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Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association

170

Acute kidney injury (AKI) is a common consequence of systemic illness or injury and it complicates several forms of major surgery. Two major difficulties have hampered progress in AKI research and clinical management. AKI is difficult to detect early and its pathogenesis is still poorly understood. We recently reported results from multi-center studies where two urinary markers of cell-cycle arrest, tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) were validated for development of AKI well ahead of clinical manifestations-azotemia and oliguria. Cell-cycle arrest is known to be involved in the pathogenesis of AKI and this ‘dark side’ may also involve progression to chronic kidney disease. However, cell-cycle arrest has a ‘light side’ as well, since this mechanism can protect cells from the disastrous consequences of entering cell division with damaged DNA or insufficient bioenergetic resources during injury or stress. Whether we can use the light side to help prevent AKI remains to be seen, but there is already evidence that cell-cycle arrest biomarkers are indicators of both sides of this complex physiology.

Concepts: DNA, Renal failure, Chronic kidney disease, Kidney, Nephrology, Cell nucleus, Cell, Cell division

167

Since the discovery that proteins mutated in different forms of polycystic kidney disease (PKD) are tightly associated with primary cilia, strong efforts have been made to define the role of this organelle in the pathogenesis of cyst formation. Cilia are filiform microtubular structures, anchored in the basal body and extending from the apical membrane into the tubular lumen. Early work established that cilia act as flow sensors, eliciting calcium transients in response to bending, which involve the two proteins mutated in autosomal dominant PKD (ADPKD), polycystin-1 and -2. Loss of cilia alone is insufficient to cause cyst formation. Nevertheless, a large body of evidence links flow sensing by cilia to aspects relevant for cyst formation such as cell polarity, Stat6- and mammalian target of rapamycin signalling. This review summarizes the current literature on cilia and flow sensing with respect to PKD and discusses how these findings intercalate with different aspects of cyst formation.

Concepts: Immune system, Kidney, Cell, Genetic disorder, Golgi apparatus, Cytoskeleton, Polycystic kidney disease, Cilium

147

Identification of acute kidney injury (AKI) can be challenging in patients with underlying chronic disease, and biomarkers often perform poorly in this population. In this study we examined the performance characteristics of the novel biomarker panel of urinary tissue inhibitor of metalloproteinases-2 (TIMP2) and insulin-like growth factor-binding protein 7 ([IGFBP7]) in patients with a variety of comorbid conditions.

Concepts: Medicine, Cell nucleus, Blood, Medical terms, Glucose, Chronic, DNA replication, Acute

139

The NEPROCHECK test (Astute Medical, San Diego, CA, USA) combines urinary tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) to identify patients at high risk for acute kidney injury (AKI). In a US Food and Drug Administration registration trial (NCT01573962), AKI was determined by a three-member clinical adjudication committee. The objectives were to examine agreement among adjudicators as well as between adjudicators and consensus criteria for AKI and to determine the relationship of biomarker concentrations and adjudicator agreement.

Concepts: Blood, Insulin-like growth factor 1, California, Adjudicator

29

Background The main objective of this study was to theoretically quantify the fluctuations of fluid volume excess for different modes of intermittent ultrafiltration schedules and to compare the prediction for the typical and asymmetric thrice-weekly schedule to clinical, physiological and biophysical markers of volume expansion in a group of stable haemodialysis patients. Methods Overall volume excess (V(OVE)) was described as the sum of a time-independent (V(0)) and a time-dependent component (V). An exact relationship was developed to relate V to variable treatment frequency, treatment spacing and net volume accumulation rate. In a single-centre haemodialysis population, body mass profiling was combined with volume state evaluation by bioimpedance analysis, N-terminal pro-B-type natriuretic peptide (NT-pro BNP) levels, clinical signs, a volume questionnaire and blood pressure levels. Results In 23 patients following the typical thrice-weekly schedule, the time-averaged volume excess (V) during the whole week (1.1 ± 0.5 L) was significantly larger than that during the midweek interval (0.9 ± 0.4 L) (P < 0.002) by a factor comparable to that of 1.21 obtained from the theoretical analysis. V(OVE) was 1.3 ± 1.7 L and significantly related to pre- (P < 0.001) and post-dialysis levels of NT-pro BNP (P < 0.001). Conclusion Asymmetric treatment spacing such as with the typical thrice-weekly treatment schedule leads to a significant increase in time-averaged volume excess. The theoretical analysis allows for comparison of time-averaged volume excess in treatments varying with regard to treatment frequency and regularity and could be helpful to prescribe post-treatment volume (target weight) for such variable treatment modes.

Concepts: Dialysis, Hemodialysis, Ultrafiltration, Thermodynamics, Summation, Aquapheresis

28

Idiopathic focal segmental glomerulosclerosis (FSGS) is among the most common, morbid and treatment-resistant conditions faced by nephrologists. While glucocorticoids have traditionally been the mainstay of initial treatment, they induce remission in only a minority of patients. A variety of other immunosuppressants have been utilized against steroid-resistant FSGS, but few have been rigorously examined in well-controlled trials. Recently, the results were published from a National Institutes of Health (NIH)-sponsored multicenter randomized trial comparing cyclosporine (CSA) with a combination of mycophenolate mofetil (MMF) and pulse dexamethasone (DEX) for the treatment of steroid-resistant FSGS. No difference in treatment effectiveness was shown between the two groups, and adverse effects were comparable. This was the largest randomized trial ever undertaken in FSGS, but it was unfortunately underpowered to show clinically relevant differences in response rates. This shortcoming, along with particularities of the study population and outcome measures, makes it challenging to draw definitive conclusions from the trial results. Despite these limitations, the trial does provide valuable insights into treatment strategies for FSGS and offers important lessons for planning future research.

Concepts: Clinical trial, Effectiveness, Clinical research, The Trial, Immunosuppressants, Mycophenolic acid, Focal segmental glomerulosclerosis, Glomerulosclerosis

28

BackgroundFollowing advice from the Scottish Antimicrobial Prescribing Group, we switched our antibiotic prophylaxis for elective hip and knee replacement surgery from cefuroxime to flucloxacillin with single-dose gentamicin in order to reduce the incidence of Clostridium difficile associated diarrhoea (CDAD). A clinical impression that more patients subsequently developed acute kidney injury (AKI) led us to examine this possibility in more detail.MethodsWe examined the incidence of AKI in 198 consecutive patients undergoing elective hip or knee surgery. These patients were given the following prophylactic antibiotics: cefuroxime (n = 48); then high-dose (HD) flucloxacillin (5-8 g) with single-dose gentamicin (n = 52); then low-dose (LD) flucloxacillin (3-4 g) with single-dose gentamicin (n = 46) and finally cefuroxime again (n = 52).ResultsPatients receiving HD flucloxacillin required more vasopressors during surgery (P = 0.02); otherwise, there were no statistically significant differences in pre- and peri-operative characteristics between the four groups. The proportion of patients with any form of AKI by RIFLE criteria was first cefuroxime (8%), HD flucloxacillin with gentamicin (52%), LD flucloxacillin with gentamicin (22%) and second cefuroxime (14%; P < 0.0001). Odds ratios for AKI derived from a multivariate logistic regression model, adjusted also for sex and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, with the first cefuroxime group as a reference category were: HD flucloxacillin with gentamicin 14.53 (4.25-49.71); LD flucloxacillin with gentamicin 2.96 (0.81-10.81) and second cefuroxime 2.01 (0.52-7.73). Three patients required temporary haemodialysis. Biopsies in two of these showed acute tubulo-interstitial nephritis. All three patients belonged to the HD flucloxacillin with gentamicin group. None of the patients developed CDAD.ConclusionsWe have shown an association between the prophylactic antibiotic regimen and subsequent development of AKI following primary hip and knee arthroplasty that appeared to be due to the use of HD flucloxacillin with single-dose gentamicin. We found no evidence to suggest that this association was confounded by any of the co-variates we measured.

Concepts: Regression analysis, Kidney, Statistical significance, Acute kidney injury, Antibiotic, Knee replacement, Clostridium difficile, Interstitial nephritis

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Iron-deficiency anemia in non-dialysis-dependent chronic kidney disease (NDD-CKD) frequently requires parenteral iron replacement, but existing therapies often require multiple administrations. We evaluated the efficacy and cardiovascular safety of ferric carboxymaltose (FCM), a non-dextran parenteral iron permitting large single-dose infusions, versus iron sucrose in patients with iron-deficiency anemia and NDD-CKD.

Concepts: Hemoglobin, Renal failure, Chronic kidney disease, Kidney, Nephrology, Erythropoietin, Medicine, Iron

27

In many fields, including the field of nephrology, missing data are unfortunately an unavoidable problem in clinical/epidemiological research. The most common methods for dealing with missing data are complete case analysis-excluding patients with missing data-mean substitution-replacing missing values of a variable with the average of known values for that variable-and last observation carried forward. However, these methods have severe drawbacks potentially resulting in biased estimates and/or standard errors. In recent years, a new method has arisen for dealing with missing data called multiple imputation. This method predicts missing values based on other data present in the same patient. This procedure is repeated several times, resulting in multiple imputed data sets. Thereafter, estimates and standard errors are calculated in each imputation set and pooled into one overall estimate and standard error. The main advantage of this method is that missing data uncertainty is taken into account. Another advantage is that the method of multiple imputation gives unbiased results when data are missing at random, which is the most common type of missing data in clinical practice, whereas conventional methods do not. However, the method of multiple imputation has scarcely been used in medical literature. We, therefore, encourage authors to do so in the future when possible.

Concepts: Scientific method, Data analysis, Normal distribution, Missing values, Expectation-maximization algorithm, MCAR, Imputation

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BackgroundOptimal management of acute kidney injury (AKI) remains controversial, particularly with respect to acutely unwell patients in the intensive care unit (ICU). This is likely to be attributable to the currently poor evidence base. Attempts to introduce guidance and consistency have been made over recent years, such as the AKI Network (AKIN) staging system and, in the UK, recommendations from the 2009 National Confidential Enquiry into Patient Outcome and Death (NCEPOD) report into AKI. We wished to ascertain how AKI is investigated and managed in intensive care units in the UK, and whether these recent initiatives have made any difference to clinical practice.MethodsThis is an online survey of all general adult UK ICUs between December 2009 and May 2010.ResultsOne hundred and eighty-eight out of two hundred and thirty-three units (80%) started the survey; 167 (72%) completed it. Only 19.2% of respondents routinely use AKIN or Risk, Injury, Failure, Loss, End-stage kidney disease (RIFLE) criteria for diagnosis and staging of AKI. A nephrologist is never or rarely consulted about patients with AKI in over 40% of the units. Only 46.4% have 24-h access to a renal ultrasound service. Continuous venovenous haemofiltration (CVVH) is the most commonly used form of renal replacement therapy (RRT) but intermittent haemodialysis (IHD) is used infrequently. Continuous RRTs (CRRTs) are managed almost exclusively by intensivists, whereas IHD is managed predominantly by nephrologists. The most frequently used criteria for initiating RRT are hyperkalaemia, fluid overload and pH. Most units have a standard RRT protocol and 35 mL/kg/h is the most frequently prescribed dose of CVVH. Only 51% of the units assess the delivered dose of RRT.ConclusionsConsiderable variation exists in the investigation and management of AKI in UK ICUs. Despite increasing recognition of the importance of AKI, few ICUs are aware of RIFLE and AKIN criteria.

Concepts: Renal failure, Chronic kidney disease, Kidney, Nephrology, Dialysis, Intensive care medicine, Hemodialysis, Hemofiltration