[Computer morphometry of peripheral blood lymphocytes in elderly patients with chronic pyelonephritis.]

The aim of the study was to investigate the peculiarities of morphometric parameters of peripheral blood lymphocytes in chronic pyelonephritis in elderly patients in comparison with young and middle-aged patients. A total of 81 patients with chronic pyelonephritis in the exacerbation phase were examined. All patients were divided into three age groups according to WHO recommendations: the 1st - 42patients of young age (18-44 years); the 2nd - 17 patients of middle age (45-59 years); the 3rd - 22 elderly patients (60-74 years). Computer morphometry of lymphocytes was performed in all examined patients. In elderly patients with chronic pyelonephritis the size and сytoplasmic-nuclear ratio of lymphocytes increase. This indicates the preservation of lymphocyte defense responses at this age. In male patients with chronic pyelonephritis in the 1st and 2nd age groups the size of lymphocytes increases, and in female patients - decreases. The сytoplasmic-nuclear ratio increases in males of these age groups, while it remains unchanged or decreases in females. Indirect indications of reduced immunity in young and middle-aged women with chronic inflammation in the kidneys have been obtained.

[Influence of standard treatment on changes in the structural and functional properties of circulation red blood cells in obstructive and non-obstructive acute pyelonephritis].

AIM: To determine the effect of standard treatment on changes in the structural and functional properties of erythrocytes in obstructive and non-obstructive acute pyelonephritis. MATERIALS AND METHODS: The structural and functional properties of erythrocytes and their intracellular metabolism in 78 patients with a diagnosis of primary non-obstructive and secondary obstructive acute pyelonephritis, randomized by age, gender, and the minimum number of concomitant diseases were investigated. RESULTS AND DISCUSSION: In acute non-obstructive pyelonephritis, changes of the content of proteins in circulating erythrocytes responsible for the structure formation and stabilization of the plasma membrane (-spectrin, anion transport protein, pallidin, protein 4.1), intracellular metabolism (anion transport protein, glutathione-S-transferase), membrane flexibility and shape (actin, tropomyosin) are insignificant, alike from acute obstructive pyelonephritis. In addition, processes of lipid peroxidation inside red blood cells are intensified, and oxidative stress develops with a decrease in the sorption capacity of erythrocytes, as well as the content and ratio of lipid fractions in the plasma membrane, which form the basis of the lipid components and play the main role in the sequencing of protein macromolecules and the normal metabolism of red blood cells. CONCLUSION: In acute obstructive pyelonephritis, changes in the content and ratio of proteins and lipids in the erythrocyte membrane lead to functional rearrangements that are not corrected by standard treatment.

The prognostic value of serum procalcitonin in acute obstructive pyelonephritis.

PURPOSE: To evaluate the prognostic value of procalcitonin (PCT) in the occurrence of infectious complications in the management of acute obstructive pyelonephritis (AOP) compared with other biological parameters (leucocyte count, C-reactive protein [CRP]). METHODS: We conducted a retrospective study including patients who were treated for AOP and performed serum PCT tests in our center between January 1, 2017 and December 31, 2017. Upper urinary tract obstruction was confirmed by either ultrasound or CT urography. Clinical examinations and laboratory tests including leukocyte count, CRP, urine and blood cultures, and serum PCT measurements were performed in the emergency unit. Treatment included early renal decompression using indwelling ureteral stents or nephrostomy and empiric antibiotic therapy. The primary endpoint was occurrence of severe sepsis (SS), a composite criterion including urosepsis and/or septic shock and/or admission to the intensive care unit (ICU) and/or death. RESULTS: A total of 110 patients (median age: 61 years) were included, of whom 56.3% were female. SS occurred in 39 cases (35.4%). Multivariate regression analysis showed that serum PCT (OR 1.08; 95% CI 1.03-1.17; p = 0.01), CRP (OR 1.007; 95% CI 1.001-1.015; p = 0.03), and diabetes mellitus (OR 5.1; 95% CI 1.27-27.24; p = 0.04) were independent predictors for SS. Serum PCT was the biological marker associated with the highest accuracy to predict SS (ROC 0.912 (95% CI 0.861-0.962) and was superior to CRP (p < 0.001): the sensitivity and specificity of PCT to predict SS were 95% and 77%, respectively, with a serum PCT cutoff value of 1.12 µg/L. CONCLUSIONS: PCT levels > 1.12 µg/L could help physicians to identify high-risk patients who could benefit from early and aggressive management in collaboration with intensive care specialists.

Procalcitonin, C-reactive protein, and erythrocyte sedimentation rate for the diagnosis of acute pyelonephritis in children.

BACKGROUND: In children with urinary tract infection (UTI), only those with pyelonephritis (and not cystitis) are at risk for developing long-term renal sequelae. If non-invasive biomarkers could accurately differentiate children with cystitis from children with pyelonephritis, treatment and follow-up could potentially be individualized. This is an update of a review first published in 2015. OBJECTIVES: The objectives of this review were to 1) determine whether procalcitonin (PCT), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) can replace the acute DMSA scan in the diagnostic evaluation of children with UTI; 2) assess the influence of patient and study characteristics on the diagnostic accuracy of these tests, and 3) compare the performance of the three tests to each other. SEARCH METHODS: We searched MEDLINE, EMBASE, DARE, Web of Science, and BIOSIS Previews through to 17th December 2019 for this review. The reference lists of all included articles and relevant systematic reviews were searched to identify additional studies not found through the electronic search. SELECTION CRITERIA: We only considered published studies that evaluated the results of an index test (PCT, CRP, ESR) against the results of an acute-phase 99Tc-dimercaptosuccinic acid (DMSA) scan (conducted within 30 days of the UTI) in children aged 0 to 18 years with a culture-confirmed episode of UTI. The following cut-off values were used for the primary analysis: 0.5 ng/mL for procalcitonin, 20 mg/L for CRP and 30 mm/hour for ESR. DATA COLLECTION AND ANALYSIS: Two authors independently applied the selection criteria to all citations and independently abstracted data. We used the bivariate model to calculate pooled random-effects pooled sensitivity and specificity values. MAIN RESULTS: A total of 36 studies met our inclusion criteria. Twenty-five studies provided data for the primary analysis: 12 studies (1000 children) included data on PCT, 16 studies (1895 children) included data on CRP, and eight studies (1910 children) included data on ESR (some studies had data on more than one test). The summary sensitivity estimates (95% CI) for the PCT, CRP, ESR tests at the aforementioned cut-offs were 0.81 (0.67 to 0.90), 0.93 (0.86 to 0.96), and 0.83 (0.71 to 0.91), respectively. The summary specificity values for PCT, CRP, and ESR tests at these cut-offs were 0.76 (0.66 to 0.84), 0.37 (0.24 to 0.53), and 0.57 (0.41 to 0.72), respectively. AUTHORS' CONCLUSIONS: The ESR test does not appear to be sufficiently accurate to be helpful in differentiating children with cystitis from children with pyelonephritis. A low CRP value (< 20 mg/L) appears to be somewhat useful in ruling out pyelonephritis (decreasing the probability of pyelonephritis to < 20%), but unexplained heterogeneity in the data prevents us from making recommendations at this time. The procalcitonin test seems better suited for ruling in pyelonephritis, but the limited number of studies and the marked heterogeneity between studies prevents us from reaching definitive conclusions. Thus, at present, we do not find any compelling evidence to recommend the routine use of any of these tests in clinical practice.

Presepsin and procalcitonin as predictors of sepsis based on the new Sepsis-3 definitions in obstructive acute pyelonephritis.

BACKGROUND: Acute pyelonephritis (APN) with obstructive uropathy often causes sepsis. Recently, sepsis was redefined using the sequential organ failure assessment (SOFA) score, based on the new Sepsis-3 criteria. We investigated predictors for sepsis using this new definition in patients with obstructive APN associated with upper urinary tract calculi. METHODS: We retrospectively evaluated patients who were admitted to our hospital for treatment of obstructive APN associated with upper urinary tract calculi. Blood and urine samples were collected before treatment of obstructive APN. Treatment included adequate antimicrobial therapy and emergency drainage to decompress the renal collecting system. We diagnosed sepsis using the new Sepsis-3 definition. We assessed predictors for sepsis by multivariate logistic regression analysis. RESULTS: Sixty-one patients were included in this study. Overall, all patients underwent emergency drainage, and 11 (18.0%) patients showed sepsis. There were no significant differences in performance status or comorbidities between sepsis and non-sepsis groups. Platelet count and serum albumin level were significantly lower in the sepsis group than in the non-sepsis group (p = 0.001 and p = 0.016, respectively). Procalcitonin (PCT) and presepsin (PSEP) levels were significantly higher in the sepsis group than in the non-sepsis group (p < 0.001 and p < 0.001, respectively). Multivariate analysis showed that PCT elevation (OR = 13.12, p = 0.024) and PSEP elevation (OR = 13.13, p = 0.044) were independent predictors for sepsis. CONCLUSIONS: Elevation of PCT and PSEP levels before treatment might predict the development of sepsis in patients with obstructive APN.

Application of the Hartford Hospital Nomogram for Plazomicin Dosing Interval Selection in Patients with Complicated Urinary Tract Infection.

Plazomicin is a new FDA-approved aminoglycoside antibiotic for complicated urinary tract infections (cUTI). In the product labeling, trough-based therapeutic drug management (TDM) is recommended for cUTI patients with renal impairment to prevent elevated trough concentrations associated with serum creatinine increases of ≥0.5 mg/dl above baseline. Herein, the utility of the Hartford nomogram to prevent plazomicin trough concentrations exceeding the TDM trough of 3 µg/ml and optimize the area under the curve (AUC) was assessed. The AUC reference range was defined as the 5th to 95th percentile AUC observed in the phase 3 cUTI trial (EPIC) (121 to 368 µg · h/ml). Observed 10-h plazomicin concentrations from patients in EPIC (n = 281) were plotted on the nomogram to determine an eligible dosing interval (every 24 h [q24h], q36h, q48h). Based on creatinine clearance (CLcr), a 15- or 10-mg/kg of body weight dose was simulated with the nomogram-derived interval. The nomogram recommended an extended interval (q36h and q48h) in 31% of patients. Compared with the 15 mg/kg q24h regimen received by patients with CLcr of ≥60 ml/min in EPIC, the nomogram-derived interval reduced the proportion of patients with troughs of ≥3 µg/ml (q36h, 27% versus 0%, P = 0.021; q48h, 57% versus 0%, P = 0.002) while significantly increasing the number of patients within the AUC range. Compared with the 8 to 12 mg/kg q24h regimen (received by patients with CLcr of >30 to 59 ml/min in EPIC), the nomogram-derived interval significantly reduced the proportion of troughs of ≥3µg/ml in the q48h cohort (72% versus 0%, P < 0.001) while maintaining a similar proportion of patients in the AUC range. Simulated application of the Hartford nomogram optimized plazomicin exposures in patients with cUTI while reducing troughs to <3 µg/ml.

Host and Bacterial Markers that Differ in Children with Cystitis and Pyelonephritis.

OBJECTIVE: To determine whether treatment for urinary tract infections in children could be individualized using biomarkers for acute pyelonephritis. STUDY DESIGN: We enrolled 61 children with febrile urinary tract infections, collected blood and urine samples, and performed a renal scan within 2 weeks of diagnosis to identify those with pyelonephritis. Renal scans were interpreted centrally by 2 experts. We measured inflammatory proteins in blood and urine using LUMINEX or an enzyme-linked immunosorbent assay. We evaluated serum RNA expression using RNA sequencing in a subset of children. Finally, for children with Escherichia coli isolated from urine cultures, we performed a polymerase chain reaction for 4 previously identified virulence genes. RESULTS: Urinary markers that best differentiated pyelonephritis from cystitis included chemokine (C-X-C motif) ligand (CXCL)1, CXCL9, CXCL12, C-C motif chemokine ligand 2, INF γ, and IL-15. Serum procalcitonin was the best serum marker for pyelonephritis. Genes in the interferon-γ pathway were upregulated in serum of children with pyelonephritis. The presence of E coli virulence genes did not correlate with pyelonephritis. CONCLUSIONS: Immune response to pyelonephritis and cystitis differs quantitatively and qualitatively; this may be useful in differentiating these 2 conditions.

Could platelet to leucocytic count ratio (PLR) predict sepsis and clinical outcomes in patients with emphysematous pyelonephritis?

OBJECTIVES: To study risk factors for sepsis and mortality evaluating the role of platelet to leucocytic count ratio (PLR) as a marker for urosepsis and clinical outcomes in cases of emphysematous pyelonephritis (EPN). MATERIALS: Patients with EPN were retrospectively reviewed. Patients' age, sex, diabetes mellitus (DM), Body Mass Index (BMI), hydronephrosis, types of EPN, air locules volume, serum creatinine, leucocytic count, and platelet count, PLR, albumin, INR and the line of treatment were analyzed as risk factors of sepsis. Correlation between PLR and other variables was done using Pearson correlation coefficient. Univariate and multivariate analyses for sepsis and mortality were performed. RESULTS: Of fifty four patients, 38 patients had SIRS ≥2 criteria on admission. Twenty patients developed sepsis requiring ICU admission. In univariate analysis, male gender, lower BMI, higher INR, higher WBCs count and lower PLR were associated with sepsis (P = 0.0001, 0.009, 0.04, 0.003 and 0.001, respectively). In multivariate analysis, PLR ≤18.4, male sex and BMI ≤24.2 were independent risk factors. Lower PLR directly correlated with serum albumin (P = 0.01) and inversely correlated with serum creatinine and random blood glucose level and Klebsiella infection (P = 0.001, 0.007 and 0.005, respectively). Also, it was correlated with a higher total score of qSOFA and SOFA (P = 0.02 and 0.04). Lower PLR was independent risk factors for death in EPN patients with (P = 0.003). CONCLUSION: EPN is associated with sepsis development. Lower PLR is an independent simple predictor for sepsis and mortality in patients with EPN.

[Immune disturbances in acute pyelonephritis. Part I].

In the part I of a literature review of modern national and foreign publications dedicated to the problem of immune disorders in acute pyelonephritis, information on the role of innate and adaptive immunity in the pathogenesis of acute pyelonephritis is summarized and systematized. The relationship between the pathogens and immune system, in particular the ability of pathogens to overcome the protective immune mechanisms are discussed. The role of neutrophilic granulocytes as well as cellular immunity in the pathogenesis of acute pyelonephritis is shown. The changes in level of pro- and anti-inflammatory cytokines are separately highlighted. In conclusion, perspective directions for the studies in the area of immune disorders in acute pyelonephritis are proposed.

[Specific features of the immune status and blebbing of the plasmatic membrane of lymphocytes patients with urolithiasis complicated by the pyelonephritis].

INTRODUCTION: According to the epidemiological studies, prevalence of urolithiasis is nearly 10% worldwide. The course of the disease is often complicated by the development of pyelonephritis, the pathogenesis of which is rather multifactorial. Along with urinary tract obstruction, increasing virulence of microorganisms and immune insufficiency in patients also plays a major role. AIM: To define specific features of immune insufficiency in patients who develop pyelonephritis as a complication of urolithiasis. MATERIALS AND METHODS: A total of 150 patients with urolithiasis complicated by pyelonephritis were prospectively enrolled into our study in order to develop a novel method. All patients were divided into two clinical groups. Group I consisted of 75 patients with urolithiasis complicated by serous pyelonephritis and Group II included 75 patients with urolithiasis complicated by purulent pyelonephritis. In all patients an evaluation of the immune status with a determination of CD3, CD4, CD8, CD16, CD19 level and phagocyte activity of immune system was carried out. The state of lymphocytes plasmatic membrane was evaluated by phase contrast microscopy. RESULTS: It is established that development of pyelonephritis in patients with urolithiasis is accompanied by a lymphopenia, the decrease in relative contents T-helpers, natural killers, as well as a decrease in the immuno-regulatory index and an increase in indicators of terminal and total lymphocytes blebbing. The most pronounced changes were noted in purulent pyelonephritis, where suppressed immune status was confirmed by the high level of lymphocyte with terminal blebbing state.

Population Pharmacokinetic Analysis of Cefiderocol, a Parenteral Siderophore Cephalosporin, in Healthy Subjects, Subjects with Various Degrees of Renal Function, and Patients with Complicated Urinary Tract Infection or Acute Uncomplicated Pyelonephritis.

Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent efficacy against most Gram-negative bacteria, including carbapenem-resistant strains. The aim of this study was to perform a population pharmacokinetic (PK) analysis based on plasma cefiderocol concentrations in healthy subjects, subjects with various degrees of renal function, and patients with complicated urinary tract infection (cUTI) or acute uncomplicated pyelonephritis (AUP) caused by Gram-negative pathogens and to calculate the fraction of the time during the dosing interval where the free drug concentration in plasma exceeds the MIC (fTMIC). Population PK models were developed with three renal function markers, body surface area-adjusted estimated glomerular filtration rate (eGFR), absolute eGFR, and creatinine clearance, on the basis of 2,571 plasma concentrations from 91 subjects without infection and 238 patients with infection. The population PK models with each renal function marker adequately described the plasma cefiderocol concentrations. Clear relationships of total clearance (CL) to all renal function markers were observed. Body weight and disease status (with or without infection) were also significant covariates. The CL in patients with infection was 26% higher than that in subjects without infection. The fTMIC values were more than 75% in all patients (and were 100% in most patients), suggesting that a sufficient exposure to cefiderocol was provided by the tested dose regimens (2 g every 8 h as the standard dose regimen) for the treatment of cUTI or AUP caused by Gram-negative pathogens.

D-dimer as a marker of acute pyelonephritis in infants younger than 24 months with urinary tract infection.

BACKGROUND: D-dimer, as well as other biomarkers related to coagulation, is significantly increased during severe bacterial infection and sepsis. The aim of this study was to evaluate the usefulness of serum D-dimer as a biological marker in diagnosing acute pyelonephritis (APN) and in predicting vesicoureteric reflux (VUR) in infants with urinary tract infection (UTI). METHODS: We retrospectively analyzed the data of 177 young infants (<2 years) with febrile UTI between 2005 and 2014, grouped as APN and lower UTI groups. Conventional inflammatory markers (white blood cell count (WBC), erythrocyte sedimentation rates (ESR), C-reactive protein (CRP)), and D-dimer were measured. RESULTS: The WBC counts (P = 0.002), ESR (P < 0.0001), CRP (P < 0.0001), D-dimer levels (P = 0.006) and the presence of VUR (P < 0.0001) were significantly higher in the APN group than in the lower UTI group. Multiple logistic regression analyses showed that D-dimer (odds ratio [OR]:1.003, 95% CI: 1.001-1.006, P = 0.002) was an independent predictive factor for VUR in young children with UTI. The area under the curve (AUC) value from the receiver operating characteristic (ROC) curve of D-dimer (0.621, P = 0.046, 95% CI: 0.499-0.743) for prediction of VUR was higher than other inflammatory markers, but was inferior to CRP in predicting APN. CONCLUSIONS: Our results demonstrate that D-dimer can be used as an inflammatory marker in infants with febrile UTI in addition to other inflammatory markers.

BIOMARKERS OF RENAL INJURY RISK IN CHILDREN WITH PYELONEPHRITIS.

The most common cause of fever in case of anomalies of the urinary system is pyelonephritis (PN). Despite the fact that an intensive search for informative clinical and laboratory markers of PN in children is being conducted in recent years, this problem remains unresolved. Objective - to examine the content of organ-specific enzymes (neutral α-glucosidase (NAG), L-alanine aminopeptidase (AAP), γ-glutamyltranspeptidase (GGTP) in urine and galectin 3 (Gal -3), C-reactive protein (CPR) in blood serum. A prospective, comprehensive clinical and laboratory-instrumental examination was performed in 75 children under the age of 1. The activity of organ-specific enzymes (NAG, AAP, GGTP) in urine and CPR, Gal-3 in the serum of blood were estimated as markers of proximal tubules' damage. The majority (62.99 ± 5.33%) of hospitalized children with febrile temperature and urine changes were diagnosed with PN, which often arose with underlying congenital malformations of the urinary tract. Among children with PN underlaying with VUR, the II and III grades of activity were significantly more frequent. An increase of the level of the enzymes in the urine is observed in the active phase of PN, which correlated with the level of leukocyturia and the level of CRP. During the inactive phase of PN with VUR, the level of enzymes was also higher than the one in children with PN without VUR. High values of Gal-3 were detected in case of underlying VUR, which increased together with increased activity and duration of the inflammatory process in kidneys and correlated with the level of CRP. The Gal-3 can be used for an early diagnosis of fibrotic changes of the renal parenchyma in adolescent children with PN and underlying VUR.

Distinctive inflammatory profile between acute focal bacterial nephritis and acute pyelonephritis in children.

BACKGROUND: Acute focal bacterial nephritis (AFBN) is a severe form of upper urinary tract infection (UTI) with neurological manifestations and focal renal mass lesions on computed tomography (CT). Prolonged antibiotic therapy may improve the renal outcome, but the early differential diagnosis of AFBN from acute pyelonephritis (APN) is challenging. We searched for effective biomarkers of AFBN based on the pathophysiology of upper UTIs. METHODS: Of 52 upper UTI cases treated at Yamaguchi University between 2009 and 2016, 38 pediatric patients with AFBN (n=17) or APN (n=21) who underwent ultrasonography and/or CT were enrolled. The clinical data and serum cytokine concentrations were analyzed to differentiate AFBN from APN. RESULTS: AFBN patients tended to be older, and have a higher body temperature, longer febrile period, more frequent neurological symptoms, higher immature neutrophil count, lower lymphocyte count, higher procalcitonin and urine ß2-microglobulin levels. AFBN patients showed higher serum levels of IFN-γ, IL-6, IL-10 and soluble TNF-receptor 1 (sTNFR1) (all p<0.05). Although the cytokine levels were variably correlated among each other, multiple logistic regression analysis revealed that combination of IFN-γ and IL-6 levels were most relevant for distinguishing AFBN from APN. The discriminant power of the logistic equation was 0.86 in terms of the area under the curve by the ROC analysis. CONCLUSIONS: Circulating 4 out of 7 cytokines in AFBN patients were at higher levels compared with those in APN patients. IFN-γ and IL-6 levels might most effectively distinguish AFBN from APN.

Role of antioxidant defence, renal toxicity markers and inflammatory cascade in disease progression of acute pyelonephritis in experimental rat model.

Urinary tract infections are the most common bacterial infections affecting millions of people each year worldwide. The animal model provides an excellent and suitable system for studying cystitis and pyelonephritis caused by Escherichia coli and other uropathogens. Using this established model, we evaluate the role of antioxidant defence system, renal injury markers, and blood parameters in the diseases progression during Escherichia coli infection on 0th day, 12h and 7th day. The antioxidant enzymes like SOD, CAT, GSH, GPx, GR levels were evaluated. The blood parameters like AST, ALT, ALP, Total protein, BUN, creatinine level were estimated in infection model. The relative organ weights, anti microbial status of kidney, CRP, WBC count were done for the evaluation of inflammatory response associated with the infection. The oxidative stress marker like MDA was also evaluated. Histopathological analysis of renal tissue provides direct vision to tissue damage. The antioxidant status of renal tissue was decreased during the 7th day of infection. Likewise, renal toxicity markers were significantly increased during bacterial infection. The inflammatory markers like CRP, WBC count and oxidative stress marker like MDA were significantly increased by the infection on 7th day. The histopathology of renal tissue also reveals the inflammation and tissue damage associated with acute pyelonephritis.

Plasma neutrophil gelatinase-associated lipocalin: a marker of acute pyelonephritis in children.

OBJECTIVES: This study was designed to compare the diagnostic accuracy of plasma neutrophil gelatinase-associated lipocalin (NGAL) with procalcitonin (PCT), C-reactive protein (CRP), and white blood cells (WBCs) for predicting acute pyelonephritis (APN) in children with febrile urinary tract infections (UTIs). MATERIALS AND METHODS: In total, 138 children with febrile UTIs (APN 59, lower UTI 79) were reviewed retrospectively. Levels of NGAL, PCT, CRP, and WBCs in blood were measured on admission. The diagnostic accuracy of the biomarkers was investigated. Independent predictors of APN were identified by multivariate logistic regression analysis. RESULTS: Receiver operating curve (ROC) analyses showed good diagnostic profiles of NGAL, PCT, CRP, and WBCs for identifying APN [area under the curve (AUC) 0.893, 0.855, 0.879, and 0.654, respectively]. However, multivariate analysis revealed only plasma NGAL level was an independent predictor of APN (P = 0.006). At the best cutoff values of all examined biomarkers for identifying APN, sensitivity (86 %), specificity (85 %), positive predictive value (81 %), and negative predictive value (89 %) of plasma NGAL levels were the highest. The optimal NGAL cutoff value was 117 ng/ml. The positive likelihood ratio [odds ratio (OR) 5.69, 95 % confidence interval (CI) 3.56-8.78], and negative likelihood ratio (OR 0.16, 95 % CI 0.08-0.29) of plasma NGAL for APN diagnosis also showed it seemed to be more accurate than serum PCT, CRP, and WBCs. CONCLUSION: Plasma NGAL can be more useful than serum PCT, CRP, and WBC levels for identifying APN in children with febrile UTIs.

Role of genetic mutations in development of immunological and clinical disorders in children with chronic pyelonephritis.

INTRODUCTION: At the present time, the study of mechanisms of recognition of foreign agents, which is realized by means of Toll-like receptors (TLR) of the innate immune system, has become one of the main tasks of clinical immunology. The aim of our study was to investigate the prevalence of polymorphism of Toll-like receptor 4 (Asp299Gly, Gly299Gly) among children with chronic pyelonephritis (CP) and determine the association of this TLR4 polymorphism with phenotypic features of chronic pyelonephritis and level of interleukin-6 (IL-6). MATERIALS AND METHODS: The clinical and laboratory examination of 60 children with chronic pyelonephritis during the stage of exacerbation, who were under inpatient treatment at the pediatric department of Children's Regional Clinical Hospital in Poltava, was performed. The group of healthy patients included 95 people, living in the Poltava region. RESULTS: Significantly higher frequency of the mutant allele 299Gly among children with CP was revealed. Significant correlation between the presence of 299Gly TLR4, association of U. urealyticum and M. hominis in lower sections of urinary tract and highest levels of IL-6 concentration was reflected. Sick children with polymorphous locus of TLR4 gene had higher risk of CP early manifestation and formation of its recurrent course with protracted urinary syndrome and unstable remission in comparison with the carriers of "wild" genotype. CONCLUSIONS: Obtained results prove the important role of TLR4 in the realization of innate immune response in children with CP and allow considering the TLR4 polymorphism as an additional prognostic indicator in this category of patients.

Cefotaxime and Amoxicillin-Clavulanate Synergism against Extended-Spectrum-ß-Lactamase-Producing Escherichia coli in a Murine Model of Urinary Tract Infection.

We investigated the efficacies of cefotaxime (CTX) and amoxicillin (AMX)-clavulanate (CLA) (AMC) against extended-spectrum-ß-lactamase (ESBL)-producing Escherichia coli in vitro and in a murine model of urinary tract infection (UTI). MICs, the checkerboard dilution method, and time-kill curves were used to explore the in vitro synergism between cefotaxime and amoxicillin-clavulanate against two isogenic E. coli strains-CFT073-RR and its transconjugant, CFT073-RR Tc bla(CTX-M-15)-harboring a bla(CTX-M-15) plasmid and a bla(OXA-1) plasmid. For in vivo experiments, mice were separately infected with each strain and treated with cefotaxime, amoxicillin, and clavulanate, alone or in combination, or imipenem, using therapeutic regimens reproducing time of free-drug concentrations above the MIC (fT≥MIC) values close to that obtained in humans. MICs of amoxicillin, cefotaxime, and imipenem were 4/>1,024, 0.125/1,024, and 0.5/0.5 mg/liter, for CFT073-RR and CFT073-RR Tc bla(CTX-M-15), respectively. The addition of 2 mg/liter of clavulanate (CLA) restored the susceptibility of CFT073-RR Tc bla(CTX-M-15) to CTX (MICs of the CTX-CLA combination, 0.125 mg/liter). The checkerboard dilution method and time-kill curves confirmed an in vitro synergy between amoxicillin-clavulanate and cefotaxime against CFT073-RR Tc bla(CTX-M-15). In vivo, this antibiotic combination was similarly active against both strains and as effective as imipenem. In conclusion, the cefotaxime and amoxicillin-clavulanate combination appear to be an effective, easy, and already available alternative to carbapenems for the treatment of UTI due to CTX-M-producing E. coli strains.

Are first-generation cephalosporins obsolete? A retrospective, non-inferiority, cohort study comparing empirical therapy with cefazolin versus ceftriaxone for acute pyelonephritis in hospitalized patients.

OBJECTIVES: Literature is lacking regarding the utilization of first-generation cephalosporins for the treatment of acute pyelonephritis. The aim of this study was to determine whether cefazolin is non-inferior to ceftriaxone for the empirical treatment of acute pyelonephritis in hospitalized patients. The primary outcome included a composite of symptomatic resolution plus either defervescence at 72 h or normalization of serum white blood cell count at 72 h (non-inferiority margin 15%). Secondary outcomes included length of stay and 30 day readmission. A subgroup analysis of the composite outcome was also conducted for imaging-confirmed pyelonephritis. METHODS: This was a retrospective, non-inferiority, multicentre, cohort study comparing cefazolin versus ceftriaxone for the empirical treatment of acute pyelonephritis in hospitalized patients. RESULTS: Overall, 184 patients received one of the two treatments between July 2009 and March 2015. The composite outcome was achieved in 80/92 (87.0%) in the cefazolin group versus 79/92 (85.9%) in the ceftriaxone group (absolute difference 1.1%, 95% CI -11.1% to 8.9%, P = 0.83), meeting the pre-defined criteria for non-inferiority. The composite outcome for patients with imaging-confirmed pyelonephritis was achieved in 46/56 (82.1%) versus 42/50 (84.0%) for the cefazolin group and the ceftriaxone group, respectively (absolute difference 1.9%, 95% CI -12.8% to 16.5%, P = 0.80). Additionally, there were no statistically significant differences in length of stay or 30 day readmission for cystitis or pyelonephritis. CONCLUSIONS: Cefazolin was non-inferior to ceftriaxone with regard to clinical response for the treatment of hospitalized patients with acute pyelonephritis in this study. No difference was observed for length of stay or 30 day readmission.

Reverse kinetics of angiopoietin-2 and endotoxins in acute pyelonephritis: Implications for anti-inflammatory treatment?

Based on former studies showing an antagonism between angiopoietin-2 (Ang-2) and bacterial endotoxins (LPS), we investigated the role of Ang-2 as immunomodulatory treatment. At first, kinetics of circulating LPS in Gram-negative pyelonephritis developing after urinary obstruction was studied. Serum LPS, interleukin (IL)-6 and Ang-2 were measured in 25 patients with acute pyelonephritis and sepsis before and after removal of the obstruction performed either with insertion of a pigtail catheter (n=12) or percutaneous drainage (n=13). At a second stage, Ang-2 was given as anti-inflammatory treatment in 40 rabbits one hour after induction of acute pyelonephritis by ligation of the ureter at the level of pelvo-ureteral junction and upstream bacterial inoculation. Survival was recorded; blood mononuclear cells were isolated and stimulated for the production of tumour necrosis factor-alpha (TNFα). The decrease in circulating LPS was significantly greater among patients undergoing drainage than pigtail insertion. This was accompanied by reciprocal changes of Ang-2 and IL-6. Treatment with Ang-2 prolonged survival from Escherichia coli pyelonephritis despite high levels of circulating LPS. When Ang-2 was given as treatment of Pseudomonas aeruginosa pyelonephritis, sepsis-induced decrease of TNFα production by circulating mononuclear cells was reversed without an effect on tissue bacterial overgrowth. It is concluded that Ang-2 and LPS follow reverse kinetics in acute pyelonephritis. When given as experimental treatment, Ang-2 prolongs survival through an effect on mononuclear cells.