The hyponatremic patient: practical focus on therapy.
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Acute Disease↗
Biomedical subjects
T Berl
Publications and source records attributed to T Berl.
Nephrology core curriculum. The American Society of Nephrology and the American Society of Nephrology Training Program Directors Committee.
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Curriculum↗
Protein kinases in the action of vasopressin.
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Animals↗
Predictors of the progression of renal insufficiency in patients with insulin-dependent diabetes and overt diabetic nephropathy. The Collaborative Study Group.
We designed a prospective, double-blind controlled trial to determine predictors of loss of renal function in patients with insulin dependent diabetes and established nephropathy. A total of 409 insulin-dependent diabetic patients with established nephropathy enrolled in a trial on the effect of Captopril on the rate of progression of renal disease. Baseline demographic, clinical (history and physical) and laboratory parameters were analyzed as risk factors for time to progression. Dichotomous characteristics were compared by Fisher's exact test and continuous characteristics with the Wilcoxon rank-sum test. Univariate proportional hazards regression analysis was used to estimate relative risk of nephropathy progression, and bivariate proportional hazard regression to identify interactions with the treatment group assignment. Multivariate proportional hazard regression was employed to determine which characteristics were independent risk factors. We found that a number of demographic and clinical characteristics were significantly associated with nephropathy progression even after adjustment for treatment group. However, after multivariate analysis, the risk factors that independently predicted progression were onset of IDDM later in life, parental diagnosis of IDDM, the presence of edema, increased mean arterial pressure, and an abnormal electrocardiogram. Likewise, a number of laboratory characteristics were also predictive of nephropathy progression. A low hematocrit, high blood sugar, and higher protein excretion predicted nephropathy progression as did a higher serum creatinine, particularly in the face of a normal serum albumin. In conclusion, this study identifies a number of clinical and laboratory risk factors that can predict which patients with insulin-dependent diabetes with established nephropathy are more likely to sustain a clinically important decrease in renal function over a median follow-up of three years.
Adolescent↗
Evaluation and management of severe hyponatremia.
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Humans↗
Expression of GTPase-deficient Ras inhibits vasopressin signaling in cultured cortical collecting duct cells.
Cross-talk between signaling pathways is increasingly recognized as integral to cellular function. We investigated whether the mitogen-activated protein kinase (MAPK) pathway alters vasopressin (AVP) stimulation of protein kinase A (PKA) by specifically studying the role of Ras. Mouse cortical collecting duct cells (M-1) were transfected with a cDNA encoding oncogenic Ras. Transfection was confirmed by Western blot analysis and functionally by enhanced basal MAPK activity. When compared with basal MAPK activity of 26.4 +/- 6.6 pmol/mg/min in controls, basal MAPK activity varied widely in Ras-transfected clones from 29.0 +/- 6.6 to 96.6 +/- 13.4 pmol/mg/min. Clones that functionally expressed activated Ras displayed complete abolition of AVP-stimulated PKA activity, whereas those that failed to express elevated basal MAPK activity showed intact AVP-stimulated PKA. The correlation between expression of high basal MAPK activity and inhibition of AVP-induced PKA yielded a correlation coefficient of -0.92 (P = 0.009). Exposure to 10 microM forskolin or 1 microgram/ml cholera toxin resulted in comparable activation of PKA in all clones. We found no correlation between PKC activity of the clones and PKA inhibition. To assess whether the observed effect was due to one known Ras target, cells were transfected with constitutively activated Raf. M-1 cells expressing activated Raf exhibited elevated MAPK activity. The Raf clones showed no impairment of AVP-stimulated PKA activity. We conclude that expression of activated Ras is inhibitory of AVP-induced PKA activation in the M-1 cortical collecting duct cell line at a site proximal to G alpha s protein. The failure of Raf to influence AVP signaling indicates that the action of Ras is through a pathway independent of this Ras target.
Amino Acid Sequence↗
Pharmacokinetics of fluconazole in renal failure.
Fluconazole (FLU) is a widely used antifungal agent. The multiple-dose pharmacokinetics of FLU in renal impairment have not been previously investigated. The following groups were studied: volunteers with creatinine clearances (CLcr, > 50 mL/min) of 107 mL/min, given a loading dose of 400 mg and a daily dose of 200 mg/day for 9 days (Group 1); subjects with CLcr between 21 and 50 mL/min with a mean of 38 mL/min, given a loading dose of 200 mg and a maintenance dose of 100 mg/day for 9 days (Group 2); subjects with CLcr between 11 and 20 mL/min with a mean of 14.8 ml/min, given a loading dose of 100 mg and a maintenance dose of 50 mg/day for 9 days (Group 3); and subjects on hemodialysis (three times per week) receiving a loading dose of 200 mg and then 100 mg after each of four dialysis sessions (Group 4) (N = 10 per group). After the administration of the loading dose on Day 1, the mean area under the curve (AUC) (0-24) measurements were approximately proportional to the dose of FLU and independent of renal function. After 10 days of FLU dosing, the mean renal clearance of FLU decreased as CLcr decreased for Groups 1 to 3, and the Day 10 mean half-lives were inversely related to mean CLcr (36.7 h in Group 1, 84.5 h in Group 2, and 101.9 h in Group 3). The mean AUC (0-24) on Day 10 was similar for Group 1 compared with Group 2, despite a reduction in the maintenance dose by 50%. (ABSTRACT TRUNCATED AT 250 WORDS)
Creatinine↗
Increased cytosolic Ca2+ inhibits AVP-stimulated adenylyl cyclase activity in rat IMCT cells by activation of PKC.
In rat inner medullary collecting tubule (RIMCT) cells increasing cytosolic Ca2+ with a calcium ionophore inhibits arginine vasopressin (AVP)-stimulated adenylyl cyclase (AC). Inhibition by Ca2+ is not observed in pertussis toxin (PT)-treated cells, indicating a role for the inhibitory G protein, Gi. The mechanism of activation of Gi remains to be determined. We examined the hypothesis that inhibition of AVP-stimulated AC by increased cytosolic Ca2+ is due to activation of protein kinase C (PKC). Preincubation of RIMCT cells with ionophore results in inhibition of AVP-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) formation. To assess whether stimulation of phospholipase C (PLC) and therefore activation of PKC occurs with ionophore and AVP, inositol trisphosphate (IP3) production was measured. Incubation of RIMCT cells with either 10(-7) M AVP or ionophore results in IP3 production that is no different from basal. However, simultaneous exposure to 100 nM AVP with ionophore results in marked enhancement of IP3 production clearly reflecting stimulation of PLC in this setting. Stimulation of PLC is not observed in PT-treated cells. Likewise, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), an inhibitor of PKC, mimics the effect of PT to prevent inhibition of AVP-stimulated AC by ionophore, but N-(2-[methylamino]ethyl)-5-isoquinolinesulfonamide (H-8), an inhibitor of protein kinase A (PKA), does not. As is the case when PKC is stimulated directly with a phorbol ester, exposure to ionomycin inhibits the response to AVP but does not alter the response to isoproterenol. These studies demonstrate that increased cytosolic Ca2+ does not, as previously postulated, inhibit AC by a direct effect on Gi. Rather, when cytosolic Ca2+ is increased, AVP stimulates PLC; the ensuring activation of PKC inhibits cAMP formation.
Adenylyl Cyclase Inhibitors↗
Hormonal regulation of MAP kinase in cultured rat inner medullary collecting tubule cells.
Mitogen-activated protein (MAP) kinase is a widely expressed protein serine/threonine kinase that serves as a convergence point for many signaling pathways including receptor tyrosine kinases, G protein-coupled receptors, and protein kinase C (PKC). The hormonal regulation of MAP kinase was studied in cultured established rat inner medullary collecting tubule (RIMCT) cells. Neither vasopressin nor beta-adrenergic agonists stimulated MAP kinase, despite clear stimulation of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase. In contrast, carbachol, ATP, and epidermal growth factor (EGF), which are known to antagonize vasopressin action in the RIMCT, stimulated the MAP kinase pathway. This stimulation was mimicked by the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate, which directly activates PKC. The potency with which EGF and carbachol activated MAP kinase was similar to the potency with which they inhibited vasopressin-stimulated cAMP accumulation. To assess the role of Gi proteins in these stimulatory events, RIMCT cells were pretreated with pertussis toxin to inhibit Gi-mediated signaling. Pertussis toxin did not influence ATP- or EGF-stimulated MAP kinase, but completely inhibited carbachol stimulation, suggesting that Gi proteins mediate muscarinic stimulation. Prolonged exposure of RIMCT cells to high phorbol ester concentrations to downregulate PKC ablated carbachol- and ATP-stimulated MAP kinase, but not EGF-stimulated MAP kinase, suggesting that PKC is a component of the network involved in MAP kinase activation by purinergic and muscarinic agonists. Investigation of the sidedness of the hormonal stimulations indicated that EGF-stimulated MAP kinase was highly polarized, occurring exclusively from the basolateral surface, whereas carbachol stimulated MAP kinase similarly from either cell surfaces.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
A molecular map of G protein alpha chains in microdissected rat nephron segments.
Membrane-associated guanine nucleotide binding proteins regulate many receptor-mediated signals. Heterogeneity of biochemical and functional properties in nephron segments could be due to differences in G protein expression. To ascertain whether such heterogeneity of G proteins is present in various nephron segments, this study examines the distribution and relative abundance of G protein alpha chains in microdissected medullary thick ascending limb, cortical collecting tubules, outer medullary collecting tubules, proximal inner medullary tubules, and distal inner medullary tubules. Reverse transcription and polymerase chain reactions were employed using oligonucleotides encoding highly conserved regions of all known alpha chains. The cDNA was sequenced for alpha chain identification. The alpha i2 versus alpha s distribution was different in the outer medullary collecting tubules, when compared with the medullary thick ascending limb (P < 0.001) or the cortical collecting tubule, the proximal inner medullary tubules, and the distal inner medullary tubules (P < 0.05). These latter four segments did not significantly differ from each other. A similar analysis was applied to the frequently used line of kidney cells, LLC-PK1, whose exact cellular origin remains unclear. Interestingly, we detected both alpha i2 and alpha i3, while only alpha i2 was detected in the rat distal nephron. No alpha o or alpha z reverse transcription PCR products were detected. In contrast alpha 11 and alpha 14 members of the more recently described alpha q family were detected in the outer medullary collecting tubules and the proximal inner medullary tubules, respectively. We conclude that the majority of nephron segments have a relatively constant distribution of G protein alpha chains.
Animals↗
Regulation of atrial natriuretic peptide-stimulated cGMP production in the inner medulla.
Studies were performed to examine the regulation of atrial natriuretic peptide- (ANP) stimulated guanylate cyclase in the the inner medulla. Primary cultures of rat inner medullary collecting tubular cells exposed to 10(-7) M ANP increased cGMP formation to 31.2 +/- 1.8 compared to the basal production of 2.1 +/- 0.6 fm/micrograms protein. This response did not appear to be transduced via a Gi protein, as preincubation with pertussis toxin did not alter the response to 10(-7) M ANP, and saponized cells exposed to 10 microM GTP gamma S did not enhance the response to ANP (77.3 +/- 5.9 vs. 86.7 +/- 6.3 g/micrograms). Likewise, changes in extracellular Ca2+ from 0.5 to 3.0 mM, decrements in intracellular Ca2+ with EGTA or increments in intracellular Ca2+ with ionomycin (5 microM) did not significantly alter the response to ANP. Neither activation of protein kinase A with forskolin (36.5 +/- 5.1) nor of protein kinase C with s,n-1,2-dioctanoylglycerol (33.2 +/- 2.5) altered the response to 10(-7) M ANP (32.2 +/- 3.3, NS). As the inner medullary environment was hypertonic, the effect of altering tonicity was studied. Cells grown for 48 hours in hypertonic media (600 mOsm/kg H2O) displayed enhanced response to 10(-8) and 10(-7) M ANP when osmolality was raised by either Na+ alone or in combination with urea, but not by urea alone. Our studies demonstrate that ANP-stimulated guanylate cyclase is insensitive to alterations in either intra- or extracellular Ca2+, is not subject to inhibition by protein kinase, and does not involve a pertussis-sensitive G protein.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Plasmapheresis does not increase the risk for infection in immunosuppressed patients with severe lupus nephritis. The Lupus Nephritis Collaborative Study Group.
OBJECTIVE: To determine whether plasmapheresis increases the risk for infection in immunosuppressed patients. DESIGN: Randomized, controlled trial. SETTING: Multicenter. PATIENTS: Eighty-six patients enrolled in a trial of plasmapheresis for severe diffuse proliferative lupus nephritis. INTERVENTIONS: Forty-six of the patients received high-dose steroid therapy plus cyclophosphamide therapy for 8 weeks. Thereafter, cyclophosphamide therapy was discontinued, and steroid therapy was tapered (standard treatment group). Forty patients received identical treatment and had 12 plasmapheresis procedures during the first 4 weeks of the treatment. MEASUREMENTS: Patients were examined for the development of infection. MAIN RESULTS: No statistical difference in age, sex, race, serum creatinine level, proteinuria, or complement levels was found between the two groups. Over a follow-up period of 5376 patient-weeks, 74% of patients in the standard treatment group had 62 infections, yielding an aggregate infection rate of 1.15 infections per 100 weeks (median individual infection rate, 1.08; 25th and 75th percentiles, 0.0 and 2.44). This rate was comparable to that seen in the plasmapheresis-treated patients who were followed for 4187 patient-weeks: 68% had 51 infections, for an aggregate infection rate of 1.22 infections per 100 weeks (median individual infection rate, 0.94; 25th and 75th percentiles, 0.0 and 2.32). The infection rate was also comparable in the initial acute phase of the study, despite the fact that patients who received plasmapheresis then had significantly lower immunoglobulin (IgG) levels (P less than 0.001). Neither the site (superficial compared with systemic) nor the nature (conventional compared with unconventional) of infection differed statistically between the two groups. Of 14 patient deaths, 7 were from infection (4 in control group and 3 in the plasmapheresis group). CONCLUSION: Plasmapheresis did not increase the risk for infection in immunosuppressed patients with severe lupus nephritis.
Adult↗
ANP stimulates phospholipase C in cultured RIMCT cells: roles of protein kinases and G protein.
We examined the possibility that, in addition to stimulation of guanylate cyclase (GC), atrial natriuretic peptide (ANP) also activates phospholipase C (PLC) in cultured rat inner medullary collecting tubule (RIMCT) cells. ANP (10(-12)M) causes marked release of inositol trisphosphate (IP3) at a concentration that does not stimulate GC. Concentrations of ANP that stimulate GC (greater than or equal to 10(-10) M) result in attenuated IP3 release. Similarly, exogenous dibutyryl guanosine 3',5'-cyclic monophosphate (10(-6) M) markedly inhibits the response to 10(-10) M ANP. Inhibition of cyclic nucleotide-dependent protein kinase by H 8, but not inhibition of protein kinase C by H 7, restores the response to 10(-8) and 10(-6) M ANP. Therefore, activation of cyclic nucleotide-dependent protein kinase inhibits ANP-stimulated PLC activity. Activation of protein kinase C by phorbol 12-myristate-13-acetate (PMA) decreases ANP-stimulated IP3 production. Pretreatment with H 7, but not H 8, prevents inhibition by PMA. To explore a potential role for G proteins, we examined the effect of guanine nucleotide analogues on ANP-stimulated IP3 production in saponin-permeabilized cells. ANP-stimulated IP3 production is enhanced by GTP gamma S and is inhibited by GDP beta S. Similarly, preincubation with pertussis toxin prevents ANP-stimulated IP3 release. We conclude that ANP stimulates PLC in RIMCT cells via a pertussis toxin-sensitive G protein. Stimulation of PLC is inhibited on activation of either cyclic nucleotide or Ca2+-phospholipid dependent protein kinases.
Animals↗
Myo-inositol uptake by rat cultured inner medullary collecting tubule cells: effect of osmolality.
Myo-inositol (MI) is involved in the adaptation to hyperosmolality. Its uptake by rat inner medullary collecting duct (RIMCD) cells has not been studied. Compared with cells grown in isotonic media, those grown in hyperosmolality display marked enhancement in [3H]MI uptake [counts/min (cpm).microgram protein-1.2 h-1] from 217 +/- 23 to 718 +/- 64, P less than 0.001. This is mimicked by the supplementation with 300 mM mannitol (638 +/- 59, P less than 0.001) but not by 300 mM urea. The increment in [3H]MI is observed at 37 degrees C but not at 4 degrees C. MI uptake is Na+ dependent in cells grown both in hyperosmolal or isotonic media. At least 12 h of hyperosmolality are needed to enhance MI uptake, and reexposure to isotonic media for at least 24 h is required for the enhancement to reverse. The effects of the microtubular inhibitor, nocodazole (10 micrograms/ml), and the protein synthesis inhibitor, cycloheximide (30 micrograms/ml), were studied. Cells grown with nocodazole show unimpaired enhancement of MI uptake. Cycloheximide exposure (16 h) does not affect MI uptake in isotonic media (182 +/- 23 vs. 191 +/- 15), but inhibited enhanced MI uptake in hyperosmolality (822 +/- 53 in the absence vs. 331 +/- 24 in the presence of cycloheximide, P less than 0.001). We conclude that hyperosmolality stimulates the synthesis of a protein, most likely an Na-MI cotransporter, that markedly enhances MI uptake. This process may be critical to the osmoregulation of RIMCD cells.
Animals↗
Determinants of survival and recovery in acute renal failure patients dialyzed in intensive-care units.
The survival rate of critically ill patients who develop acute renal failure is extremely low, in spite of the sophisticated support systems, including dialysis. Therefore, it would be advantageous to identify, early in the disease course, those few survivors. We reviewed the clinical course of 43 consecutive critically ill patients who developed acute renal failure and were first dialyzed in an intensive-care unit setting to define comorbid conditions, present at the time of first dialysis, that were predictive of outcome. Mortality rate was 88%. Adult respiratory distress syndrome (p less than 0.05), requirement for antibiotics (p less than 0.01) and ventilatory failure (p less than 0.01) impacted negatively on recovery of renal function. The most powerful predictor of mortality was the need for ventilatory support (p less than 0.001). The presence of ventilatory failure at the initiation of dialysis predicted a 100% mortality (89-100%; 95% confidence limits). The initiation of dialysis in intensive-care unit patients with acute renal failure requiring ventilatory support did not alter the uniformly fatal outcome.
Acute Kidney Injury↗
Treating hyponatremia: what is all the controversy about?
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Animals↗
Altered water metabolism in tuberculosis: role of vasopressin.
PURPOSE: Patients with hyponatremia due to tuberculosis have shown variable responses to water loading in previous small studies, ranging from persistent antidiuresis to a normal diuresis. Although tuberculosis is considered a cause of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), circulating vasopressin has been documented in only a few cases. We studied a larger group of patients to determine whether it can be suppressed by a short-term reduction in osmolality. PATIENTS AND METHODS: Twenty-eight hyponatremic patients (mean age +/- SD: 40 +/- 10 years) with pulmonary or miliary tuberculosis underwent a clinical evaluation, measurement of blood and urine chemistry values, and (in 22) a water load of 20 mL/kg. Volume status was evaluated by urine sodium concentration, blood and urine urea nitrogen, and plasma renin activity. Endocrine, renal, and other recognized causes of SIADH were excluded. RESULTS: All 22 patients exhibited a decline in urine osmolality and an increase in free water clearance after water loading. Water excretion was fully normal in seven of 22, with the remainder showing variable impairment of diluting ability and/or volume excreted. Plasma vasopressin, measured in 11 of 22 patients as well as in six others not subjected to water loading, was detectable despite hypo-osmolality in 16 of 17. Vasopressin levels declined after water loading, from 1.85 +/- 1.32 to 0.77 +/- 0.25 pg/mL (p less than 0.05). The majority of patients had the euthyroid sick syndrome but normal adrenal responses to cosyntropin. Although several patients had mild volume depletion when studied, this factor did not appear to explain the defect in water excretion. Hyponatremia resolved predictably within days to weeks of antituberculous therapy. CONCLUSIONS: Circulating vasopressin remains detectable in hyponatremic patients with tuberculosis and is responsive to changes in osmolality. A downsetting of osmoregulation induced by active tuberculosis ("reset osmostat") could explain this abnormality, but we cannot exclude an unidentified non-osmotic stimulus that can be counteracted by water loading.
Adult↗
Effects of lithium on cAMP generation in cultured rat inner medullary collecting tubule cells.
The effects of lithium (Li) on the cAMP system in rat inner medullary collecting tubule cells were studied. While acute exposure to 5 mM Li was without effect, 10 mM, 25 mM and 50 mM Li significantly decreased AVP-stimulated cAMP formation. In contrast, cells grown in 5 mM Li for 72 hours which caused no morphologic changes enhanced cAMP formation (fmol/microgram protein) in response to both 10 nM AVP (114.5 +/- 9.2 vs. 71.6 +/- 7.4, P less than 0.005) and 100 nM AVP (182 +/- 14 vs. 120 +/- 8.3, P less than 0.001), N = 16. A similar enhancement was observed when cAMP formation was stimulated by a post-receptor agonist, cholera toxin. The role of eicosanoids was examined with 5 microM meclofenamate which reversed Li-enhanced cAMP formation in response to both AVP and cholera toxin. To define the eicosanoid responsible, cyclooxygenase products were measured. Prostaglandin E2 and thromboxane B2 synthesis were unchanged by Li, but the production of prostacyclin was significantly (P less than 0.02) increased. Prostacyclin (3 microM) mimicked the effect of Li to enhance the response to 10 nM AVP as cAMP levels increased from 100 +/- 11 to 173 +/- 13, P less than 0.05. The experiments suggest that acute exposure of Li at concentrations of 10 mM or greater inhibit cAMP formation but prolonged Li exposure enhances cAMP formation by increasing the formation of prostacyclin.
Animals↗