Therapeutic Drug Monitoring in Patients with Systemic Lupus Erythematosus: Utility and Gaps.

Despite advances in the treatment of patients with systemic lupus erythematous (SLE), outcomes have remained suboptimal. Persistent disease activity, patient comorbidities and drug toxicities contribute to the accrual of progressive irreversible damage and high rates of morbidity and mortality. Currently, similar drug doses and regimens are promulgated in the treatment guidelines for all SLE patients, despite the vast differences in patient and environmental factors that affect the drugs' metabolism and blood concentrations. This causes a disconnect between drug dosing and drug blood concentrations, which can then result in unpredictability in drug toxicities and therapeutic effects. In this review, we discuss commonly used oral immunosuppressive medications in SLE, their pharmacogenomics, and factors affecting their metabolism and blood concentrations. Further, we highlight the role of therapeutic drug monitoring in SLE, which is the first accessible step to individualising therapy.

Extrapulmonary manifestations and complications of severe acute respiratory syndrome coronavirus-2 infection: a systematic review.

Introduction: We aimed to describe the extrapulmonary manifestations of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, including their frequency, onset with respect to respiratory symptoms, pathogenesis and association with disease severity. Methods: We searched the MEDLINE and Embase databases for SARS-CoV-2-related studies. Meta-analysis, observational studies, case series and case reports published in English or Chinese between 1 January 2020 and 1 May 2020 were included. Reports with only paediatric or obstetric cases were excluded. Results: 169 articles were included. Early manifestations (preceding respiratory symptoms until Day 6 of onset) included olfactory and gustatory disturbance (self-reported in up to 68% and 85% of cases, respectively), gastrointestinal symptoms (up to 65.9%) and rash (up to 20.4%). From Day 7 onwards, hypercytokinaemia, paralleled multi-organ complications including acute cardiac injury (pooled incidence of 17.7% in 1,412 patients, mostly with severe disease and 17.4% mortality), kidney and liver injury (up to 17% and 33%, respectively) and thrombocytopenia (up to 30%). Hypercoagulability resulted in venous thromboembolic events in up to 31% of all patients. Uncommon disease presentation and complications comprised Guillain-Barré syndrome, rhabdomyolysis, otitis media, meningoencephalitis and spontaneous pneumomediastinum. Conclusion: Although the systemic manifestations of SARS-CoV-2 infection are variegated, they are deeply interwoven by shared mechanisms. Two phases of extrapulmonary disease were identified: (a) an early phase with possible gastrointestinal, ocular and cutaneous involvement; and (b) a late phase characterised by multiorgan dysfunction and clinical deterioration. A clear, multidisciplinary consensus to define and approach thromboinflammation and cytokine release syndrome in SARS-CoV-2 is needed.

Elevated Urinary Tissue Inhibitor of Metalloproteinase-2 and Insulin-Like Growth Factor Binding Protein-7 Predict Drug-Induced Acute Kidney Injury.

BACKGROUND: Urinary tissue inhibitor of metalloproteinase-2 (TIMP2) and insulin-like growth factor binding protein-7 (IGFBP7) predict severe acute kidney injury (AKI) in critical illness. Earlier but subtle elevation of either biomarker from nephrotoxicity may predict drug-induced AKI. METHODS: A prospective study involving serial urine collection in patients treated with vancomycin, aminoglycosides, amphotericin, foscarnet, or calcineurin inhibitors was performed. Urinary TIMP2 and IGFBP7, both absolute levels and those normalized with urine creatinine, were examined in days leading to AKI onset by KDIGO criteria in cases or at final day of nephrotoxic therapy in non-AKI controls, who were matched for age, baseline kidney function, and nephrotoxic exposure. RESULTS: Urinary biomarker analyses were performed in 21 AKI patients and 28 non-AKI matched-controls; both groups had comparable baseline kidney function and duration of nephrotoxic drug therapy. Significantly higher absolute, normalized, and composite levels of TIMP2 and IGFBP7 were observed in AKI cases versus controls as early as 2-3 days before AKI onset (all P<0.05); >70% of patients with corresponding levels above 75th percentile developed AKI. Normalized TIMP2 at 2-3 days pre-AKI predicted AKI with the highest average AUROC of 0.81, followed by that of composite [TIMP2]x[IGFBP7] (0.78) after cross-validation. [TIMP2]x[IGFBP7] >0.01 (ng/mL)2/1000 predicted AKI with a sensitivity of 79% and specificity of 60%. CONCLUSION: Elevated urinary TIMP2 or IGFBP7 predicts drug-induced AKI with a lead-time of 2-3 days; an opportune time for interventions to reduce nephrotoxicity.

Ensuring Sustainability of Continuous Kidney Replacement Therapy in the Face of Extraordinary Demand: Lessons From the COVID-19 Pandemic.

With the exponential surge in patients with coronavirus disease 2019 (COVID-19) worldwide, the resources needed to provide continuous kidney replacement therapy (CKRT) for patients with acute kidney injury or kidney failure may be threatened. This article summarizes subsisting strategies that can be implemented immediately. Pre-emptive weekly multicenter projections of CKRT demand based on evolving COVID-19 epidemiology and routine workload should be made. Corresponding consumables should be quantified and acquired, with diversification of sources from multiple vendors. Supply procurement should be stepped up accordingly so that a several-week stock is amassed, with administrative oversight to prevent disproportionate hoarding by institutions. Consumption of CKRT resources can be made more efficient by optimizing circuit anticoagulation to preserve filters, extending use of each vascular access, lowering blood flows to reduce citrate consumption, moderating the CKRT intensity to conserve fluids, or running accelerated KRT at higher clearance to treat more patients per machine. If logistically feasible, earlier transition to intermittent hemodialysis with online-generated dialysate, or urgent peritoneal dialysis in selected patients, may help reduce CKRT dependency. These measures, coupled to multicenter collaboration and a corresponding increase in trained medical and nursing staffing levels, may avoid downstream rationing of care and save lives during the peak of the pandemic.

Transitional care program to facilitate recovery following severe acute kidney injury.

BACKGROUND: Patients with acute kidney injury needing prolonged renal replacement therapy (AKI-RRT) may benefit from a structured care process in form of an AKI transitional care program (ATCP), to facilitate RRT weaning and recovery. METHODS: We examined outcomes following ATCP implementation in adults with AKI-RRT from a tertiary institution (versus pre-ATCP controls), including mortality, cumulative hospital days, and renal function over one year; RRT and haemodialysis catheter days in initial 90 days. RESULTS: We studied 89 patients with age 62 ( ± 15) years. 47% had septic AKI, 20% cardiorenal syndrome, and 29% had baseline eGFR < 30 mL/min/1.73 m2. Comparing 45 ATCP patients with 44 controls: 64% and 45% received continuous RRT (CRRT) (p = 0.07), with comparable rates of heart failure (24% versus 25%), ICU care (67% versus 70%), RRT successfully weaned (71% versus 75%), respectively; corresponding mortality rates were 24% and 32% (p = 0.44), hospital days of 205 (197-213) and 223 (215-232) per 1000 patient-days alive over one year (p = 0.002); with comparable RRT and catheter days. Serial serum creatinine in months following RRT cessation were comparable between either survivor-group. On multivariate analysis, heart failure or having received CRRT independently predicted mortality and longer hospital days (p < 0.05); ATCP was independently associated with reduced hospital days (p < 0.001). 17 ATCP patients and 14 controls required outpatient RRT weaning, with catheter days of 607 (568-648) and 683 (638-731) per 1000 patient-days in initial 90 days, respectively (p = 0.01). CONCLUSIONS: Implementing a structured care pathway in patients with AKI-RRT may help reduce hospitalization, and reduce haemodialysis catheter days in the subgroup for outpatient RRT weaning.

The influence of timing of polysomnography on diagnosis of obstructive sleep apnea in patients presenting with acute myocardial infarction and stable coronary artery disease.

BACKGROUND: We aimed to determine if timing of polysomnography (PSG) influences the diagnosis of obstructive sleep apnea (OSA) in acute myocardial infarction (AMI) or stable coronary artery disease (CAD). METHODS: A total of 160 patients admitted with AMI or stable CAD were consecutively recruited for either in-hospital (n=80) or postdischarge (n=80) PSG. RESULTS: The median time from admission to PSG for the in-hospital and postdischarge groups was 1 day and 17 days, respectively (P<.001). Overall, 59 patients (36.9%) were diagnosed with OSA (apnea-hypopnea index [AHI] > or = 15), and they were more likely to have diabetes mellitus (DM), hypertension, hyperlipidemia, chronic renal failure, and a greater body mass index (BMI) (P<.05 for all). The diagnosis of OSA was significantly higher (P=.037) in patients who had a PSG performed as an inpatient than those who had a PSG as an outpatient. There was a significant interaction between clinical presentation and the effect of PSG timing on the diagnosis of OSA (P=.003). For the patients presenting with AMI but not those with stable CAD, in-hospital PSG was an independent predictor of OSA (adjusted odds ratio, 3.84 [95% confidence interval, 1.42-10.41]; P=.008). CONCLUSION: The timing of PSG influenced the diagnosis of OSA in patients who presented with AMI but not in those who presented with stable CAD.