eGFRcystatinC/eGFRcreatinine ratio < 0.6 in patients with SARS-CoV-2 pneumonia: a prospective cohort study.

BACKGROUND: Shrunken Pore Syndrome (SPS), defined as a reduced ratio between two estimated filtration rates (based on cystatin C and creatinine) is an increasingly recognized risk factor for long-term mortality. Although some patients with other conditions might be erroneously identified as SPS. Our aim was to bring the focus on possible pathophysiologic mechanisms influencing the ratio in the setting of SARS-CoV-2 pneumonia and acute kidney injury. METHODS: A single-centered prospective cohort study was conducted to investigate biomarkers in symptomatic COVID-19 pneumonia patients admitted to a hospital in Latvia. Nineteen biomarkers were measured in blood and three in urine samples. Associations were sought between these biomarkers, chronic diseases and the estimated GFRcystatinC/eGFRcreatinine ratio < 0.6, mortality rates, and acute kidney injury development. Data analysis was performed using SPSS Statistics, with significance set at p < 0.05. RESULTS: We included 59 patients (average age 65.5 years, 45.8% female) admitted with COVID-19. Acute kidney injury occurred in 27.1%, and 25.4% died. Ratio < 0.6 was seen in 38.6%, associated with female sex, diabetes, hypothyroidism, and higher age. Ratio < 0.6 group had mortality notably higher - 40.9% vs. 16.2% and more cases of acute kidney injury (40.9% vs. 18.9%). Cystatin C showed strong associations with the ratio < 0.6 compared to creatinine. Urea levels and urea/creatinine ratio were higher in the ratio < 0.6 group. After excluding acute kidney injury patients, ratio < 0.6 remained associated with higher cystatin C and urea levels. Other biomarkers linked to a kidney injury as NGAL, and proteinuria did not differ. CONCLUSION: We prove that reduced ratio is common in hospitalized patients with SARS-CoV-2 pneumonia and is associated with increased mortality during hospitalization. Factors that influence this ratio are complex and, in addition to the possible shrinkage of pores, other conditions such as thickening of glomerular basal membrane, comorbidities, prerenal kidney failure and others may play an important role and should be addressed when diagnosing SPS. We highlight the need for additional diagnostic criteria for SPS and larger studies to better understand its implications in acute COVID-19 settings.

Successful Bacteriophage-Antibiotic Combination Therapy against Multidrug-Resistant Pseudomonas aeruginosa Left Ventricular Assist Device Driveline Infection.

There is considerable interest in the use of bacteriophages (phages) to treat Pseudomonas aeruginosa infections associated with left ventricular assist devices (LVADs). These infections are often challenging to manage due to high rates of multidrug resistance and biofilm formation, which could potentially be overcome with the use of phages. We report a case of a 54-year-old man with relapsing multidrug-resistant P. aeruginosa LVAD driveline infection, who was treated with a combination of two lytic antipseudomonal phages administered intravenously and locally. Treatment was combined with LVAD driveline repositioning and systemic antibiotic administration, resulting in a successful outcome with clinical cure and eradication of the targeted bacteria. However, laboratory in vitro models showed that phages alone could not eradicate biofilms but could prevent biofilm formation. Phage-resistant bacterial strains evolved in biofilm models and showed decreased susceptibility to the phages used. Further studies are needed to understand the complexity of phage resistance and the interaction of phages and antibiotics. Our results indicate that the combination of phages, antibiotics, and surgical intervention can have great potential in treating LVAD-associated infections. More than 21 months post-treatment, our patient remains cured of the infection.

Factors associated with time to first dialysis-associated peritonitis episode: Data from the Peritonitis Prevention Study (PEPS).

INTRODUCTION: Peritonitis remains a potentially serious complication of peritoneal dialysis (PD) treatment. It is therefore important to identify risk factors in order to reduce the incidence of peritonitis. The aim of the present analysis was to identify factors associated with time to first peritonitis episode. METHODS: Incident PD patients from 57 centres in Europe participated in the prospective randomised controlled Peritonitis Prevention Study (PEPS) from 2010 to 2015. Peritonitis-free, self-care PD patients ≥18 years were randomised to a retraining or a control group and followed for 1-36 months after PD initiation. The association of biochemical, clinical and prescription data with time to first peritonitis episode was studied. RESULTS: A first peritonitis episode was experienced by 33% (223/671) of participants. Univariable Cox proportional hazard regression showed a strong association between the time-updated number of PD bags connected per 24 h (PD bags/24 h) and time to first peritonitis episode (HR 1.35; 95% confidence interval (CI) 1.17-1.57), even after inclusion of PD modalities in the same model. Multivariable Cox regression revealed that the factors independently associated with time to first peritonitis episode included age (HR 1.16 per 10 years; 95% CI 1.05-1.28), PD bags/24 h (HR 1.32; 95% CI 1.13-1.54), serum albumin <35 versus >35 g/L (HR 1.39; 95% CI 1.06-1.82) and body weight per 10 kg (HR 1.10; 95% CI 1.01-1.19). CONCLUSION: This study of incident PD patients indicates that older age, greater number of PD bags connected/24 h, higher body weight and hypoalbuminaemia are independently associated with a shorter time to first peritonitis episode.

Anti-Biofilm Effect of Bacteriophages and Antibiotics against Uropathogenic Escherichia coli.

Escherichia coli is a common cause of biofilm-associated urinary tract infections. Bacteria inside the biofilm are more resistant to antibiotics. Six E. coli strains isolated from patients with urinary tract infections were screened for biofilm-forming capability and antimicrobial susceptibility. Two of the most significant biofilm-producing strains were selected for minimal inhibitory concentration and minimal biofilm eradication concentration in vitro testing using amoxicillin-clavulanic acid, ciprofloxacin, and three commercial bacteriophage cocktails (Pyobacteriophag, Ses, and Intesti). In case of a low phage effect, an adaptation procedure was performed. Although the biofilms formed by strain 021UR were resistant to amoxicillin-clavulanic acid and ciprofloxacin, the three phage cocktails were able to reduce biofilm formation. In contrast, phages did not affect the 01206UR strain against planktonic and biofilm-forming cells. After Pyobacteriophag adaptation, the effect improved, and, regardless of the concentration, the adapted phage cocktail could destroy both planktonic cells and the biofilm of strain 01206UR. Bacteriophages capable of killing bacteria in biofilms can be used as an alternative to antibiotics. However, each case should be considered individually due to the lack of clinical trials for phage therapy. Antimicrobial and phage susceptibility should be determined in biofilm models before treatment to achieve the desired anti-biofilm effect.

Leucine-Rich Alpha-2-Glycoprotein (LRG-1) as a Potential Kidney Injury Marker in Kidney Transplant Recipients.

BACKGROUND Kidney transplantation is the treatment of choice for most patients with end-stage renal disease. To improve patient and transplant survival, non-invasive diagnostic methods for different pathologies are important. Leucine-rich alpha-2-glycoprotein (LRG-1) is an innovative biomarker that is elevated in cases of angiogenesis, inflammation, and kidney injury. However, there are limited data about the diagnostic role of LRG-1 in kidney transplant recipients. The aim of this study was to evaluate the association between serum LRG-1, urine LRG-1, and kidney transplant function and injury. MATERIAL AND METHODS We enrolled 35 kidney transplant recipients in the study. LRG-1 in the serum and urine was detected using ELISA. We evaluated the correlation of serum and urine LRG-1 with traditional serum and urine kidney injury markers. RESULTS A higher level of serum LRG-1 correlates with a higher level of urine LRG-1. Serum LRG-1 has a positive correlation with transplant age, serum urea, serum creatinine, serum cystatin C, proteinuria, and fractional excretion of sodium (FENa) and a negative correlation with hemoglobin and estimated glomerular filtration rate (eGFR). Urine LRG-1 has a positive correlation with serum cystatin C, proteinuria, and urine neutrophil gelatinase-associated lipocalin (NGAL). CONCLUSIONS Higher levels of serum and urine LRG-1 are associated with kidney transplant injury and functional deterioration. Thus, LRG-1 might be also as a biomarker for tubular dysfunction in patients after kidney transplantation.

First-year mortality in incident dialysis patients: results of the Peridialysis study.

BACKGROUND: Controversy surrounds which factors are important for predicting early mortality after dialysis initiation (DI). We investigated associations of predialysis course and circumstances affecting planning and execution of DI with mortality following DI. METHODS: Among 1580 patients participating in the Peridialysis study, a study of causes and timing of DI, we registered features of predialysis course, clinical and biochemical data at DI, incidence of unplanned suboptimal DI, contraindications to peritoneal dialysis (PD) or hemodialysis (HD), and modality preference, actual choice, and cause of modality choice. Patients were followed for 12 months or until transplantation. A flexible parametric model was used to identify independent factors associated with all-cause mortality. RESULTS: First-year mortality was 19.33%. Independent factors predicting death were high age, comorbidity, clinical contraindications to PD or HD, suboptimal DI, high eGFR, low serum albumin, hyperphosphatemia, high C-reactive protein, signs of overhydration and cerebral symptoms at DI. Among 1061 (67.2%) patients who could select dialysis modality based on personal choice, 654 (61.6%) chose PD, 368 (34.7%) center HD and 39 (3.7%) home HD. The 12-months survival did not differ significantly between patients receiving PD and in-center HD. CONCLUSIONS: First-year mortality in incident dialysis patients was in addition to high age and comorbidity, associated with clinical contraindications to PD or HD, clinical symptoms, hyperphosphatemia, inflammation, and suboptimal DI. In patients with a "free" choice of dialysis modality based on their personal preferences, PD and in-center HD led to broadly similar short-term outcomes.

Use of Phage Cocktail BFC 1.10 in Combination With Ceftazidime-Avibactam in the Treatment of Multidrug-Resistant Pseudomonas aeruginosa Femur Osteomyelitis-A Case Report.

High-energy trauma with severe bone fractures can be complicated by infection, leading to the development of osteomyelitis. Pseudomonas aeruginosa is an important causative agent of such infections because of its high virulence profile and ability to develop resistance against a wide range of antimicrobials quickly. P. aeruginosa biofilms cause treatment failure and relapsing infections. Bacteriophages are viruses that can be used to treat biofilm-associated infections. Moreover, the combination of phages with certain antimicrobials have demonstrated synergistic and additive effects. We present a case of a 21-year-old patient with relapsing multidrug-resistant (MDR) P. aeruginosa femur osteomyelitis that developed after a road accident, with a proximal right femoral Grade III B open fracture and severe soft tissue damage. Despite extensive antimicrobial treatment and multiple surgical interventions with wound debridement, the infection persisted, with subsequent development of femoral osteomyelitis with a fistula. Patient care management included femoral head excision with wound debridement, intravenous (IV) ceftazidime-avibactam, and the local application of the lytic Pseudomonas bacteriophage cocktail BFC 1.10. Nine months after the intervention, the patient did not show any clinical, radiological, or laboratory signs of inflammation; therefore, hip replacement was performed. Nevertheless, recurrent P. aeruginosa infection evolved at the distal side of the femur and was successfully treated with conventional antimicrobials. In this case, wound debridement combined with antibiotics and bacteriophages resulted in bacterial eradication of proximal femoral segment, avoiding leg amputation, but failed to treat osteomyelitis in distal bone segment. An in vitro assessment of the isolated MDR P. aeruginosa strain for biofilm formation and phage susceptibility was performed. Additionally, the antimicrobial effects of ceftazidime-avibactam and BFC 1.10 were determined on planktonic cell growth and bacterial biofilm prevention was evaluated. The isolated bacterial strains were susceptible to the bacteriophage cocktail. Strong biofilm formation was detected 6 h after inoculation. Ceftazidime-avibactam combined with BFC 1.10 was most effective in preventing planktonic cell growth and biofilm formation. In both cases, the required concentration of ceftazidime-avibactam decreased two-fold. This study demonstrates the possible use of bacteriophages and antibiotics in difficult-to-treat bone and soft tissue infections, where the additive effects of phages and antibiotics were observed.

Choice of dialysis modality among patients initiating dialysis: results of the Peridialysis study.

BACKGROUND: In patients with end-stage kidney disease (ESKD), home dialysis offers socio-economic and health benefits compared with in-centre dialysis but is generally underutilized. We hypothesized that the pre-dialysis course and institutional factors affect the choice of dialysis modality after dialysis initiation (DI). METHODS: The Peridialysis study is a multinational, multicentre prospective observational study assessing the causes and timing of DI and consequences of suboptimal DI. Clinical and biochemical data, details of the pre-dialytic course, reasons for DI and causes of the choice of dialysis modality were registered. RESULTS: Among 1587 included patients, 516 (32.5%) were judged unsuitable for home dialysis due to contraindications [384 ( 24.2%)] or no assessment [106 (6.7%); mainly due to late referral and/or suboptimal DI] or death [26 (1.6%)]. Older age, comorbidity, late referral, suboptimal DI, acute illness and rapid loss of renal function associated with unsuitability. Of the remaining 1071 patients, 700 (65.4%) chose peritoneal dialysis (61.7%) or home haemodialysis (HD; 3.6%), while 371 (34.6%) chose in-centre HD. Somatic differences between patients choosing home dialysis and in-centre dialysis were minor; factors linked to the choice of in-centre dialysis were late referral, suboptimal DI, acute illness and absence of a 'home dialysis first' institutional policy. CONCLUSIONS: Given a personal choice with shared decision making, 65.4% of ESKD patients choose home dialysis. Our data indicate that the incidence of home dialysis potentially could be further increased to reduce the incidence of late referral and unplanned DI and, in acutely ill patients, by implementing an educational programme after improvement of their clinical condition.

Suboptimal dialysis initiation is associated with comorbidities and uraemia progression rate but not with estimated glomerular filtration rate.

BACKGROUND: Despite early referral of uraemic patients to nephrological care, suboptimal dialysis initiation (SDI) remains a common problem associated with increased morbimortality. We hypothesized that SDI is related to pre-dialysis care. METHODS: In the 'Peridialysis' study, time and reasons for dialysis initiation (DI), clinical and biochemical data and centre characteristics were registered during the pre- and peri-dialytic period for 1583 end-stage kidney disease patients starting dialysis over a 3-year period at 15 nephrology departments in the Nordic and Baltic countries to identify factors associated with SDI. RESULTS: SDI occurred in 42%. Risk factors for SDI were late referral, cachexia, comorbidity (particularly cardiovascular), hypoalbuminaemia and rapid uraemia progression. Patients with polycystic renal disease had a lower incidence of SDI. High urea and C-reactive protein levels, acidosis and other electrolyte disorders were markers of SDI, independently of estimated glomerular filtration rate (eGFR). SDI patients had higher eGFR than non-SDI patients during the pre-dialysis period, but lower eGFR at DI. eGFR as such did not predict SDI. Patients with comorbidities had higher eGFR at DI. Centre practice and policy did not associate with the incidence of SDI. CONCLUSIONS: SDI occurred in 42% of all DIs. SDI was associated with hypoalbuminaemia, comorbidity and rate of eGFR loss, but not with the degree of renal failure as assessed by eGFR.

S. aureus Colonization, Biofilm Production, and Phage Susceptibility in Peritoneal Dialysis Patients.

Peritonitis caused by Staphylococcusaureus is of major importance in peritoneal dialysis (PD) patients due to its great virulence profile and biofilm formation ability. Bacteriophages are a potential tool to treat peritonitis resulting from biofilm-associated infections. We screened S. aureus colonization in 71 PD patients from the nasal cavity, groin, and PD exit-site regions and analyzed clinical outcomes in these patients. We performed biofilm-formation testing of different strains and compared the isolates of one patient to detect phenotypic differences in S. aureus. Phage cocktails were used to detect S. aureus in vitro susceptibility. An adaptation procedure was performed in cases of bacterial resistance. Around 30% of PD patients (n = 21) were found to be S. aureus carriers; from these, a total of 34 S. aureus strains were isolated, of which 61.8% (n = 21) produced a strong biofilm. Phenotypic differences in strain biofilm production were detected in eight patients out of ten. All strains were sensitive to commonly used antibiotics. Broadly positive phage lytic activity (100%) was observed in six cocktails out of seven, and bacterial resistance towards phages was overcome using adaptation. Overall phages showed a promising in vitro effect in biofilm-forming S. aureus strains.

Retraining for prevention of peritonitis in peritoneal dialysis patients: A randomized controlled trial.

BACKGROUND: Peritonitis is more common in peritoneal dialysis (PD) patients nonadherent to the PD exchange protocol procedures than in compliant patients. We therefore investigated whether regular testing of PD knowledge with focus on infection prophylaxis could increase the time to first peritonitis (primary outcome) and reduce the peritonitis rate in new PD patients. METHODS: This physician-initiated, open-label, parallel group trial took place at 57 centers in Sweden, Denmark, Norway, Finland, Estonia, Latvia, the Netherlands, and the United Kingdom from 2010 to 2015. New peritonitis-free PD patients were randomized using computer-generated numbers 1 month after the start of PD either to a control group (n = 331) treated according to center routines or to a retraining group (n = 340), which underwent testing of PD knowledge and skills at 1, 3, 6, 12, 18, 24, 30, and 36 months after PD start, followed by retraining if the goals were not achieved. RESULTS: In all, 74% of the controls and 80% of the retraining patients discontinued the study. The groups did not differ significantly regarding cumulative incidence of first peritonitis adjusted for competing risks (kidney transplantation, transfer to hemodialysis and death; hazard ratio 0.84; 95% confidence interval (CI) 0.65-1.09) nor regarding peritonitis rate per patient year (relative risk 0.93; 95% CI 0.75-1.16). CONCLUSIONS: In this randomized controlled trial, we were unable to demonstrate that regular, targeted testing and retraining of new PD patients increased the time to first peritonitis or reduced the rate of peritonitis, as the study comprised patients with a low risk of peritonitis, was underpowered, open to type 1 statistical error, and contamination between groups.

Predictors of Hyperuricemia after Kidney Transplantation: Association with Graft Function.

BACKGROUND: In kidney transplant recipients (KTR), hyperuricemia (HU) is a commonly-observed phenomenon, due to calcineurin inhibitors and reduced kidney graft function. Factors predicting HU, and its association with graft function, remains equivocal. METHODS: We conducted a retrospective longitudinal study to assess factors associated with HU in KTR, and to determine risk factors associated with graft function, measured as glomerular filtration rate (GFR). Moreover, GFR > 60 mL/min/1.73 m2 was considered normal. HU was defined as a serum uric acid level of > 416 µmol/L (4.70 mg/dL) in men and >357 µmol/L (4.04 mg/dL) in women, or xanthine-oxidase inhibitor use. We built multiple logistic regression models to assess predictors of HU in KTR, as well as the association of demographic, clinical, and biochemical parameters of patients with normal GFR after a three-year follow-up. We investigated the effect modification of this association with HU. RESULTS: There were 144 patients (mean age 46.6 ± 13.9), with 42.4% of them having HU. Predictors of HU in KTR were the presence of cystic diseases (OR = 9.68 (3.13; 29.9)), the use of diuretics (OR = 4.23 (1.51; 11.9)), and the male gender (OR = 2.45 (1.07; 5.56)). Being a younger age, of female gender, with a normal BMI, and the absence of diuretic medications increased the possibility of normal GFR. HU was the effect modifier of the association between demographic, clinical, and biochemical factors and a normal GFR. CONCLUSIONS: Factors associated with HU in KTR: Presence of cystic diseases, diuretic use, and male gender. HU was the effect modifier of the association of demographic, clinical, and biochemical factors to GFR.

Why do physicians prescribe dialysis? A prospective questionnaire study.

INTRODUCTION: The incidence of unplanned dialysis initiation (DI) with consequent increased comorbidity, mortality and reduced modality choice remains high, but the optimal timing of dialysis initiation (DI) remains controversial, and there is a lack of studies of specific reasons for DI. We investigated why and when physicians prescribe dialysis and hypothesized that physician motivation for DI is an independent factor which may have clinical consequences. METHODS: In the Peridialysis study, an ongoing multicenter prospective study assessing the causes and timing of DI and consequences of unplanned dialysis, physicians in 11 hospitals were asked to describe their primary, secondary and further reasons for prescribing DI. The stated reasons for DI were analyzed in relation to clinical and biochemical data at DI, and characteristics of physicians. RESULTS: In 446 patients (median age 67 years; 38% females; diabetes 25.6%), DI was prescribed by 84 doctors who stated 23 different primary reasons for DI. The primary indication was clinical in 63% and biochemical in 37%; 23% started for life-threatening conditions. Reduced renal function accounted for only 19% of primary reasons for DI but was a primary or contributing reason in 69%. The eGFR at DI was 7.2 ±3.4 ml/min/1.73 m2, but varied according to comorbidity and cause of DI. Patients with cachexia, anorexia and pulmonary stasis (34% with heart failure) had the highest eGFR (8.2-9.8 ml/min/1.73 m2), and those with edema, "low GFR", and acidosis, the lowest (4.6-6.1 ml/min/1.73 m2). Patients with multiple comorbidity including diabetes started at a high eGFR (8.7 ml/min/1.73 m2). Physician experience played a role in dialysis prescription. Non-specialists were more likely to prescribe dialysis for life-threatening conditions, while older and more experienced physicians were more likely to start dialysis for clinical reasons, and at a lower eGFR. Female doctors started dialysis at a higher eGFR than males (8.0 vs. 7.1 ml/min/1.73 m2). CONCLUSIONS: DI was prescribed mainly based on clinical reasons in accordance with current recommendations while low renal function accounted for only 19% of primary reasons for DI. There are considerable differences in physicians´ stated motivations for DI, related to their age, clinical experience and interpretation of biochemical variables. These differences may be an independent factor in the clinical treatment of patients, with consequences for the risk of unplanned DI.

Gallbladder Perforation with Postoperative Preservation of Peritoneal Dialysis Catheter.

A patient undergoing peritoneal dialysis was admitted with acute peritoneal dialysis-related peritonitis. On the 10th day of intraperitoneal antibacterial therapy, the patient's dialysate developed a green color. Gallbladder perforation was revealed. The patient underwent a conventional cholecystectomy with a preserved peritoneal catheter. There are few cases in the medical literature about green dialysate. In all of them, peritoneal dialysis catheters were removed after cholecystectomy. The present case report shows a patient with an intact peritoneal catheter and with no further complications. LEARNING POINTS: Bilirubin measurement in a dialysate helps to differentiate gallbladder perforation from other causes of peritonitis.Urgent diagnostics and treatment is required in patients with changes in dialysate colour.Preservation of perithoneal catheter can be considered after a laparotomy.