Aspects of Lupus Nephritis

This thesis explores the clinical outcomes of patients with systemic lupus erythematosus (SLE), focussing on Lupus nephritis (LN), specifically on the impact and results of renal replacement therapies on patients and their disease with reference to adherence to treatment. It comprises three separate but related studies. It also reviews the risk factors for renal disease in SLE and their clinical implications as well as the safety of pharmacological treatment options for lupus nephritis. This thesis reviews a combined cohort of adult SLE patients receiving renal transplants (rTp) over a 40-year period (1975-2015) in two tertiary United Kingdom centres, the Royal Free Hospital (RFH) and University College London Hospital (UCLH), and investigates factors influencing mortality, transplant outcome and disease relapses. My research examines the impact of pre-transplant time on dialysis on survival in patients with LN, and investigates the role of non-adherence in graft survival. It also explores further adherence patterns in the LN population of the combined cohort in UCLH and RFH and compares it with one other autoimmune condition, notably vasculitis. Study 1 investigated the time spent on dialysis before rTp and survival following rTp in a cohort of SLE patients. This was a retrospective analysis of 40 adult SLE patients receiving rTp over a 40-year period (1975-2015) and identified that time on dialysis before rTp was the only modifiable survival risk predictor (with a hazard ratio of 1.01 for each additional month spent on dialysis) and suggested that more than 24 months on dialysis adversely affected mortality. No other modifiable predictors associated with mortality, supporting that longer time on dialysis pre-transplantation is an independent modifiable risk factor of mortality in LN. Study 2 examined whether non-adherence is associated with increased rTp graft rejection and/ or failure in patients with LN in the same cohort as Study 1. The role of non-adherence and other potential predictors of graft rejection/ failure were investigated using logistic regression. During a median follow-up of 8.7 years, 17/40 (42.5%) of the patients had evidence of non-adherence. Non-adherent patients had a trend towards increased graft rejection, odds ratio 4.38, (95% confidence interval= 0.73-26.12, p = 0.11.) Interestingly, patients who spent more time on dialysis before rTp were more likely to be subsequently adherent to medication, p=0.01. Study 3 determined self-reported adherence to medication utilising an anonymised questionnaire-based survey and explored influencing factors in LN and renal vasculitis clinics at UCLH and RFH. I compared 114 patients with LN and 80 patients with renal vasculitis to identify emerging patterns, behaviours and differences that could potentially introduce barriers to adherence. Lupus patients were more likely to be female, younger and with longer disease duration (p<0.001). Their adherence decreased with time compared to vasculitis patients (p<0.001). Conversely, the patients with vasculitis had higher attendance at clinic appointments (p=0.02), and were more confident they could manage to take their tablets correctly. "Forgetfulness" regarding medication, and keeping track of hospital appointments were the most common reasons given for non-adherence rather than deliberate non-adherence. Increasing age and taking prednisolone associated with better adherence. In contrast, missing even one outpatient clinic appointment associated with worse adherence. Utilising responses from the survey, a prediction model was proposed to further risk-stratify patients regarding their potential adherence patterns that can identify the "at-risk" patient and alert clinicians to the possibility of poor adherence

Impact of pre-transplant time on dialysis on survival in patients with lupus nephritis

Lupus nephritis (LN) is an important cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE) often leading to end-stage renal failure (ESRF) and necessitating renal transplantation (rTp). Optimal timing of rTp in SLE patients with ESRF is uncertain and could potentially affect survival. We investigated the time spent on dialysis before rTp and survival following rTp in a cohort of SLE patients. Retrospective analysis of all adult SLE patients receiving rTp over a 40-year period (1975–2015) in two tertiary UK centres. Cox proportional hazard regression and receiver operator curves (ROC) were used to determine the risk associated with time on dialysis before rTp and other potential predictors. Forty patients (age 35 ± 11 years, 34 female, 15 Caucasian, 15 Afro–Caribbean and 10 South Asian) underwent rTp. During a median follow-up of 104 months (IQR 80,145), eight (20%) patients died and the 5-year survival was 95%. Univariate analysis identified time on dialysis prior to rTp as the only potentially modifiable risk predictor of survival with a hazard ratio of 1.013 for each additional month spent on dialysis (95% CI = 1.001–1.026, p = 0.03). ROC curves demonstrated that > 24 months on dialysis had an adverse effect with sensitivity of 0.875 and specificity 0.500 for death. No other modifiable predictors were significantly associated with mortality, indicating that time on dialysis had an independent effect. Increased time on dialysis pre-transplantation is an independent modifiable risk factor of mortality in this cohort of patients with lupus nephritis

Risk factors associated with post-COVID-19 condition: A systematic review and meta-analysis

IMPORTANCE: Post-COVID-19 condition (PCC) is a complex heterogeneous disorder that has affected the lives of millions of people globally. Identification of potential risk factors to better understand who is at risk of developing PCC is important because it would allow for early and appropriate clinical support. OBJECTIVE To evaluate the demographic characteristics and comorbidities that have been found to be associated with an increased risk of developing PCC. DATA SOURCES: Medline and Embase databases were systematically searched from inception to December 5, 2022. STUDY SELECTION: The meta-analysis included all published studies that investigated the risk factors and/or predictors of PCC in adult (≥18 years) patients. DATA EXTRACTION AND SYNTHESIS: Odds ratios (ORs) for each risk factor were pooled from the selected studies. For each potential risk factor, the random-effects model was used to compare the risk of developing PCC between individuals with and without the risk factor. Data analyses were performed from December 5, 2022, to February 10, 2023. MAIN OUTCOMES AND MEASURES: The risk factors for PCC included patient age; sex; body mass index, calculated as weight in kilograms divided by height in meters squared; smoking status; comorbidities, including anxiety and/or depression, asthma, chronic kidney disease, chronic obstructive pulmonary disease, diabetes, immunosuppression, and ischemic heart disease; previous hospitalization or ICU (intensive care unit) admission with COVID-19; and previous vaccination against COVID-19. RESULTS: The initial search yielded 5334 records of which 255 articles underwent full-text evaluation, which identified 41 articles and a total of 860 783 patients that were included. The findings of the meta-analysis showed that female sex (OR, 1.56; 95% CI, 1.41-1.73), age (OR, 1.21; 95% CI, 1.11-1.33), high BMI (OR, 1.15; 95% CI, 1.08-1.23), and smoking (OR, 1.10; 95% CI, 1.07-1.13) were associated with an increased risk of developing PCC. In addition, the presence of comorbidities and previous hospitalization or ICU admission were found to be associated with high risk of PCC (OR, 2.48; 95% CI, 1.97-3.13 and OR, 2.37; 95% CI, 2.18-2.56, respectively). Patients who had been vaccinated against COVID-19 with 2 doses had a significantly lower risk of developing PCC compared with patients who were not vaccinated (OR, 0.57; 95% CI, 0.43-0.76). CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis demonstrated that certain demographic characteristics (eg, age and sex), comorbidities, and severe COVID-19 were associated with an increased risk of PCC, whereas vaccination had a protective role against developing PCC sequelae. These findings may enable a better understanding of who may develop PCC and provide additional evidence for the benefits of vaccination

Osteoprotegerin and Myocardial Fibrosis in Patients with Aortic Stenosis

Left ventricular myocardial fibrosis in patients with aortic stenosis (AS) confers worse prognosis. Plasma osteoprotegerin (OPG), a cytokine from the TNF receptor family, correlates with the degree of valve calcification in AS, reflecting the activity of the tissue RANKL/RANK/OPG (receptor activator of nuclear factor κΒ ligand/RANK/osteoprotegerin) axis, and is associated with poorer outcomes in AS. Its association with myocardial fibrosis is unknown. We hypothesised that OPG levels would reflect the extent of myocardial fibrosis in AS. We included 110 consecutive patients with AS who had undergone late-gadolinium contrast enhanced cardiovascular magnetic resonance (LGE-CMR). Patients were characterised according to pattern of fibrosis (no fibrosis, midwall fibrosis, or chronic myocardial infarction fibrosis). Serum OPG was measured with ELISA and compared between groups defined by valve stenosis severity. Some 36 patients had no fibrosis, 38 had midwall fibrosis, and 36 had chronic infarction. Patients with midwall fibrosis did not have higher levels of OPG compared to those without fibrosis (6.78 vs. 5.25 pmol/L, p = 0.12). There was no difference between those with midwall or chronic myocardial infarction fibrosis (6.78 vs. 6.97 pmol/L, p = 0.27). However, OPG levels in patients with chronic myocardial infarction fibrosis were significantly higher than those without fibrosis (p = 0.005)

The safety of pharmacological treatment options for lupus nephritis

INTRODUCTION: The management of lupus nephritis (LN) has changed significantly over the last 10 years due to emerging evidence from large randomised clinical trials that produced good quality data and guided the formulation of two key concepts: the induction of remission and the maintenance phase of immunosuppressive therapy. Areas covered: Optimizing cyclophosphamide and glucocorticoid regimens and the introduction of mycophenolate mofetil for proliferative and membranous LN has been pivotal. Nevertheless, concerns remain about treatment toxicity especially long term glucocorticoid use and exposure to cumulative cyclophosphamide doses. Here we discuss the conventional and newer pharmacological options for managing LN focusing on drug safety and toxicity issues. Expert opinion: The need for effective and less toxic treatments led to the development of the role of targeted biologic therapies in LN. However, evidence from the initial randomized controlled trials has been disappointing, although this reflects inadequate trial design rather than true lack of efficacy

Preliminary report: the effect of a 6-month dietary glycemic index manipulation in addition to healthy eating advice and weight loss on arterial compliance and 24-hour ambulatory blood pressure in men: a pilot study

We aimed to determine whether altering dietary glycemic index (GI) in addition to healthy eating and weight loss advice affects arterial compliance and 24-hour blood pressure (BP), both coronary heart disease (CHD) risk factors. Middle-aged men with at least 1 CHD risk were randomized to a 6-month low-GI (LGI) or high-GI (HGI) diet. All were advised on healthy eating and weight loss. They were seen monthly to assess dietary compliance and anthropometrics. Carotid-femoral pulse wave velocity (PWV), fasting blood lipid profile, and glucose and insulin concentrations were measured at baseline and at months 3 and 6. Six-hour postprandial glucose and insulin responses and 24-hour ambulatory BP were also assessed at baseline and month 6. Thirty-eight subjects (HGI group, n = 16; LGI group, n = 22) completed the study. At month 6, groups differed in dietary GI, glycemic load, and carbohydrate intake (P < .001). Fasting insulin concentration and insulin resistance (calculated by homeostatic model assessment) were lower in the LGI than the HGI group (P < .01). The reduction in total cholesterol and 24-hour BP was bigger in the LGI than the HGI group (P < .05); and only the LGI group had significant reductions (P < .05) in PWV, low-density lipoprotein cholesterol, and triacylglycerol concentration. There were no differences in postprandial glucose or insulin responses between the groups. The results suggest that an LGI diet may be more beneficial in reducing CHD risk, including PWV and 24-hour BP, even in the setting of healthy eating and weight loss; and thus, further study is warranted