Association of marital status with access to renal transplantation.

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.

Bradykinin-stimulated electrolyte secretion in rabbit and guinea pig intestine. Involvement of arachidonic acid metabolites.

Bradykinin (BK) increases short-circuit current (Isc) when added to the serosal side of rabbit or guinea pig ileum or rabbit colon. Significant effects on Isc are seen at concentrations as low as 10(-10) M. Anion substitution experiments and unidirectional 36Cl flux measurements indicate that this effect of BK on Isc is due to Cl secretion. The effect of BK on Isc can be partially blocked (60-70% inhibition) by cyclooxygenase inhibitors (indomethacin and/or naproxen) and completely blocked by the phospholipase inhibitor, mepacrine. The combined cyclooxygenase/lipoxygenase inhibitors BW 755 and eicosa-5,8,11,14-tetraynoic acid (ETYA) also completely block the effect of BK on Isc but the slow-reacting substance of anaphylaxis (SRS-A) antagonist FPL 55712 has no effect. None of the above inhibitors diminish the effect on Isc of other exogenously added secretory stimuli such as vasoactive intestinal peptide (VIP), theophylline, or prostaglandin E2 (PGE2). Prior desensitization of rabbit ileum to PGE2 blocks the effect on Isc of BK but not those of VIP or theophylline. Conversely, prior desensitization of rabbit ileum to BK greatly reduces the effect of PGE2 on Isc. BK also stimulates the synthesis of PGE2 in rabbit ileal and colonic mucosa and this effect can be blocked by prior addition of either indomethacin or mepacrine. These effects of BK are similar to those of exogenously added arachidonic acid (AA). AA also stimulates Cl secretion and increases PGE2 synthesis and its effect on Isc can be inhibited by prior desensitization to PGE2 or by prior addition of indomethacin. The above results indicate that BK stimulates active Cl secretion in both small and large intestine and suggest that this effect is due to the intracellular release of AA. Although the prostaglandins appear to be the major products of AA metabolism contributing to the secretory response, lipoxygenase products may also play a role.

Control of hypertension and reversal of renal failure in undifferentiated connective tissue disease by enalapril.

Activation of the renin angiotensin system is important in the development of accelerated hypertension and progression to acute renal failure in scleroderma and undifferentiated connective tissue disease. Inhibition of angiotensin-converting enzyme activity may effectively control blood pressure and ameliorate renal insufficiency. To our knowledge, we describe the first reversal of dialysis-dependent renal insufficiency by enalapril maleate and recovery and maintenance of near-normal renal function in a patient suffering from undifferentiated connective tissue disease with sclerodermatous features. The pathophysiologic mechanisms and long-term treatment implications with angiotensin-converting enzyme inhibitors in this setting are discussed.

Chronologic aging alters the response to ultraviolet-induced inflammation in human skin.

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.

Phosphate homeostasis and hypophosphatemia.

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.

Prostaglandins and hypertension.

Generalized arteriolar vasoconstriction is the dominant element in essential hypertension. Although the proximate cause of this process remains elusive, several lines of evidence suggest that abnormalities in prostaglandin and thromboxane metabolism may contribute to the pathophysiology of hypertension. Diminished endogenous synthesis of vasodilator prostaglandins and enhanced formation of the vasoconstrictor thromboxane may participate in this process, particularly in the kidney. The use of nonsteroidal anti-inflammatory drugs, which inhibit prostaglandin synthesis, may aggravate blood pressure control, especially when used with certain diuretics and other antihypertensive medications. Attempts to enhance endogenous synthesis of prostaglandin metabolites expressing potent vasodilator properties by supplementation of the diet with polyunsaturated fatty acids may provide a new strategy to control blood pressure.

A defect in platelet aggregation in Bartter's syndrome.

A defect in both the first and second phase of platelet aggregation was found in four subjects with Bartter's syndrome, although template bleeding times were normal. The platelet abnormality was exacerbated by restriction of dietary sodium and lessened by the administration of inhibitors of prostaglandin synthesis. The aggregation defect was not found in other hypokalemic patients or in sodium-restricted normal control subjects. Platelet rich plasma from the subjects with Bartter's syndrome had an abnormally high content of cyclic adenosine 5'-monophosphate (AMP), which may have been responsible for the disordered platelet function. Plasma of these subjects induced both the high content of cyclic AMP and the aggregation defect in normal platelets, whereas suspension of the subjects' platelets in normal plasma improved their aggregation. These findings describe a unique defect of platelet aggregation in Bartter's syndrome, which may be associated with the altered prostaglandin metabolism found in this condition.

Islet cell transplantation tolerance.

Curative islet transplantation for type 1 diabetes currently requires lifelong systemic immunosuppression. Induction of islet transplantation tolerance would be far preferable. We have previously demonstrated that blockade of costimulation by the administration of a donor-specific transfusion in combination with anti-CD154 monoclonal antibody leads to permanent islet and prolonged skin allograft survival in mice. The protocol requires the presence of CD4+ T cells, interferon-gamma, and CTLA4, and involves the deletion of CD8+ alloreactive T cells. Translation of this strategy into clinical practice will, however, require attention to at least two issues. First, we have observed that the presence of viral infection during tolerance interferes with tolerance induction. Second, we have observed that our tolerance induction protocol is ineffective in autoimmune nonobese diabetic mice. We hypothesize that resistance to tolerance induction in nonobese diabetic mice is due to the presence of memory autoreactive cells. To overcome the deleterious effects of viral infection and of primed memory responses, it may be necessary to modify current tolerance induction strategies based on costimulatory blockade. These modifications may require patient isolation, the generation of hematopoietic chimerism, or treatments that target the specific T-cell populations, cytokines, and/or costimulatory factors responsible for resistance. Such modifications may make it possible to extend tolerance induction to the "real world" situation of individuals with type 1 diabetes who are likely to harbor both memory allo-and autoreactive immune cells.

Immunohistochemical evidence for neural mediation of VIP activity in the dogfish rectal gland.

Vasoactive intestinal peptide (VIP) has been shown to increase chloride secretion from the rectal gland of the spiny dogfish, Squalus acanthias. Immunohistochemistry was used to localize the distribution of immunoreactive VIP (iVIP). Rectal glands were perfused with either buffered acrolein or paraformaldehyde/glutaraldehyde, sectioned (20 micron) and processed by either avidin-biotin complex (ABC) or peroxidase anti-peroxidase (PAP) methods. At the light microscopic level, iVIP was observed in thick fibers which traversed the fibromembranous capsule of the rectal gland. In the parenchyma, smaller iVIP-containing fibers were noted within connective tissue and in close approximation to tubule cells. At the ultrastructural level, iVIP axons in the fibromembranous capsule were unmyelinated. Immunoreactive fibers within the parenchyma frequently terminated on the basal side of tubule cells. Within the glands, iVIP bouton terminals were observed and contained vesicles of different sizes, with reaction product in dense core vesicles (60-120 nm). We conclude that iVIP is distributed in nerve fibers throughout the dogfish rectal gland. The anatomic distribution suggests that VIP may act as a neurotransmitter in this model of chloride ion transport.

Evidence that circulating 6keto prostaglandin E1 causes the platelet defect of Bartter's syndrome.

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.

Predictors of liver donation without kidney recovery in a cohort of expanded criteria donors: identifying opportunities to improve expanded criteria donor kidney utilization.

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.

Prostaglandin synthesis is independent of androgen levels in rat male genitalia.

We examined the hypothesis that androgens influence prostaglandin (PG) biosynthesis in rat male genitalia. Prostaglandin synthesis was measured on the basis of the amount of prostaglandin released per unit weight of tissue over time. On this basis, castration increased the synthesis rate of radioimmunoassayable PGE2 from 1.3 +/- 2.5 to 7.4 +/- 2.5 ng/mg protein/180 min (P less than 0.01) in slices of prostate gland, and from 8.5 +/- 1.5 to 24.9 +/- 4.1 ng/mg protein/180 min (P less than 0.01) in slices of seminal vesicle, but decreased PGE2 formation from 27.8 +/- 2.0 to 14.3 +/- 1.2 ng/mg protein/180 min (P less than 0.01) in the vas deferens. Castration had no effect on synthesis of PGE2 in slices of renal cortex or liver. The peak effect of castration for each tissue was variable, ranging from 4 to 14 days. Treatment of castrated animals with testosterone reversed the effect of castration on prostatic prostaglandin biosynthesis: control 1.62 +/- 0.26 ng/mg protein/180 min, castrate 6.05 +/- 1.10 ng/mg protein/180 min, and castrate treated with testosterone T 1.72 +/- 0.16 ng/mg protein/180 min. Testosterone administration also decreased PGE2 formation in normal (noncastrate) animals from 1.62 +/- 0.26 to 0.91 +/- 0.23 ng/mg protein/180 min (P less than 0.04). Similar patterns of stimulation or reduction in biosynthesis of PGF2 alpha and 6-keto-PGF1 alpha were also observed. When considered for the whole gland and not per slice, all the differences disappeared. These results demonstrate that the androgenic effect on the male genitalia occurs in a component of the gland that is unrelated to the production of prostaglandins and that prostaglandin synthesis is maintained despite the occurrence of widespread atrophy.

Direct hemodynamic effect of insulin in the isolated perfused kidney.

The hemodynamic effect of insulin was examined in isolated perfused kidneys. Experiments were designed to study the effect of the hormone on basal hemodynamics and in the presence of angiotensin II (ANG II). Physiological insulin concentrations caused both renal vasodilation and increased glomerular filtration rate (GFR) during basal perfusion periods and attenuated the vasoconstrictor action of ANG II while limiting the ANG II-induced reduction of GFR. Insulin also increased fractional sodium reabsorption and diminished the natriuretic effect of ANG II. The addition of insulin to perfusions in which ANG II was infused from the start caused renal vasodilation, although supraphysiological concentrations were required. Kidneys perfused with hyperoncotic albumin to prevent filtration similarly demonstrated a vasodilatory effect of insulin that did not require glomerular filtration. Inhibition of prostaglandin (PG) synthesis with indomethacin prevented the vasodilatory effects of insulin. These data support the hypothesis that insulin causes renal vasodilation by a PG-dependent process.

Role of prostaglandins and calcium in the effects of Entamoeba histolytica on colonic electrolyte transport.

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 E2 (10(-5) M), indomethacin (10(-6) M), piroxicam (5 x 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 E2 as measured by sensitive radioimmunoassay. Amebic lysates stimulated prostaglandin E2 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 E2, 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 E2 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.