Distinct inflammatory profile underlies pathological increases in creatinine levels associated with <i>Plasmodium vivax</i> malaria clinical severity

<div><p>Background</p><p>Although <i>Plasmodium vivax</i> infection is a frequent cause of malaria worldwide, severe presentations have been more regularly described only in recent years. In this setting, despite clinical descriptions of multi-organ involvement, data associating it with kidney dysfunction are relatively scarce. Here, renal dysfunction is retrospectively analyzed in a large cohort of vivax malaria patients with an attempt to dissect its association with disease severity and mortality, and to determine the role of inflammation in its progression.</p><p>Methods</p><p>A retrospective analysis of a databank containing 572 individuals from the Brazilian Amazon, including 179 patients with <i>P</i>. <i>vivax</i> monoinfection (161 symptomatic malaria, 12 severe non-lethal malaria, and 6 severe lethal disease) and 165 healthy controls, was performed. Data on levels of cytokines, chemokines, C-reactive protein (CRP), fibrinogen, creatinine, hepatic enzymes, bilirubin levels, free heme, and haptoglobin were analyzed to depict and compare profiles from patients per creatinine levels.</p><p>Results</p><p>Elevated creatinine levels were found predominantly in women. Vivax malaria severity was highly associated with abnormal creatinine increases, and nonsurvivors presented the highest values of serum creatinine. Indication of kidney dysfunction was not associated with parasitemia levels. IFN-γ/IL-10 ratio and CRP values marked the immune biosignature of vivax malaria patients, and could distinguish subjects with elevated creatinine levels who did not survive from those who did. Patients with elevated serum creatinine or severe vivax malaria displayed indication of cholestasis. Biomarkers of hemolysis did not follow increases in serum creatinine.</p><p>Conclusion</p><p>These findings reinforce the hypothesis that renal dysfunction is a key component in <i>P</i>. <i>vivax</i> malaria associated with clinical severity and mortality, possibly through intense inflammation and immune imbalance. Our study argues for systematic evaluation of kidney function as part of the clinical assessment in vivax malaria patients, and warrants additional studies in experimental models for further mechanism investigations.</p></div

Characteristics of the <i>Plasmodium vivax</i> malaria patients with elevated or normal creatinine levels.

<p>Characteristics of the <i>Plasmodium vivax</i> malaria patients with elevated or normal creatinine levels.</p

Inflammatory profile of patients with acute <i>Plasmodium vivax</i> malaria exhibiting abnormally high levels of creatinine.

<p>(A) Overall profile of plasma concentrations of several biochemical parameters, cytokines and chemokines in uninfected controls (n = 165) as well as in vivax malaria patients presenting with creatinine levels within the normal range (n = 90) or abnormally elevated (n = 89). Data were processed using hierarchical cluster analysis (Ward’s method) with 100X bootstrap. Dendograms represent hierarchical distance. Asterisks indicate parameters which were statistically different between the groups of malaria patients with normal or elevated creatinine levels assessed using the Mann-Whitney <i>U</i> test. Scatter plots of these parameters are shown in (B). The IFN-γ/IL-10 ratio, which has been shown to correlate with the inflammatory imbalance in vivax malaria (4), was also compared between the study groups. Bars represent median values.</p

Distribution of serum creatinine levels and clinical outcomes in patients with acute <i>Plasmodium vivax</i> malaria.

<p>(A) Histogram representing serum creatinine levels of the 179 patients with <i>P</i>. <i>vivax</i> monoinfection; the patients are colored accordingly to the disease outcome. Survivors are colored in grey, while nonsurvivors are colored in red. Reference intervals for men and women are displayed by transversal lines, with lower limit representing its reference for women, and upper limit representing its reference for men. (B) Scatter-plot of the creatinine levels presented by the subgroups of nonsurvivors and survivors amongst the subjects with elevated serum creatinine. Data analysis was performed using the Mann-Whitney <i>U</i> test. Bars represent median values.</p

Summary of the sampling methods used in the study.

<p>A total of 2,398 students were registered in the medical school within the period of the study, from 1994 to 2003. Two different approaches were used to assess the two major objectives of the study. (A) In order to predict the academic performance over time, only students with registered scores in the first, second and eight semesters from 1994 until 2003 were included (n = 1,071). (B) With an attempt to evaluate the different courses' long-term patterns, mean scores from all the students in each course (n = 2,398) was calculated in each year of the study period.</p

Scores distribution in different types of course assessments.

<p>A retrospective observation was performed from 1994 to 2003, evaluating grades from all students regularly registered in the mandatory courses from the curriculum of the School of Medicine, Federal University of Bahia (UFBA). Three major patterns of grade distribution were noted and representative courses were used to illustrate the differences. Thus, some courses presented growth assessment over time (upward trend; A) while others presented oscillating (erratic trend; B) or regular (low variation trend; C) assessments during the period of the study. Full vertical lines represent the global means for each course. Dashed lines represent ±1 standard deviation (SD). Dots and whiskers represent the mean grade and standard error of each semester.</p

Prediction of student grade performance in later semesters of medical study using scores from the first semester.

<p>Linear regression was performed to estimate the causal effect of the performance on the first semester on the second or eighth semesters. A total of 1,071 students registers were used. 95%CI: 95% confidence interval.</p><p>*p<0.05.</p

Correlation between scores of the students from the first and second or eighth semesters.

<p>The global score obtained from each student in the first semester of medical school was correlated with the scores obtained in the second (A) or eighth (B) semesters using the Pearson coefficient (n = 1,071). Linear regression was used to illustrate the general trend of the correlations. The p and r values are plotted in each graph.</p

Establishing a cut-off grade in the first semester to predict students' performances in the second or eighth semesters.

<p>ROC curves were built to identify a cut-off grade in the first semester that can predict the students' performances in the second (A) or in the eighth (B) semesters. The cut-off value represents the average grade in the first semester that presented the higher sensitivity and specificity with a considerable likelihood ratio to predict that the further grades will be place in the lower quartile in the subsequent semesters. C-statistics are illustrated next to the curves and were used to verify the validation of the ROC curves and to establish the predictive power of the cut-off grade. AUC, area under the curve; CI, confidence interval.</p

Zinc/copper imbalance reflects immune dysfunction in human leishmaniasis: an ex vivo and in vitro study-2

<p><b>Copyright information:</b></p><p>Taken from "Zinc/copper imbalance reflects immune dysfunction in human leishmaniasis: an ex vivo and in vitro study"</p><p>BMC Infectious Diseases 2004;4():50-50.</p><p>Published online 17 Nov 2004</p><p>PMCID:PMC534101.</p><p>Copyright © 2004 Van Weyenbergh et al; licensee BioMed Central Ltd.</p> ng/ml), Cu (10 μM CuCl) or both. Bars represent mean (+/-SEM) IFN-γ concentration in supernatants from six different donors. Unstimulated cells or cells stimulated with Cu alone did not produce IFN-γ. *p < 0.05 . anti-CD3-stimulated cells (Wilcoxon signed rank test)