Diagnosing COVID-19; towards a feasible COVID-19 rule-out protocol.

INTRODUCTION: We present the results of the COVID-19 rule-out protocol at Ghent University Hospital, a step-wise testing approach which included repeat NFS SARS-CoV-2 rRT-PCR, respiratory multiplex RT-PCR, low-dose chest CT and bronchoscopy with BAL to confirm or rule-out SARS-CoV-2 infection in patients admitted with symptoms suggestive of COVID-19. RESULTS: Between 19 March 2020 and 30 April 2020, 455 non-critically ill patients with symptoms suspect for COVID-19 were admitted. The initial NFS for SARS-CoV-2 rRT-PCR yielded 66.9%, the second NFS 25.4% and bronchoscopy with BAL 5.9% of total COVID-19 diagnoses. In the BAL fluid, other respiratory pathogens were detected in 65% (13/20) of the COVID-19 negative patients and only in 1/7 COVID-19 positive patients. Retrospective antibody testing at the time around BAL sampling showed a positive IgA or IgG in 42.9 % of the COVID-19 positive and 10.5% of the COVID-19 negative group. Follow-up serology showed 100% COVID-19 positivity in the COVID-19 positive group and 100% IgG negativity in the COVID-19 negative group. CONCLUSION: In our experience, bronchoscopy with BAL can have an added value to rule-in or rule-out COVID-19 in patients with clinical and radiographical high-likelihood of COVID-19 and repeated negative NFS testing. Furthermore, culture and respiratory multiplex PCR on BAL fluid can aid to identify alternative microbial etiological agents in this group. Retrospective analysis of antibody development in this selected group of patients suggests that the implementation of serological assays in the routine testing protocol will decrease the need for invasive procedures like bronchoscopy.

Treating potassium disturbances: kill the killers but avoid overkill.

OBJECTIVES: In this publication, we review the definitions, symptoms, causes, differential diagnoses and therapies of hypokalemia and hyperkalemia. METHODS: Comprehensive tables and diagnostic algorithms are provided when appropriate. RESULTS AND CONCLUSIONS: Although both hypokalemia and hyperkalemia may be life-threatening, this is essentially the case with severe changes (serum potassium < 2.5 or > 6.5 mmol/L), the presence of symptoms or electrocardiographic deviations, the association with aggravating factors (e.g. digitalis intake) and/or rapid acute changes. Only these truly need an emergency therapeutic approach. In all other cases, a careful consideration of the causes and their correction should prevail over additional approaches to modify serum potassium concentration. Although most therapeutic approaches to both hypokalemia and hyperkalemia have been well established since many years, recently two new intestinal potassium binders have been introduced on the market. It remains to be elucidated whether these drugs truly have an additional role on top of the existing treatments.

Compliance with a structured bedside handover protocol: An observational, multicentred study.

BACKGROUND: Bedside handover is the delivery of the nurse-to-nurse shift handover at the patient's bedside. The method is increasingly used in nursing, but the evidence concerning the implementation process and compliance to the method is limited. OBJECTIVES: To determine the compliance with a structured bedside handover protocol following ISBARR and if there were differences in compliance between wards. DESIGN: A multicentred observational study with unannounced and non-participatory observations (n = 638) one month after the implementation of a structured bedside handover protocol. SETTINGS AND PARTICIPANTS: Observations of individual patient handovers between nurses from the morning shift and the afternoon shift in 12 nursing wards in seven hospitals in Flanders, Belgium. METHODS: A tailored and structured bedside handover protocol following ISBARR was developed, and nurses were trained accordingly. One month after implementation, a minimum of 50 observations were performed with a checklist, in each participating ward. To enhance reliability, 20% of the observations were conducted by two researchers, and inter-rater agreement was calculated. Data were analysed using descriptive statistics, one-way ANOVAs and multilevel analysis. RESULTS: Average compliance rates to the structured content protocol during bedside handovers were high (83.63%; SD 11.44%), and length of stay, the type of ward and the nursing care model were influencing contextual factors. Items that were most often omitted included identification of the patient (46.27%), the introduction of nurses (36.51%), hand hygiene (35.89%), actively involving the patient (34.44%), and using the call light (21.37%). Items concerning the exchange of clinical information (e.g., test results, reason for admittance, diagnoses) were omitted less (8.09%-1.45%). Absence of the patients (27.29%) and staffing issues (26.70%) accounted for more than half of the non-executed bedside handovers. On average, a bedside handover took 146 s per patient. CONCLUSIONS: When the bedside handover was delivered, compliance to the structured content was high, indicating that the execution of a bedside handover is a feasible step for nurses. The compliance rate was influenced by the patient's length of stay, the nursing care model and the type of ward, but their influence was limited. Future implementation projects on bedside handover should focus sufficiently on standard hospital procedures and patient involvement. According to the nurses, there was however a high number of situations where bedside handovers could not be delivered, perhaps indicating a reluctance in practice to use bedside handovers.

Can increased vigilance for chronic kidney disease in hospitalised patients decrease late referral and improve dialysis-free survival?

BACKGROUND: Insufficient vigilance for renal insufficiency is associated with late referral, increased morbidity and mortality. The present study examines whether increased vigilance for chronic kidney disease (CKD) leads to quicker referral to and better follow-up by a nephrologist, and whether it is associated with an improved outcome. METHODS: Patients with an eGFR < 45 ml/min/1.73 m2 during hospitalisation at the Ghent University Hospital were enrolled during a period of 100 days. The patients were interviewed about their awareness of CKD. Both the patients and their general practitioner were subsequently informed about CKD. The primary endpoint was the number of patients referred for nephrological follow-up within three months. The secondary endpoint was need for dialysis and mortality from any cause one year after inclusion. RESULTS: Of the 72 included patients, 54 had proven CKD, with eGFR consistently < 45 ml/min/1.73 m2 during at least three months before inclusion. Merely 65% was aware of having CKD and only 41% was in regular nephrological follow-up. After intervention, the percentage of patients with CKD in follow-up increased from 41% to 71% (p = 0.002). The proportion reaching the secondary endpoint was significant lower in the patients who were referred quickly than in those who were not (p = 0.015). Similarly, the proportion was significant lower in the patients who received nephrological follow-up than in those who did not (p = 0.006). CONCLUSION: Vigilance for CKD is poor. Simple interventions to augment the vigilance for CKD, as presented in this study, lead to a quicker referral to and follow-up by a nephrologist, which may result in better outcome.

Development and validation of an ultra-high performance liquid chromatography-tandem mass spectrometry method to measure creatinine in human urine.

Despite decades of creatinine measurement in biological fluids using a large variety of analytical methods, an accurate determination of this compound remains challenging. Especially with the novel trend to assess biomarkers on large sample sets preserved in biobanks, a simple and fast method that could cope with both a high sample throughput and a low volume of sample is still of interest. In answer to these challenges, a fast and accurate ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed to measure creatinine in small volumes of human urine. In this method, urine samples are simply diluted with a basic mobile phase and injected directly under positive electrospray ionization (ESI) conditions, without further purification steps. The combination of an important diluting factor (10(4) times) due to the use of a very sensitive triple quadrupole mass spectrometer (XEVO TQ) and the addition of creatinine-d3 as internal standard completely eliminates matrix effects coming from the urine. The method was validated in-house in 2012 according to the EMA guideline on bioanalytical method validation using Certified Reference samples from the German External Quality Assessment Scheme (G-Equas) proficiency test. All obtained results for accuracy and recovery are within the authorized tolerance ranges defined by G-Equas. The method is linear between 0 and 5 g/L, with LOD and LOQ of 5 × 10(-3) g/L and 10(-2) g/L, respectively. The repeatability (CV(r) = 1.03-2.07%) and intra-laboratory reproducibility (CV(RW) = 1.97-2.40%) satisfy the EMA 2012 guideline. The validated method was firstly applied to perform the German G-Equas proficiency test rounds 51 and 53, in 2013 and 2014, respectively. The obtained results were again all within the accepted tolerance ranges and very close to the reference values defined by the organizers of the proficiency test scheme, demonstrating an excellent accuracy of the developed method. The method was finally applied to measure the creatinine concentration in 210 urine samples, coming from 190 patients with a chronic kidney disease (CKD) and 20 healthy subjects. The obtained creatinine concentrations (ranging from 0.12 g/L up to 3.84 g/L) were compared, by means of a Passing Bablok regression, with the creatinine contents obtained for the same samples measured using a traditional compensated Jaffé method. The UHPLC-MS/MS method described in this paper can be used to normalize the concentration of biomarkers in urine for the extent of dilution.

The paradox of bardoxolone methyl: a call for every witness on the stand?

People with type 2 diabetes and chronic kidney disease (CKD) remain an extremely vulnerable population with increased cardiovascular morbidity, mortality and mounting societal costs. As such, any effort to improve their dismal outcome is heavily supported. Yet, most drugs fail to replicate the promising signals of early experiments in humans in large and methodologically sound trials. As a recent example, an independent data and safety committee advised the termination of a phase 3 trial due to excessive cardiovascular disease and especially heart failure in patients allocated to the antioxidant synthetic triterpenoid bardoxolone methyl versus placebo. We evaluate the reasons why this outcome in hindsight was possibly not totally unexpected and develop a mechanistic model that shows that the consistent drop in serum magnesium concentration in patients exposed to bardoxolone methyl might have contributed to the development of heart failure. As such, this trial, despite its negative outcome, might provide additional pieces of the puzzle enabling us to get a better grip on diseases that share increased inflammation and oxidative stress, such as type 2 diabetes, metabolic syndrome, heart failure and CKD.

AKI in early sepsis is a continuum from transient AKI without tubular damage over transient AKI with minor tubular damage to intrinsic AKI with severe tubular damage.

PURPOSE: The pathophysiology of septic acute kidney injury (AKI) is incompletely understood, and there is controversy on the role of renal hypoperfusion in early sepsis. We hypothesized that renal hypoperfusion plays a role in early sepsis and that there is a continuum between transient AKI without tubular damage, transient AKI with minor tubular damage, and intrinsic AKI. METHODS: A total of 107 consecutive patients with sepsis were included. Fractional excretion of sodium (FENa), urinary, and serum neutrophil gelatinase-associated lipocalin were measured at admission (T0) and 4 h (T4) and 24 h later (T24). Patients were classified according to FENa quartiles (FENaQ). Transient and intrinsic AKI were respectively defined as AKI that did or did not recover to no AKI in the following 5 days. RESULTS: A total of 57 developed transient AKI, 22 developed intrinsic AKI, and 28 did not have AKI. Of the ten patients with transient AKI classified in the two lowest FENa quartiles (FENa < 0.36 %) and without signs of local tubular damage, seven still did not show signs of tubular damage 24 h later. Also, 50 % of patients with intrinsic AKI classified in the same FENaQ did not show signs of local tubular damage at admission but did so 24 h later. CONCLUSIONS: There is a continuum between transient AKI without tubular damage, transient AKI with minor tubular damage, and intrinsic AKI in sepsis. Renal hypoperfusion seems to be the instigator for the development of AKI in the majority of patients with early sepsis. Other mechanisms in some patients cannot be excluded.

Questioning the Pathogenic Role of the GLA p.Ala143Thr "Mutation" in Fabry Disease: Implications for Screening Studies and ERT.

Fabry disease is an X-linked inborn error of glycosphingolipid metabolism caused by quantitative or qualitative defects in the lysosomal enzyme alfa-Galactosidase A (aGAL A), ultimately resulting in vital organ dysfunction. Mainly the kidneys, the heart, and the central nervous system are involved. While the classical phenotype of Fabry disease is readily recognizable, screening studies have identified clinical variants. Here, we report the phenotype associated with the GLA p.Ala143Thr (c.427G>A) mutation in 12 patients aged 42-83 years. None of the patients had classical Fabry signs or symptoms as angiokeratoma, hypohidrosis, acroparesthesia, or cornea verticillata. Possible Fabry manifestations were renal failure (5/12), stroke (7/12), and left ventricular hypertrophy (5/12), but these were not necessarily attributable to the p.Ala143Thr mutation, as a cardiac biopsy in one female and left ventricular hypertrophy and kidney biopsies in two males with renal failure and microalbuminuria lacked Gb-3 deposits. The literature data on this mutation as well as data collected in the Fabry Outcome Survey (FOS) database confirm these findings. The association of renal failure, stroke, and left ventricular hypertrophy with this mutation could be the result of selection bias, as most patients were detected in screening studies.We conclude that care should be taken with attribution of vital organ dysfunction to GLA sequence alterations. In case of the p.Ala143Thr mutation, and possibly also other mutations associated with an attenuated phenotype, diagnostic tools such as biopsy and imaging should critically evaluate the relation of end-organ failure with Fabry disease, as this has important consequences for enzyme replacement therapy.

Blood pressure management in patients with chronic kidney disease: an appraisal and summary of existing guidelines.

BACKGROUND: Hypertension is a prevalent problem with huge impact on health and health care budgets. Several guidelines on how to manage blood pressure have been published, and it is unclear which one should be preferred. METHODS: Eight guidelines dealing with blood pressure management of chronic kidney disease patients were evaluated for methodological quality by the AGREE II instrument by 4 appraisers. They were also analysed for consistency in their recommendations. RESULTS: Most problematic domains were "applicability", "stakeholder involvement" and "editorial independence". Three guidelines scored below 50% for 5, and one for 4 of the 6 AGREE II domains. The guideline produced by Canadian Hypertension Education Program was preferred most, followed by KDIGO. There were discrepancies between the different guidelines with regard to blood pressure targets and thresholds, with the best and most recent advocating 140/90 mmHg. There was a consensus on the use of ACE-I/ARB's in patients with but not for those without proteinuria. However, only two guidelines specify a second line treatment (thiazides), whereas others do not, although it is well known that most patients need more than one drug to control their blood pressure. Three out of eight guidelines did not provide guidance on life-style modification. Those who did, advocated different levels of sodium restriction,, weight control, and physical activity. Remarkably, 5 out of 8 guidelines did not specify how exactly blood pressure should be measured. CONCLUSION: Blood pressure guidelines seem to be of low methodological quality, with clear improvements for the ones produced the latest. Especially the "applicability" domain, evaluating how the guideline can be put into practice, seems problematic, with as biggest hurdles that it is unclear what should be second or third line treatments, and how blood pressure should be measured or defined. The most recent guidelines advocate an office blood pressure of 140/90 mmHg for patients with chronic kidney disease.

What is the difference between prerenal and renal acute kidney injury?

This paper discusses the somewhat artificial distinction between the traditional classification of acute kidney injury in prerenal AKI and established acute tubular necrosis. The primary focus in the setting of a rising SCr should not be assigning the diagnosis of"prerenal" or "renal" AKI but should be determining where the dysfunction lies on the spectrum between purely "functional"and completely structural kidney damage. The new definitions and classification systems of AKI are summarised and the approach to the patient with acute rising serum creatinine and/or acute decline in urinary output is described. The role of the recently introduced novel biomarkers is discussed but it is believed that these biomarkers have not yet proven to be more discriminative in the differential diagnosis between"pure prerenal AKI"and established acute tubular necrosis, beyond a careful clinical evaluation of the patient and the use of the more "traditional" blood and urine parameters.

Advantages of new hemodialysis membranes and equipment.

Chronic kidney disease is characterized by the progressive retention of a number of compounds, several of which have the potential to cause cardiovascular damage. Many of these are difficult to remove by standard dialysis strategies. Removal of the larger middle molecules (mostly larger peptidic compounds) can be obtained by increasing dialyzer pore size and/or by applying convective strategies. For protein-bound solutes, convection (essentially hemodiafiltration) positively affects removal. The HEMO study demonstrated outcome superiority for the large-pore high-flux hemodialysis membranes in a number of subgroup analyses. Likewise, the Membrane Permeability Outcome study showed outcome superiority for high flux in patients with serum albumin <4 g/dl, the group for which the study had originally been designed. Apart from a small controlled trial, data suggesting superiority for convective strategies are all observational.

Posttransplantation hypomagnesemia and its relation with immunosuppression as predictors of new-onset diabetes after transplantation.

New-onset diabetes after transplantation (NODAT) is a frequent complication and has an impact on patient and graft survival. Hypomagnesemia is common in both renal transplant recipients and in diabetics. This study examines the relationship between hypomagnesemia, NODAT and the type of immunosuppression in renal transplant recipients. We conducted a retrospective single-center analysis (2002-2008) in order to assess NODAT the first year posttransplantation as defined by American Diabetes Association criteria. Serum magnesium (Mg) levels were defined as the median of all Mg levels registered during the first month posttransplantation. Patients with NODAT (N = 75; 29.5%) versus non-NODAT had lower Mg levels (p < 0.001). Patients with an Mg level < versus > or = 1.9 mg/dL showed a faster development of NODAT (log-rank p < 0.001). Mg levels were lower in patients on calcineurin inhibitors (CNI) versus no CNI patients (p < 0.001). Mg levels, albumin, BMI, triglycerides, posttransplantation hyperglycemia, tacrolimus levels and the use of sirolimus were predictors of NODAT in the multivariate analysis. Hypomagnesemia was an independent predictor of NODAT in renal transplant recipients. We confirm that the use of CNI is associated with NODAT, but, to a large extent, this effect seems attributable to the induction of hypomagnesemia. After adjustment for Mg, sirolimus was also associated with NODAT.

Acute central hemodynamic effects of peritoneal dialysis.

BACKGROUND: The supposed lack of a hemodynamic impact of peritoneal dialysis (PD) has been challenged recently in different studies, although the observed effects are still far below those seen on hemodialysis (HD), and the underlying mechanisms are unclear. METHODS: Literature overview based on Pubmed search with key words 'peritoneal dialysis, acute dwell, hemodialysis'. DISCUSSION: Hemodynamic effects of an acute PD dwell seem to be consistent, but rather limited. Increasing peritoneal pressure, causing enhanced preload and thus better cardiac output, and vasoactive reactions induced by incompatibility of the dialysis fluid seem to be the most prominent causes. The role of hyperglycemia is a matter of debate. In view of the repetitive character of the insults, especially during APD, more in depth investigation of this phenomenon is warranted.

Impact of hemodialysis duration on the removal of uremic retention solutes.

Several studies have stressed the importance of dialysis time in the removal of uremic retention solutes. To further investigate this, nine stable chronic hemodialysis patients were dialyzed for 4, 6, or 8 h processing the same total blood and dialysate volume by the Genius system and high-flux FX80 dialyzers. Inlet blood and outlet dialysate were analyzed for urea, creatinine, phosphorus, and beta2-microglobulin at various times. Total solute removal, dialyzer extraction ratios, and total cleared volumes were significantly larger during prolonged dialysis for urea, creatinine, phosphorus, and beta2-microglobulin. Reduction ratios increased progressively, except for phosphate and beta2-microglobulin, where the ratios remained constant after 2 h. In contrast, no significant difference was found for the reduction ratios of all solutes and Kt/V(urea) between the three different sessions. With longer dialyses, solutes are efficiently removed from the deeper compartments of the patient's body. Our study shows that care must be taken when using Kt/Vurea or reduction ratios as the only parameters to quantify dialysis adequacy.

Peritoneal dialysis: how we can achieve improvement of PD penetration.

Peritoneal dialysis (PD) is a well established renal replacement therapy (RRT). It appears to have some excellent properties as a first line RRT, as it preserves residual renal function, improves clearance of middle and larger solutes and preserves vascular access. To improve PD penetration, it is necessary to have a well established pre-dialysis programme, as information seems to be the clue in the choice and the success of PD. Furthermore, it is important that patients and nurses are well educated in the practice of PD. This reduces the need for hypertonic bags by better compliance with the salt restrictive diet, reduces exposure to dialysate per se by adapting the number and length of the dwells to the needs of the patient, and increases peritonitis-free survival, thus prolonging the survival of the peritoneal membrane. In addition, it is clear that the use of new low glucose degradation products and normal pH solutions will also improve the technical success of PD. The collaboration of industry with local health care providers could be a necessity in overcoming the costs induced by the import of dialysate solutions paid for in foreign currency.

Intermittent hemodialysis for renal replacement therapy in intensive care: new evidence for old truths.

Acute renal failure requiring dialysis is a frequent complication in critically ill patients with a high morbidity and mortality. Until recently, no evidence-based guidelines on the optimal treatment modality for renal replacement in the ICU could be issued because of a lack of well-performed randomized controlled trials (RCT). Over the last years however, some important new concepts and RCTs have been published on this topic. An important concept is the understanding that 'chronic dialysis strategies' are not suitable for acute renal failure patients in the ICU. From this understanding the necessity of daily dialysis followed, and later on, the need for flexible treatments related to the patients' need, using slow long extended daily dialysis (SLEDD). Several recent papers compared continuous renal replacement therapy and intermittent hemodialysis (IHD) in ICU patients, pointing to a lack of differences in outcome, but there were less practical problems using IHD, even in unstable patients. In conclusion, it can be stated that all patients can be treated with IHD when available, without jeopardizing their outcome. Slow extended daily dialysis emerged as a hybrid renal replacement therapeutic modality and has promising features because it combines the advantages of both continuous renal replacement therapy and IHD, but until now, no studies evaluating whether SLEDD is superior to 'regular IHD' are available.

The role of the International Society of Nephrology/Renal Disaster Relief Task Force in the rescue of renal disaster victims.

Disasters are a major cause of distress and material as well as corporal damage. Next to direct trauma, the crush syndrome inducing multiorgan problems as a consequence of muscle compression and the release of muscular contents into the bloodstream is the most important cause of death; this is to a large extent related to the induction of severe acute kidney injury, for which dialysis is a life-saving therapy. The practical means (both hardware and personnel) to do so are, however, often lacking in disaster conditions. The Renal Disaster Relief Task Force (RDRTF) offered support for renal problems in the aftermath of several disasters, e.g. the Marmara earthquake (1999) in Turkey, the Bam earthquake (2003) in Iran, and the Kashmir earthquake (2005) in Pakistan. A preconceived intervention plan is followed with adaptations according to local conditions. Material and personnel are dispatched to the disaster areas. These interventions have been life-saving for a substantial number of victims. The current article describes the structure and approach of the RDRTF.