Steroids as treatment for glomerulonephritis: time for a rethink.

Glucocorticoids have been a cornerstone of treatment for inflammatory and autoimmune kidney diseases for almost 70 years, yet it is fair to say, we still do not know how 'best' to use them. Significant adverse events are associated with their continued use, which contribute to premature patient mortality. Steroid avoidance or minimization is possible and has been tested in various glomerular diseases, as a result of novel agents or innovative regimens using established therapeutics. It is now time to seriously address our use of steroids and educate physicians on better ways of managing inflammatory kidney diseases.

The use of life-saving extracorporeal membrane oxygenation (ECMO) for pregnant woman with status asthmaticus.

INTRODUCTION: Status asthmaticus can develop into a life-threatening disorder that requires mechanical ventilation. Severe respiratory failure during pregnancy can worsen maternal and fetal outcomes. Previous case studies have demonstrated extracorporeal membrane oxygenation (ECMO) as a life-saving measure for pregnant women with acute respiratory distress syndrome (ARDS) as well as non-pregnant patients with status asthmaticus. CASE STUDY: A 25-year-old woman, who was 5 weeks pregnant, was admitted with status asthmaticus and severe hypercapnic respiratory failure. Despite rescue therapies such as pressure control ventilation with high inspiratory pressures, inhaled beta2 agonists and antimuscarinic drugs, intravenous salbutamol, methylprednisolone and magnesium sulfate, her condition gradually deteriorated. Veno-venous ECMO was initiated for respiratory support and the patient's clinical condition as well as the gas exchange improved within the next few days. ECMO was removed and the patient was extubated after 2 days. Sonography, however, revealed a retrochorial hematoma; the patient was diagnosed with abortus imminens and successfully treated with magnesium substitution and bed rest. Finally, she gave birth to a healthy boy at 38 weeks of gestation. CONCLUSIONS: This is the first case report on the successful use of ECMO in a pregnant woman with severe respiratory insufficiency due to status asthmaticus, who failed to respond to invasive mechanical ventilation and maximum pharmacological treatment. Despite this life-threatening condition, the use of ECMO in our patient has greatly improved the chance of survival for the mother and the baby, who was born without any complications.

Determinants of active energy expenditure in haemodialysis patients.

BACKGROUND: Less active haemodialysis patients have an increased risk of mortality. We wished to determine which factors were associated with active energy expenditure (AEE). METHODS: We used the validated recent physical activity questionnaire to determine AEE and estimated dietary protein intake and creatinine generation rates. We measured extracellular and total body water ratio (ECW/TBW) and appendicular lean muscle with bioimpedance and arm strength by hand grip strength (HGS). Patients were graded using the Charlson co-morbidity and the Clinical Frailty Score (CFS). RESULTS: AEE was calculated in 98 patients (64 male), mean age 62.1 ± 15.5 years, and AEE was negatively associated with CFS (r = -0.48), ECW/TBW (r = -0.47) and age (r = -0.4), all p < 0.001, Charlson co-morbidity score (-0.27, p = 0.007), and positively with serum creatinine (r = 0.38, p < 0.010), and HGS (r = 0.25, p = 0.016). Although protein nitrogen accumulation and creatinine generation were associated with resting energy expenditure (r = 0.70 and r = 0.44 respectively, both p < 0.0001), neither were associated with AEE. On multivariable analysis only CFS remained independently associated with AEE (ß = -0.031, 95% limits: -0.057 to -0.004, p = 0.024), although both age (negative p = 0.07), and ALM (positive p = 0.081) were retained in the model. CONCLUSIONS: We found that AEE was lower with increasing frailty, age, loss of cell mass, co-morbidity and inflammation, and greater AEE in patients with higher serum creatinine and albumin, and greater muscle strength on univariate analysis, but only frailty remained independently associated on multivariable analysis. Whether exercise programmes designed to increase AEE in haemodialysis patients can improve frailty scores, and so reduce mortality risk reman to be determined.

Characteristics of Frailty in Haemodialysis Patients.

Background: Both frailty and cachexia increase mortality in haemodialysis (HD) patients. The clinical frailty score (CFS) is a seven-point scale and less complex than other cachexia and frailty assessments. We wished to determine the characteristics of frail HD patients using the CFS. Methods: Single centre cross-sectional study of HD patients completing physical activity questionnaires with bioimpedance measurements of body composition and hand grip strength (HGS). Results: We studied 172 HD patients. The CFS classified 54 (31.4%) as frail, who were older (70.4±12.2 vs 56.2 ± 16.1 years, p < 0.001), greater modified Charlson co-morbidity (3 (2-3) versus 1.5 (0-3), p < 0.001), and body fat (33 (25.4-40.2) versus 26.2 (15.8-34) %, p < 0.01), but lower total energy expenditure (1720 (1574-1818) versus 1870 (1670-2194) kcal/day, p < 0.01), lean muscle mass index (9.1 (7.7-10.1) versus 9.9 (8.9-10.8) kg/m2), and HGS (15.3 (10.3-21.9) versus 23.6 (16.7-34.4) kg), both p < 0.001. On multivariable logistic analysis, frailty was independently associated with lower active energy expenditure (odds ratio (OR) 0.98, 95% confidence limits (CL) 0.98-0.99, p = 0.001), diabetes (OR 5.09, CL 1.06-16.66) and HGS (OR 0.92, CL 0.86-0.98). Discussion: Frail HD patients reported less active energy expenditure, associated with reduced muscle mass and strength. Frail patients were more likely to have greater co-morbidity, particularly diabetes. Whether physical activity programmes can improve frailty remains to be determined.

Integration of population pharmacokinetics and pharmacogenetics: an aid to optimal nevirapine dose selection in HIV-infected individuals.

BACKGROUND: Nevirapine is metabolized by CYP2B6 and polymorphisms within the CYP2B6 gene partly explain inter-patient variability in pharmacokinetics. The aim of this study was to model the complex relationship between nevirapine exposure, weight and genetics (based on combined analysis of CYP2B6 516G > T and 983T > C single nucleotide polymorphisms). METHODS: Non-linear mixed-effects modelling was used to estimate pharmacokinetic parameters from 275 patients. Simulations of the nevirapine concentration profile were performed with dosing regimens of 200 mg twice daily and 400 mg once daily for individuals with body weights of 50, 70 and 90 kg in combination with CYP2B6 genetic variation. RESULTS: A one-compartment model with first-order absorption best described the data. Population clearance was 3.5 L/h with inter-patient variability of 24.6%. 516T homozygosity and 983C heterozygosity were associated with 37% and 40% lower clearance, respectively. Body weight was the only significant demographic factor influencing clearance, which increased by 5% for every 10 kg increase. For individuals with higher body weight, once-daily nevirapine was associated with a greater risk of sub-therapeutic drug exposure than a twice-daily regimen. This risk was offset in individuals who were 516T homozygous or 983C heterozygous in which drug exposure was optimal for  >  95% of patients with body weight of ≤ 70 kg. CONCLUSIONS: The data suggest that a 400 mg once-daily dose could be implemented in accordance with CYP2B6 polymorphism and body weight. However, the use of nevirapine once daily (immediate release; off-label) in the absence of therapeutic drug monitoring is not recommended due to the risk of inadequate exposure to nevirapine in a high proportion of patients. There are different considerations for the extended-release formulation (nevirapine XR) that demonstrate minimal peak-to-trough fluctuations in plasma nevirapine levels.

Cytochrome P450 2B6 (CYP2B6) and constitutive androstane receptor (CAR) polymorphisms are associated with early discontinuation of efavirenz-containing regimens.

OBJECTIVES: Cytochrome P450 2B6 (CYP2B6) is responsible for the metabolic clearance of efavirenz and single nucleotide polymorphisms (SNPs) in the CYP2B6 gene are associated with efavirenz pharmacokinetics. Since the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) correlate with CYP2B6 in liver, and a CAR polymorphism (rs2307424) and smoking correlate with efavirenz plasma concentrations, we investigated their association with early (<3 months) discontinuation of efavirenz therapy. METHODS: Three hundred and seventy-three patients initiating therapy with an efavirenz-based regimen were included (278 white patients and 95 black patients; 293 male). DNA was extracted from whole blood and genotyping for CYP2B6 (516G → T, rs3745274), CAR (540C → T, rs2307424) and PXR (44477T → C, rs1523130; 63396C → T, rs2472677; and 69789A → G, rs763645) was conducted. Binary logistic regression using the backwards method was employed to assess the influence of SNPs and demographics on early discontinuation. RESULTS: Of the 373 patients, 131 withdrew from therapy within the first 3 months. Black ethnicity [odds ratio (OR) = 0.27; P = 0.0001], CYP2B6 516TT (OR = 2.81; P = 0.006), CAR rs2307424 CC (OR = 1.92; P = 0.007) and smoking status (OR = 0.45; P = 0.002) were associated with discontinuation within 3 months. CONCLUSIONS: These data indicate that genetic variability in CYP2B6 and CAR contributes to early treatment discontinuation for efavirenz-based antiretroviral regimens. Further studies are now required to define the clinical utility of these associations.

Identifying prognostic risk factors for poor outcome following COVID-19 disease among in-centre haemodialysis patients: role of inflammation and frailty.

INTRODUCTION: The pandemic of coronavirus disease (COVID-19) has highly affected patients with comorbidities and frailty who cannot self-isolate, such as individuals undergoing haemodialysis. The aim of the study was to identify risk factors for mortality and hospitalisation, which may be useful in future disease spikes. METHODS: We collected data retrospectively from the electronic medical records of all patients receiving a diagnosis of COVID-19 between 11th March and 10th May 2020 undergoing maintenance haemodialysis at four satellite dialysis units from the Royal Free London NHS Foundation Trust, London, UK. Mortality was the primary outcome, and the need for hospitalization was the secondary one. RESULTS: Out of 746 patients undergoing regular haemodialysis, 148 symptomatic patients tested positive for SARS-CoV-2 by RT-PCR and were included in the analysis. The overall mortality rate was 24.3%. By univariate analysis, older age, ischaemic heart disease, lower systolic blood pressure, lower body mass index (BMI) and higher frailty scores were associated with higher rates of mortality (all p value < 0.05). The laboratory factors associated with mortality were higher values of WBC, neutrophil counts, neutrophil to lymphocyte ratios (NLR), C-reactive protein (CRP), bilirubin, ferritin, troponin, and lower serum albumin level (all p value < 0.05). In the logistic regression, mortality was associated with older age and higher CRP, while high levels of NLR and CRP were associated with the need for hospitalization. DISCUSSION: Haemodialysis patients are susceptible to COVID-19 and have a high mortality rate. Our study identifies prognostic risk factors associated with poor outcome including age, frailty and markers of inflammation, which may support more informed clinical decision-making.

Frailty score before admission as risk factor for mortality of renal patients during the first wave of the COVID pandemic in London.

Background: Frailty is a known predictor of mortality and poor outcomes during hospital admission. In this large renal retrospective cohort study, we investigated whether frailer COVID-19 positive renal patients had worse outcomes. Design: All SARS-Cov-2 positive renal patients aged ≥18 years who presented to the emergency department at the Royal Free Hospital or at the satellite dialysis centres from 10th of March until the 10th of May 2020, with recent data on frailty, were included. The follow up was until 26th of May 2020. Age, gender, ethnicity, body mass index, chronic kidney disease stage, modality of renal replacement therapy, co-morbidities, Rockwood clinical frailty score (CFS), C reactive protein and the neutrophil-to-lymphocyte count were collected at presentation. The primary outcome was the overall mortality rate following COVID-19 diagnosis. Secondary outcomes included the need for hospital admission. Results: A total of 200 renal patients were SARS-Cov-2 positive. In the 174 patients who had a CFS recorded, the age was 65.4 years ± 15.8 (mean ± SD) and 57,5% were male. At the end of follow up, 26% had died. Frail patients (CFS 5-7) were more than three times more likely to die compared to less frail patients (CFS of 1-4) (odds ratio (OR) 3.3, 95% confidence interval (CI) 1.0-10.6). 118 patients (68%) required admission, but there was no difference in hospital admission rates for frail vs non-frail patients (OR 0.6, CI 0.3-1.7). Conclusions: Frailty is a better predictor of mortality than age and co-morbidities in COVID-19 positive renal patients.

Impact of CYP2B6 983T>C polymorphism on non-nucleoside reverse transcriptase inhibitor plasma concentrations in HIV-infected patients.

OBJECTIVES: The aim of this study was to investigate the frequency of CYP2B6 polymorphisms (according to ethnicity) and the influence of heterozygosity and homozygosity on plasma concentrations of efavirenz and nevirapine. METHODS: Following written informed consent, 225 Caucasians and 146 Blacks were recruited from the German Competence Network for HIV/AIDS. Plasma concentrations of efavirenz and nevirapine were assessed by HPLC, and genotyping for 516G>T, 983T>C and 1459T>C polymorphisms in CYP2B6 was conducted by real-time PCR-based allelic discrimination. RESULTS: The minor allele frequency for 516G>T, 983T>C and 1459T>C was 0.29, 0 and 0.08 in Caucasians and 0.34, 0.07 and 0.02 in Blacks, respectively. Two Black patients with the 983C allele receiving efavirenz were identified and both were withdrawn from therapy within 1 week of sampling due to toxicity. In multivariate analyses, efavirenz and nevirapine plasma concentrations were significantly associated with 983T>C (P < 0.0001 and P = 0.02, respectively), 516G>T (P < 0.0001 and P = 0.002, respectively) and time of drug analysis post-dose (P < 0.0001 for both). Body mass index was independently related to efavirenz (P = 0.04) but not nevirapine concentrations, and age was related to nevirapine (P = 0.05) but not efavirenz concentrations. Consistent with other studies, 1459C>T was not associated with plasma concentrations of either drug (P > 0.05 for both drugs). CONCLUSIONS: This is the first report that the 983T>C genotype (part of the CYP2B6*18 haplotype) impacts on nevirapine plasma concentrations and the first study to assess the impact of 983C homozygosity on efavirenz concentrations. These data have implications for administration of non-nucleoside reverse transcriptase inhibitors to Black patients.

A high impact intervention for a high impact intervention: Improving documentation of peripheral venous access insertion in theatre.

The Department of Health's 'High Impact Intervention (HII) - Peripheral intravenous cannula care bundle' lists six actions to be performed at the time of peripheral intravenous cannulation. Audit of compliance to these requires documentation. We assessed documentation on the anaesthetic charts of 50 surgical patients. Purpose-made stickers were then placed on all anaesthetic charts. Re-assessment of a further 50 patients' charts demonstrated a significant improvement in documentation of the bundle post intervention (Fisher's exact test P < 0.0001). This is an example of how a low-tech intervention can produce a high impact improvement in documentation.