak [Ca2+]i inhibition by 1 microM iloprost 35 +/- 3%). Similarly, non-receptor activation of adenylate cyclase by 10 microM forskolin inhibited basal and agonist-stimulated Na+/Ca2+ exchange by 52 +/- 4 and 66 +/- 4%, respectively. Dibutyryl-cAMP (0.1 mM) also inhibited stimulated Na(+)-dependent Ca2+ influx by 72 +/- 2%. The particulate guanylate cyclase agonist, atriopeptin III, and the soluble guanylate cyclase activator, glyceryltrinitrate, also inhibited both basal and angiotensin II-stimulated Na+Ca2+ exchange (to a maximum of 53 +/- 5 and 62 +/- 3%, respectively). Dibutyryl-cGMP (1 mM) mimicked the effects of cGMP stimuli, reducing stimulated Na+/Ca2+ exchange by 79 +/- 2%. Therefore, similar to PKC, cyclic nucleotide activation of PKA and PKG regulates Na+/Ca2+ exchange, providing a functional link between transmembrane signalling systems for vasoactive agents in cultured human mesangial cells.

The glomerular polyanion comprises all anionic sites of glomerular cell surfaces, basement membranes and extracellular matrix. Charged structures may play a critical pathophysiologic role within the glomerular microcirculation, as loss of charges results in altered permselectivity of the filtration barrier and proteinuria. Neutralization of cell surface negative charges of cultured glomerular epithelial and mesangial cells by the polycation poly-L-lysine (PL) is accompanied by increased prostanoid synthesis. Recent studies have shown that PL enhances mesangial cell proliferation in culture. Conversely, the polyanion heparin prevents the effect of PL, and inhibits the growth-stimulatory effect of serum. Thus, our data suggest that the glomerular polyanion, in addition to maintaining the integrity of the filtration barrier, regulates key cell functions such as eicosanoid biosynthesis and proliferation.

Mesangial cells are contractile pericytes of the kidney glomerulus. Mesangial contraction/relaxation contributes to the regulation of glomerular hemodynamics. Additionally, mesangial cells process filtered macromolecules, synthesize extracellular matrix, respond to and release a number of cytokines and vasoactive mediators. Cultured mesangial cells express receptors for circulating and local agents that affect glomerular function. These receptors are coupled to distinct signaling pathways, namely phospholipase C and A2, transducing vasoconstrictor stimuli, and adenylate/guanylate cyclase, transducing vasodilators. Early intracellular signals include changes of cytosolic ions and cyclic nucleotides. They translate into short-term responses, such as cell depolarization and contraction, and later events, such as prostanoid synthesis and cell proliferation. Studies of mesangial cell behavior in culture may largely enhance our current understanding of glomerular pathophysiology.

Treatment of secondary hyperparathyroidism and the osteodystrophy of predialysis chronic renal failure (CRF) with 1,25(OH)2D3 has been advocated by several authors, but also opposed by others for alleged renal toxicity. However, current concepts of the pathogenesis of the early occurrence of secondary hyperparathyroidism in predialysis CRF point to deficiency of 1,25(OH)2D3 as a primary factor. The aim of this study was to evaluate if administration of 1,25(OH)2D3 (0.25 microgram daily) in a dose which would not induce hypercalcemia, would improve humoral and bone histomorphometric parameters in predialysis CRF. 15 patients with predialysis CRF (mean age 51.2 +/- 16.9 years, range 13-73 years), serum creatinine 4.93 +/- 1.7 mg/dl, were treated with the vitamin D metabolite for an average of 16.2 +/- 11.3 months, at the end of which a transiliac bone biopsy for histomorphometry was performed. In addition, 23 patients comparable for age, serum creatinine and causes of renal failure, served as controls. Treatment did not induce hypercalcemia nor adversely modify the rate of decline of renal function. Alkaline phosphatase fell significantly while immunoreactive parathyroid hormone (iPTH) and osteocalcin showed a moderate, not significant, decrease. Compared to the control patients, the bone histomorphometric parameters active resorption surface and active osteoblastic surface were significantly lower and almost normalized by treatment. In conclusion, the study provides conclusive evidence of the absence of toxicity of the metabolite at the low doses employed, together with good therapeutic response on bone histology. Treatment at this dosage could be made in the early stages of predialysis CRF without need of close and continuous monitoring of serum biochemical parameters.