Acute kidney injury due to antimicrobial therapy.

One of the common causes of acute kidney injury (AKI) is drug nephrotoxicity. A large group of drugs associated with AKI includes a considerable number of antimicrobials. Clinical manifestations range from mild forms of tubular damage to significant deterioration of renal function requiring renal replacement therapy. Several mechanisms have been described, although the most common are acute interstitial nephritis, acute tubular necrosis, crystalic nephropathy or proximal/distal tubulopathy with electrolyte abnormalities. General risk factors for antimicrobial-induced AKI include pre-existing chronic kidney disease and concomitant use of drugs with nephrotoxic potential. Prevention and early recognition of AKI are the standard approach to mitigate AKI and avoid morbidity.

Combined Use of Presepsin and (1,3)-ß-D-glucan as Biomarkers for Diagnosing Candida Sepsis and Monitoring the Effectiveness of Treatment in Critically Ill Patients.

New biomarker panel was developed and validated on 165 critically ill adult patients to enable a more accurate invasive candidiasis (IC) diagnosis. Serum levels of the panfungal biomarker (1,3)-ß-D-glucan (BDG) and the inflammatory biomarkers C-reactive protein, presepsin (PSEP), and procalcitonin (PCT) were correlated with culture-confirmed candidemia or bacteremia in 58 and 107 patients, respectively. The diagnostic utility was evaluated in sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). BDG was the best marker for IC, achieving 96.6% sensitivity, 97.2% specificity, 94.9% PPV, and 98.1% NPV at a cut-off of 200 pg/mL (p ≤ 0.001). PSEP exhibited 100% sensitivity and 100% NPV at a cut-off of 700 pg/mL but had a lower PPV (36.5%) and low specificity (5.6%). Combined use of PSEP and BDG, thus, seems to be the most powerful laboratory approach for diagnosing IC. Furthermore, PSEP was more accurate for 28-day mortality prediction the area under the receiver operating characteristic curve (AUC = 0.74) than PCT (AUC = 0.31; PCT cut-off = 0.5 ng/mL). Finally, serum PSEP levels decreased significantly after only 14 days of echinocandin therapy (p = 0.0012). The probability of IC is almost 100% in critically ill adults with serum BDG and PSEP concentrations > 200 pg/mL and >700 pg/mL, respectively, defining a borderline between non-invasive superficial Candida colonization and IC.

Expression and 7-day time course of circulating microRNAs in septic patients treated with nephrotoxic antibiotic agents.

BACKGROUND: Through regulation of signaling pathways, microRNAs (miRNAs) can be involved in sepsis and associated organ dysfunction. The aims of this study were to track the 7-day time course of blood miRNAs in patients with sepsis treated with vancomycin, gentamicin, or a non-nephrotoxic antibiotic and miRNA associations with neutrophil gelatinase-associated lipokalin (NGAL), creatinine, procalcitonin, interleukin-6, and acute kidney injury (AKI) stage. METHODS: Of 46 adult patients, 7 were on vancomycin, 20 on gentamicin, and 19 on another antibiotic. Blood samples were collected on days 1, 4, and 7 of treatment, and miRNAs were identified using quantitative reverse transcription PCR. RESULTS: The results showed no relationship between miRNA levels and biochemical variables on day 1. By day 7 of gentamicin treatment miR-15a-5p provided good discrimination between AKI and non-AKI (area under curve, 0.828). In patients taking vancomycin, miR-155-5p and miR-192-5p positively correlated with creatinine and NGAL values, and miR-192-5p and miR-423-5p positively correlated with procalcitonin and interleukin-6 in patients treated with a non-nephrotoxic antibiotic. In patients together we found positive correlation between miR-155-5p and miR-423-5p and all biochemical markers. CONCLUSION: The results suggest that these four miRNAs may serve as diagnostic or therapeutic tool in sepsis, renal injury and nephrotoxic treatment. TRIAL REGISTRATION: ClinicalTrials.gov , ID: NCT04991376 . Registered on 27 July 2021.

Galactose-Deficient IgA1 B cells in the Circulation of IgA Nephropathy Patients Carry Preferentially Lambda Light Chains and Mucosal Homing Receptors.

BACKGROUND: IgA nephropathy (IgAN) primary glomerulonephritis is characterized by the deposition of circulating immune complexes composed of polymeric IgA1 molecules with altered O-glycans (Gd-IgA1) and anti-glycan antibodies in the kidney mesangium. The mesangial IgA deposits and serum IgA1 contain predominantly λ light (L) chains, but the nature and origin of such IgA remains enigmatic. METHODS: We analyzed λ L chain expression in peripheral blood B cells of 30 IgAN patients, 30 healthy controls (HCs), and 18 membranous nephropathy patients selected as disease controls (non-IgAN). RESULTS: In comparison to HCs and non-IgAN patients, peripheral blood surface/membrane bound (mb)-Gd-IgA1+ cells from IgAN patients express predominantly λ L chains. In contrast, total mb-IgA+, mb-IgG+, and mb-IgM+ cells were preferentially positive for kappa (κ) L chains, in all analyzed groups. Although minor in comparison to κ L chains, λ L chain subsets of mb-IgG+, mb-IgM+, and mb-IgA+ cells were significantly enriched in IgAN patients in comparison to non-IgAN patients and/or HCs. In contrast to HCs, the peripheral blood of IgAN patients was enriched with λ+ mb-Gd-IgA1+, CCR10+, and CCR9+ cells, which preferentially home to the upper respiratory and digestive tracts. Furthermore, we observed that mb-Gd-IgA1+ cell populations comprise more CD138+ cells and plasmablasts (CD38+) in comparison to total mb-IgA+ cells. CONCLUSIONS: Peripheral blood of IgAN patients is enriched with migratory λ+ mb-Gd-IgA1+ B cells, with the potential to home to mucosal sites where Gd-IgA1 could be produced during local respiratory or digestive tract infections.

Acute Kidney Injury in Septic Patients Treated by Selected Nephrotoxic Antibiotic Agents-Pathophysiology and Biomarkers-A Review.

Acute kidney injury is a common complication in critically ill patients with sepsis and/or septic shock. Further, some essential antimicrobial treatment drugs are themselves nephrotoxic. For this reason, timely diagnosis and adequate therapeutic management are paramount. Of potential acute kidney injury (AKI) biomarkers, non-protein-coding RNAs are a subject of ongoing research. This review covers the pathophysiology of vancomycin and gentamicin nephrotoxicity in particular, septic AKI and the microRNAs involved in the pathophysiology of both syndromes. PubMED, UptoDate, MEDLINE and Cochrane databases were searched, using the terms: biomarkers, acute kidney injury, antibiotic nephrotoxicity, sepsis, miRNA and nephrotoxicity. A comprehensive review describing pathophysiology and potential biomarkers of septic and toxic acute kidney injury in septic patients was conducted. In addition, five miRNAs: miR-15a-5p, miR-192-5p, miR-155-5p, miR-486-5p and miR-423-5p specific to septic and toxic acute kidney injury in septic patients, treated by nephrotoxic antibiotic agents (vancomycin and gentamicin) were identified. However, while these are at the stage of clinical testing, preclinical and clinical trials are needed before they can be considered useful biomarkers or therapeutic targets of AKI in the context of antibiotic nephrotoxicity or septic injury.

Acute toxic kidney injury.

Substances toxic to the kidney are legion in the modern world. The sheer number and variety, their mutual interactions and, metabolism within the body are a challenge to research. Moreover, the kidney is especially prone to injury owing to its physiology. Acute kidney injury (AKI) induced by poisonous or primarily nephrotoxic substances, may be community acquired with ingestion or inhalation or nosocomial. Many nephrotoxic plants, animal poisons, medications, chemicals and illicit drugs can induce AKI by varying pathophysiological pathways. Moreover, the epidemiology of toxic AKI varies depending on country, regions within countries, socioeconomic status and health care facilities. In this review, we have selected nephrotoxic insults due to medication, plants, animal including snake venom toxicity, environmental, (agri)chemicals and also illicit drugs. We conclude with a section on diagnosis, clinical presentation and management of poisoning accompanied by various organ dysfunction and AKI.

Renal cell carcinoma: Review of etiology, pathophysiology and risk factors.

BACKGROUND AND AIMS: The global incidence of renal cell cancer is increasing annually and the causes are multifactorial. Early diagnosis and successful urological procedures with partial or total nephrectomy can be life-saving. However, only up to 10% of RCC patients present with characteristic clinical symptoms. Over 60% are detected incidentally in routine ultrasound examination. The question of screening and preventive measures greatly depends on the cause of the tumor development. For the latter reason, this review focuses on etiology, pathophysiology and risk factors for renal neoplasm. METHODS: A literature search using the databases Medscape, Pubmed, UpToDate and EBSCO from 1945 to 2015. RESULTS AND CONCLUSIONS: Genetic predisposition/hereditary disorders, obesity, smoking, various nephrotoxic industrial chemicals, drugs and natural/manmade radioactivity all contribute and enviromental risks are a serious concern in terms of prevention and the need to screen populations at risk. Apropos treatment, current oncological research is directed to blocking cancer cell division and inhibiting angiogenesis based on a knowledge of molecular pathways.

Acute kidney injury due to rhabdomyolysis and renal replacement therapy: a critical review.

Rhabdomyolysis, a clinical syndrome caused by damage to skeletal muscle and release of its breakdown products into the circulation, can be followed by acute kidney injury (AKI) as a severe complication. The belief that the AKI is triggered by myoglobin as the toxin responsible appears to be oversimplified. Better knowledge of the pathophysiology of rhabdomyolysis and following AKI could widen treatment options, leading to preservation of the kidney: the decision to initiate renal replacement therapy in clinical practice should not be made on the basis of the myoglobin or creatine phosphokinase serum concentrations.

Vancomycin pharmacokinetics during high-volume continuous venovenous hemofiltration in critically ill septic patients.

AIMS: To assess the influence of continuous venovenous hemofiltration (CVVH) at a filtration rate of 45 mL/kg/h on vancomycin pharmacokinetics in critically ill septic patients with acute kidney injury (AKI). METHODS: Seventeen adult septic patients with acute kidney injury treated with CVVH and vancomycin were included. All patients received first dose of 1.0 g intravenously followed by 1.0 g/12 h if not adjusted. In sixteen patients vancomycin was introduced on the day of the start of CRRT therapy. Blood samples and ultrafiltrates were obtained before and 0.5, 1, 6 and 12 h after vancomycin administration. RESULTS: On the first day, the median total vancomycin clearance (Cltot) was 0.89 mL/min/kg (range 0.31 - 2.16). CRRT clearance accounted for around 50-60% of the total clearance of vancomycin found in a population with normal renal function (0.97 mL/min/kg). Vancomycin serum concentrations after the first dose were below the required target of 10 mg/L as early as 6 h in 10 patients, AUC0-24/MIC ≥ 400 ratio was achieved in 10 patients on the first day. CONCLUSIONS: CVVH at a filtration rate of 45 mL/kg/h leads to high and rapid extracorporeal removal of vancomycin in critically ill patients. Due to the rapid change in patient clinical status it was impossible to predict a fixed dosage regimen. We recommend blood sampling as early as 6 h after first vancomycin dose with maintenance dose based on vancomycin serum level monitoring.

Acute kidney injury following acute pancreatitis: A review.

UNLABELLED: BACKROUND. Acute kidney injury (AKI) is a common serious complication of severe acute pancreatitis (SAP) and an important marker of morbidity and mortality in critically ill septic patients. AKI due to severe acute pancreatitis can be the result of hypoxemia, release of pancreatic amylase from the injured pancreas with impairment of renal microcirculation, decrease in renal perfusion pressure due to abdominal compartment syndrome, intraabdominal hypertension or hypovolemia. Endotoxins and reactive oxygen species (ROS) also play an important role in the pathophysiology of SAP and AKI. Knowledge of the pathophysiology and diagnosis of AKI following SAP might improve the therapeutic outcome of critically ill patients. METHODS AND RESULTS: An overview of the pathophysiology, diagnosis and potential treatment options based on a literature search of clinical human and experimental studies from 1987 to 2013. CONCLUSIONS: Early recognition of AKI and SAP in order to prevent severe complication like septic shock, intraabdominal hypertension or abdominal compartment syndrome leading to multiple organ dysfunction syndrome is a crucial tool of therapeutic measures in intensive care.

The role of adrenomedullin and galanin in recurrent vasovagal syncope: a case control study.

AIMS: Orthostatic stimuli are known to elicit changes in vasoactive peptide levels. The hypothesis of no difference in adrenomedullin and/or galanin levels in patients with recurrent vasovagal syncope and healthy controls was tested in a passive 35-min head-up tilt test (HUTT). METHODS: Twenty eight persons (14 patients and 14 healthy controls) were tested in a 35-min/60° head-up tilt test with telemetry monitoring. Three blood samples were evaluated for each person during the HUTT. Plasma levels of adrenomedullin and galanin were analysed by the Kruskal-Wallis test for all sampling periods. Vagal influence was indirectly assessed by the break index. RESULTS: There were no significant differences between groups in median values for either adrenomedullin or galanin plasma levels (all 6 p-values were greater than 0.4). For adrenomedullin, no significant difference between groups was found. For galanin, the rate of change between the 1st and 2nd measurement was significantly greater for patients (P=0.04), regardless of HUTT result but between the 2(nd) and 3(rd) measurement it was insignificant (P=0.36). In the group of positive cases, the break index increased significantly (P=0.02). CONCLUSION: We confirmed that there is a different galanin secretion pattern during orthostatic provocation in patients with recurrent vasovagal syncope than healthy individuals. For adrenomedullin, no significant difference was found. A significant increment of the break index confirmed increased vagal influence in the subgroup of positive cases.

Vancomycin removal during low-flux and high-flux extended daily hemodialysis in critically ill septic patients.

AIMS: To determine the extent of vancomycin removal and vancomycin pharmacokinetics in septic patients with AKI using daily hemodialysis with polysulphone high-flux and low-flux membrane. METHODS: Five patients received 6 h daily dialysis with low-flux polysulphone membrane, four patients with high-flux polysulphone membrane. Vancomycin was administered over the last hour of dialysis. The maintenance dose was adjusted based on pre-hemodialysis serum concentrations. Patients were followed up for two days. RESULTS: Median percentage of vancomycin removal by low-flux membrane dialysis was 17% (8-38%) and by high-flux membrane dialysis was 31% (13-43%). Vancomycin clearance was only moderately higher in high-flux membrane dialysis (median 3.01 L/h, range 2.34-3.5 L/h) compared to low-flux dialysis (median 2.48 L/h, range 0.53-5.68 L/h) in the first day of the study. About two-fold higher vancomycin clearance in high-flux dialysis (median 3.62 L/h, range 1.37-5.07 L/h) was observed on the second day of the study than low-flux dialysis (median 1.74 L/h, range 0.75-30.94 L/h). CONCLUSIONS: Both high-flux and low-flux membrane dialysis remove considerable amounts of vancomycin in critically ill septic patients with AKI. Application of vancomycin after each dialysis was required to maintain therapeutic concentrations.

Gentamicin pharmacokinetics during continuous venovenous hemofiltration in critically ill septic patients.

OBJECTIVE: Current dosing recommendations for administration of gentamicin to septic patients with acute kidney injury (AKI) on continuous venovenous hemofiltration (CVVH) at a filtration rate of 45 ml/kg/h are missing. AIM: To describe gentamicin pharmacokinetics and to find an optimal dosing regimen in patients on CVVH. METHODS: Seven adult patients were included. Patients received loading dose of 240 mg followed by application of maintenance dose every 24 hours. Maintenance dose was adjusted according to gentamicin C(max)/MIC ratio and drug levels simulation using a pharmacokinetic programme. RESULTS: Median total clearance (0.59-0.79 ml/min/kg) was similar to patients with normal renal function; median volume of distribution was higher than observed in non-septic patients (about 0.5 l/kg versus 0.25 l/kg). Patients with diuresis required an increase of gentamicin dose to reach C(max)/MIC ratio. CONCLUSION: Septic patients with AKI on CVVH (45 ml/kg/h) require a loading dose of 240 mg, followed by therapeutic drug monitoring to optimize maintenance dose.