Impaired Na(+)-H+ exchanger activity of hepatocytes in chronic renal failure.

Available data indicate that cation transport is impaired in many cells in chronic renal failure (CRF). The information on the activity of the Na(+)-H+ exchanger in CRF is variable, and both increased and reduced activity have been reported. The mechanisms through which CRF may exert an effect on the Na(+)-H+ transport are not known. Data exist indicating that PTH inhibits the Na(+)-H+ exchange in kidney and liver, and this action of hormone is most likely due to its ability to raise cytosolic calcium ([Ca2+]i). Therefore, it is possible that excess PTH in CRF may adversely affect the activity of the Na(+)-H+ antiport. This study examines the activity of Na(+)-H+ antiport, intracellular pH (pHi), and buffering capacity of hepatocytes obtained from rats after 6 wk of CRF, from CRF parathyroidectomized animals, and from CRF rats and normal rats treated with verapamil. The pHi and the buffering capacity of hepatocytes were not different in all groups of animals. The activity of the Na(+)-H+ antiport of hepatocytes from CRF animals was significantly (P < 0.01) lower than in hepatocytes from normal rats, CRF parathyroidectomized rats, CRF rats treated with verapamil, and normal rats treated with verapamil, and the values in the latter four groups of animals were not different. This impaired activity of Na(+)-H+ antiport in CRF was observed in all external concentrations of sodium (25, 50, 75, 100, 125, and 150 mM). Thus, CRF altered the kinetics of the transporter in that its Vmax decreased and its K(m) increased. The data show that: (1) CRF is associated with reduction in the activity of Na(+)-H+ antiport in hepatocytes; (2) this defect is due to the state of secondary hyperparathyroidism of CRF; and (3) excess PTH mediates its effect by elevating [Ca2+]i of hepatocytes because treatment of CRF animals with verapamil, which blocks the PTH-induced rise in [Ca2+]i of these cells, prevented the impairment in the activity of the Na(+)-H+ antiport.

Effects of parathyroid hormone on hepatocyte pHi and Na(+)-H+ exchanger activity.

Parathyroid hormone (PTH) induces a rise in cytosolic calcium--[Ca2+]i--in many cells. A rise in [Ca2+]i activates the Na(+)-H+ antiport, but PTH inhibits the Na(+)-H+ exchanger in kidney cells. Since PTH induces a rise in [Ca2+]i of hepatocytes, we examined the effect of PTH on their Na(+)-H+ antiport and intracellular pH(pHi). PTH caused an initial activation of Na(+)-H+ exchanger, and this stimulation is amiloride sensitive. The activation of the Na(+)-H+ exchanger was followed by progressive inhibition. This inhibitory effect was dose dependent and occurred over a wide range of external sodium concentrations. PTH also caused a progressive rise in hepatocyte pHi which became apparent after the initial activation of the Na(+)-H+ antiport. This alkalinization of hepatocytes occurred when the cells were placed in sodium or potassium media. These actions of PTH were mimicked by dibutyryl cyclic AMP and 12-o-tetradecanoylphorbol-13-acetate(TPA) and were abolished by H-89 (an inhibitor of protein kinase A), staurosporine (an inhibitor of protein kinase C), and the calcium channel blockers verapamil or nifedipine. The data are consistent with the formulation that PTH, through the activation of the cAMP-protein kinase A pathway, protein kinase C, and calcium channels inhibitable by verapamil or nifedipine, induces a rise in [Ca2+]i of hepatocytes. The latter event causes an initial activation of Na(+)-H+ antiport which is followed by a rise in pHi. Also, PTH may facilitate a Ca2+/2H+ exchange across the hepatocyte membrane and causes an initial and persistent rise in pHi, since the rise in pHi occurred under conditions where Na(+)-H+ antiport is inactive (potassium media). In addition, PTH either directly or through activation of second messenger(s) leads to an increased ammonia content of hepatocytes which could maintain a high pHi. Consequently, the Na(+)-H+ antiport is inhibited in an effort to restore the pHi back to normal.

Mechanisms of PTH-induced rise in cytosolic calcium in adult rat hepatocytes.

Available data indicate that the liver is a target organ for parathyroid hormone (PTH) and that this effect is most likely mediated by PTH-induced calcium entry into hepatocytes. The present study examined the effects of both PTH-(1-84) and its amino-terminal fragment [PTH-(1-34)] on cytosolic calcium concentration ([Ca2+]i) of hepatocytes and explored the cellular pathways that mediate this potential action of PTH. Both moieties of PTH produced a dose-dependent rise in [Ca2+]i, but the effect of PTH-(1-84) was greater (P < 0.01) than an equimolar amount of PTH-(1-34). This effect required calcium in the medium and was totally [PTH-(1-34)] or partially [PTH-(1-84)] blocked by PTH antagonist ([Nle8,18,Tyr34]bPTH-(7-34)-NH2] and by verapamil or nifedipine. Sodium or chloride channel blockers did not modify this effect. 12-O-tetradecanoylphorbol 13-acetate (TPA), an activator of protein kinase C, dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP), and G protein activator also produced a dose-dependent rise in [Ca2+]i. Staurosporine abolished the effect of TPA, and both staurosporine and calphostin C partially inhibited the effect of PTH. Staurosporine and verapamil together produced greater inhibition of PTH action than each alone. Rp-cAMP, a competitive inhibitor of cAMP binding to the R subunit of protein kinase A, and N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89), a protein kinase A inhibitor, blocked the effect of both DBcAMP and PTH, but the effect of these agents was greater (P < 0.01) on DBcAMP action. G protein inhibitor and pertussis toxin partially blocked the action of PTH. The data indicate that 1) PTH increases [Ca2+]i of hepatocytes; 2) this action of the hormone is receptor mediated; 3) the predominant pathway for this PTH action is the stimulation of a G protein-adenylate cyclase-cAMP system, which then leads to stimulation of a calcium transport system inhibitable by verapamil or nifedipine or activation of L-type calcium channels; 4) activation of protein kinase C is also involved; and 5) the PTH-induced rise in [Ca2+]i is due, in major parts, to movement of extracellular calcium into the cell.

[Testing the efficacy of fluconazole in treatment of oral and throat candidiasis in patients after kidney transplantation]. / Badania skutecznosci flukonazolu w leczeniu kandydozy blon sluzowych jamy ustnej i gardla u chorych po przeszczepieniu nerki.

Eleven kidney transplant recipients with the oral or/and throat candidiasis which occurred during the first 3 months after transplantation were studied. Fluconazole was administered orally in the dose of 50 mg each 24, 48, 72 h, according to creatinine clearance. No clinical symptoms of candidiasis on the third day of the treatment were observed. In all patients, negative mucosal cultures were noted at the 8th day after first fluconazole dose. During fluconazole was with in normal range. Furthermore, no changes in serum bilirubin alanine transaminase, lactate dehydrogenase and alkaline phosphatase activities were observed. Serum creatinine decreased during this follow-up. In the 30th day after fluconazole administration cessation the mycological evidence of Candida p. reinfection were noted in 25% of patients. Fluconazole is highly efficient and safe agent to manage the oral and throat candidiasis in renal transplant recipients.

[Acute failure of transplanted kidney after administration of angiotensin converting enzyme inhibitors (iACE)]. / Ostra niewydolnosc nerki przeszczepionej wywolana podaniem inhibitorów konwertazy angiotensyny i (iACE).

Treatment of kidney transplant recipients with inhibitors of angiotensin-converting enzyme (iACE) is associated with increased risk of deterioration of renal function. Between 1988-1992 in Transplantation Institute, 71 renal allograft recipients were treated with iACE. 44 of them received iACE in order to reduce proteinuria, 18 due to secondary polycythemia and 9 recipients received iACE because of hypertension resistant to at least 3 hypotensive drugs. Acute renal failure developed in 5 patients and all of them received iACE as treatment of resistant hypertension. After resumption of renal function, in 3 of 5 patients artery stenosis of the transplanted kidney was found. In 1 recipient acute renal failure occurred despite normal renal arteriography and normal indexes of the flow through renal arteries determined by Doppler ultrasound examination. In 2 patients acute renal failure appeared after a single minimal dose of iACE. Severe arterial hypertension in patients with transplanted kidney is a particular risk factor for development of acute renal failure after iACE. The normal arteriography in transplanted kidney and normal arterial blood flow measured by means of Doppler ultrasound do not exclude the possibility of development of acute renal failure after iACE.