Natural history of branch duct intraductal papillary-mucinous neoplasms of the pancreas without mural nodules: long-term follow-up results.

BACKGROUND AND AIMS: Although branch duct intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas without mural nodules are frequently observed in asymptomatic subjects, the natural history of these lesions has never been studied. The aim of this study was to elucidate the natural history of branch duct IPMNs without mural nodules. METHODS: Eighty-two patients who had no apparent mural nodules on initial examination were selected for follow-up. All subjects underwent examinations by imaging modalities including endoscopic retrograde pancreatography, and were followed-up by regular examinations once or twice a year. Serial changes of the maximum cystic diameter and the appearance of mural nodules were studied during the observation periods ranging from 14 to 148 months (median, 61 months). RESULTS: Nine (11.0%) of 82 patients exhibited obvious progression of cystic dilatation (median, 59 months). Of these nine patients with cystic enlargement, six continued with regular follow-up examinations. Three cases underwent surgical resection, and were pathologically diagnosed as adenoma in two and borderline in one. Four patients (4.9%) showed newly developed mural nodules in dilated branch ducts (median, 105 months). Histological analysis revealed three cases classified as adenoma and one as carcinoma in situ. None of the remaining 69 patients (84.1%) showed any changes in dilated branch ducts (median, 57 months). CONCLUSIONS: Most branch duct IPMNs without mural nodules remained unchanged during long-term follow-up. Although follow-up with careful examination is required to detect newly developed mural nodules in dilated branch ducts, branch duct IPMNs without mural nodules can be followed-up without surgery.

Mechanism of apical and basolateral Na(+)-independent Cl-/base exchange in the rabbit superficial proximal straight tubule.

The present study was undertaken to determine the magnitude and mechanism of base transport via the apical and basolateral Na(+)-independent Cl-/base exchangers in rabbit isolated perfused superficial S2 proximal tubules. The results demonstrate that there is an apical Na(+)-independent Cl-/base exchanger on both membranes. HCO3- fails to stimulate apical Cl-/base exchange in contrast to the basolateral exchanger. Inhibition of endogenous HCO3- production does not alter the rate of apical Cl-/base exchange in Hepes-buffered solutions. Both exchangers are inhibited by H2DIDS and furosemide; however, the basolateral anion exchanger is more sensitive to these inhibitors. The results indicate that the apical and basolateral Cl-/base exchangers differ in their transport properties and are able to transport base equivalents in the absence of formate. The formate concentration in rabbit arterial serum is approximately 6 microM and in vitro tubule formate production is < 0.6 pmol/min per mm. Formate in the micromolar range stimulates Jv in a dose-dependent manner in the absence of a transepithelial Na+ and Cl- gradient and without a measurable effect on Cl(-)-induced equivalent base flux. Apical formic acid recycling cannot be an important component of any cell model, which accounts for formic acid stimulation of transcellular NaCl transport in the rabbit superficial S2 proximal tubule. We propose that transcellular NaCl transport in this nephron segment is mediated by an apical Na+/H+ exchanger in parallel with a Cl-/OH- exchanger and that the secreted H+ and OH- ions form H2O in the tubule lumen.

Functional profile of the isolated uremic nephron: potassium adaptation in the rabbit cortical collecting tubule.

As a renal function declines in patients and experimental animals with chronic renal disease, potassium homeostasis is maintained by a progressive increase in potassium secretion by the surviving nephrons, a phenomenon known as potassium adaptation. To determine the nephron site and the underlying mechanisms responsible for this phenomenon, studies were performed on normal and 75% nephrectomized rabbits maintained on normal or high-potassium diets. Cortical collecting tubules (CCT) were dissected from the normal and remnant kidneys and perfused in vitro in an artificial solution. In normal CCT mean (+/- SE) net K secretion, JK, (peq/cm per s) was 1.26 +/- 0.43 (normal diet) and 3.27 +/- 0.66 (high-K diet). In uremic CCT, JK was 3.55 +/- 0.60 (normal diet) and 6.83 +/- 0.58 (high-K diet). By reducing the dietary intake of potassium in proportion to the reduction of renal mass in these uremic animals, the adaptation in K secretion was prevented (JK: 1.22 +/- 0.40). Transepithelial potential difference was similar in CCT from normal and uremic animals on a normal diet despite the fact that JK was significantly greater in the latter group. However, in both normal and uremic CCT, the increase in JK caused by potassium loading was associated with an increase in luminal negativity. Uremic CCT underwent significant compensatory hypertrophy regardless of the dietary intake or potassium secretory rates. Plasma aldosterone levels were elevated only in the uremic-high potassium rabbits suggesting that a mineralocorticoid effect on the CCT may be exaggerated when potassium loading is superimposed upon decreased excretory capacity. The activity of Na-K ATPase was comparable in normal and uremic CCT from rabbits on either normal or high-K diets indicating that potassium adaptation may occur independently of changes in the activity of this enzyme. Intracellular potassium content measured chemically and by 42K exchange, was not significantly altered in either normal or uremic CCT when dietary potassium intake was increased, despite the fact the JK was increased under these circumstances. These data indicate that the CCT is an important site of potassium adaptation in the surviving nephrons of animals with reduced renal mass. This adaptation is an intrinsic property of the CCT and is expressed in the absence of a uremic milieu. Potassium adaptation by the uremic CCT is not fixed according to the degree of compensatory hypertrophy but varies according to the excretory requirements of the animal. Transepithelial potential difference and circulating aldosterone levels contribute to the adaptation but neither factor can entirely account for the phenomenon. Potassium adaptation by the CCT occurs in the absence of changes in Na-K ATPase activity and intracellular potassium content.

Functional profile of the isolated uremic nephron. Evidence of proximal tubular "memory" in experimental renal disease.

In experimental models of glomerular and nonglomerular renal disease, single nephron filtration rate and proximal tubular reabsorption of fluid decrease or increase in parallel in the same nephron. To assess whether intrinsic adaptations in proximal tubular function, i.e., changes that are independent of the peritubular or humoral milieu, contribute to this phenomenon, segments of rabbit late superficial proximal convoluted tubules (PCT) were studied by in vitro perfusion. PCT were obtained from normal kidneys, from remnant kidneys, and from kidneys embolized with microspheres. Single nephron filtration rates are increased in the remnant and decreased in the embolized kidneys. Whereas the embolized-kidney rabbits were nonazotemic (the contralateral kidney was left in situ), the remnant-kidney animals were uremic. In order to study a nonazotemic model of increased single nephron filtration rate, PCT were also obtained from uninephrectomized rabbits. Significant compensatory hypertrophy occurred in the PCT of the remnant kidney. Net fluid reabsorption (Jv) per unit length was increased by approximately 60%; Jv per unit luminal surface area was the same as in the normal PCT. Transepithelial potential difference (PD) was significantly greater than normal. This was associated with a reversal of the normal permselective properties (P(Cl) > P(Na)) of the late superficial PCT so that P(Na) exceeded P(Cl). The changes could not be ascribed to some undetermined effect of the uremic state in vivo, since increases in tubule size, Jv per unit length, and PD also occurred in PCT from nonazotemic uninephrectomized rabbits. In contrast, Jv, per unit length or per unit luminal surface area, was decreased by approximately 50% in PCT from embolized kidneys and PD was also reduced. In these tubules, the normal permselective properties were also reversed. Tubule size, however, was not significantly different from normal. The increases or decreases in Jv that occurred in the different disease models were not dependent on tubular fluid flow rate or the uremic milieu in vitro. These studies indicate that intrinsic proximal tubular function is modified by the disease state in vivo and that the "memory" of this adaptation is expressed in the in vitro situation. The changes in Jv observed in vitro parallel the increases or decreases in single nephron filtration rates that occur in vivo. Compensatory hypertrophy, with an attendant increase in luminal surface area, could explain the increased Jv per millimeter in the remnant kidneys, but the adaptation observed in the embolized kidneys cannot be ascribed to changes in tubule size.

[Positron emission tomography (PET)-computed tomography (CT) suggesting small intestinal metastasis from lung cancer; report of a case].

A 75-year-old man admitted to our hospital due to an abnormal X-ray shadow detected during an annual health check-up. Chest computed tomography (CT) revealed 3.0 cm solid nodules with chest wall invasion in the left lung. We could not get a definitive diagnosis by transbronchial lung biopsy or CT-guided needle biopsy. Positron emission tomography (PET)-CT revealed positive findings in the tumor, aortopulmonary window lymph node and splenic flexure. Under a diagnosis of suspected lung cancer, thoracotomy was performed. As intraoperative diagnosis revealed a moderately differentiated squamous cell carcinoma, the patient underwent a left upper lobectomy, mediastinal lymph node dissection, and combined chest wall resection. Pathological stage was T3N2M0, stage IIIA. Ten days after surgery, the patient suffered from ileus and emergent surgery was performed. Subsequent pathological examination revealed lung cancer metastasis in the small intestine.

[Mediastinal granular cell tumor: report of a case].

Mediastinal granular cell tumor is rare. We report a case of 16-year-old woman with a granular cell tumor in the right upper-middle mediastinum. Chest computed tomography (CT) and magnetic resonance imaging (MRI) revealed a 4.0 x 2.5 x 5.5 cm well circumscribed mass in the right upper-middle mediastinum. Tumor resection was performed. It was found that the tumor involved right vagus nerve. The tumor was completely excised with combined resection of the right vagus nerve peripheral to the right recurrent nerve. Histopathologically, the tumor consisted of round to polygonal cells with abundant eosinophilic granular cytoplasm, and diagnosed a granular cell tumor.

[Surgical resection of metachronous multiple lung cancer after complete response of small cell lung cancer; report of a case].

A 76-year-old man underwent combination chemotherapy with cisplatin and etoposide and 50 Gy radiotherapy for left-sided small cell lung cancer in 1999. He achieved clinical complete response and showed no sign of recurrence on follow-up study. In December 2004, chest computed tomography (CT) revealed a 1 cm nodule in the right lung. Although no diagnosis could be made by bronchoscope, we suspected metachronous multiple lung cancer because of high 18fluorodeoxyglucose uptake with positron emission tomography (PET). The patient underwent video-assisted thoracoscopic surgery in May 2005; the frozen section diagnosis was adenocarcinoma.

[Small sclerosing hemangioma combined with primary lung cancer; report of a case].

A 56-year-old woman underwent a surgery for right breast cancer when she was 51-year-old. In February 2002, computed tomography (CT) was performed as a part of a follow-up study and showed 2 small nodules in the lower lobe of her right lung: one was 10 mm nodule in S9, and another was 5 mm in S6. On a follow-up CT in March 2005, the S9 nodule had enlarged to 19 mm and was looked as ground glass opacity (GGO). We thought it was primary lung cancer. In contrast, the nodule in S6 had not enlarged and it was thought to be benign. In May 2005, right lower lobectomy was performed. The S9 nodule was diagnosed as adenocarcinoma, and the S6 nodule as sclerosing hemangioma.

Riboflavin uptake by rat liver basolateral membrane vesicles.

The present study examined riboflavin (RF) uptake by purified rat liver basolateral membrane vesicle (BLMV). Uptake of RF was found to be Na(+)- and pH-independent in nature. Studies on RF uptake by BLMV as a function of incubation medium osmolarity have indicated that the uptake is the result of transport (66.5%) into the intravesicular space as well as binding (33.5%) to membrane surfaces. The process of RF uptake by BLMV was saturable as a function of substrate concentration with an apparent Km of 3.55 +/- 0.70 microM and Vmax of 39.89 +/- 3.24 pmol/mg protein/5 s, respectively. cis-Addition of unlabeled RF and its structural analogs lumaflavin and lumichrome inhibited the uptake of [3H]RF while trans-addition of unlabeled RF stimulated the efflux of [3H]RF from preloaded vesicles. No effect on RF uptake was found by the membrane transport inhibitors probenecid, 4,4-diisothiocyanotostilbene-2,2-disulfonic acid (DIDS) and 4-acetamido-4-isothiocyanatostilbene-2,2'-disulfonic acid (SITS). Induction of a transient positive intravesicular space led to a slight stimulation of RF uptake, while induction of a negative intravesicular space led to a slight inhibition in RF uptake. These results demonstrate the existence of a membrane-associated carrier system for RF uptake by liver BLMV. This system appears to be Na(+)- and pH-independent and is influenced to a certain degree by changes in transmembrane electrical potential.

Riboflavin transport by rabbit renal brush border membrane vesicles.

The present study examined riboflavin (RF) uptake by isolated rabbit renal brush border membrane (BBM). RF uptake was linear for up to 30 s and leveled off thereafter reaching an equilibrium with longer incubation. Studies on RF uptake as a function of incubation medium osmolarity indicated that the uptake was the results of transport (61.4%) into the intravesicular space as well as binding (38.6%) to membrane surfaces. The process of RF uptake was saturable as a function of substrate concentration with an apparent Km of 25.7 +/- 7.6 microM and Vmax of 75.6 +/- 14.7 pmol/mg protein/10 s. cis-Addition of unlabeled RF and its structural analogues, lumiflavin and lumichrome, inhibited the uptake of [3H]RF significantly, indicating the involvement of a carrier-mediated process in RF uptake by renal BBM. RF uptake by renal BBM was partly Na+-dependent so that when Na+ was replaced by potassium, choline, lithium or tetramethylammonium, the RF uptake was reduced to ca. 60% of the control. This Na+-dependency was unlikely to be due to Na+-cotransport mechanism because RF uptake occurred without the characteristic 'overshoot' phenomenon as for other Na+-cotransport systems and the elimination of transmembrane Na+-gradient by preloading Na+ to the intravesicular space did not affect RF uptake. In contrast, removal of Na+ eliminated the binding component of RF uptake, suggesting the requirement of Na+ for RF binding to BBM. The RF uptake was not affected when extravesicular pH was varied within the physiological pH range of 6.5 to 8.5. No effect on BBM [3H]RF uptake was found when the transmembrane electrical potential was altered by either the presence of anions with different membrane permeability (Cl- = NO3- > SO4- > gluconate-) or by using nigericin (10 microg/mg protein) with an outwardly or inwardly directed transmembrane K+ gradient. The uptake of RF by BBM vesicles was, however, inhibited by probenecid and organic anion transport inhibitors, 4,4-diiso-thiocyanatostilbene-2,2-disulfonic acid (DIDS, 1 mM) and 4-acetamido-4-isothiocyanatostilbene-2,2-disulfonic acid (SITS, 1 mM). In summary, these results demonstrate the existence of a membrane-associated, and organic anion inhibitor-sensitive, carrier system for RF uptake by renal BBM.

Riboflavin transport by rabbit renal basolateral membrane vesicles.

The present study examined riboflavin (RF) uptake by isolated rabbit renal basolateral membrane (BLM). RF uptake was linear during the initial 10 seconds and leveled off thereafter with longer incubation. Studies on RF uptake as a function of incubation medium osmolarity indicated that the BLM RF uptake was the results of transport (approximately 45%) into the intravesicular space as well as binding (approximately 55%) to membrane surfaces. The RF binding to BLM was Na+-dependent so that replacement of Na+ by other cations eliminated the binding component of RF uptake. The process of BLM RF uptake was saturable as a function of substrate concentration and was significantly inhibited by cis-addition of its structural analogs, lumiflavin and lumichrome, indicating the involvement of a carrier-mediated process. The BLM RF uptake was affected by changes in extravesicular pH so that, as compared to pH 7.5, RF uptake was lower at pH 6.5 and higher at pH 8.5. The effect of extravesicular pH persisted when the transmembrane H+ gradient was dissipated by FCCP, indicating the direct effect of pH on BLM RF uptake. The BLM RF uptake was not affected by alterations of the transmembrane electrical potential, induced by either the presence of anions with different membrane permeability (Cl-=NO-3>SO-4>gluconate-) or using nigericin (10 microg/mg protein) with an outwardly or inwardly directed transmembrane K+ gradient. The BLM RF uptake was, however, inhibited by probenecid and p-aminohippurate, and was enhanced by trans-RF. In summary, these results demonstrate the existence of a Na+-dependent BLM binding of RF and a membrane-associated carrier system for RF uptake by renal BLM.

Thiol redox and phosphate transport in renal brush-border membrane. Effect of nicotinamide.

In the present study, the effect of thiol redox and its possible role in the inhibitory effect of nicotinamide on renal brush-border membrane (BBM) phosphate uptake was examined. Addition of thiol reducing agent, dithiothreitol (DTT, 5 mM), caused an increase, while addition of thiol oxidant, diamide (DM, 5 mM) caused a reversible decrease in sodium-dependent BBM phosphate uptake. Kinetic analyses revealed an increase in both Vmax and Km by DTT, and a decrease in Vmax by DM. These results suggest that thiol redox influences BBM phosphate uptake with sulfhydryl (SH) groups relate to its capacity and disulfide (SS) groups to its affinity for phosphate. Since changes in cytosolic NAD levels may affect BBM thiol redox through changes in redox states of NADP and glutathione systems, we have examined such possibility by studying the effect of nicotinamide (NM). Incubation of proximal tubules with NM (10 mM) induced an oxidative effect on redox states of cytosolic NAD, NADP systems as inferred from decreased cellular lactate/pyruvate, malate/pyruvate, respectively. Measurements of cytosolic glutathiones and BBM thiols also revealed that NM pretreatment shifted the cytosolic glutathione redox (GSH/GSSG) and BBM thiol redox (SH/SS) toward more oxidized state. On the other hand, incubation of proximal tubules with NM suppressed phosphate uptake by the subsequently isolated BBM vesicles. The lower phosphate uptake by NM-pretreated BBM vesicles was reversed by DTT and was resistant to the inhibitory effect of DM. These results thus suggest that BBM thiol oxidation may be involved in the inhibitory effect of NM on BBM phosphate uptake.

Lower serum magnesium levels are associated with more rapid decline of renal function in patients with diabetes mellitus type 2.

AIMS: Hypomagnesemia has been implicated in adversely affecting diabetic complications. This is a retrospective study designed to determine whether there is any association between serum magnesium concentration [Mg2+] and the rate of renal function deterioration, as determined by the slope of serum creatinine reciprocals versus time (1/SCr-vs-t), in patients with diabetes mellitus type 2 (DM2). MATERIALS AND METHODS: DM2 patients without known kidney disease seen at Olive View-UCLA Medical Center for any reason during January-March 2001 were included. For each patient, all available data from our electronic database for [Mg2+], hemoglobin A(1C) (HbA(1C), serum creatinine (SCr), lipid profiles, routine urinary analysis, as well as history of hypertension and pharmacy profiles were retrieved. The average of all parameters obtained and linear regression analyses for the slope of 1/SCr-vs-t plot were performed for each patient. Patients were stratified by gender and divided into four groups based on increasing [Mg2+]. Correlations between each parameter including the slope of 1/SCr-vs-t and the four magnesium groups were analyzed. RESULTS: 252 males and 298 females with a mean follow-up of 62.6 +/- 22.5 months were included. Patients belonging to lower [Mg2+] groups for both genders had significantly worse slopes of 1/SCr-vs-t plot independent of the presence of hypertension and use of ACEI/ARB, diuretics, HMG-CoA enzyme inhibitors or aspirin. In a multivariate regression analysis controlling for age, HbA(1C) and various components of the lipid profile, [Mg2+] remained an independent predictor for the slope of 1/SCr-vs-t. A trend for worse proteinuria based on routine urinary analysis was observed among patients belonging to the lowest [Mg2+] group. CONCLUSIONS: Lower [Mg2+] is associated with a faster renal function deterioration rate in DM2 patients.

Altered proximal tubule glucose metabolism in X-linked hypophosphatemic mice.

In the present study we examined renal proximal tubule glucose metabolism in the X-linked hypophosphatemic (Hyp/Y) mouse. Compared to those in its normal (+/Y) littermate, Hyp/Y mouse proximal tubules showed a higher rate of glucose production when using glutamine or alpha-ketoglutarate as a substrate. The glucose production rate was not, however, different when using malate or fructose as the substrate. PTH stimulated glucose production in +/Y, but not Hyp/Y, mouse proximal tubules. The PTH resistance in Hyp/Y mouse involves steps at and post-cAMP formation, because in Hyp/Y mouse proximal tubules PTH effects a lesser stimulation of cAMP generation, and addition of 8-bromo-cAMP failed to increase the glucose production rate. The rate of glucose utilization as a whole was not different in the two groups, but the rate of glucose metabolized through the pentose cycle (PC) pathway was markedly lower in Hyp/Y mouse proximal tubules. The lower PC activity in Hyp/Y mouse proximal tubules did not result from a defect of PC enzymes, because both glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase enzyme activities were intact, and phenazine methosulfate was able to stimulate PC activity. The higher rate of glucose production and the lower rate of PC activities persisted in the in vitro cultured Hyp/Y mouse proximal tubular cells. These results suggest that the altered glucose metabolism in the Hyp/Y mouse proximal tubule is not maintained by external influences and may be an abnormality intrinsic to these cells.

Potential role of 12 hydroxyeicosatetraenoic acid in angiotensin II-induced calcium signal in rat glomerulosa cells.

Recent evidence suggests that 12 hydroxyeicosatetraenoic acid (12HETE), a product of the 12 lipoxygenase (LO) pathway of arachidonic acid metabolism, may have a role in mediating angiotensin II (AII)-induced aldosterone secretion. The present study examined the possible role of the 12 LO product 12HETE in AII-induced calcium ([Ca++]i) signals in rat glomerulosa cells. The addition of 12HETE to glomerulosa cells induced a dose-dependent (10(-6)-10(-8) M) rise in [Ca++]i levels that was sustained over 15 min. The effects of 12HETE on [Ca++]i were attenuated but not blocked by nifedipine (5 x 10(-6) M) and were preserved in a calcium-free medium, suggesting mobilization of intracellular calcium stores. Furthermore, the 12HETE-mediated rise in [Ca++]i was almost entirely abolished by dantrolene. In parallel, 12HETE reversed the inhibitory effect of nifedipine on AII-induced aldosterone secretion [AII (10(-9) M) - 36 +/- 7, AII + nifedipine (5 x 10(-6) M) - 13 +/- 2, AII + nifedipine + 12HETE (5 x 10(-8) M) - 27 +/- 4 ng/10(6) cells]. Dantrolene also inhibited AII-dependent aldosterone secretion (AII 10(-9) M - 75.8 +/- 5.6, AII + dantrolene 10(-6) M 45.5 +/- 8.8 ng/10(-6) cells), but this inhibition could not be reversed by 12HETE 10(-8) M (45.4 +/- 10.6 ng/10(6) cells). The LO blockers baicalein and BW755C inhibited the effect of AII on aldosterone production and on [Ca++]i in a parallel fashion. During LO blockade, the addition of 12HETE (10(-7) M) restored the AII-induced rise in [Ca++]i. Collectively, these observations suggest that activation of the LO pathway in the rat adrenal glomerulosa contributes to change in cytosolic calcium, which may be important for the steroidogenic effect of AII.

Modulation of aortic smooth muscle cell membrane potential by extracellular calcium.

Removal of extracellular calcium may result in depolarization of the resting cell membrane potential. This has been attributed to the stabilizing action of calcium on the ionic permeability of the cell membrane. It is unknown whether this phenomenon is exclusively mediated by extracellular calcium or through associated changes in intracellular calcium. To examine this, we exposed rat aortic smooth muscle cells in culture to different calcium concentrations and studied their effects on the resting membrane potential and intracellular calcium activity. The resting membrane potential was dependent on the extracellular potassium concentration. Exposure to reduced extracellular calcium concentrations (0.25 and 0.5 mM) caused a steep and reversible depolarization of the membrane potential, but intracellular calcium, measured with fura 2-AM, was not reduced below that measured in control conditions (1.8 mM). Atomic absorption spectrophotometric measurements did not indicate a measurable gain in cell sodium after reduction of extracellular calcium levels. We conclude that extracellular calcium controls the resting cell membrane potential of vascular smooth muscle through a mechanism that is independent of cytosolic Ca2+ activity.

Pharmacokinetics of fosinopril in patients with various degrees of renal function.

Single-dose kinetics of fosinopril, a new phosphorus-containing angiotensin-converting enzyme inhibitor and its active diacid, fosinoprilat, were investigated in patients with mild, moderate, or severe renal impairment and in those with normal renal function. After an intravenous dose of 14C-fosinoprilat (7.5 mg), total body clearance of fosinoprilat was significantly greater (p less than 0.05) in patients with normal renal function than in renally impaired patients but was not related to the degree of renal impairment in patients with creatinine clearance values of 11 to 72 ml/min/1.73 m2. Decreases in renal clearance were compensated for by increases in hepatic clearance, so that total clearance was maintained. After oral 14C-fosinopril (10 mg), plasma kinetics and bioavailability of fosinoprilat were similar for the three groups of renally impaired patients. The dual elimination of fosinoprilat by the liver and the kidney distinguishes fosinopril from other angiotensin-converting enzyme inhibitors.

Potential role for local luminal angiotensin II in proximal tubule sodium transport.

As a target site for angiotensin II (A-II), renal proximal tubule is unique in that it may be equipped with a local A-II generating system and that both basolateral and apical membranes may be accessible for the action of A-II. We have recently conducted studies to examine these possibilities. With in vitro cultured proximal tubular cells, we have demonstrated de novo synthesis of angiotensinogen and renin. With isolated renal brush border membrane (BBM), we have confirmed the presence of A-II receptors and found that A-II directly stimulated BBM Na+/H+ exchange. In search of the signal transduction mechanism, we have found that A-II also activated BBM phospholipase A2 (PLA) and that BBM contained a pertussis toxin-sensitive guanine nucleotide binding protein (G-protein) which mediates the effects of A-II. Further studies showed that prevention of PLA activation abolished the effect of A-II on Na+/H+ exchange, and that activation of PLA by mellitin and the addition of arachidonic acid similarly enhanced BBM Na+/H+ exchange activity, suggesting that PLA activation may mediate the stimulatory effect of A-II on BBM Na+/H+ exchange. These results thus indicate that a local signal transduction mechanism involving G-protein mediated PLA activation exists in renal BBM which mediates the effect of A-II on Na+/H+ exchange. Taken together, we propose that, independent of A-II in the circulation, local luminal A-II may serve as an important regulatory system on sodium transport in renal proximal tubule.

Assessment of hyperphosphatemia and hypophosphatemia.

Methodologic aspects including causes of factitious hyperphosphatemia and hypophosphatemia are summarized. The differential diagnosis of hyperphosphatemia is reviewed under its three broad causes: decreased glomerular filtration rate, increased exogenous or endogenous phosphate load, and increased renal tubular phosphate reabsorption. The differential diagnosis of hypophosphatemia is reviewed under its three broad causes: inadequate gastrointestinal input, excess phosphate losses, and transcellular shifts. The consequences of hyperphosphatemia and hypophosphatemia are outlined with a focus on pathophysiologic and clinicochemical sequelae. A laboratory perspective is emphasized in outlining management strategies.

Cyclosporine A--calcium channels interaction: a possible mechanism for nephrotoxicity.

Rabbit PTC concentrated CsA rapidly and reached saturation by two to three minutes. CsA uptake was temperature dependent but was not altered by replacement of uptake medium Na with K or mannitol, changes in extracellular pH, and the presence of metabolic inhibitors or organic anions and cations. The organic Ca channel blockers verapamil and diltiazem and the inorganic Ca channel blocker cadmium caused significant inhibition in both Ca and CsA uptake by PTC. Other Ca transport modulators, ruthenium red and trifluoroperazine, decreased PTC Ca uptake, and A23187 increased PTC Ca uptake, but they were all without effect on CsA uptake. We propose that the CsA uptake pathway through PTC is situated at or close to Ca channels so that changes induced by Ca channel blockers also affect transit of CsA through the CsA "passageway." The close spatial relationship between CsA and Ca channels also raises the possibility that CsA uptake may intiate Ca channel-related activities, thereby leading to a cascade of Ca-dependent processes and causing nephrotoxicity. A hypothesis is depicted in Fig 1.