Neutrophil-Macrophage Imbalance Drives the Development of Renal Scarring during Experimental Pyelonephritis.

BACKGROUND: In children, the acute pyelonephritis that can result from urinary tract infections (UTIs), which commonly ascend from the bladder to the kidney, is a growing concern because it poses a risk of renal scarring and irreversible loss of kidney function. To date, the cellular mechanisms underlying acute pyelonephritis-driven renal scarring remain unknown. METHODS: We used a preclinical model of uropathogenic Escherichia coli-induced acute pyelonephritis to determine the contribution of neutrophils and monocytes to resolution of the condition and the subsequent development of kidney fibrosis. We used cell-specific monoclonal antibodies to eliminate neutrophils, monocytes, or both. Bacterial ascent and the cell dynamics of phagocytic cells were assessed by biophotonic imaging and flow cytometry, respectively. We used quantitative RT-PCR and histopathologic analyses to evaluate inflammation and renal scarring. RESULTS: We found that neutrophils are critical to control bacterial ascent, which is in line with previous studies suggesting a protective role for neutrophils during a UTI, whereas monocyte-derived macrophages orchestrate a strong, but ineffective, inflammatory response against uropathogenic, E. coli-induced, acute pyelonephritis. Experimental neutropenia during acute pyelonephritis resulted in a compensatory increase in the number of monocytes and heightened macrophage-dependent inflammation in the kidney. Exacerbated macrophage-mediated inflammatory responses promoted renal scarring and compromised renal function, as indicated by elevated serum creatinine, BUN, and potassium. CONCLUSIONS: These findings reveal a previously unappreciated outcome for neutrophil-macrophage imbalance in promoting host susceptibility to acute pyelonephritis and the development of permanent renal damage. This suggests targeting dysregulated macrophage responses might be a therapeutic tool to prevent renal scarring during acute pyelonephritis.

Renal Denervation Exacerbates LPS- and Antibody-induced Acute Kidney Injury, but Protects from Pyelonephritis in Mice.

BACKGROUND: Renal denervation (RDN) is an invasive intervention to treat drug-resistant arterial hypertension. Its therapeutic value is contentious. Here we examined the effects of RDN on inflammatory and infectious kidney disease models in mice. METHODS: Mice were unilaterally or bilaterally denervated, or sham operated, then three disease models were induced: nephrotoxic nephritis (NTN, a model for crescentic GN), pyelonephritis, and acute endotoxemic kidney injury (as a model for septic kidney injury). Analytical methods included measurement of renal glomerular filtration, proteinuria, flow cytometry of renal immune cells, immunofluorescence microscopy, and three-dimensional imaging of optically cleared kidney tissue by light-sheet fluorescence microscopy followed by algorithmic analysis. RESULTS: Unilateral RDN increased glomerular filtration in denervated kidneys, but decreased it in the contralateral kidneys. In the NTN model, more nephritogenic antibodies were deposited in glomeruli of denervated kidneys, resulting in stronger inflammation and injury in denervated compared with contralateral nondenervated kidneys. Also, intravenously injected LPS increased neutrophil influx and inflammation in the denervated kidneys, both after unilateral and bilateral RDN. When we induced pyelonephritis in bilaterally denervated mice, both kidneys contained less bacteria and neutrophils. In unilaterally denervated mice, pyelonephritis was attenuated and intrarenal neutrophil numbers were lower in the denervated kidneys. The nondenervated contralateral kidneys harbored more bacteria, even compared with sham-operated mice, and showed the strongest influx of neutrophils. CONCLUSIONS: Our data suggest that the increased perfusion and filtration in denervated kidneys can profoundly influence concomitant inflammatory diseases. Renal deposition of circulating nephritic material is higher, and hence antibody- and endotoxin-induced kidney injury was aggravated in mice. Pyelonephritis was attenuated in denervated murine kidneys, because the higher glomerular filtration facilitated better flushing of bacteria with the urine, at the expense of contralateral, nondenervated kidneys after unilateral denervation.

Clinical manifestations, laboratory markers, and renal ultrasonographic examinations in 1-month to 12-year-old Iranian children with pyelonephritis: a six-year cross-sectional retrospective study.

BACKGROUND: Upper urinary tract infection (UTI) or pyelonephritis may increase the pathogenesis rate and risk of severe complications in children due to kidney atrophy. OBJECTIVE: A set of clinical symptoms, laboratory markers, and ultrasound findings were assessed to achieve the early diagnosis and prognosis of pyelonephritis in hospitalized pediatrics. METHODS: A cross-sectional study with 104 Iranian children (95 girls and 9 boys) aged 1 month to 12 years with acute pyelonephritis during 2012-2018 was conducted. The ultrasound examination of kidneys and urinary tract during hospitalization, the incidence of clinical symptoms, and laboratory markers in blood and urine were monitored to identify the best predictive factors of early diagnosis of this bacterial infection. RESULTS: Three-fourth of the patients had one of the four clinical symptoms of abdominal pain, constipation, dysuria, and vomiting, while others were asymptomatic. A much frequency of pyuria (88.46%), Escherichia coli in urine (92.31%), leukocytosis (81.73%), and high ESR (> 10 mm/h, 92.30%) and CRP (> 10 mg/L, 82.82%) was observed. The kidney and urinary tract ultrasonography only in 32.7% of children revealed findings in favor of pyelonephritis (cystitis, ureteral stones, and hydronephrosis). CONCLUSION: There was a high frequency of clinical signs and laboratory markers associated with pyelonephritis. Ultrasound alone was not an efficient tool to track febrile UTI as most patients presented normal sonography.

The diagnosis and management of a patient with acute pyelonephritis.

Lower urinary tract infections account for more than 224 000 hospital admissions each year and nearly all of these have the pathophysiological possibility to develop into pyelonephritis, known clinically as an upper urinary tract infection. Acute pyelonephritis is characterised by inflammation of the renal parenchyma caused by bacteriuria ascending from the bladder, up the ureters to the kidneys. Effective history taking, combined with refined physical examination skills, are the two most powerful tools to differentiate upper and lower urinary tract infections as well as assisting the practitioner to exclude other differential diagnoses. Utilisation of these skills by the practitioner, together with the recognised presenting symptom triad of flank pain, fever and nausea in this case study, enabled the diagnosis of acute pyelonephritis to be given.

Qualitative and quantitative radiological analysis of non-contrast CT is a strong indicator in patients with acute pyelonephritis.

OBJECTIVE: To evaluate the performance of non-contrast computed tomography (CT) by reporting the difference in attenuation between normal and inflamed renal parenchyma in patients clinically diagnosed with acute pyelonephritis (APN). MATERIAL AND METHODS: This is a retrospective study concerned with non-contrast CT evaluation of 74 patients, admitted with a clinical diagnosis of APN and failed to respond to 48h antibiotics treatment. Mean attenuation values in Hounsfield units (HU) were measured in the upper, middle and lower segments of the inflamed and the normal kidney of the same patient. Independent t-test was performed for statistical analysis. Image evaluation included receiver operating characteristic (ROC), visual grading characteristic (VGC) and kappa analyses. RESULTS: The mean attenuation in the upper, middle and lower segments of the inflamed renal cortex was 32%, 25%, and 29% lower than the mean attenuation of the corresponding cortical segments of the contralateral normal kidney, respectively (p<0.01). The mean attenuation in the upper, middle, and lower segments of the inflamed renal medulla was 48%, 21%, and 30%, lower than the mean attenuation of the corresponding medullary segments of the contralateral normal kidney (p<0.02). The mean attenuation between the inflamed and non-inflamed renal cortex and medulla was 29% and 30% lower respectively (p<0.001). The AUCROC (p<0.001) analysis demonstrated significantly higher scores for pathology detection, irrespective of image quality, compared to clinical and laboratory results with an increased inter-reader agreement from poor to substantial. CONCLUSION: Non-contrast CT showed a significant decrease in the parenchymal density of the kidney affected with APN in comparison to the contralateral normal kidney of the same patient. This can be incorporated in the diagnostic criteria of APN in NCCT in the emergency setting.

INTENSITY OF THE ANTIOXIDANT PROTECTION SYSTEM AND OXIDATIVE STRESS FACTORS IN PATIENTS WITH NON-ALCOHOLIC STEATOHEPATITIS DEPENDING ON THE FORM OF CHRONIC KIDNEY DISEASE.

The article presents a theoretical generalization of the research results the intensity of the antioxidant protection system and oxidative stress factors in patients with non-alcoholic steatohepatitis depending on the form of chronic kidney disease. The objective of the article - determining the pathogenetic role of the processes of antioxidant protection system in the development and interconnection mechanisms of non-alcoholic steatohepatitis (NASH) and obesity depending on the form and stage of chronic kidney disease (CKD). 177 patients were examined for this purpose, including: 35 patients with NASH with concomitant obesity of І-ІІ degree (1st group), 36 patients with NASH with accompanying obesity of І-ІІ degree and CKD І-ІІ stage: Chronic bilateral pyelonephritis in the phase of exacerbation (2A group), 35 patients with NASH on the background of obesity I-II st. with CKD of the 3rd stage: Chronic bilateral peyelonephritis, exacerbation (2B group), 37 patients with NASH with obesity I-II stage and gouty nephropathy (group 3), 34 patients with NASH, which developed on the background of obesity I-II stages that developed from asymptomatic hyperuricemia (AHU) (group 4). The control group consisted of 30 practically healthy persons (PHP). For the comorbidity of NASH from CKD of the I-III stages. In the form of chronic pyelonephritis, the intensity of oxidative stress increases: the accumulation of intermediate (isolated double bonds, diene conjugates) and terminal (malonic aldehyde, ketodienes and conjugated triines) products of lipids peroxide oxidation, oxidation proteins modification (aldehyde and ketone dinitrophenyl hydrazones of the main and neutral) against the background of the disintegration of the activity of antiradical protection factors (reduction of content in erythrocytes of recovered glutathione, activity of superoxide dismutase, the growth of catalase activity, glutathion-dependent enzymes). Due to the comorbidity of non-alcoholic steatohepatitis with gouty nephropathy and in conditions of asymptomatic hyperuricemia, the degree of oxidative stress is significantly lower due to the strong antioxidant properties of uric acid, but the degree of endotoxicosis predominates in steatohepatitis without kidney damage. The uncontrolled intensification of the processes of free radical oxidation of lipids and proteins in patients with non-alcoholic steatohepatitis that developed on the background of obesity and CKD I-III stages, determines the degree of pathological process activity in the liver and the degree of endotoxicosis.

Carbohydrate-Lectin Interactions: An Unexpected Contribution to Affinity.

Uropathogenic E. coli exploit PapG-II adhesin for infecting host cells of the kidney; the expression of PapG-II at the tip of bacterial pili correlates with the onset of pyelonephritis in humans, a potentially life-threatening condition. It was envisaged that blocking PapG-II (and thus bacterial adhesion) would provide a viable therapeutic alternative to conventional antibiotic treatment. In our search for potent PapG-II antagonists, we observed an increase in affinity when tetrasaccharide 1, the natural ligand of PapG-II in human kidneys, was elongated to hexasaccharide 2, even though the additional Siaα(2-3)Gal extension is not in direct contact with the lectin. ITC studies suggest that the increased affinity results from partial desolvation of nonbinding regions of the hexasaccharide; this is ultimately responsible for perturbation of the outer hydration layers. Our results are in agreement with previous observations and suggest a general mechanism for modulating carbohydrate-protein interactions based on nonbinding regions of the ligand.

Pyelonephritis can lead to life-threatening complications.

Acute pyelonephritis is suggested by the constellation of fever (temperature ≥ 38.5° C), flank pain (typically unilateral), nausea and vomiting, and costovertebral angle tenderness. Complaints typical of lower UTI are variably present. The severity of symptoms ranges from a mild pyrexial illness to life-threatening sepsis. The diagnosis of acute pyelonephritis should be suspected on the basis of the history and clinical examination. If the urine dipstick is negative for nitrites and leukocyte esterase this does not exclude the diagnosis, but it should prompt a re-evaluation of the clinical features and consideration of other potential diagnoses. Antibiotic therapy should be initiated without delay; this can be modified subsequently depending on the culture result. Antibiotics that are typically effective in lower urinary tract infections are frequently inadequate in acute pyelonephritis, and more prolonged therapy is necessary. Review of the clinical course and urine culture results is necessary to ensure that the patient is improving. Patients who have not improved within two days of commencing antimicrobial treatment should be referred to secondary care unless the infecting pathogen is not susceptible to the agent originally used, an alternative appropriate antibiotic is available, and the patient remains well enough for community care.

Urological evaluation of patients that had undergone in utero myelomeningocele closure: A prospective assessment at first presentation and early follow-up. Do their bladder benefit from it?

AIMS: To report our data on initial urological presentation after in utero myelomeningocele (MMC) closure. METHODS: A prospective urological assessment at first presentation was designed for patients that had undergone in utero MMC closure and referred to our urological facility. The protocol consisted of detailed medical history, renal sonography, voiding cystourethrogram, and urodynamic evaluation. RESULTS: In utero MMC closure was performed in 19 patients at gestational age of 25.6 weeks 25-27. Birth occurred at a mean gestational age of 31.8 weeks 26-36. Hyperactive bladder was observed in 89.5% 17/19. Bladder compliance was normal in two cases (10.5%), was markedly reduced in 10 patients (52.6%) and not possible to be determined due to urinary leakage in 7 patients (36.8%). We observed normal bladder capacity in 8 patients (42.1%), reduced in 11 (57.9%), and detrusor-sphincter dyssynergia in 9 patients (47.4%). Underactive bladder was diagnosed in one case. Clean Intermittent Catheterization was initiated by 11 patients (57.9%) mostly in association with anticholinergics 10/11. Vesicoureteral reflux was found in 5 patients (26.3%) and 9 had pyelonephritis at a mean follow-up of 5.4 months 2-17. CONCLUSIONS: Our data suggested that despite in utero MMC surgery, patients are at risk for bladder abnormal function and renal deterioration and should be aggressively treated, not differently from those operated in the post-natal term. This study has the merit of being a prospectively set evaluation performed by one investigator, including the urodynamic study. We acknowledge the need of long-term follow up.

Early-Onset Graft Pyelonephritis Is Predictive of Long-Term Outcome of Renal Allografts.

Urinary tract infection (UTI) is the most common bacterial infection encountered in kidney transplant recipients. Graft pyelonephritis (GPN) is associated with acute kidney injury and renal allograft scarring. However, the influence of GPN on renal allograft outcome in kidney transplant recipients remains controversial. Two hundred sixty-five kidney transplant recipients were evaluated for the impact of early-onset GPN on renal allograft functions between January 2001 and December 2011. Early-onset GPN was defined as the first GPN episode occurring within 6 months after kidney transplantation. Thirty recipients (11.3%) were diagnosed with early-onset GPN. During the mean follow-up period of 69.1 ± 28.9 months, 56 (21.1%) recipients showed renal allograft outcomes of a > 30% reduction in the estimated glomerular filtration rate (eGFR) over 2 years. The poor outcome was significantly more frequent in the early-onset GPN group (13 patients; 43.3%) than in those without early-onset GPN (43 patients; 18.3%) (P = 0.002). Moreover, the linear mixed model revealed a significant difference in the eGFR decline rate over time between the two groups (P < 0.001). Kaplan-Meier analysis showed that renal allograft event-free survival was significantly lower in the early-onset GPN group (P = 0.006). Multivariate Cox regression analyses revealed that early-onset GPN was independently predictive of poor renal allograft outcomes (hazard ratio, 1.96; 95% confidence interval, 1.02-3.77; P = 0.04). In conclusion, early-onset GPN is independently associated with impaired renal functions in kidney transplant recipients. Thus, early-onset GPN could be a predictor for long-term outcome of renal allografts.

[CHARACTERISTICS OF THE URETER CONTRACTIONS IN CHILDREN WITH CHRONIC PYELONEPHRITIS].

The article presents results of electrophysiological study of the function of the ureter in the frequency range of 0.6-35 Hz, conducted in 100 children aged 5 to 13 years with chronic pyelonephritis. Data of 35 healthy people were used as a control. It was shown that the features of ureter contractions were significantly different in the two groups. Marked decrease of amplitudes of signal harmonics was found at a frequency of 1.4 Hz in patients with pyelonephritis compared to controls. Myostimulation in pyelonephritis group has led to an approximation of harmonic amplitudes to the values of the control group.

[USE OF PHYTOTHERAPY IN COMBINATION TREATMENT OF CHRONIC PYELONEPHRITIS].

The present paper reports results of a comparative study of 48 patients with latent chronic pyelonephritis and 3-18 years of duration of the disease. Patients assigned to group 1 (n=23) received standard treatment. In patients of group 2 (n=25) standard treatment was supplemented by the administration of 30-day course of Kanferon N 2 dragees twice daily. Kanferon N supplementation was found to be effective as an anti-inflammatory-measure due to its positive impact on renal microcirculation and urinary bacterial composition. It reduces the level of proinflammatory cytokines, stimulates humoral and cellular immunity thus preventing further disease progression.

Preventive effect of phosphodiesterase 5 inhibitor tadalafil on experimental post-pyelonephritic renal injury in rats.

BACKGROUND: To evaluate the effects of Tadalafil, a phosphodiesterase 5 enzyme inhibitor, on Escherichia coli-induced renal damage in an acute pyelonephritis (PN) rat model. METHODS: Experimental PN was induced in 32 Wistar rats, and four groups were formed: group 1 (no treatment), group 2 (antibiotic), group 3 (Tadalafil), and group 4 (antibiotic + Tadalafil). Antibiotic was given on days 3 to 8, and Tadalafil was administered between days 0 and 28 of bacterial inoculation. Half of the rats were killed on the ninth day (early period) and histopathological parameters, immunohistochemical renal fibrosis markers, and oxidant/antioxidant system activities were evaluated. The rest of the rats were killed at the sixth week of the study and evaluated for histopathological parameters and renal fibrosis markers. RESULTS: Inflammatory activity was significantly milder in rats treated with antibiotic + Tadalafil versus no treatment group both in the early and late periods. In the late period, interstitial fibrosis or tubular atrophy was lower in the antibiotic + Tadalafil group versus the no treatment and antibiotic groups, and in Tadalafil versus antibiotic group. Tadalafil administration significantly reduced renal malondialdehyde and nitric oxide levels and enhanced superoxide dismutase and catalase activities. In addition, circulating tumor necrosis factor α, interleukin 1ß was greatly reduced in Tadalafil group versus the no treatment group. CONCLUSIONS: We have provided the first evidence that phosphodiesterase 5 enzyme inhibitor Tadalafil ameliorates circulating inflammatory cytokines, reverses oxidant/antioxidant dysfunction and eventually possesses an overall protective effect on renal tissue from Escherichia coli-induced PN-related kidney injury. Phophodieterase 5 inhibitor might be a novel therapeutic target for PN.

Severe acute pyelonephritis: a review of clinical outcome and risk factors for mortality.

OBJECTIVE. To review demographics of patients with acute pyelonephritis, their outcomes of severe upper urinary tract infection, and to identify risk factors for long hospital stay and mortality. DESIGN. Case series. SETTING. A regional hospital in Hong Kong. PATIENTS. Patients admitted between June 2007 and June 2012 for acute pyelonephritis were identified. Those with the most severe outcomes were analysed of their mortality, need for care in the intensive care unit, or necessitation of urological intervention. RESULTS. Overall, 68 patients fulfilled our criteria for severe acute pyelonephritis. The female-to-male ratio was 7:3. Their mean age was 58 years. Overall, 57% of the patients had impaired renal function and 37% were diabetic; 47% developed shock after admission and 56% required further intensive care unit care; 75% of the patients demonstrated radiological evidence of urinary tract obstruction and required subsequent drainage procedures. Five patients died due to severe acute pyelonephritis. The prevalence of bacteraemia and bacteriuria was 57% and 74%, respectively. Escherichia coli accounted for the majority of causative organisms. Four risk factors-bacteraemia, shock, need for intensive care, and suppurative pyelonephritis-were associated with hospital stay of longer than 14 days. Old age (≥65 years), male sex, deranged renal function, and presence of disseminated intravascular coagulation were associated with mortality. CONCLUSION. There was high prevalence of bacteraemia and septic shock in patients with severe acute pyelonephritis. The factors of old age (≥65 years), male sex, deranged renal function, and presence of disseminated intravascular coagulation were associated with mortality. With the support of intensive care, early recognition of urinary tract obstruction and timely drainage, patients with severe acute pyelonephritis generally carry a good prognosis.

[Potentials for the phytotherapy in patients with chronic pyelonephritis].

We observed 66 patients with chronic pyelonephritis in the exacerbation phase who received standard treatment with antibacterial drugs based on susceptibility of causative agents. All patients were randomly divided into two groups. Patients of study group have received phytodrug prolit super septo 2 capsules 2 times a day for 4 weeks in addition to standard treatment. Patients of control group have received standard therapy only. As a result of treatment, high effectiveness of therapy and reduction of length of treatment was noted in the study group. There were no subjective symptoms of disease in all patients at the end of treatment. Reduction of leykocituria and bacteriuria, normalization of body temperature, normalization of blood analysis and restoration of intrarenal blood flow were observed earlier in the study group compared with the control group. Recurrence of disease 3 months after end of treatment was not revealed in none of the patient in the study group, whereas it was noted in 14% of patients in the control group.

[Characteristics of lipid peroxidation and activity of sympathetic nervous system in patients with chronic calculous pyelonephritis].

108 patients (89 women and 19 men) aged from 18 to 59 years with chronic pyelonephritis (CP) on the background of urolithiasis in a phase of active inflammation were evaluated. Along with the standard methods of examination, survey plan included the use of specific biochemical diagnostic methods. The latter included an evaluation of lipid peroxidation, the level of fat-soluble antioxidant alpha-tocopherol, fractions of phospholipids and cholesterol in the membranes of polymorphonuclear leukocytes (PMN). As a result of examination, The changes in the activity of lipid peroxidation and structure of the lipid phase of PMN membranes were identified. There was an increase in urinary excretion of catecholamines (epinephrine and norepinephrine), which indirectly indicates an increase in the activity of sympathetic nervous system contributing to the progression of CP.

[The clinical diagnostic importance of detection of vascular endothelial growth factor in evaluation of progression of pyelonephritis in children].

The article deals with evaluation of clinical diagnostic importance of detection of vascular endothelial growth factor under pyelonephritis in children. The study was implemented on sampling of 60 patients with various degree of compensation process. The level of vascular endothelial growth factor increased significantly in patients proportionally to severity of process and its value correlated with velocity of glomerular filtration and vascularization of kidney.

[Estimation of the functional condition of a fetus of pregnancy in chronic pyelonephritis].

UNLABELLED: Aim of this study was to investigate the condition of the fetus and feto placental system in chronic pyelonephritis by identifying features in the fetoplacental blood flow and middle cerebral artery system. PATIENTS AND METHODS: We examined 68 pregnant women with chronic pyelonephritis and 50 healthy pregnant women as a control group. The study conducted a qualitative assessment of fetus and placental blood flow and blood flow in the middle cerebral artery of the fetus. The data on the condition of feto-placental blood flow and blood flow in the middle cerebral artery in the examined pregnant and control group show a higher incidence of elevated systolic and diastolic performance ratio in the umbilical artery in patients with chronic pyelonephritis than somatically healthy women. RESULTS: Studies have shown that the most accurate and informative indicator of violations feto-placental circulation is an increase in the umbilical artery whose value (2,9 and above) reflects the high degree of suffering of the fetus on a background of chronic pyelonephritis. CONCLUSIONS: Diagnostically significant is the indicator of the middle cerebral artery blood flow, which reflects the mechanism of enhancement of cerebral circulation in chronic hypoxia due to violation of feto-placental circulation in patients with renal disease.