Search

We report two cases of successful renal transplantation with allografts from donors who suffered anoxic brain injury as the primary cause of death from house fires. Each was treated prophylactically with hydroxocobalamin (Cyanokit) for suspected cyanide toxicity. During organ procurement, gross examination was notable for deep discoloration of the parenchymal tissues. Approximately 6 and 18 months after transplantation, both recipients have excellent renal graft function and remain independent from hemodialysis (HD). Hydroxocobalamin is the antidote for suspected acute cyanide toxicity. While largely tolerated by the recipient, there is concern over the potential functional implications of the associated side effects of dramatic tissue discoloration and development of oxalate crystals. Furthermore, difficulties performing hemodialysis in patients treated with hydroxocobalamin have been reported due to discoloration of the effluent fluid impacting the colorimetric sensor, causing false alarms and repetitive interruptions. As such, many transplant centers in the United States (US) continue to reject these organs. We seek to highlight two cases of successful transplantation following donor administration of hydroxocobalamin (Cyanokit) and present the first documented case of successful perioperative intermittent hemodialysis following transplantation of an allograft exposed to hydroxocobalamin. Furthermore, we emphasize the importance of optimal organ utilization and caution against unnecessary refusal.

Background We sought to develop an improved 12 lead ECG model to diagnose hyperkalemia by use of traditional and novel parameters. Methods We retrospectively analyzed ECGs in consecutive hyperkalemic patients (serum potassium (K) > 5.3 mEq/L) by blinded investigators with normokalemic ECGs as internal controls. Potassium levels were modeled using general linear mixed models followed by refit with standardized variables. Optimum sensitivity and specificity were determined using cut point analysis of ROC-AUC. Results The training set included 236 ECGs (84 patients) and validation set 97 ECGs (23 patients). Predicted K = (5.2354) + (0.03434*descending T slope) + (−0.2329*T width) + (−0.9652*reciprocal of new QRS width > 100 msec). ROC-AUC in the validation set was 0.78 (95% CI 0.69–0.88). Maximum specificity of the model was 84% for K > 5.91 with sensitivity of 63%. Conclusion ECG model incorporating T-wave width, descending T-wave slope and new QRS prolongation improved hyperkalemia diagnosis over traditional ECG analysis.

Background: The impact of an episode of hyperkalemia on long term mortality is not well studied. Such a study is vital for development of a utilization strategy for new drugs for the treatment of hyperkalemia. To study the long term impact of hyperkalemia on mortality, we conducted a retrospective, observational casecontrol study in a tertiary care emergency department. We compared cases of non-hemolyzed serum potassium >5.3 mEq/L with normokalemic controls. Allcause mortality and causes of death were determined from social security death index, national death index, and medical record review over a follow-up period of 490 patient years. Methods and Findings: A total of 287 consecutive subjects (223 cases, 64 controls) were identified among 14,483 patients. Cox proportional hazard regression showed that for each 1 mEq/L increase in admit potassium, all-cause mortality Hazard Ratio was 1.54, 95% Confidence Interval: 1.22-1.96. Subgroup analyses showed higher mortality in acute kidney injury and heart failure patients. Conclusion: Hyperkalemia predicted all-cause mortality, when adjusted for age, sex, Charlson comorbidity index, and significant covariates (heart failure and end stage renal disease). The deleterious effect of admit hyperkalemia persisted in survivors from index episode throughout the study period. Cardiovascular mortality was statistically more prevalent. Future studies are needed for risk stratification strategies and mortality impact of newer drugs.

Kidney transplantation from live donors achieves an excellent outcome regardless of human leukocyte antigen (HLA) mismatch. This development has expanded the opportunity of kidney transplantation from unrelated live donors. Nevertheless, the hazard of hyperacute rejection has usually precluded the transplantation of a kidney from a live donor to a potential recipient who is incompatible by ABO blood type or HLA antibody crossmatch reactivity. Region 1 of the United Network for Organ Sharing (UNOS) has devised an alternative system of kidney transplantation that would enable either a simultaneous exchange between live donors (a paired exchange), or a live donor/deceased donor exchange to incompatible recipients who are waiting on the list (a live donor/list exchange). This Regional system of exchange has derived the benefit of live donation, avoided the risk of ABO or crossmatch incompatibility, and yielded an additional donor source for patients awaiting a deceased donor kidney. Despite the initial disadvantage to the list of patients awaiting an O blood type kidney, as every paired exchange transplant removes a patient from the waiting list, it also avoids the incompatible recipient from eventually having to go on the list. Thus, this approach also increases access to deceased donor kidneys for the remaining candidates on the list.

n/a

The updated data on 61 consecutive cadaveric transplants performed at our institution from 1987 to 1990 (followup 31 to 82 months, median 54 months) were analyzed with emphasis on cyclosporine monitoring and long-term results. All patients received triple therapy with cyclosporine induction, azathioprine and prednisone regardless of graft function, and they were preferentially placed on the calcium blocker nifedipine. We monitored 12-hour cyclosporine trough levels in whole blood using high performance liquid chromatography and the dose was adjusted to maintain levels at 150 ng./ml. or greater for the first 3 months. In 17 of 61 patients (28 percent) 22 rejection episodes occurred and 20 nephrotoxicity episodes occurred in 17 of 61 patients (28 percent). There was no significant difference in the mean cyclosporine levels among 32 rejection, nonrejection, nephrotoxic and nonnephrotoxic cases at any interval. Rejection occurred by 1 month in 13 (76 percent) and by 3 months in 15 (88 percent) of 17 p...

To maximize deceased donation, it is necessary to facilitate organ recovery from expanded criteria donors (ECDs). Utilization of donors meeting the kidney definition for ECDs increases access to kidney transplantation and reduces waiting times; however, ECDs often do not proceed to kidney recovery. Based on a prospective study of three Organ Procurement Organizations in the United States, we describe the characteristics of donors meeting the Organ Procurement and Transplant Network (OPTN) ECD kidney definition (donor age 60+ or donor age 50-60 years with two of the following: final serum creatinine > 1.5 mg/dL, history of hypertension, or death from cerebral vascular accident) who donated a liver without kidney recovery. ECDs with organs recovered between February 2003 and September 2005 by New England Organ Bank, Gift of Life Michigan, and LifeChoice Donor Services were studied (n = 324). All donors were declared dead by neurological criteria. Data on a wide range of donor characteristics were collected, including donor demographics, medical history, cause of death, donor status during hospitalization, serological status, and donor kidney quality. Logistic regression models were used to identify donor characteristics predictive of liver-alone donation. Seventy-four of the 324 donors fulfilling the ECD definition for kidneys donated a liver alone (23%). History of diabetes, final serum creatinine > 1.5 mg/dL, age 70+, and presence of proteinuria were associated with liver-alone donation in univariate models. On multivariate analysis, only final serum creatinine > 1.5 mg/dL and age 70+ were independently predictive of liver donation alone. Older age and elevated serum creatinine may be perceived as stronger contraindications to kidney donation than the remaining elements of the ECD definition. It is likely that at least a proportion of these liver-alone donors represent missed opportunities for kidney transplantation.

High risk renal transplant recipients experience excess graft loss despite overall improvements in the results of cadaveric renal transplantation. We evaluated a novel immunosuppression regimen consisting of simultaneous administration of OKT3, cyclosporine, azathioprine and prednisone. Of the 12 high risk patients studied 5 received 2 transplants, 1 received 3 transplants and 8 had peak panel reactive antibodies of greater than 60%. The protocol consisted of cyclosporine (7 mg./kg. orally or 3 mg./kg. intravenously per day) starting from the day of transplant regardless of graft function; 5 mg. OKT3 per day for 10 to 14 days starting intraoperatively; 5 mg./kg. azathioprine per day for 2 days, then 1.5 mg./kg. per day and adjusted according to white blood cell counts, and prednisone taper at 2 to 0.4 mg./kg. per day on day 10. The dose of cyclosporine was increased to 14 mg./kg. per day orally when serum creatinine was less than 3 mg./dl. The cyclosporine whole blood levels (measured by high performance liquid chromatography) were maintained between 250 and 400 ng./ml. in the first 3 months. Followup evaluations ranged from 3 to 28 months (median 8.5). Seven patients (58.3%) had acute tubular necrosis and required dialysis support for 2 to 5 weeks. Six patients (including 5 with acute tubular necrosis) experienced 1 episode of acute rejection in the first 3 months (2 of these were due to accelerated vascular rejection). Two rejections responded to pulse steroid treatment, while 4 (including 2 with vascular rejection) were treated with antilymphoblast globulin rescue therapy for 10 to 14 days. Symptomatic cytomegalovirus pneumonia occurred in 3 patients (25%). There were no deaths or graft losses. No case of malignancy was observed to date. The serum creatinine is less than 2 mg./dl. in 9 patients, and 2.5 to 2.9 mg./dl. in the remaining 3. We conclude that simultaneous quadruple immunosuppressive regimen that includes induction cyclosporine and OKT3 is a highly effective therapy for high risk patients, yielding excellent short-term and intermediate success rates. Long-term results of this regimen, including neoplastic potentiation, cannot be addressed because of the limited followup of these patients.

A 51-year-old white woman 6 months status post cadaveric renal transplant developed a mild case of primary varicella-zoster (VZ). It is hypothesized that the limited nature of her illness was due to infection with vaccine-type VZ virus instead of wild-type VZ. Approximately 1 month prior, she had daily household contact with a child who had developed a rash after immunization with live attenuated varicella vaccine. This case highlights several important questions. Should special precautions be undertaken with renal transplant recipients naive to varicella infection after vaccination of household contacts? Should pretransplant immunization with varicella vaccine be performed routinely in naive patients? Should naive patients transplanted and maintained on immunosuppressive therapy be vaccinated? Until there are clinical trials to answer these questions, it may be instructive to consider the recommendations for pediatric and immunocompromised patients. © 2002 by the National Kidney Foundation, Inc.

In this report we evaluated the association of marital status with access to renal transplantation. We analyzed data from the USRDS. In patients with ESRD aged ≥27 (mean age of first marriage in the US), we analyzed the association of marital status with two outcomes: (1) likelihood of being placed on the waiting list for renal transplantation or first transplant, (2) likelihood of receiving kidney transplant in patients already listed. We analyzed marital status as a categorical variable: (1) not married (including never been married and widowed); (2) divorced or separated; and (3) currently married. Subgroups based on age, race, sex, donor type and diabetic status were also analyzed. After adjustments for the included independent variables and compared to individuals never married or widowed, those who were divorced/separated (HR 1.55, p < 0.001) and currently married (HR 1.54, p < 0.001) had a higher likelihood of being placed on the transplant waiting list. Once listed, married individuals had higher chances of getting transplanted as well (HR 1.28, p = 0.033). This trend was consistent in most of the subgroups studied. We demonstrated that being married is associated with better access to renal transplantation compared to those who were never married/widowed.

In order to assess the effects of age on blood pressure, pulse, and neurohumoral responses to hypotensive stress, we infused nitroprusside into healthy young and old men until mean arterial blood pressure was reduced 20% from basal. Elderly subjects were much more sensitive to nitroprusside. Pulse increases in response to this hypotensive stress were markedly reduced in the elderly, but renin, vasopressin, and norepinephrine responses were not different between young and old. We conclude that cardioacceleration, one of the primary defenses against hypotension, is impaired with age. However, neurohumoral responses to hypotension are intact in the elderly.

Bartter's syndrome is associated with activation of prostaglandin metabolism. In the present study we provide several lines of evidence that a circulating metabolite of prostacyclin, 6ketoPGE1 is responsible for a defect in platelet function present in patients with Bartter's syndrome. In platelet aggregometry studies, plasma from patients contained platelet inhibitory activity which was fully neutralized by coincubation with antibody directed against 6ketoPGE1. Fractionation of lipophilic extracts of plasma by high pressure liquid chromatography yielded a platelet inhibitory fraction which comigrated with authentic 6ketoPGE1 and was neutralized by anti 6ketoPGE1 antibody. Lastly, direct measure of the plasma concentration of 6ketoPGE1 by specific radioimmunoassay indicates a 2-fold increase in patients with Bartter's syndrome (133 +/- 9.1 vs 60.7 +/- 12.3 picograms/ml; p less than 025). These studies provide firm evidence that the platelet dysfunction present in patients with Bartter's syndrome is attributable to an increase in the plasma concentration of 6ketoPGE1. In addition, these data provide further evidence in support of the centrality of activation of prostaglandin metabolism in the pathophysiology of Bartter's syndrome.

We have previously shown that Entamoeba histolytica lysates contain the neurohormones serotonin, neurotensin, immunoreactive substance P, and probably acetylcholine, and that amebic lysates inhibit sodium and chloride absorption and stimulate chloride secretion in the rat descending colon as measured by the Ussing chamber-voltage clamp technique. We now demonstrate that these transport effects have both calcium-dependent and calcium-independent components. In addition, arachidonic acid metabolites of the cyclooxygenase pathway are probably involved in the Entamoeba histolytica -induced changes in colonic transport that are not dependent on Ca ++ entry. Prostaglandin E 2 (10 −5 M), indomethacin (10 −6 M), piroxicam (5 × 10 −5 M), and mepacrine (10 −4 M) partially inhibited the amebic lysate effect on active transport in the rat descending colon. In addition, verapamil (10 −4 M) partially inhibited the effect of amebic lysates. The effect of verapamil was additive with that of indomethacin, totally blocking the effect of amebic lysate on short-circuit current. However, amebic lysates do not contain prostaglandin E 2 as measured by sensitive radioimmunoassay. Amebic lysates stimulated prostaglandin E 2 release from rat colonic mucosal strips. Amebic lysate significantly increased colonic cyclic adenosine monophosphate content. Piroxicam inhibited the lysate-induced increase in colonic cyclic adenosine monophosphate content. These results indicate that although amebic lysate does not contain prostaglandin E 2 , it caused arachidonic acid metabolites to be produced by the cyclooxygenase pathway, and these are probably involved in the Entamoeba histolytica -induced changes in colonic transport. Neurohormones in Entamoeba histolytica may act directly on colonic tissue to stimulate intestinal secretion, probably via a Ca ++ -dependent mechanism that is blockable by verapamil, or indirectly via stimulation of prostaglandin E 2 generation and release from the rat colon via a cyclic adenosine monophosphate-dependent mechanism. These effects appear separate. The cyclic adenosine monophosphate-dependent secretion is the predominant mechanism in this model of colonic amebic diarrhea.

Post-transplantation bladder leak, a potentially serious complication, is traditionally managed by reexploration and closure, and may require percutaneous placement of a nephrostomy tube. We report intractable bladder leakage that persisted following reclosure in a patient who also had cyclosporine nephrotoxicity. The attendant oligoanuria obviated the need for nephrostomy drainage and allowed healing of the bladder leak. The patient subsequently recovered from cyclosporine injury and regained renal function.

The renal effects of nonsteroidal anti-inflammatory drugs are reviewed with special emphasis on the clinical, pathophysiologic, and risk factors for acute renal failure. Renal papillary necrosis and chronic renal insufficiency can occur with the prolonged use of these drugs, although the prevalence of this manifestation of nonsteroidal anti-inflammatory drug nephrotoxicity is unknown. Current recommendations based on a critical literature survey are provided, along with a list of suggested areas in which more research is needed.

Group I included 105 consecutive primary renal transplants prospectively followed using a triple protocol of MMF (1 gm P.O. BID), ME-CsA (8-12mg/kg per day) and prednisone taper (60mg to 30mg over eight days). These included 34 Cadaver donors (CAD)(32.4%), 20 living unrelated donors (LUD)(19%), and 51 living related donors (LRD)(48.6%) that included five HLA identical and 46 haplo-identical and non-identical grafts. Group II included 137 consecutive transplant recipients with similar pretransplant demographics; CAD: 60/137 (43.8%), LUD 5 10/137 (7.3%), LRD 5 67/137 (48.9%), that included 11 HLA identical, and 56 HLA haplo-identical or nonidentical grafts. The number of retransplants in Group I (MMF) was five (4.76%) and in Group II 5 seven (5.11%). CsA dosing was diligently applied according to CsA target trough levels as previously reported. All patients received anti-CMV prophylaxis using high dose Acyclovir 3200 mg/day for D1/R2 and D2/R1 and Ganciclovir if ATG or OKT3 were used for rejection treatment.

Prostaglandin E2 (PGE2) impairs the hydrosmotic effect of vasopressin in toad bladder and mammalian kidney. Because some studies in animals have suggested that potassium depletion enhances renal PGE2 production, the present study examined whether the renal concentrating defect of potassium depletion in humans is mediated by PGE2. Five normal volunteers were studied before and after moderate potassium depletion achieved by 10 days of dietary potassium restriction and administration of a polystyrene sulfonate potassium exchange resin (Kayexalate). Maximal urinary osmolality (Umax) decreased from 1,094 +/- 58 (mean +/- SEM) to 820 +/- 26 mmol/kg (mOsm/kg) (P less than 0.01) following potassium depletion, but urinary PGE2 excretion did not change (496 +/- 145 and 435 +/- 186 ng/d, respectively). Indomethacin suppressed PGE2 excretion significantly, but failed to increase Umax in either the normal or the potassium-depleted state (1,094 +/- 34 and 825 +/- 56 mmol/kg, respectively). It is concluded that the renal concentrating defect produced by moderate potassium restriction in humans is not mediated by PGE2.

NONSTEROIDAL antiinflammatory drugs (NSAIDs) have become an integral part of the therapy of rheumatologic disorders.1 The number of new agents available on the market has more than tripled in the p...

Renin release was measured in the isolated rat kidney perfused with a recirculating artificial medium containing bovine serum albumin at 6.7 g per 100 ml of 11 g per 100 ml. At the higher concentration of albumin, glomerular filtration ceased and the rate of renin release over 70 minutes of perfusion was increased 6-fold. The addition of ouabain to the perfusate containing 11 g per 100 ml inhibited the release of renin, suggesting that inhibition of Na-K-ATPase or the related changes in cellular volume or composition prevented renin release. Lowering the osmolality of the perfusate by reducing the concentration of sodium chloride also prevented the increase in renin secretion produced by perfusion with 11 g per 100 ml albumin. Increasing the osmolality of the perfusate with mannitol restored the augmented renin release. These results are consistent with the hypothesis that alterations in the volume of certain cells, perhaps in the juxtaglomerular apparatus itself, can control renin release.

Salt secretion by the isolated perfused rectal gland of the spiny dogfish shark, Squalus acanthias, is stimulated by synthetic rat atrial natriuretic peptide (ANP II) as well as extracts of shark heart, but not by 8-bromo-cyclic guanosine 5'-monophosphate. Cardiac peptides have no effect on isolated rectal gland cells or perfused tubules, suggesting that stimulation requires an intact gland. The stimulation of secretion by ANP II is eliminated by maneuvers that block neurotransmitter release. These include: perfusion with procaine (10(-2) M), perfusion with high Mg2+ (9.5 mM) and low Ca2+ (0.5 mM) concentrations, and addition to the perfusate of the calcium channel blockers nifedipine (10(-6)M), diltiazem (5 X 10(-5)M), or verapamil (10(-4)M). Cardiac peptides stimulate the release of vasoactive intestinal peptide (VIP), known to be present in rectal gland nerves, into the venous effluent or perfused glands in parallel with their stimulation of salt secretion, but the release of VIP induced by ANP II is prevented by perfusion with procaine. Cardiac peptides thus appear to regulate rectal gland secretion by releasing VIP from neural stores within the gland. It is possible that other physiological effects of these hormones might be explained by an action to enhance local release of neurotransmitters.

Prior in vivo studies have shown that indomethacin, which inhibits prostaglandin (PG) synthesis, affects fluid transport in the small bowel, enhancing spontaneous fluid absorption and reducing the amount of fluid that accumulates in response to cholera toxin and other secretory stimuli. To further explore the mechanisms involved, we determined the effects of indomethacin on ion transport, cAMP concentration, and PGE 2 production in rabbit ileal mucosa in vitro. Indomethacin (1 mM), when added alone, had no significant effect on short-circuit current (either basal or glucose-stimulated), Cl fluxes, or cAMP concentration. Indomethacin did, however, inhibit the ion transport changes caused by several secretagogues: Effects of theophylline, Ca-ionophore A23187, and arachidonate were reversibly inhibited by at least 65%, whereas effects of dibutyryl cAMP, 16,16-dimethyl PGE 2 , cholera toxin, and heat-stable Escherichia coli enterotoxin were inhibited by about 30%. Indomethacin also inhibited the theophylline-evoked increase in cAMP concentration. Indomethacin decreased PGE 2 production under basal conditions and in the presence of theophylline and A23187, which may partly explain the antisecretory action of the drug. Since arachidonate increased PGE 2 release from the mucosa more than 10-fold and indomethacin did not inhibit this effect, indomethacin at high concentration (0.5–1 mM) appears to also inhibit the action of intestinal secretagogues by a prostaglandin-independent mechanism. This study also demonstrates that the antisecretory effect of indomethacin is not simply due to stimulation of an unrelated absorptive process.

Secretion of chloride from blood to lumen is accomplished in the rectal gland of elasmobranchs by a process of secondary active transport involving the co-transport of Cl− with Na+ across the basolateral membranes of rectal gland cells. Energy is provided by ATP via membrane Na-K-ATPase, which establishes an electrochemical gradient favouring Na+ influx into the cell. The involvement of K+ in the co-transport mechanism, so as to provide a ratio of 1 Na+: 1 K+: 2 Cl− entering the cell, would increase the energetic efficiency of the process, and is consistent with the CI/O2 ratio of 27–30 observed in secreting rectal glands. Secretion is stimulated by cyclic AMP (cAMP) and by vasoactive intestinal peptide (VIP) and adenosine, which activate adenylate cyclase. Activation of the gland in vivo probably occurs via VIP-secreting nerves as well as circulating agents; it is inhibited by somatostatin. Cyclic AMP probably stimulates chloride secretion by at least three mechanisms: (1) increasing chloride conductance across the luminal cell membrane, (2) enhancing the co-transport pathway for transmembrane movements of Na+, K+ and Cl− and (3) activating Na-K-ATPase.

Prostaglandins (PG's) increase short-circuit current (Isc), inhibit NaCl absorption, and stimulate Cl secretion in rabbit ileum. These changes occur with the following PGs; E2, E1, nitrilo-I2 and, to a lesser extent, with A2, D2, and F2 alpha. Arachidonic acid (AA) also stimulates secretion. The PG- or AA-stimulated Isc does not persist, however, and on prolonged exposure tachyphylaxis develops. Resensitization of the Isc response to PGE2 is rapid, being essentially complete in 15 min after the PG is removed. Desensitization to AA is not reflected by diminished PG generation. PGE2 release from the mucosa after AA addition is constant, although the AA-stimulated Isc decreases. Isc measurements indicate that PGE2 at slightly below its EC50 partially desensitizes and a near-maximal concentration completely desensitizes to PGE2 but does not, however, inhibit the subsequent change in Isc caused by theophylline or vasoactive intestinal peptide (VIP). Adenosine 3',5'-cyclic monophosphate (cAMP) measurements suggest that desensitization applies to cAMP production. PGE2 (10(-5) M) increases mucosal cAMP three- to sevenfold, but this elevation is transient; a second challenge dose, which fails to elicit a Isc change, also fails to increase mucosal cAMP. Adenylate cyclase measurements from untreated and PGE2-treated enterocytes demonstrate a decrease in stimulation by PGE2 but not in stimulation by VIP, fluoride, or 5-guanylylimidodiphosphate.

The E prostaglandins (and to a lesser extent PGF 2α ) stimulate active electrolyte secretion in mammalian small intestine and colon. They do so by stimulating intestinal mucosal adenylate cyclase and thereby increasing cAMP concentration. The diarrheagenic action of the prostaglandins is seen as a side effect of their therapeutic use, in certain hormone-secreting tumors, and in inflammatory lesions of the bowel in which leukocyte infiltrates are the probable sources of prostaglandin excess. Prostaglandins are also normally synthesized by intestinal epithelial cells and appear to play an important role in the physiologic regulation of intestinal fluid transport. In recent in vitro studies, we have shown that addition of arachidonic acid ( K 1 2 ⋍ 10 −6 M ) also stimulates secretion, cAMP accumulation, and PGE 2 production in rabbit ileal mucosa. In the continued presence of arachidonate, tachyphylaxis develops: both secretory and cAMP responses have a half-life of about twenty minutes and subsequent additions of arachidonate produce little or no further response. In contrast, PGE 2 production continues undiminished. Similar tachyphylaxis develops when PGE 2 itself is added. Resensitization following removal of PGE 2 is rapid, 50% of the initial sensitivity being restored in 6–7 min. Prostaglandin desensitization has been noted in other cell systems and appears to be exerted on adenylate cyclase.

We measured the short-circuit current (Isc) across canine tracheal epithelium and the intracellular cAMP levels of the surface epithelial cells in the same tissues to assess the role of cAMP as a mediator of electrogenic Cl secretion. Secretogogues fall into three classes: (i) epinephrine, prostaglandin (PG) E1, and theophylline decrease both Isc and cellular cAMP levels; (ii) PGF2 alpha and calcium ionophore, A23187, increase Isc without affecting cell cAMP levels at the doses employed; and (iii) acetylcholine, histamine, and phenylephrine do not alter either Isc or cAMP levels. These findings indicate that: (i) increases in cAMP or Ca activity stimulate electrogenic Cl secretion by the columnar cells of the surface epithelium; (ii) cAMP mediates the effects of PGE1 and beta-adrenergic agonists; (iii) a strict correlation between cAMP levels and Cl secretion rate is not apparent from spontaneous variations in these parameters or from dose-response relations of Isc and cAMP to epinephrine concentration; and (iv) acetylcholine, histamine, and phenylephrine, agents that stimulate electrically-neutral NaCl secretion by submucosal glands, do not evoke cAMP-mediated responses by the surface epithelium. Addition of 10(-6) M indomethacin (or other prostaglandin synthesis inhibitors) to the mucosal solution decreases Isc and cellular cAMP levels and reduces the release of PGE2 into the bathing media by 80%. Indomethacin does not interfere with the subsequent secretory response to PGE1. This suggests that endogenous prostaglandin production underlies the spontaneous secretion of Cl across canine tracheal epithelium under basal conditions.

In order to determine the effect of age on the capacity of human skin to mount an inflammatory response, the sunburn reaction was studied quantitatively in 4 subjects aged 22-26 yr and 7 subjects aged 62-86 yr. Buttock skin of each subject was exposed to 3 time his minimal erythema dose, using the Hanovia mercury vapor lamp; 1 micrometer histologic sections and determinations of histamine and prostaglandin E2 (PGE2) from suction blister aspirates were used to monitor the reaction. Clinically, erythema and edema were less (p less than .05) in irradiated skin of the old subjects during the first 24 hr. Nonirradiated skin contained less histamine and PGE2 in old adults (p less than .05), approximately 50% of young adult levels. Histamine levels rose early in the reaction and returned to baseline by 24 hr; 4 hr peak values averaged 9.2 ng/ml in old vs. 18.3 ng/ml in young adults. PGE2 rose more slowly in blister aspirates from old adults (P less than .05), but reached comparable peaks, 6-9 pg/T.V., in both groups at 24 hr. Biopsies of control skin from old adult specimens contained fewer mast cells and venules (P less than .01). At 4 and 24 hr, old specimens revealed fewer sunburn cells and less striking alterations of perivenular mast cells and endothelial cells, but at 72 hr these changes were more prominent than in young adult specimens. The data suggest that with advancing age the sunburn reaction is quantitatively reduced and evolves more slowly following a standardize ultraviolet exposure.

A membrane fraction, rich in basal-lateral plasma membranes, was prepared from the rectal gland of the spiny dogfish,Squalus acanthias, and the uptake of22Na into the plasma membrane vesicles was investigated by a rapid filtration technique. Sodium uptake was greatest in the presence of a chloride gradient directed into the vesicles; it was strikingly reduced when chloride was replaced with nitrate and was even slower with gluconate. If the membrane vesicles were pre-equilibrated with potassium chloride or potassium nitrate plus valinomycin, to minimize any electrical driving forces on sodium movement, the uptake of sodium was still greatest in the presence of chloride and remarkably decreased in the presence of nitrate. Furosemide, 10−3 and 10−4 M, decreased sodium uptake into the vesicles in a dose dependent manner only in the presence of chloride. Furthermore, saturation of sodium uptake by increasing sodium chloride concentrations was observed. The above results provide direct evidence for a coupling of sodium and chloride fluxes across the plasma membrane of the rectal gland via a cotransport system sensitive to furosemide. They support the hypothesis that chloride secretion of the rectal gland is a secondary active transport and is driven by the sodium gradient across the basal-lateral membranes of the cell.

The clinical importance of an understanding of phosphate metabolism is derived from the crucial role of this anion in the regulation of many cellular functions. In recent years, a greater appreciation of disorders of phosphate metabolism has been recognized because of more frequent monitoring of serum phosphate concentration as well as the increased utilization of therapeutic interventions that profoundly affect overall phosphate balance. The present review focuses on the factors tha regulate phosphate homeostasis, explores the pathophysiology and manifestations of the phosphate depletion syndrome and provides a framework for the diagnosis and rational treatment of patients with abnormalities in phosphate metabolism.

The mechanisms by which endogenous renal prostaglandins regulate water excretion were investigated in these studies. Inhibition of prostaglandin synthesis slowed water diuresis in water-loaded unanesthetized Sprague-Dawley rats and in Brattleboro rats with hereditary diabetes insipidus owing to absence of endogenous vasopressin. In both strains, treatment with indomethacin or meclofenamate increased the osmolality of the renal papilla by raising sodium and urea content, and also increased the osmolality of the urine. Endogenous creatinine clearance and solute excretion were unchanged. The data are consistent with an effect of prostaglandins on solute transport by renal tubules and demonstrate that endogenous prostaglandins influence water excretion by a mechanism independent of the presence of antidiuretic hormone.

The isolated rectal gland of Squalus acanthias was stimulated to secrete chloride against an electrical and a chemical gradient when perfused in vitro by theophylline and/or dibutyryl cyclic AMP. Chloride secretion was depressed by ouabain which inhibits Na-K-ATPase. Thiocyanate and furosemide also inhibited chloride secretion but ethoxzolamide, a carbonic anhydrase inhibitor, did not. Chloride transport was highly dependent on sodium concentration in the perfusate. The intracellular concentration of chloride averaged 70-80 meq/liter in intact glands, exceeding the level expected at electrochemical equilibrium and suggesting active transport of chloride into the cell. These features suggest a tentative hypothesis for chloride secretion by the rectal gland in which the uphill transport of chloride into the cytoplasm is coupled through a membrane carrier to the downhill movement of sodium along its electrochemical gradient. The latter is maintained by the Na-K-ATPase pump while chloride is extruded into the duct by electrical forces.

Recent studies regarding the mechanism by which adrenal steroid hormones influence the transport and permeability effects of cyclic-AMP (c-AMP) in the toad urinary bladder are summarized. Aldosterone increases the sodium transport and the water-permeability response of the toad urinary bladder to antidiuretic hormone and to its intracellular mediator, c-AMP. This action of the steroid appears to involve inhibition of the degradation of c-AMP. In response to vasopressin, or to theophylline, c-AMP levels are higher in aldosterone-treated tissue; and the activity of cyclic nucleotide phosphodiesterase—the enzyme that catalyzes the degradation of c-AMP—is depressed.

Vasopressin and theophylline both increase the content of adenosine 3′:5′-cyclic monophosphate (cAMP) in epithelial cells of the urinary bladder of toads ( Bufo marinus ). Incubation of the tissue with 0.2 μM aldosterone markedly increases this response to the two agents; incubation for a similar time without steroid reduces the response. The permeability responses (sodium transport and water flow) of the intact tissue to vasopressin, theophylline, and exogenous cAMP are also considerably greater in bladders incubated with aldosterone than without. The results are interpreted as indicating that the foregoing permissive effects of aldosterone on the permeability responses to vasopressin and theophylline are mediated by a steroid-dependent increase in the accumulation of cAMP in the pertinent epithelial cells, probably as a consequence of a diminution in the rate of degradation of the intracellular nucleotide.

Cyclic AMP phosphodiesterase activity was assayed in the 700 xg supernatant solution of homogenates of epithelial cells scraped from toad urinary bladders. The activity of the enzyme was lower in cells obtained from bladders incubated with aldosterone for 24 hours than in cells from paired tissue incubated without aldosterone. This difference may well account for the permissive effect of aldosterone on the physiologic and biochemical responses of the toad bladder to vasopressin.