A prospective observational cohort study to identify inflammatory biomarkers for the diagnosis and prognosis of patients with sepsis.

BACKGROUND: Sepsis is a life-threatening organ dysfunction. A fast diagnosis is crucial for patient management. Proteins that are synthesized during the inflammatory response can be used as biomarkers, helping in a rapid clinical assessment or an early diagnosis of infection. The aim of this study was to identify biomarkers of inflammation for the diagnosis and prognosis of infection in patients with suspected sepsis. METHODS: In total 406 episodes were included in a prospective cohort study. Plasma was collected from all patients with suspected sepsis, for whom blood cultures were drawn, in the emergency department (ED), the department of infectious diseases, or the haemodialysis unit on the first day of a new episode. Samples were analysed using a 92-plex proteomic panel based on a proximity extension assay with oligonucleotide-labelled antibody probe pairs (OLink, Uppsala, Sweden). Supervised and unsupervised differential expression analyses and pathway enrichment analyses were performed to search for inflammatory proteins that were different between patients with viral or bacterial sepsis and between patients with worse or less severe outcome. RESULTS: Supervised differential expression analysis revealed 21 proteins that were significantly lower in circulation of patients with viral infections compared to patients with bacterial infections. More strongly, higher expression levels were observed for 38 proteins in patients with high SOFA scores (> 4), and for 21 proteins in patients with worse outcome. These proteins are mostly involved in pathways known to be activated early in the inflammatory response. Unsupervised, hierarchical clustering confirmed that inflammatory response was more strongly related to disease severity than to aetiology. CONCLUSION: Several differentially expressed inflammatory proteins were identified that could be used as biomarkers for sepsis. These proteins are mostly related to disease severity. Within the setting of an emergency department, they could be used for outcome prediction, patient monitoring, and directing diagnostics. TRAIL REGISTRATION NUMBER: clinicaltrial.gov identifier NCT03841162.

Haemodynamic or metabolic stimulation tests to reveal the renal functional response: requiem or revival?

Renal stimulation tests document the dynamic response of the glomerular filtration rate (GFR) after a single or a combination of stimuli, such as an intravenous infusion of dopamine or amino acids or an oral protein meal. The increment of the GFR above the unstimulated state has formerly been called the renal functional reserve (RFR). Although the concept of a renal reserve capacity has not withstood scientific scrutiny, the literature documenting renal stimulation merits renewed interest. An absent or a blunted response of the GFR after a stimulus indicates lost or diseased nephrons. This information is valuable in preventing, diagnosing and prognosticating acute kidney injury and pregnancy-related renal events as well as chronic kidney disease. However, before renal function testing is universally practiced, some shortcomings must be addressed. First, a common nomenclature should be decided upon. The expression of RFR should be replaced by renal functional response. Second, a simple protocol must be developed and propagated. Third, we suggest designing prospective studies linking a defective stimulatory response to emergence of renal injury biomarkers, to histological or morphological renal abnormalities and to adverse renal outcomes in different renal syndromes.

Immunogenicity of a standard trivalent influenza vaccine in patients on long-term hemodialysis: an open-label trial.

BACKGROUND: Disturbances in acquired immunity are considered to be responsible, at least in part, for the high infection rate and inadequate response to vaccinations observed in hemodialysis (HD) patients. The present prospective trial aimed to: (1) evaluate the immunogenicity of a standard influenza vaccine in HD patients, and (2) identify determinants of the immune response. STUDY DESIGN: Prospective interventional open-label study. SETTING & PARTICIPANTS: 201 long-term HD patients and 41 healthy volunteers. INTERVENTION: Vaccination with a standard trivalent inactivated influenza vaccine. OUTCOMES: The primary outcome was seroprotection rate, defined as percentage of participants with an antibody titer of 40 or greater 1 month after vaccination. MEASUREMENTS: All antibody titers were determined in duplicate by using the hemagglutination inhibition assay. Regression analyses were performed to investigate the association between demographics, uremic retention solutes (including p-cresol), inflammation, nutrition, iron status, trace elements, and immune response in HD patients. RESULTS: More than 80% of HD patients showed seroprotection after vaccination. The immune response of HD patients was similar to that of healthy volunteers. Booster vaccination did not improve the immune response. High serum ferritin level was the only parameter independently associated with a better vaccination-induced antibody response in HD patients. LIMITATIONS: A high seroprotection rate at baseline undermined the power to identify clinical determinants of the immune response. CONCLUSIONS: Influenza vaccination is as efficacious in HD patients as in healthy volunteers. With the exception of serum ferritin, none of the investigated parameters of nutrition, inflammation, and dialysis adequacy had a significant impact on the immune response. Our data support annual vaccination of HD patients and question the clinical relevance of disturbances in acquired immunity in contemporary HD patients.

Long-term efficacy and tolerability of lanthanum carbonate: results from a 3-year study.

BACKGROUND: Control of serum phosphate over the long term is essential in patients with end-stage renal disease. Six-month and 2-year extensions to a 6-month study evaluated the long-term safety, tolerability and efficacy of the new phosphate binder lanthanum carbonate. METHODS: Patients who participated in a 6-month, randomized trial comparing lanthanum carbonate with calcium carbonate were eligible for a 24-week, open-label extension. Lanthanum carbonate-treated patients continued taking their established maintenance dose ('continued-lanthanum group') and calcium carbonate-treated patients switched to lanthanum carbonate, 375-3,000 mg/day ('switch group'). Patients could also enter a further 2-year extension. Efficacy parameters, including serum phosphate, were monitored. RESULTS: Mean serum phosphate was approximately 1.80 mmol/l throughout the trial. The percentage of patients with controlled serum phosphate (< or =1.80 mmol/l) after the 6-month extension was 63.3 and 58.4% in the continued-lanthanum and switch groups, respectively; after the 2-year extension, 54.4% of patients had controlled serum phosphate. After discontinuation of calcium carbonate and initiation of lanthanum carbonate, the hypercalcemia incidence was 2.7%, compared with 20.2% during the double-blind phase. Calcium x phosphate product was maintained at an acceptable level. Lanthanum carbonate was well tolerated; adverse events were mild/moderate and mainly gastrointestinal. CONCLUSIONS: Lanthanum carbonate maintains effectiveness with continued tolerability for up to 3 years.

Mycophenolate mofetil in IgA nephropathy: results of a 3-year prospective placebo-controlled randomized study.

BACKGROUND: Because humoral immunity is believed to play a pivotal role in the pathogenesis of IgA nephropathy (IgAN), a prospective placebo-controlled randomized study was started in patients with IgAN using mycophenolate mofetil (MMF). METHODS: A total of 34 patients with IgAN were treated with salt intake restriction, angiotensin-converting enzyme (ACE) inhibition and MMF 2 g per day (N= 21) or placebo (N= 13). After 36 months of follow-up clinical, biochemical, and radiologic data were analyzed using linear mixed models for longitudinal data and Kaplan-Meier survival analysis. RESULTS: Therapy had to be stopped prematurely in five patients. Two patients (MMF group) evolved to end-stage renal disease (ESRD). There was no difference between groups in the percentage of patients with a decrease of 25% or more in the inulin clearance or with a serum creatinine increase of 50% or more over 3 years. There was also no significant difference between groups in annualized rate of change of serum creatinine, computed by linear regression analysis. No significant difference was noted between groups for inulin clearance, serum creatinine, proteinuria, blood pressure, or other parameters of renal function. Hemoglobin and C-reactive protein were significantly lower in the MMF group compared with the placebo group. As a function of time, a significant decline in both groups was noted of proteinuria, parenchymal thickness of the kidneys and C3d. CONCLUSION: In patients with IgAN at risk for progressive disease, no beneficial effect of 3-year treatment with MMF 2 g per day could be demonstrated on renal function/outcome or proteinuria. However, larger randomized studies are needed to confirm or reject these results.

The value of tuberculin skin testing in haemodialysis patients.

BACKGROUND: Chronic haemodialysis patients are at increased risk for developing tuberculosis (TB). Appropriate screening methods to detect latent Mycobacterium tuberculosis infection are required. The aim of this prospective multi-centre study was to evaluate the tuberculin skin test (TST) as a screening method for detection of M.tuberculosis infection in haemodialysis patients. METHODS: A total of 224 patients in two haemodialysis centres were prospectively tested, using 2 units of tuberculin PPD RT23. Up to three booster injections were given with a 7 day interval to patients not responding to the previous test. The results were compared with clinical and radiological data. RESULTS: The cumulative prevalence of a positive TST was 14.7% for the first test, 27.8% for the second test and 32.6% for the fourth test. There was no influence of age, gender, haemodialysis centre, dialysis efficiency, nutritional state, levels of zinc, vitamin D therapy, primary renal disease, (previous or active) immunosuppressive therapy or response to hepatitis B vaccination. There was a significant, but weak, correlation between TST positivity and a history of positive TST or TB. Chest radiography and positive TST were not correlated, yet a positive chest X-ray increased the detection of patients with latent M.tuberculosis infection up to 47.8%. CONCLUSIONS: In haemodialysis patients, a positive response of >30% to repeated TST was obtained. Two consecutive TSTs were sufficient to recruit most of the booster reactions. Since only a weak correlation was found with anamnestic data, regular TST evaluation in combination with a chest X-ray, is a useful tool to detect infection with M.tuberculosis in haemodialysis patients.

Regional citrate anticoagulation for hemodialysis using a conventional calcium-containing dialysate.

Regional citrate anticoagulation is currently a frequently applied technique for hemodialysis patients at increased risk of bleeding. Most experience exists with isotonic citrate in combination with a calcium-free dialysate and separate substitution with calcium chloride. This method is effective, but rather cumbersome and laborious. In search for a less demanding, but equally safe and effective technique, we performed 203 double-needle hemodialysis sessions in 45 patients at high risk of bleeding using regional anticoagulation with hypertonic trisodium citrate (TSC) and a conventional calcium-containing dialysate. At the start of dialysis, citrate was infused at a rate of 75 mL/h; adjustments were made during dialysis according to the degree of anticoagulation and level of ionized calcium within the systemic circuit. The efficacy and short-term safety of regional anticoagulation with TSC as compared with heparin anticoagulation was ascertained in a cohort of 19 stable hemodialysis patients. Systemic anticoagulation did not occur, and plasma-ionized calcium remained on a stable level. Manifestations of citrate toxicity or hypocalcemia were not observed. Clotting within the dialyzer was noted in 18 of the 203 sessions (8.87%) and resulted in early termination of dialysis in only 3 cases (1.48%). In conclusion, the use of hypertonic TSC and a conventional calcium-containing dialysate was shown to be safe and effective. The risk of clotting of the extracorporeal circuit is limited and outweighed by the advantage of reduced procedural complexity. Compared with the use of a calcium-free dialysate, the number of analyses can be reduced substantially, making this method financially attractive.