Human Proenkephalin A 119-159 (PenKid) in extracorporeal therapies: Ex-Vivo Sieving Coefficient, Diffusive Clearance and Hemoadsorption Kinetics.

Enkephalins are involved in the regulation of renal function. Proenkephalin A, also known as PenKid, has been demonstrated to be a reliable biomarker for kidney function and its plasma concentration correlates with measured glomerular filtration rate. PenKid is used for prediction and diagnosis of AKI, and need of renal replacement therapy (RRT). PenKid has also been used to predict the successful weaning from RRT in patients with AKI. Whether the concentration of PenKid is affected or not by RRT, is a controversial point and there are no studies describing the kinetics of the molecule. The low molecular weight (4.5 kDa) would imply free removal by the glomerulus and the dialysis membranes. During RRT, this reduction could not be detected due to the complex kinetics involving either low dialytic clearance or increased production in response to impaired kidney function. The aim of this study is to determine the sieving coefficient and the diffusive clearance of PenKid in conditions of in vitro continuous veno-venous hemofiltration (CVVH) and continuous veno-venous hemodialysis (CVVHD), respectively and also Penkid removal ratio in conditions of in vitro hemoadsorption (HA) using a synthetic microporous resin. In each experiment, the blood batch was adjusted at 1000 mL, maintained at 37° and stirred; blood was spiked with a lyophilized PenKid peptide. Samples were collected from blood, ultrafiltrate, and effluent at different times. Sieving, clearance and removal ratio were calculated. Significant removal of PenKid was observed in CVVH (sieving 1.04±0.27), CVVHD (clearance 23.08±0.89) and HA (removal ratio 76.1±1% after 120 minutes). PenKid is effectively removed by extracorporeal therapies. In presence of anuria, PenKid generation kinetics can be calculated based on extracorporeal removal and volume variation. In steady state conditions, declining values may be the result of an initial renal function recovery and may suggest discontinuation and successful liberation from RRT.

The vascular disease of diabetic kidney disease.

The incidence of cardiovascular disease (CVD) is increased in patients with diabetic kidney disease (DKD). Aortic stiffness is a well-accepted biomarker for cardiovascular (CV) events in all stages of CKD. The worldwide prevalence of diabetes continues to grow, as does the prevalence of DKD. Insulin resistance, hyperglycaemia, hypertension and the metabolic abnormalities of type-2 diabetes are all involved in the pathogenesis of CVD. The effect of these toxins on cardiac and vascular function is amplified by the worsening of renal function and the parallel rise of uraemic toxins. In this narrative review, we analysed why arterial stiffening can be considered a vascular mediator between diabetes and cardiac dysfunction, and we discussed the strong CV and nephroprotective effects of sodium-glucose cotransporter type 2 inhibitors (SGLT2i).

Ultrasonographic Assessment of Atherosclerotic Renal Artery Stenosis in Elderly Patients with Chronic Kidney Disease: An Italian Cohort Study.

Although atherosclerotic renal artery stenosis (ARAS) is strictly associated with high cardiovascular risk and mortality, it often may remain unrecognized being clinically silent and frequently masked by co-morbidities especially in elderly patients with coexisting chronic kidney disease (CKD). The present observational study was conducted in elderly CKD-patients with atherosclerosis on other arterial beds. The aims were assessment of (1) ARAS prevalence; (2) best predictor(s) of ARAS, using duplex ultrasound; and (3) cardiovascular and renal outcomes at one-year follow-up. The cohort was represented by 607 consecutive in-patients. Inclusion criteria were age ≥65 years; CKD stages 2−5 not on dialysis; single or multiple atherosclerotic plaque on epiaortic vessels, abdominal aorta, aortic arch, coronary arteries, peripheral arteries that had been previously ascertained by one or more procedures. Duplex ultrasound was used to detect ARAS. Multiple regression analysis and ROS curve were performed to identify the predictors of ARAS. ARAS was found in 53 (44%) out of 120 patients who met the inclusion criteria. In univariate analysis, GFR (b = −0.021; p = 0.02); hemoglobin (b = −0.233; p = 0.02); BMI (b = 0.134; p = 0.036) and atherosclerosis of abdominal aorta and/or peripheral vessels (b = 1.025; p < 0.001) were associated with ARAS. In multivariable analysis, abdominal aorta and/or peripheral atherosclerosis was a significant (p = 0.002) predictor of ARAS. The area under the ROC curve was 0.655 (C.I. = 0.532−0.777; p = 0.019). ARAS is common in older CKD patients with extra-renal atherosclerosis, with the highest prevalence in those with aortic and peripheral atherosclerosis. ARAS may pass by unnoticed in everyday clinical practice.

["Naked" exit-site for peritoneal dialysis catheters].

Exit site infections (ESI) and peritoneal catheter tunnel infections are strongly associated with peritonitis. Alternative exit-site dressings can include the use of water and soap and the absence of sterile gauze. This article reports our experience with "naked" exit-sites, meaning without any kind of gauze to cover them. From January 2017 to October 2020, we enrolled 38 patients of the Nephrology and Dialysis Unit of the "San Martino" Hospital in Belluno. Nine of these patients had a "naked" exit-site. At the end of the study, no significant differences were found in the percentage of ESI-free patients, in the incidence rate of ESI, in the relative risk of developing ESI and in the incidence rate of peritonitis.

[Home hemodialysis: multicenter observational study].

Home dialysis is a primary objective of Italian Ministry of Health. As stated in the National Chronicity Plan and the Address Document for Chronic Renal Disease, it is mostly home hemodialysis and peritoneal dialysis to be carried out in the patient's home. Home hemodialysis has already been used in the past and today has found new technologies and new applications. The patient's autonomy and the need for a caregiver during the sessions are still the main limiting factors. In this multicenter observational study, 7 patients were enrolled for 24 months. They underwent six weekly hemodialysis sessions of 180' each; periodic medical examinations and blood tests were performed (3, 6, 12, 18 and 24 months). After 3-6 months of home hemodialysis there was already an improvement in the control of calcium-phosphorus metabolism (improvement in phosphorus values, (p <0.01), a reduction in parathyroid hormone (p <0.01)); in the number of phosphorus binders used (p <0.02); in blood pressure control (with a reduction in the number of hypotensive drugs p <0.02). Home hemodialysis, although applicable to a small percentage of patients (10-15%), has improved blood pressure control, calcium-phosphorus metabolism and anemia, reducing the need for rhEPO.

Role of Contrast-Enhanced Ultrasound (CEUS) in Native Kidney Pathology: Limits and Fields of Action.

Gray scale ultrasound has an important diagnostic role in native kidney disease. Low cost, absence of ionizing radiation and nephrotoxicity, short performance time, and repeatability even at the bedside, are the major advantages of this technique. The introduction of contrast enhancement ultrasound (CEUS) in daily clinical practice has significantly reduced the use of contrast enhancement computed tomography (CECT) and contrast enhancement magnetic resonance (CEMR), especially in patients with renal disease. Although there are many situations in which CECT and CEMRI are primarily indicated, their use may be limited by the administration of the contrast medium, which may involve a risk of renal function impairment, especially in the elderly, and in patients with acute kidney injury (AKI) and moderate to severe chronic kidney disease (CKD). In these cases, CEUS can be a valid diagnostic choice. To date, numerous publications have highlighted the role of CEUS in the study of parenchymal micro-vascularization and renal pathology by full integration with second level imaging methods (CECT and CEMRI) both in patients with normal renal function and with diseased kidneys. The aim of this review is to offer an updated overview of the limitations and potential applications of CEUS in native kidney disease.

COVID-19-related mortality in kidney transplant and haemodialysis patients: a comparative, prospective registry-based study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has exposed haemodialysis (HD) patients and kidney transplant (KT) recipients to an unprecedented life-threatening infectious disease, raising concerns about kidney replacement therapy (KRT) strategy during the pandemic. This study investigated the association of the type of KRT with COVID-19 severity, adjusting for differences in individual characteristics. METHODS: Data on KT recipients and HD patients diagnosed with COVID-19 between 1 February 2020 and 1 December 2020 were retrieved from the European Renal Association COVID-19 Database. Cox regression models adjusted for age, sex, frailty and comorbidities were used to estimate hazard ratios (HRs) for 28-day mortality risk in all patients and in the subsets that were tested because of symptoms. RESULTS: A total of 1670 patients (496 functional KT and 1174 HD) were included; 16.9% of KT and 23.9% of HD patients died within 28 days of presentation. The unadjusted 28-day mortality risk was 33% lower in KT recipients compared with HD patients {HR 0.67 [95% confidence interval (CI) 0.52-0.85]}. In a fully adjusted model, the risk was 78% higher in KT recipients [HR 1.78 (95% CI 1.22-2.61)] compared with HD patients. This association was similar in patients tested because of symptoms [fully adjusted model HR 2.00 (95% CI 1.31-3.06)]. This risk was dramatically increased during the first post-transplant year. Results were similar for other endpoints (e.g. hospitalization, intensive care unit admission and mortality >28 days) and across subgroups. CONCLUSIONS: KT recipients had a greater risk of a more severe course of COVID-19 compared with HD patients, therefore they require specific infection mitigation strategies.

Diagnostic capability of ultrasound in peritoneal catheter malfunction compared to videolaparoscopy.

BACKGROUND: The approach to peritoneal catheter malfunction consists usually in a diagnostic and therapeutic sequence of laxative prescription, abdominal radiography, brushing of the catheter, guide-wire manipulation or fluoroscopy and in the end of a videolaparoscopy (VLS) rescue intervention. Ultrasound (US) is able to find out major causes of peritoneal catheter malfunction, however without a clearly defined diagnostic value. The aim of the study was to validate the diagnostic capability of US in catheter malfunction compared to the diagnostic reference of VLS. METHODS: US scans of the subcutaneous and intraperitoneal segment of the catheter were performed prior to a VLS intervention in 40 adult patients presenting persistent catheter malfunction within a prospective multicentre study. Laxative prescription and brushing of the catheter lumen were undertaken prior to US scan. US diagnosis was compared to the corresponding at VLS, kappa coefficient calculated and the causes of mismatch analysed. RESULTS: In US, causes of persistent malfunction were catheter dislocation combined with omental wrapping in 21 cases, omental wrapping without dislocation in 11 cases, dislocation only in 4 cases, adherences to non-omental structures in 3 cases and entrapment in the lateral inguinal fossa in 1 case. The US diagnosis corresponded to the respective at VLS in 36 of 40 cases, resulting in a kappa coefficient of 0.89 (95% CI: 0.78-1.00). The discrepancies were due to improper visualization of the catheter between omentum and intestinal loops, resulting in an erroneous US diagnosis of omental wrapping. CONCLUSIONS: This study suggests that US might have a pivotal role in the diagnostic approach to peritoneal catheter dysfunction.

[The COVID-19 pandemic and hemodialysis: a multicentric experience].

The SARS-CoV-2 pandemic has forced a reshaping of economic, productive, commercial and healthcare systems. The last one had the dual mandate to limit intra-hospital infections and strengthen its ability to deal with the ongoing emergency. In this paper we report the experience gained by the staff of the Nephrology and Dialysis Unit of the AULSS7 Pedemontana (Vicenza - Veneto region) and the organizational model pursued during the first wave of the pandemic.

[Therapeutic options to reduce arterial stiffness in chronic kidney disease].

Chronic kidney disease is associated with an increased cardiovascular risk. Several uremic toxins are also vascular toxins and may contribute to the increase of the cardiovascular risk through the development of aortic stiffening. In this process, oxidative stress and endothelial dysfunction play an important role. Considering that aortic stiffness is a known cardiovascular risk factor and a vascular biomarker involved in the development of chronic cardiac dysfunction, and that the reduction of aortic stiffness is associated with an improved survival of patients with end-stage kidney disease, we aim at reviewing the therapeutic options to reduce aortic stiffness and potentially the cardiovascular risk.

Neutrophil Gelatinase-Associated Lipocalin Measured on Clinical Laboratory Platforms for the Prediction of Acute Kidney Injury and the Associated Need for Dialysis Therapy: A Systematic Review and Meta-analysis.

RATIONALE & OBJECTIVE: The usefulness of measures of neutrophil gelatinase-associated lipocalin (NGAL) in urine or plasma obtained on clinical laboratory platforms for predicting acute kidney injury (AKI) and AKI requiring dialysis (AKI-D) has not been fully evaluated. We sought to quantitatively summarize published data to evaluate the value of urinary and plasma NGAL for kidney risk prediction. STUDY DESIGN: Literature-based meta-analysis and individual-study-data meta-analysis of diagnostic studies following PRISMA-IPD guidelines. SETTING & STUDY POPULATIONS: Studies of adults investigating AKI, severe AKI, and AKI-D in the setting of cardiac surgery, intensive care, or emergency department care using either urinary or plasma NGAL measured on clinical laboratory platforms. SELECTION CRITERIA FOR STUDIES: PubMed, Web of Science, Cochrane Library, Scopus, and congress abstracts ever published through February 2020 reporting diagnostic test studies of NGAL measured on clinical laboratory platforms to predict AKI. DATA EXTRACTION: Individual-study-data meta-analysis was accomplished by giving authors data specifications tailored to their studies and requesting standardized patient-level data analysis. ANALYTICAL APPROACH: Individual-study-data meta-analysis used a bivariate time-to-event model for interval-censored data from which discriminative ability (AUC) was characterized. NGAL cutoff concentrations at 95% sensitivity, 95% specificity, and optimal sensitivity and specificity were also estimated. Models incorporated as confounders the clinical setting and use versus nonuse of urine output as a criterion for AKI. A literature-based meta-analysis was also performed for all published studies including those for which the authors were unable to provide individual-study data analyses. RESULTS: We included 52 observational studies involving 13,040 patients. We analyzed 30 data sets for the individual-study-data meta-analysis. For AKI, severe AKI, and AKI-D, numbers of events were 837, 304, and 103 for analyses of urinary NGAL, respectively; these values were 705, 271, and 178 for analyses of plasma NGAL. Discriminative performance was similar in both meta-analyses. Individual-study-data meta-analysis AUCs for urinary NGAL were 0.75 (95% CI, 0.73-0.76) and 0.80 (95% CI, 0.79-0.81) for severe AKI and AKI-D, respectively; for plasma NGAL, the corresponding AUCs were 0.80 (95% CI, 0.79-0.81) and 0.86 (95% CI, 0.84-0.86). Cutoff concentrations at 95% specificity for urinary NGAL were>580ng/mL with 27% sensitivity for severe AKI and>589ng/mL with 24% sensitivity for AKI-D. Corresponding cutoffs for plasma NGAL were>364ng/mL with 44% sensitivity and>546ng/mL with 26% sensitivity, respectively. LIMITATIONS: Practice variability in initiation of dialysis. Imperfect harmonization of data across studies. CONCLUSIONS: Urinary and plasma NGAL concentrations may identify patients at high risk for AKI in clinical research and practice. The cutoff concentrations reported in this study require prospective evaluation.

[Vascular dysfunction in Cardiorenal Syndrome type 4].

The Cardiorenal Syndrome type 4 (CRS-4) defines a pathological condition in which a primary chronic kidney disease (CKD) leads to a chronic impairment of cardiac function. The pathophysiology of CRS-4 and the role of arterial stiffness remain only in part understood. Several uremic toxins, such as uric acid, phosphates, advanced glycation end-products, asymmetric dimethylarginine, and endothelin-1, are also vascular toxins. Their effect on the arterial wall may be direct or mediated by chronic inflammation and oxidative stress. Uremic toxins lead to endothelial dysfunction, intima-media thickening and arterial stiffening. In patients with CRS-4, the increased aortic stiffness results in an increase of cardiac workload and left ventricular hypertrophy whereas the loss of elasticity results in decreased coronary artery perfusion pressure during diastole and increased risk of myocardial infarction. Since the reduction of arterial stiffness is associated with an increased survival in patients with CKD, the understanding of the mechanisms that lead to arterial stiffening in patients with CRS4 may be useful to select potential approaches to improve their outcome. In this review we aim at discussing current understanding of the pathways that link uremic toxins, arterial stiffening and impaired cardiac function in patients with CRS-4.

Arterial Stiffness in the Heart Disease of CKD.

CKD frequently leads to chronic cardiac dysfunction. This complex relationship has been termed as cardiorenal syndrome type 4 or cardio-renal link. Despite numerous studies and reviews focused on the pathophysiology and therapy of this syndrome, the role of arterial stiffness has been frequently overlooked. In this regard, several pathogenic factors, including uremic toxins (i.e., uric acid, phosphates, endothelin-1, advanced glycation end-products, and asymmetric dimethylarginine), can be involved. Their effect on the arterial wall, direct or mediated by chronic inflammation and oxidative stress, results in arterial stiffening and decreased vascular compliance. The increase in aortic stiffness results in increased cardiac workload and reduced coronary artery perfusion pressure that, in turn, may lead to microvascular cardiac ischemia. Conversely, reduced arterial stiffness has been associated with increased survival. Several approaches can be considered to reduce vascular stiffness and improve vascular function in patients with CKD. This review primarily discusses current understanding of the mechanisms concerning uremic toxins, arterial stiffening, and impaired cardiac function, and the therapeutic options to reduce arterial stiffness in patients with CKD.

Stroke volume variation and serum creatinine changes during abdominal aortic aneurysm surgery: a time-integrated analysis.

BACKGROUND: Patients undergoing abdominal aortic aneurysm (AAA) surgery with suprarenal clamping are at high risk for acute kidney injury (AKI) and major cardiac and cerebrovascular events (MACCE). We aimed to assess whether the stroke volume variation (SVV), a measure of hemodynamic instability, is associated with AKI in hypertensive patients undergoing elective AAA surgery with suprarenal clamping. METHODS: In a cohort of 51 hypertensive patients, we performed serial measurements of SVV (n = 459) and serum creatinine (sCr) (n = 255). AKI was defined according to the KDIGO clinical practice guidelines. Data were analyzed by repeated-measures ANOVA and regression analysis of time-integrated changes of both SVV and sCr. RESULTS: AKI developed in 45% of patients (stage 1: 31%; stage 2: 10%; stage 3: 2%). The diuresis during surgery (beta - 0.29 Z-score 95% [CI - 0.54, - 0.05]; p = 0.02), clamp time (beta 0.29 Z-score [0.05-0.52]; p = 0.02), and time-integrated changes in SVV from baseline to 12 h after surgery (beta 0.31 Z-score [0.03-0.60]; p = 0.03) were independent predictors of the time-integrated changes in sCr from baseline to 48 h after the end of surgery. In a model adjusted for age and sex, patients with AKI had an increased risk for MACCE during a mean follow-up of 3.5 ± 1.1 years (HR 5.53 [1.52-20.06]; p = 0.004). CONCLUSIONS: SVV increases progressively during and after AAA surgery in subjects who will develop AKI. The increase of SVV precedes and predicts the rise in sCr and is a good discriminator of the development of AKI. AKI is associated with an increased long-term risk for MACCE.

Pulse wave velocity differs between ulcerative colitis and chronic kidney disease.

BACKGROUND: We hypothesized that a reversal of the physiological stiffness gradient, previously reported in end-stage renal disease, begins in the early stages of chronic kidney disease (CKD) and that chronic inflammation produces a different arterial phenotype in patients with ulcerative colitis (UC). OBJECTIVES: To assess the extent of arterial stiffening in the central (carotid-femoral pulse wave velocity, cf.-PWV) and peripheral arteries (carotid-radial pulse wave velocity, cr-PWV) and to explore the determinants of the stiffness gradient in UC and in CKD. METHODS: We enrolled 45 patients with UC, 45 patients with stage 3-4 CKD and 45 matched controls. RESULTS: Despite the comparable cf.-PWV, the cr-PWV was higher in patients with UC than in those with CKD (median: 8.7 vs. 7.5m/s; p<0.001) and, consequently, the PWV ratio was lower (median: 0.97 vs. 1.12; p<0.001). In patients with CKD a stiffness mismatch was reported starting from stage 3B. The PWV ratio was associated with age and C-reactive protein (beta: 0.08 z-score, 95%CI 0.02-0.14; p=0.01) or active disease (beta: 0.43 z-score, 95%CI 0.003-0.857; p=0.048) in patients with UC and with age and glomerular filtration rate (beta: -0.56 z-score, 95%CI -1.05 to -0.07; p=0.02) in patients with CKD. CONCLUSIONS: The arterial phenotype differed between UC and CKD. The reversal of the arterial stiffness gradient is evident in CKD patients starting from stage 3B but not in patients with UC and comparable cf.-PWV. In patients with UC, the stiffness of both elastic and muscular arteries is increased as a consequence of inflammation.

Digoxin and Hypermagnesuria.

In a recent issue of Nephron, Abu-Amer et al.[1] reported the presence of hypermagnesuria in patients following acute intravenous administration of digoxin and suggested that the Na+/K+-ATPase γ-subunit, which is the pharmacological target of digoxin, can play a role in this process. Hypermagnesuria induced by digoxin may have important clinical consequences, particularly in the presence of inherited and acquired conditions associated with hypermagnesuria and hypomagnesemia. Moreover, the co-administration of digoxin with other drugs that reduce gastrointestinal absorption (i.e., proton pump inhibitors) or increase urinary excretion (i.e., loop diuretics) may increase the likelihood of developing hypomagnesemia. In this article, we reviewed the main causes of hypermagnesuria and discussed potential drug interactions that can enhance the magnesuric effect of digoxin. We suggest that during the administration of digoxin, clinicians should consider the presence of other causes of hypomagnesemia and hypermagnesuria that could enhance the magnesuric effect of digoxin, monitor the urinary and serum levels of magnesium and prescribe an oral supplementation of magnesium.