Clara Day

Patients with Wegener's granulomatosis demonstrate a relative deficiency and functional impairment of T-regulatory cells.

An increased proportion of CD4+ CD25+ T cells has been reported in Wegener’s granulomatosis (WG) and may represent an accumulation of regulatory T cells (Treg). CD25 is also expressed on recently activated effector T cells. We have determined the relative proportion of these subsets in a large patient cohort. The fraction of Treg in peripheral blood mononuclear cells from patients and healthy controls was determined by assessment of Foxp3 expression on CD4+ CD25+ T cells. The functional activity of Treg was determined by their ability to suppress proliferation and cytokine production in response to proteinase‐3. Although WG patients demonstrated an increased fraction of CD4+ CD25+ T cells, the percentage of Foxp3‐positive cells was decreased. In addition, the percentage of Treg was inversely related to the rate of disease relapse. CD4+ CD25hi T cells were able to suppress T‐cell proliferation to proteinase‐3 in healthy controls and anti‐neutrophil cytoplasm antibody (ANCA)‐ negative patients (at time of sampling) but not in ANCA‐positive patients. In patients with active disease, an increased proportion of CD4+ Foxp3+ cells was associated with a more rapid disease remission. Patients with WG demonstrate abnormalities in the number and function of Treg and this is most pronounced in those with most active disease. This information is of value in understanding the pathogenesis and potential treatment of this disease.

Prediction of ESRD in Pauci-immune Necrotizing Glomerulonephritis: Quantitative Histomorphometric Assessment and Serum Creatinine

Background Clinical and pathologic features that predict outcome have important potential application in patients with pauci-immune necrotizing glomerulonephritis (usually antineutrophil cytoplasmic antibody–associated vasculitis). This study examines the predictive value of simple quantitative renal histologic measurements in a large cohort with extended follow-up. Study Design Cohort study. Setting & Participants 390 consecutive patients with pauci-immune necrotizing glomerulonephritis at a single hospital (1983-2002); 90 patients underwent repeated kidney biopsy during follow-up. Predictors Age and serum creatinine concentration at biopsy, antineutrophil cytoplasmic antibody specificity, percentage of normal glomeruli, percentage of glomeruli with active lesions, and index of chronic damage (quantitative measurement of established cortical damage) in the initial kidney biopsy for all patients. The same factors were assessed in both biopsy specimens for patients undergoing an additional biopsy. Outcomes & Measurements End-stage renal disease and patient survival. Results Mortality at 1 and 5 years was 23% and 40%, respectively: standardized mortality ratio, 4.74 (95% CI, 3.62-6.32). End-stage renal disease was reached by 14% and 18% at 1 and 5 years, respectively. In multivariable analysis, serum creatinine level at biopsy and percentage of normal glomeruli in the initial biopsy specimen were the best predictors of kidney survival. C Statistics were 0.80 for creatinine level alone and 0.83 for creatinine level with normal glomeruli. In patients undergoing an additional biopsy, rapid progression in the index of chronic damage and serum creatinine level at the second biopsy were associated with kidney survival in multivariable analysis. Limitations Retrospective analysis. External validity of the index of chronic damage requires further assessment. Selection bias may influence repeated biopsy analyses. Conclusions Serum creatinine level at biopsy best predicts kidney survival in patients with pauci-immune necrotizing glomerulonephritis overall.

Cholestasis in pregnancy associated with ciclosporin therapy in renal transplant recipients.

Obstetric cholestasis (OC) presents with pruritis in the second half of pregnancy and is associated with increased risk of foetal distress, intra‐uterine death and premature delivery. From a tertiary referral, renal‐obstetric clinic, we report the occurrence of OC in 5/23 pregnancies of women with renal transplants maintained on ciclosporin treatment (European incidence 0.1–1.5% of pregnancies). All required premature delivery for foetal reasons at 33–37/40 (median 34/40). Ciclosporin, at therapeutic concentrations, inhibits bile salt excretion pump (BSEP) function in rats and humans. We propose that OC developed in our patients because the mild inhibition of the canalicular pumps by ciclosporin was only revealed in pregnancy when increases in progesterone metabolites overwhelmed pump function. We suggest that all pregnant women receiving ciclosporin should be closely monitored from the second trimester for the development of OC. If detected, enhanced foetal and maternal monitoring to optimize time of delivery and pregnancy outcome is required.

Sertraline Versus Placebo in Patients with Major Depressive Disorder Undergoing Hemodialysis: A Randomized, Controlled Feasibility Trial

BACKGROUND AND OBJECTIVES Depression is common in patients on hemodialysis, but data on the benefits and risks of antidepressants in this setting are limited. We conducted a multicenter, randomized, double-blind, placebo-controlled trial of sertraline over 6 months in patients on hemodialysis with depression to determine study feasibility, safety, and effectiveness. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Patients on hemodialysis at five United Kingdom renal centers completed the Beck Depression Inventory II. Those scoring ≥16 and not already on treatment for depression were invited to undergo diagnostic interview to confirm major depressive disorder. Eligible patients with major depressive disorder were randomized to receive the study medication-either sertraline or placebo. Outcomes included recruitment and dropout rates, change in the Montgomery-Asberg Depression Rating Scale and Beck Depression Inventory II, and qualitative information to guide design of a large-scale trial. RESULTS In total, 709 patients were screened and enrolled between April of 2013 and October of 2014; 231 (32.6%) had Beck Depression Inventory II scores ≥16, and 68 (29%) of these were already receiving treatment for depression. Sixty-three underwent diagnostic interview, 37 were diagnosed with major depressive disorder, and 30 were randomized; 21 completed the trial: eight of 15 on sertraline and 13 of 15 on placebo (P=0.05). Dropouts due to adverse and serious adverse events were greater in the sertraline group. All occurred in the first 3 months. Over 6 months, depression scores improved in both groups. Beck Depression Inventory II score fell from 29.1±8.4 to 17.3±12.4 (P<0.001), and Montgomery-Asberg Depression Rating Scale score fell from 24.5±4.1 to 10.3±5.8 (P<0.001). There were no differences between sertraline and placebo groups. CONCLUSIONS Although small, this is the largest randomized trial to date of antidepressant medication in patients on hemodialysis. Our results highlight recruitment issues. No benefit was observed, but trial size and the substantial dropout render consideration of benefit inconclusive. A definitive trial could use shorter follow-up and include depressed patients already taking antidepressants.

Measuring Fatigue Using the Multidimensional Fatigue Inventory-20: A Questionable Factor Structure in Haemodialysis Patients

Background/Aims: Fatigue is recognised as a common and burdensome symptom among dialysis patients. A growing body of research is devoted to understanding fatigue in advanced kidney disease, yet its measurement is challenging within this context. Our aim was to evaluate the factor structure underlying the multidimensional fatigue inventory (MFI-20) and to examine its associations with clinical factors and mood. Methods: Data was evaluated for confirmatory factor analysis (CFA) from the screening phase of a multicentre randomised placebo-controlled trial of sertraline in haemodialysis (HD) patients. Four hundred seventy patients completed the MFI-20, which purports to measure 5 components of fatigue (general fatigue, mental fatigue, physical fatigue, reduced motivation and reduced activity). CFA models were evaluated in MPlus 7.3 using the robust maximum likelihood (MLR) estimation. Results: The evaluation of the original 5 factors revealed low internal reliability for the general factor and reduced activity, and high intercorrelations between all sum scores. CFA revealed poor model fit for the original 5-factor MFI-20 model (confirmatory fit index = 0.738; Tucker-Lewis index = 0.689; root mean squared error of approximation = 0.101). Alternative models, including 1, 3 and bi-factor models all demonstrated poor fit to the data. No reliable factor model was confirmed prohibiting the examination of factors associated with fatigue. Conclusions: We were not able to confirm the factor structure of the MFI-20 in a large sample of HD patients. Certain items may lack suitable face validity in this context.

Postdialysis recovery time is extended in patients with greater self-reported depression screening questionnaire scores

Introduction: Most patients take time to recover after a hemodialysis (HD) session. It has been suggested that recovery time is associated with intradialytic hypotension and rapid solute clearances. Other studies have reported a linkage to depression. We investigated the association between recovery time and intradialytic hypotension and depression.

Self-reported depression symptoms in haemodialysis patients: Bi-factor structures of two common measures and their association with clinical factors

OBJECTIVE To validate the factor structure of two common self-report depression tools in a large sample of haemodialysis (HD) patients and to examine their demographic and clinical correlates, including urine output, history of depression and transplantation. METHODS Factor structures of the Beck Depression Inventory (BDI-II) and Patient Health Questionnaire (PHQ-9) were evaluated using confirmatory factor analysis (CFA). Data was utilised from the screening phase (n = 709) of a placebo-controlled feasibility randomised control trial (RCT) of sertraline in HD patients with mild to moderate Major Depressive Disorder. Alternative factor models including bi-factor models for the BDI-II and PHQ-9 were evaluated. Coefficient omega and omega-hierarchical were calculated. RESULTS For both measures, bi-factor measurement models had the overall best fit to the data, with dominant general depression factors. Omega-hierarchical for the general BDI-II and PHQ-9 factors was 0.94 and 0.88 respectively. Both general factors had high reliability (coefficient omega = 0.97 and 0.94 respectively) and explained over 85% of the explained common variance within their respective models. BDI-II and PHQ-9 general depression factors were negatively associated with age and urine output and positively with a history of depression, antidepressant use within the last 3 months and a history of failed transplantation. In adjusted regression models, age, urine output and a history of depression remained significant. CONCLUSIONS These data suggest that both the BDI-II and PHQ-9 are sufficiently unidimensional to warrant the use of a total score. Younger age, lower urine output and a history of depression appear consistent correlates of depression severity among HD patients.

Humoral immunity in late-onset Pre-eclampsia and linkage with angiogenic and inflammatory markers

Pre‐eclampsia (PE) is a leading cause of maternal and foetal morbidity worldwide. Given the implication of immune mechanisms, we compared markers of humoral immunity in PE and their relationship to circulating markers of inflammation, angiogenic factors, and renal function.

High Cut Off Hemodialysis

High cut off hemodialysis (HCO-HD) uses a dialyzer membrane that provides significant clearance of molecules up to a molecular weight (MW) of albumin (65 kDa) from blood. The characteristics of the dialyzer are distinct from high-flux HD (HF-HD) and protein-permeable HD (PP-HD), which remove molecules up to a MW of 20 and 25 kDa, respectively. The clinical rationale for HCO-HD is to improve patient outcomes by removing molecules that contribute to a high mortality risk in patients who require dialysis for distinct clinical indications.

Pregnancy and the Kidney

Chronic kidney disease (CKD) is often clinically silent until renal function declines to less than 25 % of normal. CKD stages 1 and 2 (normal or mildly impaired renal function and abnormal albuminuria or structural kidney damage) affect roughly 3 % of women of child-bearing age, whilst stages 3–5 (GFR <60 ml/min) affect just less than 1 % of women in this age group [1]. Enhanced antenatal monitoring in pregnancy and increased complication rates offer an opportunity to identify women with hitherto unrecognised CKD in early pregnancy. Furthermore, around 20 % of women who develop severe early-onset (<30 weeks) pre-eclampsia (PET) have underlying CKD as the predisposing cause [2]. Whilst live birth outcomes have improved, pregnancies in women with CKD are at high risk for maternal and foetal morbidity and mortality. Their management is complex, and successful outcomes are optimised by collaborative antenatal care in regular joint clinics of nephrologist and maternal/foetal medicine specialist. All women with CKD contemplating pregnancy should be offered review in a joint preconception counselling clinic in order to plan pregnancy and optimise outcomes. This chapter explores maternal and foetal outcomes in women with CKD and offers guidance on optimal pregnancy management. The evidence base is limited being dominated by small, often retrospective uncontrolled studies highlighting the need to contribute to developing registry studies in this area.