Donal J. Sexton

Functional effects of 17alpha-hydroxyprogesterone caproate (17P) on human myometrial contractility in vitro.

Background17alpha-hydroxyprogesterone caproate (17P) administration reportedly improves outcome for women with a previous spontaneous preterm delivery. This study, using in vitro strips of human uterine smooth muscle, aimed to investigate the direct non-genomic effects of 17P on spontaneous and induced contractions in tissues obtained during pregnancy, and in the non-pregnant state.MethodsBiopsies of human myometrium were obtained at elective cesarean section, and from hysterectomy specimens, and dissected strips suspended for isometric recordings. The effects of 17P (1 nmol/L -10 micro mol/L) on spontaneous and agonist-induced (oxytocin 0.5 nmol/L for pregnant, phenylephrine 10 μmol/L for non-pregnant) contractions were measured. Integrals of contractile activity, including the mean maximal inhibition values (MMI) observed at the maximal concentration, were compared with those from simultaneously run control strips.ResultsThere was no significant direct effect exerted by 17P on pregnant or non-pregnant human myometrial contractility. The MMI ± SEM for spontaneous contractions in pregnant myometrium was 4.9% ± 7.2 (n = 6; P = 0.309) and for oxytocin-induced contractions was 2.2% ± 1.3 (n = 6; P = 0.128). For non-pregnant myometrium, the MMI ± SEM for spontaneous contractions was 8.8% ± 11.0 (n = 6; P = 0.121) and for phenylephrine induced contractions was -7.9% ± 6.5 (n = 6; P = 0.966).ConclusionsThe putative benefits of 17P for preterm labor prevention are not achieved, even partially, by a direct utero-relaxant effect. These findings outline the possibility that genomic effects of 17P, achieved over long periods of administration, are required for its reported therapeutic benefits.

ESRD From Lupus Nephritis in the United States, 1995–2010

BACKGROUND AND OBJECTIVESnWhile ESRD from lupus nephritis (ESLN) increased in the United States after the mid-1990s and racial disparities were apparent, current trends are unknown.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnRetrospective US Renal Data System data (n=1,557,117) were used to calculate standardized incidence ratios (standardized to 1995-1996) and outcomes of ESLN (n=16,649). For events occurring after initiation of RRT, follow-up ended on June 30, 2011.nnnRESULTSnOverall ESLN rates (95% confidence intervals [95% CIs]) in 1995-1996 were 3.1 (2.9 to 3.2) cases per million per year. Rates were higher for subgroups characterized by African-American race (11.1 [95% CI, 10.3 to 11.9]); other race (4.9 [95% CI, 4.0 to 5.8]); female sex (4.9 [95% CI, 4.6 to 5.2]); and ages 20-29 years (4.9 [95% CI, 4.4 to 5.4]), 30-44 years (4.6 [95% CI, 4.2 to 5.0]), and 45-64 years (4.0 [95% CI, 3.7 to 4.4]). Standardized incidence ratios for the overall population in subsequent biennia were 1.19 (1.14 to 1.24) in 1997-1998, 1.17 (1.12 to 1.22) in 1999-2000, 1.17 (1.12 to 1.22) in 2001-2002, 1.21 (1.16 to 1.26) in 2003-2004, 1.18 (1.13 to 1.23) in 2005-2006, 1.16 (1.11 to 1.21) in 2007-2008, and 1.05 (1.01 to 1.09) in 2009-2010, respectively. During a median (interquartile range) follow-up of 4.4 (6.3) years, 42.6% of patients with ESLN died, 45.3% were listed for renal transplant, and 28.7% underwent transplantation. Patients with ESLN were more likely than matched controls to be listed for and to undergo transplantation, and mortality rates were similar. Among patients with ESLN, African Americans were less likely to undergo transplantation (adjusted hazard ratio, 0.54 [0.51 to 0.58]) and more likely to die prematurely (adjusted hazard ratio, 1.23 [1.17 to 1.30]).nnnCONCLUSIONSnWhile ESLN appears to have stopped increasing in the last decade, racial disparities in outcomes persist.

ESRD From Autosomal Dominant Polycystic Kidney Disease in the United States, 2001-2010

BACKGROUNDnAutosomal dominant polycystic kidney disease (ADPKD) is amenable to early detection and specialty care. Thus, while important to patients with the condition, end-stage renal disease (ESRD) from ADPKD also may be an indicator of the overall state of nephrology care.nnnSTUDY DESIGNnRetrospective cohort study of temporal trends in ESRD from ADPKD and pre-renal replacement therapy (RRT) nephrologist care, 2001-2010 (n = 23,772).nnnSETTING & PARTICIPANTSnUS patients who initiated maintenance RRT from 2001 through 2010 (n = 1,069,343) from US Renal Data System data.nnnPREDICTORnESRD from ADPKD versus from other causes for baseline characteristics and clinical outcomes; interval 2001-2005 versus 2006-2010 for comparisons of cohort of patients with ESRD from ADPKD.nnnOUTCOMESnDeath, wait-listing for kidney transplant, kidney transplantation.nnnMEASUREMENTSnUS census data were used as population denominators. Poisson distribution was used to compute incidence rates (IRs). Incidence ratios were standardized to rates in 2001-2002 for age, sex, and race/ethnicity. Patients with and without ADPKD were matched to compare clinical outcomes. Poisson regression was used to calculate IRs and adjusted HRs for clinical events after inception of RRT.nnnRESULTSnGeneral population incidence ratios in 2009-2010 were unchanged from 2001-2002 (incidence ratio, 1.02). Of patients with ADPKD, 48.1% received more than 12 months of nephrology care before RRT; preemptive transplantation was the initial RRT in 14.3% and fistula was the initial hemodialysis access in 35.8%. During 4.9 years of follow-up, patients with ADPKD were more likely to be listed for transplantation (IR, 11.7 [95% CI, 11.5-12.0] vs 8.4 [95% CI, 8.2-8.7] per 100 person-years) and to undergo transplantation (IR, 9.8 [95% CI, 9.5-10.0] vs 4.8 [95% CI, 4.7-5.0] per 100 person-years) and less likely to die (IR, 5.6 [95% CI, 5.4-5.7] vs 15.5 [95% CI, 15.3-15.8] per 100 person-years) than matched controls without ADPKD.nnnLIMITATIONSnRetrospective nonexperimental registry-based study of associations; cause-and-effect relationships cannot be determined.nnnCONCLUSIONSnAlthough outcomes on dialysis therapy are better for patients with ADPKD than for those without ADPKD, access to predialysis nephrology care and nondeclining ESRD rates may be a cause for concern.

Expression levels of mRNA for Rho A/Rho kinase and its role in isoprostane-induced vasoconstriction of human placental and maternal vessels.

Preeclampsia is characterized by intense and prolonged vasoconstriction. Rho A—mediated calcium sensitization is central to prolonged contractility of vascular smooth muscle. The aims of this study are (1) to investigate mRNA expression levels of Rho A/Rho kinases in placental tissues from normotensive and preeclamptic women and (2) to investigate the effects of 2 isoprostanes, 8-iso prostaglandin F2 α (8-iso PGF 2α ) and 8-iso prostaglandin E2 (8-iso PGE2), on small placental and myometrial vessel resistance and to determine if their effects were mediated via the Rho kinase pathway. Real-time reverse transcription polymerase chain reaction for Rho A, ROCK I, and ROCK II was performed on total RNA from normotensive and preeclamptic placentae. The effects of 8- iso PGF 2α and 8-iso PGE2 (alone and with the specific Rho kinase inhibitor Y-27632) on placental and myometrial vessels (<400 µm) were measured and compared with control recordings. Rho A mRNA expression levels were significantly higher in placentae from preeclamptic women than in placentae from normotensive women (P < .01). There was no significant difference in expression levels of ROCK I and ROCK II between both tissue types (P > .05). Both isoprostanes exerted a significant concentration-dependent vasocontractile effect on both vessel types (P < .001). This effect was antagonized by Y-27632 in placental arteries but not in myometrial arteries. Increased Rho A mRNA expression in placentae from preeclamptic women is suggestive of a role for the Rho kinase pathway in the modulation of the placental vasculature in this condition. Isoprostanes exert their vasocontractile effect, in placental vasculature, in part via the Rho kinase pathway.

Injurious Falls and Syncope in Older Community-Dwelling Adults Meeting Inclusion Criteria for SPRINT

Injurious Falls and Syncope in Older Community-Dwelling Adults Meeting Inclusion Criteria for SPRINT The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that treating adults 75 years of age or older with hypertension to reach a systolic blood pressure target of less than 120 mm Hg compared with a systolic blood pressure target of less than 140 mm Hg reduced the numbers of cardiovascular events and death without a significant increase in the number of injurious falls or syncope.1 However, prior to the adoption of an intensive strategy to lower systolic blood pressure in the oldest segment of the population, it is prudent to determine if individuals meeting inclusion criteria for SPRINT outside the clinical trial context are similar to trial participants, especially with regard to risk for adverse outcomes. We used The Irish Longitudinal Study on Ageing2,3 (TILDA) to compare baseline rates of injurious falls and syncope in community-dwelling older adults with the rates in the standard care group of SPRINT.

Radiological remission and recovery of thirst appreciation after infliximab therapy in adipsic diabetes insipidus secondary to neurosarcoidosis

BACKGROUNDnNeurosarcoidosis is a rare and aggressive variant of systemic sarcoidosis which may result in hypothalamic-pituitary dysfunction. We report a case of hypothalamic hypopituitarism secondary to neurosarcoidosis complicated by adipsic diabetes insipidus (ADI). Initiation of anti-tumour necrosis factor-α (TNF-α) therapy resulted in both radiological disease remission and recovery of osmoregulated thirst appreciation after 3 months.nnnCASE SUMMARYnA 22-year-old man was referred to the endocrinology service with profound weight gain, polyuria and lethargy. Biochemical testing confirmed anterior hypopituitarism while posterior pituitary failure was confirmed by hypotonic polyuria responding to desmopressin. Magnetic resonance imaging (MRI) demonstrated extensive hypothalamic infiltration; neurosarcoidosis was confirmed histologically after excisional cervical lymph node biopsy. Osmoregulated thirst appreciation was normal early in the disease course despite severe hypotonic polyuria. However, subsequent subjective loss of thirst appreciation and development of severe hypernatraemia in the setting of normal cognitive function indicated onset of ADI.nnnMANAGEMENTnClinical management involved daily weighing, regular plasma sodium measurement, fixed daily fluid intake and oral desmopressin. We initiated immunosuppressive therapy with pulsed intravenous anti-TNF-α therapy (infliximab) after multidisciplinary team consultation.nnnOUTCOMEnInfliximab therapy resulted in successful radiological disease remission and complete recovery of osmoregulated thirst appreciation. This was confirmed by subjective return of thirst response and maintenance of plasma sodium in the normal range in the absence of close biochemical monitoring.

ESRD due to Multiple Myeloma in the United States, 2001–2010

Although management of multiple myeloma has changed substantially in the last decade, it is unknown whether the burden of ESRD due to multiple myeloma has changed, or whether survival of patients with multiple myeloma on RRT has improved. Regarding ESRD due to multiple myeloma necessitating RRT in the United States, we evaluated temporal trends between 2001 and 2010 for demography-adjusted incidence ratios, relative to rates in 2001-2002, and mortality hazards from RRT initiation, relative to hazards in 2001-2002. In this retrospective cohort study, we used the US Renal Data System database (n=1,069,343), 2001-2010, to identify patients with ESRD due to multiple myeloma treated with RRT (n=12,703). Demography-adjusted incidence ratios of ESRD from multiple myeloma decreased between 2001-2002 and 2009-2010 in the overall population (demography-adjusted incidence ratio 0.82; 95% confidence interval, 0.79 to 0.86) and in most demographic subgroups examined. Mortality rates were 86.7, 41.4, and 34.4 per 100 person-years in the first 3 years of RRT, respectively, compared with 32.3, 20.6, and 21.3 in matched controls without multiple myeloma. Unadjusted mortality hazards ratios declined monotonically after 2004 to a value of 0.72; 95% confidence interval, 0.67 to 0.77 in 2009-2010, and declines between 2001-2002 and 2008-2009 were observed (P<0.05) in most demographic subgroups examined. Findings were similar when adjustment was made for demographic characteristics, comorbidity markers, and laboratory test values. These data suggest the incidence of RRT from multiple myeloma in the United States has decreased in the last decade, and clinically meaningful increases in survival have occurred for these patients.

THG113.31, a specific PGF2alpha receptor antagonist, induces human myometrial relaxation and BKCa channel activation

BackgroundPGF2alpha exerts a significant contractile effect on myometrium and is central to human labour. THG113.31, a specific non-competitive PGF2alpha receptor (FP) antagonist, exerts an inhibitory effect on myometrial contractility. The BKCa channel is ubiquitously encountered in human uterine tissue and plays a significant role in modulating myometrial cell membrane potential and excitability. The objective of this study was to investigate potential BKCa channel involvement in the response of human myometrium to THG113.31.MethodsSingle and whole-cell electrophysiological BKCa channel recordings from freshly dispersed myocytes, were investigated in the presence and absence of THG113.31. Functional studies investigated the effects of THG113.31 on isolated spontaneous myometrial contractions, in the presence and absence of the BKCa channel blocker, iberiotoxin.ResultsSingle channel recordings identified the BKCa channel as a target of THG113.31. THG113.31 significantly increased the open state probability of these channels [control 0.023+/-0.006; 10 microM THG113.31 0.087+/-0.012 (P = 0.009); and 50 microM THG113.31 0.1356+/-0.018 (P = 0.001)]. In addition, THG113.31 increased whole-cell BKCa currents over a range of membrane potentials, and this effect was reversed by 100 nanoM IbTX. Isometric tension studies demonstrated that THG113.31 exerted a significant concentration-dependent relaxant effect on human myometrial tissue and pre-incubation of strips with IbTX abolished this effect on spontaneously occurring contractions.ConclusionThese data suggests that activation of the BKCa channel may contribute, at least partially, to the uterorelaxant effect of THG113.31.

Do patient-reported measures of symptoms and health status predict mortality in hemodialysis? An assessment of POS-S Renal and EQ-5D

Introduction Experience with the use of patient‐reported outcome measures such as EQ‐5D and the symptom module of the Palliative care Outcome Scale—Renal Version (POS‐S Renal) as mortality prediction tools in hemodialysis is limited.

Serum phosphate varies with degree of proteinuria in nephrotic syndrome and is associated with elevated pulse wave velocity.

BACKGROUNDnThe occurrence of vascular stiffness in the setting of the nephrotic syndrome and the influence of serum phosphate on this association is unknown.nnnMETHODSnA retrospective study of 42 prevalent, adult nephrotic patients who underwent carotid-femoral pulse wave velocity (PWV) measurement, a median of 24 months after kidney biopsy. Elevated PWV was determined using published age-specific reference ranges. The association, statistical significance and independence of serum phosphate with spot urine protein-creatinine ratio (PCR) and the association of phosphate with PWV was examined.nnnRESULTSnMean PCR was 5.5 g/g and mean eGFR (CKD-EPI) was 70 mL/min/1.73 m2. Serum phosphate was statistically significantly associated with severity of nephrotic syndrome independently of eGFR and age. Median (intra-quartile range) PWV was 7 m/s (4-11), with a linear trend for higher PWV across tertile of average serum phosphate over follow-up, P<.001. Twenty subjects (48%) had elevated age-specific PWV, which on logistic regression was statistically significantly associated with mean serum phosphate, OR (95% CI) per 0.1 mmol/L: 2.7 (1.5, 4.9), P = .001, which in separate analyses was independent of eGFR and other laboratory data.nnnCONCLUSIONSnIn this cohort of patients with the nephrotic syndrome serum phosphate was commonly elevated, despite well preserved eGFR, which was significantly and independently associated with elevated PWV over follow-up.