Representation of Patients With Chronic Kidney Disease in Clinical Trials of Cardiovascular Disease Medications: A Systematic Review.

Importance: Patients with chronic kidney disease (CKD) are at high risk for cardiovascular disease, but their systematic underrepresentation in cardiovascular randomized clinical trials (RCTs) limits the generation of appropriate evidence to guide cardiovascular risk management (CVRM). Objective: To evaluate the underrepresentation of patients with CKD in cardiovascular RCTs, and to highlight evidence gaps in CVRM medications in this population. Evidence Review: A systematic search was conducted in ClinicalTrials.gov from February 2000 through October 2021 for RCTs with full-text publications. If no full-text publications were found in ClinicalTrials.gov, MEDLINE, Embase, and Google Scholar were also searched. Eligible RCTs were those evaluating the effectiveness of antiplatelets, anticoagulants, blood pressure-lowering drugs, glucose-lowering drugs, or cholesterol-lowering drugs in adults with cardiovascular disease or cardiovascular risk factors. Trials with a sample size of fewer than 100 patients were excluded. Findings: In total, 1194 RCTs involving 2 207 677 participants (mean [SD] age, 63 [6] years; 1 343 970 males [64%]) were included. Since 2000, the percentage of cardiovascular RCTs excluding patients with CKD has increased from 66% to 79% (74% overall [884 RCTs]). In 864 RCTs (72%), more patients were excluded than anticipated on safety grounds (63% [306] of trials required no dose adjustment, and 79% [561] required dose adjustment). In total, 158 RCTs (13%) reported results for patients with CKD separately (eg, in subgroup analyses). Significant evidence gaps exist in most CVRM interventions for patients with CKD, particularly for those with CKD stages 4 to 5. Twenty-three RCTs (2%) reported results for patients with an estimated glomerular filtration rate less than 30 mL/min/1.73 m2, 15 RCTs (1%) reported for patients receiving dialysis, and 1 RCT (0.1%) reported for recipients of kidney transplant. Conclusions and Relevance: Results of this systematic review suggest that representation of patients with CKD in cardiovascular RCTs has not improved in the past 2 decades and that these RCTs excluded more patients with CKD than expected on safety grounds. Lack of reporting or underreporting of results for this patient population is associated with evidence gaps in the effectiveness of most CVRM medications in patients with all stages of CKD, particularly CKD stages 4 to 5.

Evidence for pharmacological interventions to reduce cardiovascular risk for patients with chronic kidney disease: a study protocol of an evidence map.

BACKGROUND: Patients with chronic kidney disease (CKD) require a personalised strategy for cardiovascular risk management (CVRM) to reduce their high risk of cardiovascular morbidity and mortality. Despite their high risk, patients with CKD appear to be underrepresented in randomised controlled trials (RCTs) for pharmacological CVRM interventions to reduce cardiovascular risk (pharmacological CVRM interventions). As a result, it remains unclear whether the efficacy of these interventions found in patients without CKD is similarly applicable to patients with CKD. This evidence map aims to provide an overview of the availability of the evidence from pharmacological CVRM trials for patients with CKD by assessing how often patients with reduced kidney function are specifically excluded or included from RCTs on pharmacological CVRM interventions and whether studies report efficacy estimates of interventions specifically for kidney patients. METHODS: We will perform a systematic literature search in ClinicalTrials.gov to identify relevant planned, ongoing, and completed RCTs on a broad range of CVRM medications after which we will retrieve the published protocols and papers via ClinicalTrials.gov itself, Embase, MEDLINE, or Google Scholar. We will include RCTs that investigate the efficacy of platelet inhibitors, anticoagulants, antihypertensives, glucose-lowering medication, and lipid-lowering medication on all-cause mortality, cardiovascular mortality, cardiovascular morbidity, and end-stage kidney disease in patients with a cardiovascular history or a major risk factor for cardiovascular disease. Two reviewers will independently screen trial records and their corresponding full-text publications to determine eligibility and extract data. Outcomes of interest are the exclusion of patients with reduced kidney function from RCTs and whether the study population was restricted to kidney patients or subgroup analyses were performed on kidney function. Results will be visualised in an evidence map. DISCUSSION: The availability of evidence on the efficacy and safety of pharmacological CVRM interventions in patients with CKD might be limited. Hence, we will identify knowledge gaps for future research. At the same time, the availability of evidence, or lack thereof, might warrant caution from healthcare decision-makers in making strong recommendations based on the extrapolation of results from studies to patients who were explicitly excluded from participation. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022296746.

The best solution down the line: an observational study on taurolidine- versus citrate-based lock solutions for central venous catheters in hemodialysis patients.

INTRODUCTION: To prevent infection and thrombosis of central venous catheters (CVCs) in hemodialysis patients, different CVC lock solutions are available. Taurolidine-based solutions and citrate in different concentrations are frequently used, but no definite conclusions with regard to superiority have been drawn. METHODS: In this retrospective, observational, multicenter study, we aimed to assess the risk for removal of CVC due to infection or catheter malfunction in hemodialysis patients with CVC access for different lock solutions: taurolidine, high-concentrated citrate (46.7%) and low-concentrated citrate (4 or 30%). A multivariable Cox-regression model was used to calculate hazard ratio's (HR). RESULTS: We identified 1514 patients (median age 65 years, 59% male). In 96 (6%) taurolidine-based lock solutions were used. In 1418 (94%) citrate-based lock solutions were used (high-concentrated 73%, low-concentrated 20%). Taurolidine-based lock solutions were associated with a significantly lower hazard for removal of CVC due to infection or malfunction combined (HR 0.34, 95% CI 0.19-0.64), and for removal of CVC due to infection or malfunction separately (HR 0.36, 95% CI 0.15-0.88 and HR0.33, 95% CI 0.14-0.79). High-concentrated citrate lock solutions were not associated with a decreased hazard for our outcomes, compared to low-concentrated citrate lock solutions. CONCLUSION: Removal of CVC due to infection or catheter malfunction occurred less often with taurolidine-based lock solutions. We present the largest cohort comparing taurolidine- and citrate-based lock solutions yet. However, due to the retrospective observational nature of this study, conclusions with regard to superiority should be drawn with caution.

Detection and serotyping of pneumococci in community acquired pneumonia patients without culture using blood and urine samples.

BACKGROUND: Treatment of community acquired pneumonia (CAP) patients with antibiotics before laboratory-confirmed diagnosis leads to loss of knowledge on the causative bacterial pathogen. Therefore, an increasing number of pneumococcal infections is identified using non-culture based techniques. However, methods for serotyping directly on the clinical specimen remain scarce. Here we present three approaches for detection and serotyping of pneumococci using samples from patients with CAP. METHODS: The first approach is quantitative PCR (qPCR) analysis on blood samples (n = 211) followed by capsular sequence typing (CST) to identify the serotype. The second approach, a urinary antigen assay (n = 223), designated as inhibition multiplex immunoassay (IMIA), is based on Luminex technology targeting 14 serotypes. The third approach is a multiplex immunoassay (MIA) (n = 171) also based on Luminex technology which detects serologic antibody responses against 14 serotypes. The three alternative assays were performed on samples obtained from 309 adult hospitalized CAP patients in 2007-2010 and the results were compared with those obtained from conventional laboratory methods to detect pneumococcal CAP, i.e. blood cultures, sputum cultures and BinaxNOW urinary antigen tests. RESULTS: Using qPCR, MIA and IMIA, we were able to detect the pneumococcus in samples of 56% more patients compared to conventional methods. Furthermore, we were able to assign a serotype to the infecting pneumococcus from samples of 25% of all CAP patients, using any of the three serotyping methods (CST, IMIA and MIA). CONCLUSION: This study indicates the usefulness of additional molecular methods to conventional laboratory methods for the detection of pneumococcal pneumonia. Direct detection and subsequent serotyping on clinical samples will improve the accuracy of pneumococcal surveillance to monitor vaccine effectiveness.

Addition of vitamin D status to prognostic scores improves the prediction of outcome in community-acquired pneumonia.

BACKGROUND: Vitamin D plays a role in host defense against infection. Vitamin D deficiency is common worldwide. The prognostic value of vitamin D levels in pneumonia is unknown. In this study, we aimed to investigate the impact of vitamin D status on outcome in community-acquired pneumonia (CAP). METHODS: We conducted a prospective cohort study in 272 hospitalized patients with CAP. Levels of 25-hydroxyvitamin D, leukocytes, C-reactive protein, and total cortisol and the Pneumonia Severity Index (PSI) and CURB-65 scores were measured on admission. Major outcome measures were intensive care unit (ICU) admission and 30-day mortality. RESULTS: One hundred forty-three patients (53%) were vitamin D deficient (<50 nmol/L), 79 patients (29%) were vitamin D insufficient (50-75 nmol/L), and 50 patients (18%) were vitamin D sufficient (>75 nmol/L). Vitamin D deficiency was associated with an increased risk of ICU admission and 30-day mortality. Vitamin D status was an independent predictor of 30-day mortality (area under the curve [AUC] =0.69; 95% confidence interval [CI], .57-.80). Multivariate regression analysis including all predictors for outcome resulted in a final model including vitamin D status and the PSI score, with a significantly higher prognostic accuracy compared with the PSI score alone (AUC=0.83; 95% CI, .71-.94). CONCLUSIONS: Vitamin D deficiency is associated with adverse outcome in CAP. Vitamin D status is an independent predictor of 30-day mortality and adds prognostic value to other biomarkers and prognostic scores, in particular the PSI score. CLINICAL TRIALS REGISTRATION: NCT00471640.

Dexamethasone downregulates the systemic cytokine response in patients with community-acquired pneumonia.

The influence of adjunctive corticosteroids on the cytokine response in community-acquired pneumonia (CAP) is largely unknown. In this study, we analyzed the effect of dexamethasone on the cytokine response in patients with CAP and evaluated whether this effect is dependent on the causative microorganism. We hypothesized that dexamethasone has a larger effect on the cytokine response in patients with pneumococcal pneumonia than in patients with pneumonia caused by an atypical bacterium. A total of 304 hospitalized, nonimmunocompromised patients with CAP were randomized to an adjunctive 4-day course of 5 mg dexamethasone once a day (n = 151) or a placebo (n = 153). Serum concentrations of interleukin-1 receptor antagonist (IL-1Ra), IL-6, IL-8, IL-10, IL-17, tumor necrosis factor alpha (TNF-α), gamma interferon (IFN-γ), macrophage inflammatory protein-1 alpha (MIP-1α), and monocyte chemotactic protein-1 (MCP-1) were measured on days 0, 1, 2, and 4 and at a control visit. Overall, the concentrations of IL-6 (P < 0.01), IL-8 (P < 0.01), MCP-1 (P < 0.01), and TNF-α (P < 0.01) were significantly lower on day 2 in the dexamethasone group than in the placebo group. In patients with pneumococcal pneumonia (n = 72), both treatment groups showed a rapid decrease of cytokine concentrations; only the concentration of TNF-α (P = 0.05) was significantly lower in the dexamethasone group on day 2. In patients with CAP caused by an atypical pathogen (Legionella pneumophila, Chlamydophila species, Coxiella burnetii, or Mycoplasma pneumoniae; n = 58), IL-1Ra (P < 0.01), IL-6 (P < 0.01), and MCP-1 (P = 0.03) decreased more rapidly in the dexamethasone group than in the placebo group. In conclusion, dexamethasone downregulates the cytokine response during CAP. This effect seems to be dependent on the causative microorganism. This study provides insight into which patients with CAP might benefit most from adjunctive dexamethasone.

Biomarkers define the clinical response to dexamethasone in community-acquired pneumonia.

OBJECTIVES: Adjuvant dexamethasone treatment in patients with community-acquired pneumonia (CAP) can reduce length of hospital stay. Whether there are subgroups of patients that especially might benefit from corticosteroids is unknown. We hypothesized that a discrepancy between systemic inflammation and cortisol level can define a subgroup that lacks a sufficient cortisol response during CAP, and therefore particularly might benefit from corticosteroids. METHODS: A secondary analysis was performed on data from hospitalized patients with CAP, randomized to a four-day course of dexamethasone (5 mg daily) or placebo. Subgroups were made based on plasma cytokine levels (interleukin-6 (IL-6), interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1)) and total plasma cortisol on presentation. Intensive care unit (ICU) admission and mortality were assessed. RESULTS: 275 Patients (131 dexamethasone, 144 placebo) were analyzed. In the subgroup of patients (n = 23) with a high cytokine response (IL-6 ≥ 92.5 pg/mL, IL-8 ≥ 14.8 pg/mL and MCP-1 ≥ 1154.5 pg/mL) and a discrepantly low cortisol (lowest 50%), dexamethasone treatment was associated with a significant decrease on a combined endpoint of mortality/ICU admission, as compared with placebo (0% vs. 43%, p < 0.01). In the subgroup of patients with a high cytokine response and high cortisol (n = 23), this favorable effect of dexamethasone was absent (30% vs. 39%, p: 0.67). CONCLUSIONS: In CAP patients presenting with a high pro-inflammatory cytokine response but a discrepantly low cortisol, adjuvant dexamethasone treatment was associated with a significant decrease in mortality/ICU admission.

Changes in serum cortisol levels during community-acquired pneumonia: the influence of dexamethasone.

In community-acquired pneumonia (CAP), the cortisol level on admission can be a useful biomarker for prognosis. Serial cortisol measurements during the clinical course of disease and their association with disease outcome have never been reported. Furthermore, the time to recovery of the hypothalamic-pituitary-adrenal axis after a short course of dexamethasone during infection is unclear. We analyzed data from 270 hospitalized patients with CAP. Total serum cortisol was measured on presentation, day 1, 2, 4, and on control visit (day 30). Intensive care unit (ICU) admission and mortality were assessed. Additionally, to study the influence of dexamethasone on the kinetics of the cortisol response, we analyzed serial cortisol values of 43 patients treated with a four-day regimen of dexamethasone 5 mg. During hospital stay, 26/270 patients (9.6%) were admitted to the ICU and 15/270 patients (5.6%) died. Compared to patients with an uneventful recovery, cortisol on presentation was significantly higher in patients with an adverse outcome (360 µg/L, IQR 209-597 vs. 238 µg/L, IQR 151-374) (p:0.01), and also remained significantly higher throughout the course of disease. Dexamethasone treatment resulted in nearly complete suppression of the endogenous cortisol production after the first dose, but cortisol production was fully recovered on control visit. In conclusion, we showed that an adverse outcome of CAP was associated with persisting higher total serum cortisol throughout the course of disease. Delta-cortisol could be another meaningful biomarker in CAP. Next, our data indicate that a four-day dexamethasone regimen during CAP does not lead to prolonged secondary adrenal insufficiency.

Dexamethasone treatment has no effect on the formation of pneumococcal antibodies during community-acquired pneumonia.

In this study, the effect of dexamethasone on the formation of pneumococcal antibodies during community-acquired pneumonia (CAP) was investigated. No differences between CAP patients receiving dexamethasone as additional therapy and patients receiving a placebo were found with respect to immune response rates and mean baseline and convalescent-phase antibody concentrations.

Incidence and predictive value of proteinuria in community-acquired pneumonia.

BACKGROUND/AIMS: The presence of baseline proteinuria predicts the outcome in patients with chronic kidney disease and in the general population, independent of renal function. However, the predictive value of proteinuria during an episode of acute illness has not been reported yet. Therefore, we investigated the incidence and predictive value of proteinuria in patients with community-acquired pneumonia. METHODS: An analysis of prospectively collected data, obtained from patients >18 years of age, was performed. Patients were hospitalized with community-acquired pneumonia in two hospitals in the Netherlands and participated in two consecutive clinical trials. A total protein/creatinine (P/C) ratio was measured in a urine sample from the day of admission. Patients were categorized in quartiles of P/C ratio. Primary outcome was length of hospital stay. RESULTS: 198/319 patients (62%) had a P/C ratio >23 mg/mmol creatinine. In multivariate analysis, proteinuria turned out to be an independent predictor for length of stay and admission to the intensive care unit. CONCLUSION: The incidence of proteinuria during pneumonia is high and proteinuria is an independent predictor for length of hospital stay and admission to the intensive care unit. Proteinuria is a cheap and easily accessible marker for outcome and might be used to assess the severity of pneumonia.

Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Whether addition of corticosteroids to antibiotic treatment benefits patients with community-acquired pneumonia who are not in intensive care units is unclear. We aimed to assess effect of addition of dexamethasone on length of stay in this group, which might result in earlier resolution of pneumonia through dampening of systemic inflammation. METHODS: In our double-blind, placebo-controlled trial, we randomly assigned adults aged 18 years or older with confirmed community-acquired pneumonia who presented to emergency departments of two teaching hospitals in the Netherlands to receive intravenous dexamethasone (5 mg once a day) or placebo for 4 days from admission. Patients were ineligible if they were immunocompromised, needed immediate transfer to an intensive-care unit, or were already receiving corticosteroids or immunosuppressive drugs. We randomly allocated patients on a one-to-one basis to treatment groups with a computerised randomisation allocation sequence in blocks of 20. The primary outcome was length of hospital stay in all enrolled patients. This study is registered with ClinicalTrials.gov, number NCT00471640. FINDINGS: Between November, 2007, and September, 2010, we enrolled 304 patients and randomly allocated 153 to the placebo group and 151 to the dexamethasone group. 143 (47%) of 304 enrolled patients had pneumonia of pneumonia severity index class 4-5 (79 [52%] patients in the dexamethasone group and 64 [42%] controls). Median length of stay was 6·5 days (IQR 5·0-9·0) in the dexamethasone group compared with 7·5 days (5·3-11·5) in the placebo group (95% CI of difference in medians 0-2 days; p=0·0480). In-hospital mortality and severe adverse events were infrequent and rates did not differ between groups, although 67 (44%) of 151 patients in the dexamethasone group had hyperglycaemia compared with 35 (23%) of 153 controls (p<0·0001). INTERPRETATION: Dexamethasone can reduce length of hospital stay when added to antibiotic treatment in non-immunocompromised patients with community-acquired pneumonia. FUNDING: None.

Prognostic value of serum angiotensin-converting enzyme activity for outcome of community-acquired pneumonia.

BACKGROUND: In a previous study, a relation between decreased serum angiotensin-converting enzyme (ACE) activity and physiological parameters was observed in patients with community-acquired pneumonia. The present study aims to further assess the prognostic value of serum ACE activity for outcome of community-acquired pneumonia. METHODS: This was a prospective observational study including two cohorts of patients with community-acquired pneumonia (2004-2006; n=157 and 2007-2010; n=138). Serum ACE activity was measured at time of hospital admission. Based on reference values in healthy persons, patients were divided into subgroups of serum ACE activity: normal, low and extremely low. Physiological parameters, clinical outcomes and etiology were compared between the subgroups. RESULTS: A total of 265 patients were enrolled in this study. Mean age was 60±19 years. In patients with low serum ACE activity (<20 U/L, n=53), compared to patients with normal serum ACE activity (≥20 U/L, n=212), C-reactive protein (CRP) was significantly increased, systolic blood pressure was significantly lower and there was a trend for higher heart rate and leukocyte counts. Furthermore, Streptococcus pneumoniae was significantly more identified in patients with low serum ACE activity. Serum ACE activity <24 U/L was independently associated with bacteremia (adjusted OR 3.93 [95% CI 1.57-9.87]). Low serum ACE activity was not prognostic for length of hospital stay nor mortality. CONCLUSIONS: This study did not show prognostic value for serum ACE activity regarding clinical outcome in patients with community-acquired pneumonia. Serum ACE activity <24 U/L at time of hospitalization appeared an independent indicator for the presence of bacteremia. Further research should elucidate the role of ACE in systemic infection and sepsis during pneumonia.

Longitudinal analysis of pneumococcal antibodies during community-acquired pneumonia reveals a much higher involvement of Streptococcus pneumoniae than estimated by conventional methods alone.

In up to half of all cases of community-acquired pneumonia (CAP), no pathogen can be identified with conventional diagnostic methods. The most common identified causative agent is Streptococcus pneumoniae. In this study, pneumococcal antibody responses during CAP were analyzed to estimate the contribution of the pneumococcus to all cases of CAP for epidemiological purposes. Pneumococcal antibodies against 14 different serotypes were measured in serum of hospitalized CAP patients. Patients participated in one of two consecutive clinical trials in a general 600-bed teaching hospital in the Netherlands (between October 2004 and June 2009). A significant pneumococcal immune response was defined as at least a 2-fold increase in antibody concentrations against a single serotype between an early (day 1) and a late (day 30) serum sample of each patient with an end concentration above 0.35 µg/ml. A total of 349 adult CAP patients participated in two consecutive clinical trials. For 200 patients, sufficient serum samples were available to determine antibody responses: 62 pneumococcal pneumonia patients, 57 nonpneumococcal pneumonia patients, and 81 patients with an unidentified causative agent. A significant immune response was detected in 45% (28/62 patients) of pneumococcal pneumonia patients, in 5% (3/57) of nonpneumococcal pneumonia patients, and in 28% (23/81) of patients with an unidentified causative agent. The estimated contribution of pneumococci in patients with an unidentified causative agent was calculated to be 57% (95% confidence interval, 36 to 86%). A substantial fraction of pneumococcal pneumonia patients do not elicit a serotype-specific immune response.

Mannose-binding lectin (MBL2) and ficolin-2 (FCN2) polymorphisms in patients on peritoneal dialysis with staphylococcal peritonitis.

BACKGROUND: Mannose-binding lectin (MBL) and ficolin-2 (FCN) are activators of the lectin pathway of complement and act as primary defences against infection. Single-nucleotide polymorphisms (SNPs) in the MBL2 and FCN2 genes influence the functionality of the proteins. Both proteins are capable of binding staphylococci, which are pathogens that frequently cause peritonitis in patients on continuous ambulatory peritoneal dialysis (CAPD). We studied the role of polymorphisms in the MBL2 and FCN2 genes as a risk factor for developing CAPD peritonitis caused by staphylococci. METHODS: We analysed SNPs in the MBL2 and FCN2 genes in 40 CAPD patients with staphylococcal peritonitis and in 65 CAPD patients without any history of peritonitis. Additionally, we analysed the prevalence of exit site infections and nasal Staphylococcus aureus carriage in both groups. RESULTS: The + 6359C > T SNP leading to the Thr236Met amino acid alteration in the FCN2 gene, associated with decreased substrate binding, was significantly more prevalent in CAPD patients with a history of staphylococcal peritonitis compared with patients on CAPD without a history of peritonitis (P = 0.037). No difference was found in MBL2 genotypes between the two groups. In CAPD patients with a history of staphylococcal peritonitis, exit site infection with S. aureus was also more prevalent (P < 0.01), while S. aureus carriage was not (P = 0.073). CONCLUSIONS: In addition to known risk factors such as exit site infection, the + 6359C > T SNP in the FCN2 gene might be a risk factor for staphylococcal peritonitis in CAPD patients due to decreased binding of FCN to staphylococci.