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Through improved insights into the increasing incidence and detrimental effects of acute kidney injury (AKI), its clinical relevance has become more and more apparent. Although treatment strategies for AKI have also somewhat improved, an adequate remedy still does not exist. Finding one is complicated by a multifactorial pathophysiology and by heterogeneity in the patient population. Alkaline phosphatase (ALP) has been suggested as a therapy for sepsis-associated AKI because of its protective effects against lipopolysaccharide (LPS)-induced inflammation and kidney injury in animals. However, its effectiveness as an AKI treatment has not been demonstrated definitively. Because the anti-inflammatory properties of ALP are likely not reliant on a direct effect on LPS itself, we postulate that other pathways are much more important in explaining the renoprotective properties ascribed to ALP. The re-evaluation of which properties of the ALP enzyme are responsible for the benefit seen in the lab is an important step in determining where the true potential of ALP as a treatment strategy for AKI in the clinic lies. In this review we will discuss how ALP can prevent activation of harmful pro-inflammatory receptors, redirect cell–cell signalling and protect barrier tissues, which together form the basis for current knowledge of the role of ALP in the kidney. With this knowledge in mind and by analysing currently available clinical evidence, we propose directions for new research that can determine whether ALP as a treatment strategy for AKI has a future in the clinical field. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is a growing epidemic and is independently associated with increased risk of death, chronic kidney disease (CKD) and cardiovascular events. Randomized-controlled trials (RCTs) in this domain are notoriously challenging and many clinical studies in AKI have yielded inconclusive findings. Underlying this conundrum is the inherent heterogeneity of AKI in its etiology, presentation and course. AKI is best understood as a syndrome and identification of AKI subphenotypes is needed to elucidate the disease's myriad etiologies and to tailor effective prevention and treatment strategies. Conventional RCTs are logistically cumbersome and often feature highly selected patient populations that limit external generalizability and thus alternative trial designs should be considered when appropriate. In this narrative review of recent developments in AKI trials based on the Kidney Disease Clinical Trialists (KDCT) 2020 meeting, we discuss barriers to and strategies for improved design and implementation of clinical trials for AKI patients, including predictive and prognostic enrichment techniques, the use of pragmatic trials and adaptive trials.

Background The role of macrophages in the development of rhabdomyolysis-induced acute kidney injury (RM-AKI) has been established, but an in-depth understanding of the changes in the immune landscape could help to improve targeted strategies. Whereas senescence is usually associated with chronic kidney processes, we also wished to explore whether senescence could also occur in AKI and whether senolytics could act on immune cells. Methods Single-cell RNA sequencing was used in the murine glycerol-induced RM-AKI model to dissect the transcriptomic characteristics of CD45+ live cells sorted from kidneys 2 days after injury. Public datasets from murine AKI models were reanalysed to explore cellular senescence signature in tubular epithelial cells (TECs). A combination of senolytics (dasatinib and quercetin, DQ) was administered to mice exposed or not to RM-AKI. Results Unsupervised clustering of nearly 17 000 single-cell transcriptomes identified seven known immune cell clusters. Sub-clustering of the mononuclear phagocyte cells revealed nine distinct cell sub-populations differently modified with RM. One macrophage cluster was particularly interesting since it behaved as a critical node in a trajectory connecting one major histocompatibility complex class IIhigh (MHCIIhigh) cluster only present in Control to two MHCIIlow clusters only present in RM-AKI. This critical cluster expressed a senescence gene signature, that was very different from that of the TECs. Senolytic DQ treatment blocked the switch from a F4/80highCD11blow to F4/80lowCD11bhigh phenotype, which correlated with prolonged nephroprotection in RM-AKI. Conclusions Single-cell RNA sequencing unmasked novel transitional macrophage subpopulation associated with RM-AKI characterized by the activation of cellular senescence processes. This work provides a proof-of-concept that senolytics nephroprotective effects may rely, at least in part, on subtle immune modulation. [ABSTRACT FROM AUTHOR]

Background There are no consensus definitions for evaluating kidney function recovery after acute kidney injury (AKI) and acute kidney disease (AKD), nor is it clear how recovery varies across populations and clinical subsets. We present a federated analysis of four population-based cohorts from Canada, Denmark and Scotland, 2011–18. Methods We identified incident AKD defined by serum creatinine changes within 48 h, 7 days and 90 days based on KDIGO AKI and AKD criteria. Separately, we applied changes up to 365 days to address widely used e-alert implementations that extend beyond the KDIGO AKI and AKD timeframes. Kidney recovery was based on resolution of AKD and a subsequent creatinine measurement below 1.2× baseline. We evaluated transitions between non-recovery, recovery and death up to 1 year; within age, sex and comorbidity subgroups; between subset AKD definitions; and across cohorts. Results There were 464 868 incident cases, median age 67–75 years. At 1 year, results were consistent across cohorts, with pooled mortalities for creatinine changes within 48 h, 7 days, 90 days and 365 days (and 95% confidence interval) of 40% (34%–45%), 40% (34%–46%), 37% (31%–42%) and 22% (16%–29%) respectively, and non-recovery of kidney function of 19% (15%–23%), 30% (24%–35%), 25% (21%–29%) and 37% (30%–43%), respectively. Recovery by 14 and 90 days was frequently not sustained at 1 year. Older males and those with heart failure or cancer were more likely to die than to experience sustained non-recovery, whereas the converse was true for younger females and those with diabetes. Conclusion Consistently across multiple cohorts, based on 1-year mortality and non-recovery, KDIGO AKD (up to 90 days) is at least prognostically similar to KDIGO AKI (7 days), and covers more people. Outcomes associated with AKD vary by age, sex and comorbidities such that older males are more likely to die, and younger females are less likely to recover. [ABSTRACT FROM AUTHOR]

Background Despite lack of clinical therapy in acute kidney injury (AKI) or its progression to chronic kidney disease (CKD), administration of growth factors shows great potential in the treatment of renal repair and further fibrosis. At an early phase of AKI, administration of exogenous fibroblast growth factor 2 (FGF2) protects against renal injury by inhibition of mitochondrial damage and inflammatory response. Here, we investigated whether this treatment attenuates the long-term renal interstitial fibrosis induced by ischemia–reperfusion (I/R) injury. Methods Unilateral renal I/R with contralateral nephrectomy was utilized as an in vivo model for AKI and subsequent CKD. Rats were randomly divided into four groups: Sham-operation group, I/R group, I/R-FGF2 group and FGF2-3D group. These groups were monitored for up to 2 months. Serum creatinine, inflammatory response and renal histopathology changes were detected to evaluate the role of FGF2 in AKI and followed renal interstitial fibrosis. Moreover, the expression of vimentin, α-SMA, CD31 and CD34 were examined. Results Two months after I/R injury, the severity of renal interstitial fibrosis was significantly attenuated in both of I/R-FGF2 group and FGF2-3D group, compared with the I/R group. The protective effects of FGF2 administration were associated with the reduction of high-mobility group box 1 (HMGB1)-mediated inflammatory response, the inhibition of transforming growth factor beta (TGF-β1)/Smads signaling–induced epithelial–mesenchymal transition and the maintenance of peritubular capillary structure. Conclusions A single dose of exogenous FGF2 administration 1 h or 3 days after reperfusion inhibited renal fibrogenesis and thus blocked the transition of AKI to CKD. Our findings provided novel insight into the role of FGF signaling in AKI-to-CKD progression and underscored the potential of FGF-based therapy for this devastating disease. [ABSTRACT FROM AUTHOR]

Biology has taught us that a protein as abundantly made and conserved among species as Tamm-Horsfall protein (THP or uromodulin) cannot just be a waste product serving no particular purpose. However, for many researchers, THP is merely a nuisance during urine proteome profiling or exosome purification and for clinicians an enigmatic entity without clear disease implications. Thanks to recent human genetic and correlative studies and animal modeling, we now have a renewed appreciation of this highly prevalent protein in not only guarding urinary homeostasis, but also serving as a critical mediator in systemic inter-organ signaling. Beyond a mere barrier that lines the tubules, or a surrogate for nephron mass, mounting evidence suggests that THP is a multifunctional protein critical for modulating renal ion channel activity, salt/water balance, renal and systemic inflammatory response, intertubular communication, mineral crystallization and bacterial adhesion. Indeed, mutations in THP cause a group of inherited kidney diseases, and altered THP expression is associated with increased risks of urinary tract infection, kidney stone, hypertension, hyperuricemia and acute and chronic kidney diseases. Despite the recent surge of information surrounding THP's physiological functions and disease involvement, our knowledge remains incomplete regarding how THP is normally regulated by external and intrinsic factors, how precisely THP deficiency leads to urinary and systemic pathophysiology and in what clinical settings THP can be used as a theranostic biomarker and a target for modulation to improve patient outcomes.

Background No single study contrasts the extent and consequences of inequity of kidney care across the clinical course of kidney disease. Methods This population study of Grampian (UK) followed incident presentations of acute kidney injury (AKI) and incident estimated glomerular filtration rate (eGFR) thresholds of <60, <45 and <30 mL/min/1.73 m2 in separate cohorts (2011–2021). The key exposure was area-level deprivation (lowest quintile of the Scottish Index of Multiple Deprivation). Outcomes were care processes (monitoring, prescribing, appointments, unscheduled care), long-term mortality and kidney failure. Modelling involved multivariable logistic regression, negative binomial regression and cause-specific Cox models with and without adjustment of comorbidities. Results There were 41 313, 51 190, 32 171 and 17 781 new presentations of AKI and eGFR thresholds <60, <45 and <30  mL/min/1.73 m2. A total of 6.1–7.8% of the population was from deprived areas and (versus all others) presented on average 5 years younger, with more diabetes and pulmonary and liver disease. Those from deprived areas were more likely to present initially in hospital, less likely to receive community monitoring, less likely to attend appointments and more likely to have an unplanned emergency department or hospital admission episode. Deprivation had the greatest association with long-term kidney failure at the eGFR <60 mL/min/1.73 m2 threshold {adjusted hazard ratio [HR] 1.48 [95% confidence interval (CI) 1.17–1.87]} and this association decreased with advancing disease severity [HR 1.09 (95% CI 0.93–1.28) at eGFR <30 mL/min/1.73 m2), with a similar pattern for mortality. Across all analyses the most detrimental associations of deprivation were an eGFR threshold <60 mL/min/1.73 m2, AKI, males and those <65 years of age. Conclusions Even in a high-income country with universal healthcare, serious and consistent inequities in kidney care exist. The poorer care and outcomes with area-level deprivation were greater earlier in the disease course. [ABSTRACT FROM AUTHOR]

Background Early recognition of hospital-acquired acute kidney injury (AKI) may improve patient management and outcomes. Methods This multicentre study was conducted at three hospitals (H1—intervention; H2 and H3—controls) served by a single laboratory. The intervention bundle [an interruptive automated alerts (aAlerts) showing AKI stage and baseline creatinine in the eMR, a management guide and junior medical staff education] was implemented only at H1. Outcome variables included length-of-stay (LOS), all-cause in-hospital mortality and management quality. Results Over 6 months, 639 patients developed AKI (265 at H1 and 374 at controls), with 94.7% in general wards; 537 (84%) patients developed Stage 1, 58 (9%) Stage 2 and 43 (7%) Stage 3 AKI. Median LOS was 9 days (IQR 4–17) and was not different between intervention and controls. However, patients with AKI stage 1 had shorter LOS at H1 [median 8 versus 10 days (P = 0.021)]. Serum creatinine had risen prior to admission in most patients. Documentation of AKI was better in H1 (94.8% versus 83.4%; P = 0.001), with higher rates of nephrology consultation (25% versus 19%; P = 0.04) and cessation of nephrotoxins (25.3 versus 18.8%; P = 0.045). There was no difference in mortality between H1 versus controls (11.7% versus 13.0%; P = 0.71). Conclusions Most hospitalized patients developed Stage 1 AKI and developed AKI in the community and remained outside the intensive care unit (ICU). The AKI eAlert bundle reduced LOS in most patients with AKI and increased AKI documentation, nephrology consultation rate and cessation of nephrotoxic medications. [ABSTRACT FROM AUTHOR]

Background Acute kidney injury (AKI) is a public health problem with no specific therapies in the clinic and the underlying pathogenesis of AKI remains obscure. Bombesin receptor-activated protein (BRAP, C6ORF89 protein) was initially discovered as a ligand for a previously orphan G-protein-coupled receptor bombesin-like receptor-3. At present, accepted biological effects of BRAP include cell cycle progression, wound repair and the activation of histone deacetylases. However, its role in kidney disease is unknown. In this study we have investigated the role of BRAP and underlying mechanisms involved in cisplatin (CP)-induced AKI. Methods Here we used Bc004004 (homologous of C6ORF89 in mice) knockout mice and HK2 cells to investigate the effect of BRAP on AKI in vitro and in vivo. We analyzed ChIP-Seq and RNA-Seq data to search for the upstream regulators of BRAP and downstream mediators of BRAP action in AKI. Immunostaining, real-time polymerase chain reaction (PCR), co-immunoprecipitation, a dual-luciferase reporter assay and ChIP-PCR assay were applied to reveal the upstream and downstream regulation mechanism of BRAP during cisplatin-induced AKI. Results BRAP was downregulated in mice and human kidneys with AKI. Global Bc004004 deletion alleviated tubular cell apoptosis and necroptosis in CP-induced AKI mice, whereas local overexpression of BRAP in kidneys aggravated them. Pan-caspase inhibitor Z-VAD pretreatment attenuated CP-induced blood creatinine increase and kidney injury in wild-type mice but not in BRAP -/- mice. The activation of mixed lineage kinase like-domain was magnified by Z-VAD in CP-treated mice, especially in BRAP -/- mice. The cytoprotective effect of Z-VAD was more substantial than necrostatin-1 (Nec-1, an inhibitor of necroptosis) in CP-treated human kidney proximal tubular epithelial (HK2) cells. Furthermore, Nec-1 pretreatment reduced the CP-induced cell death in BRAP overexpression HK2 cells but did not work in cells with normal BRAP levels. We determined that CP treatment activated the nuclear factor-κB subunit P65 and inhibition of P65 increased the messenger RNA (mRNA) levels of BRAP in HK2 cells. The chromatin immunoprecipitation assay and dual-luciferase reporter gene assay verified P65 binding to the C6ORF89 promoter and reduced its mRNA expression upon CP treatment. Next we found that sirtuin 2 (SIRT2) was downregulated in CP-induced AKI and BRAP levels directly impacted the protein levels of SIRT2. Our findings further confirmed that BRAP regulates the SIRT2 protein levels by affecting SIRT2's interactions with E3 ubiquitin ligase HRD1 and subsequent proteasomal degradation. Conclusions Our results demonstrated that BRAP played an important role in tubular cell apoptosis and necroptosis during CP-induced AKI. Safe and efficient BRAP inhibitors might be effective therapeutic options for AKI. [ABSTRACT FROM AUTHOR]

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease that is caused by severe ADAMTS-13 deficiency. Immune-mediated TTP develops due to autoantibodies against ADAMTS-13, whereas congenital TTP is caused by mutations in the ADAMTS13 gene. Diagnostic possibilities and treatment options in TTP have emerged in recent years, which prompted the International Society on Thrombosis and Haemostasis (ISTH) to publish clinical practice guidelines for the diagnosis and treatment of TTP in 2020. In this article, the European Renal Best Practice Working Group endorsed the ISTH guidelines and emphasizes a number of considerations, including the importance of rapid ADAMTS-13 activity testing, the use of rituximab and anti-von Willebrand factor therapies such as caplacizumab, that enhance the clinical applicability of the guidelines in Europe. [ABSTRACT FROM AUTHOR]

Background Acute kidney injury (AKI) is a common complication after high-dose melphalan and autologous stem cell transplantation (HDM/SCT) in patients with light chain (AL) amyloidosis. However, its incidence, predictors and outcomes are not well known. Methods This observational study included 223 patients with AL amyloidosis who underwent HDM/SCT. AKI was defined as an increase in serum creatinine to ≥1.5 times the baseline occurring within the first 30 days of HDM/SCT. Results The median age was 58 years (range: 30–77). Kidney and cardiac involvement were present in 86.1% and 56.8%, respectively. The median estimated glomerular filtration rate (eGFR) was 83.5 mL/min/1.73 m2 (range: 9–213) and proteinuria was 2899 mg/day (range: 0–19 966). AKI occurred in 29.1% of patients. Dialysis was initiated in 15 patients (6.7%) and of these 12 (80%) were able to discontinue dialysis. Most of the episodes of AKI occurred within the first 2 weeks; with a median follow-up of 4.5 years (range: 0.1–16.5), AKI was associated with increased overall mortality [hazard rato (HR) = 4.53, 95% confidence interval (CI) 2–10.23]. The 10-year overall survival was 87.1% without AKI, versus 56.9% with AKI. AKI was also associated with an increased risk for end-stage kidney disease (ESKD) (HR = 4.6, 95% CI 1.44–14.38). The risk of developing ESKD at 10 years was 18.9% with AKI, versus 8.1% without AKI. Several risk factors were found and using multivariate logistic regression, a prediction model was developed that included three readily available variables: eGFR <60 mL/min/1.73 m2, interventricular septal thickness in diastole >12 mm and albumin <3 g/dL. This model was able to predict AKI development with an area under the curve of 0.8. Conclusions AKI is common in the post-HDM/SCT period and it leads to increased risk for ESKD and death. Our prediction model is an easily deployable tool in clinical settings as part of the discussion with patients who are being prepared for HDM/SCT. [ABSTRACT FROM AUTHOR]

Background The lack of a well-designed prospective study of the determinants of urgent dialysis start led us to investigate its individual- and provider-related factors in patients seeing nephrologists. Methods The Chronic Kidney Disease Renal Epidemiology and Information Network (CKD-REIN) is a prospective cohort study that included 3033 patients with CKD [mean age 67 years, 65% men, mean estimated glomerular filtration rate (eGFR) 32 mL/min/1.73 m2] from 40 nationally representative nephrology clinics from 2013 to 2016 who were followed annually through 2020. Urgent-start dialysis was defined as that 'initiated imminently or <48 hours after presentation to correct life-threatening manifestations' according to the Kidney Disease: Improving Global Outcomes 2018 definition. Results Over a 4-year (interquartile range 3.0–4.8) median follow-up, 541 patients initiated dialysis with a known start status and 86 (16%) were identified with urgent starts. The 5-year risks for the competing events of urgent and non-urgent dialysis start, pre-emptive transplantation and death were 4, 17, 3 and 15%, respectively. Fluid overload, electrolytic disorders, acute kidney injury and post-surgery kidney function worsening were the reasons most frequently reported for urgent-start dialysis. Adjusted odds ratios for urgent start were significantly higher in patients living alone {2.14 [95% confidence interval (CI) 1.08–4.25] or with low health literacy [2.22 (95% CI 1.28–3.84)], heart failure [2.60 (95% CI 1.47–4.57)] or hyperpolypharmacy [taking >10 drugs; 2.14 (95% CI 1.17–3.90)], but not with age or lower eGFR at initiation. They were lower in patients with planned dialysis modality [0.46 (95% CI 0.19–1.10)] and more nephrologist visits in the 12 months before dialysis [0.81 (95% CI 0.70–0.94)] for each visit. Conclusions This study highlights several patient- and provider-level factors that are important to address to reduce the burden of urgent-start dialysis. [ABSTRACT FROM AUTHOR]

Background Electronic alerts for acute kidney injury (AKI) have been widely advocated. Our aim was to describe the changes in AKI demographics and outcomes following implementation of a national electronic AKI alert programme. Methods A prospective national cohort study was undertaken to collect data on all cases of AKI in adult patients (≥18 years of age) between 1 April 2015 and 31 March 2019. Results Over the period of data collection, there were 193 838 AKI episodes in a total of 132 599 patients. The lowest incidence of AKI was seen in the first year after implementation of electronic alerts. A 30-day mortality was highest in Year 1 and significantly lower in all subsequent years. A direct comparison of mortality in Years 1 and 4 demonstrated a significantly increased relative risk (RR) of death in Year 1: RR = 1.08 [95% confidence interval (CI) 1.054–1.114 P < 0.001]. This translates into a number needed to treat in Year 4 for one additional patient to survive of 69.5 (95% CI 51.7–106.2) when directly comparing the outcomes across the 2 years. The increase in the number of cases and improved outcomes was more pronounced in community-acquired AKI, and was associated with a significant increase in patient hospitalization. Conclusions This study represents the first large-scale dataset to clearly demonstrate that a national AKI alerting system which highlights AKI is associated with a change in both AKI demographics and patient outcomes. [ABSTRACT FROM AUTHOR]

Background Acute kidney injury (AKI) is an important complication of coronavirus disease 2019 (COVID-19), which could be caused by both systematic responses from multi-organ dysfunction and direct virus infection. While advanced evidence is needed regarding its clinical features and mechanisms. We aimed to describe two phenotypes of AKI as well as their risk factors and the association with mortality. Methods Consecutive hospitalized patients with COVID-19 in tertiary hospitals in Wuhan, China from 1 January 2020 to 23 March 2020 were included. Patients with AKI were classified as AKI-early and AKI-late according to the sequence of organ dysfunction (kidney as the first dysfunctional organ or not). Demographic and clinical features were compared between two AKI groups. Their risk factors and the associations with in-hospital mortality were analyzed. Results A total of 4020 cases with laboratory-confirmed COVID-19 were included and 285 (7.09%) of them were identified as AKI. Compared with patients with AKI-early, patients with AKI-late had significantly higher levels of systemic inflammatory markers. Both AKIs were associated with an increased risk of in-hospital mortality, with similar fully adjusted hazard ratios of 2.46 [95% confidence interval (CI) 1.35–4.49] for AKI-early and 3.09 (95% CI 2.17–4.40) for AKI-late. Only hypertension was independently associated with the risk of AKI-early. While age, history of chronic kidney disease and the levels of inflammatory biomarkers were associated with the risk of AKI-late. Conclusions AKI among patients with COVID-19 has two clinical phenotypes, which could be due to different mechanisms. Considering the increased risk for mortality for both phenotypes, monitoring for AKI should be emphasized during COVID-19. [ABSTRACT FROM AUTHOR]

As of 15 August 2020, Coronavirus disease 2019 (COVID-19) has been reported in >21 million people world-wide and is responsible for more than 750,000 deaths. The occurrence of acute kidney injury (AKI) in patients hospitalized with COVID-19 has been reported to be as high as 43%. This is comparable to AKI in other forms of pneumonia requiring hospitalization, as well as in non-infectious conditions like cardiac surgery. The impact of AKI on COVID-19 outcomes is difficult to assess at present but, similar to other forms of sepsis, AKI is strongly associated with hospital mortality. Indeed, mortality is reported to be very low in COVID-19 patients without AKI. Given that AKI contributes to fluid and acid–base imbalances, compromises immune response and may impair resolution of inflammation, it seems likely that AKI contributes to mortality in these patients. The pathophysiologic mechanisms of AKI in COVID-19 are thought to be multifactorial including systemic immune and inflammatory responses induced by viral infection, systemic tissue hypoxia, reduced renal perfusion, endothelial damage and direct epithelial infection with Severe Acute Respiratory Syndrome Coronavirus 2. Mitochondria play a central role in the metabolic deregulation in the adaptive response to the systemic inflammation and are also found to be vital in response to both direct viral damage and tissue reperfusion. These stress conditions are associated with increased glycolysis and reduced fatty acid oxidation. Thus, there is a strong rationale to target AKI for therapy in COVID-19. Furthermore, many approaches that have been developed for other etiologies of AKI such as sepsis, inflammation and ischemia–reperfusion, have relevance in the treatment of COVID-19 AKI and could be rapidly pivoted to this new disease. [ABSTRACT FROM AUTHOR]

Background Ischaemia-reperfusion (IR) injury is an important determinant of delayed graft function (DGF) affecting allograft function. Mitochondrial DNA (mtDNA) is released upon cell death and platelet activation into the extracellular environment and has been suggested to be a biomarker in several diseases. Whether extracellular mtDNA accumulates in plasma and/or urine upon renal IR and predisposes DGF is unknown. Methods C57BL/6J wild-type mice were subjected to renal IR. In addition, an observational case–control study was set up enrolling 43 patients who underwent kidney transplantation. One day post-IR in mice and a few days following renal transplantation in human, blood and urine were collected. Patients were stratified into DGF and non-DGF groups. Results mtDNA-encoded genes accumulate in urine and plasma in both mice subjected to renal IR injury and in humans following renal transplantation. In human renal transplant recipients, cold ischaemia time and renal function correlate with urinary mtDNA levels. Urinary mtDNA levels but not urinary nuclear DNA levels were significantly higher in the DGF group compared with the non-DGF group. Multiple receiver operating characteristic curves revealed significant diagnostic performance for mtDNA-encoded genes cytochrome c oxidase III (COXIII); nicotinamide adenine dinucleotide hydrogen subunit 1 (NADH-deh); mitochondrially encoded, mitochondrially encoded nicotinamide adenine dinucleotide dehydrogenase 2 (MT-ND2) with an area under the curve of, respectively, 0.71 [P = 0.03; 95% confidence interval (CI) 0.54–0.89], 0.75 (P = 0.01; 95% CI 0.58–0.91) and 0.74 (P = 0.02; 95% CI 0.58–0.89). Conclusions These data suggest that renal ischaemia time determines the level of mtDNA accumulation in urine, which associates with renal allograft function and the diagnosis of DGF following renal transplantation. [ABSTRACT FROM AUTHOR]

Background Development of acute kidney injury (AKI) following the use of antibiotics such as sulphonamides, trimethoprim and aminoglycosides is a frequently described phenomenon. More recently, an association between fluoroquinolone use and AKI has been suggested. The aim of this study was to evaluate the risk of AKI as an unintended consequence of commonly prescribed antibiotics in a large community cohort using a method that fully adjusts for underlying patient characteristics, including potential unmeasured confounders. Methods A self-controlled case study was conducted and included all individuals aged 18 years and over in the Tayside region of Scotland who had a serum creatinine measured between 1 January 2004 and 31 December 2012. AKI episodes were defined using the Kidney Disease: Improving Global Outcomes definition. Data on oral community-prescribed antibiotics (penicillins, cephalosporins, fluoroquinolones, sulphonamides and trimethoprim, macrolides and nitrofurantoin) were collected for all individuals. Incidence rate ratios (IRRs) for AKI associated with antibiotic exposure versus time periods without antibiotic exposure were calculated. Results Combined use of sulphonamides, trimethoprim and nitrofurantoin rose by 47% and incidence of community-acquired AKI rose by 16% between 2008 and 2012. During the study period 12 777 individuals developed 14 900 episodes of AKI in the community, of which 68% was AKI Stage 1, 16% Stage 2 and 16% Stage 3. The IRR of AKI during any antibiotic use was 1.16 [95% confidence interval (CI) 1.10—1.23], and this was highest during sulphonamides or trimethoprim use; IRR 3.07 (95% CI 2.81–3.35). Fluoroquinolone and nitrofurantoin use was not associated with a significantly increased rate of AKI; IRR 1.13 (95% CI 0.94–1.35) and 1.16 (95% CI 0.91–1.50), respectively. Conclusions Incidence of AKI rose by 16% between 2008 and 2012. In the same period the use of sulphonamides, trimethoprim and nitrofurantoin increased by 47%. A significant increased risk of AKI was seen with the use of sulphonamides and trimethoprim, but not with fluoroquinolones or nitrofurantoin. [ABSTRACT FROM AUTHOR]

Background Cisplatin is an effective chemotherapeutic agent. However, acute kidney injury (AKI) and subsequent kidney function decline limits its use. Dipeptidyl peptidase-4 (DPP-4) inhibitor has been reported to attenuate kidney injury in some in vivo models, but the mechanisms-of-action in tubule recovery upon AKI remain speculative. We hypothesized that DPP-4 inhibitor teneligliptin (TG) can facilitate kidney recovery after cisplatin-induced AKI. Methods In in vivo experiment, AKI was induced in rats by injecting 5 mg/kg of cisplatin intravenously. Oral administration of 10 mg/kg of TG, once a day, was started just before injecting cisplatin or from Day 5 after cisplatin injection. In an in vitro experiment, proliferation of isolated murine tubular cells was evaluated with 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, cell cycle analysis and cell counting. Cell viability was analysed by MTT assay or lactate dehydrogenase (LDH) assay. Results In in vivo experiments, we found that TG attenuates cisplatin-induced AKI and accelerates kidney recovery after the injury by promoting the proliferation of surviving epithelial cells of the proximal tubule. TG also suppressed intrarenal tumour necrosis factor-α expression, and induced macrophage polarization towards the anti-inflammatory M2 phenotype, both indirectly endorsing tubule recovery upon cisplatin injury. In in vitro experiments, TG directly accelerated the proliferation of primary tubular epithelial cells. Systematic screening of the DPP-4 substrate chemokines in vitro identified CXC chemokine ligand (CXCL)-12 as a promoted mitogenic factor. CXCL12 not only accelerated proliferation but also inhibited cell death of primary tubular epithelial cells after cisplatin exposure. CXC chemokine receptor (CXCR)-4 antagonism abolished the proliferative effect of TG. Conclusions The DPP-4 inhibitor TG can accelerate tubule regeneration and functional recovery from toxic AKI via an anti-inflammatory effect and probably via inhibition of CXCL12 breakdown. Hence, DPP-4 inhibitors may limit cisplatin-induced nephrotoxicity and improve kidney function in cancer patients. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) has a significant impact on patient morbidity and mortality as well as overall health care costs. eResearch, which integrates information technology and information management to optimize research strategies, provides a perfect platform for necessary ongoing AKI research. With the recent adoption of a widely accepted definition of AKI and near-universal use of electronic health records, eResearch is becoming an important tool in AKI research. Conducting eResearch in AKI should ideally be based on a relatively uniform methodology. This article is the first of its kind to describe a methodology for pursuing eResearch specific to AKI and includes an illustrative database example for critically ill patients. We discuss strategies for using serum creatinine and urine output in large databases to identify and stage AKI and ways to interpolate missing values and validate data. Issues specific to the pediatric population include variation in serum creatinine with growth, varied severity of illness scoring systems and medication dosage based on weight. Many of these same strategies used to optimize AKI eResearch can be applicable to real-time AKI alerts with potential integration of additional clinical variables. [ABSTRACT FROM AUTHOR]

Background Randomized trials have consistently shown lower rates of acute kidney injury (AKI) with transcatheter aortic valve replacement (TAVR) compared with surgical aortic valve replacement (SAVR). Comparative rates of AKI for TAVR versus SAVR, and predictors and prognostic implications of AKI after aortic valve replacement (AVR) have not been well studied in nationally representative real-world data. Objectives First, to compare rates of AKI and dialysis requiring AKI in TAVR versus SAVR. Second, to determine predictors of AKI and prognostic implications of AKI in patients undergoing TAVR or SAVR. Methods We used the 2011–14 National Inpatient Sample to identify all patients undergoing isolated TAVR or SAVR using validated international classification of diseases, ninth revision ICD-9 codes. Rates of AKI and AKI requiring dialysis (AKI-D) were compared between the two groups using a propensity-matched design. Predictors of AKI and prognostic impact of AKI on in-hospital outcomes were ascertained using multivariate logistic regression. Results A total of 8004 unweighted TAVR procedures and 29 355 unweighted SAVR procedures representative of 39 898 TAVR and 143 608 SAVR procedures nationwide were included in the analysis. Mean age of all patients undergoing AVR was 70.9 years and 42.3% were females. In a propensity-matched cohort of 4889 pairs of TAVR and SAVR procedures, TAVR was associated with significantly lower rates of AKI [odds ratio (OR) 0.73, 95% confidence interval (CI) 0.66–0.80, P < 0.001] and AKI-D (OR 0.69, 95% CI 0.50–0.96, P = 0.03) compared with SAVR. AKI was associated with significantly higher rates of in-hospital mortality for TAVR (OR 7.16, 95% CI 5.52–9.29, P < 0.001) as well as SAVR (OR 9.43, 95% CI 7.71–11.55, P < 0.001). Conclusions In a large propensity-matched cohort of TAVR and SAVR procedures, TAVR was associated with significantly lower rates of AKI and AKI-D compared with SAVR. AKI and AKI-D are predictors of poor in-hospital outcomes in TAVR as well as SAVR. [ABSTRACT FROM AUTHOR]

Background Iodinated contrast media (CM) used in angiography and computed tomography (CT) scans is an important cause of acute kidney injury (AKI) in hospitalized patients undergoing surgery. Contrast-induced nephropathy leads to AKI soon after CM administration. The aim of the study was to determine whether the timing of contrast media exposure related to diagnostic imaging during the immediate perioperative period influences the risk of post-operative AKI. Methods All patients aged 18 years or above who underwent diagnostic imaging within 7 days of non-cardiac surgery between 1 January 2003 and 31 December 2013 in the Tayside region of Scotland, UK were included in the analysis. The primary outcome of AKI was defined using the Kidney Disease: Improving Global Outcomes creatinine-based criteria. Multiple logistic regressions were performed to identify predictors for AKI. Results Of 9300 patients, 6224 were exposed to CM in the immediate perioperative period and 3076 were not. Post-operative AKI occurred in 678 (10.9%) of the 6224 patients who were exposed to CM. On multiple logistic regression, independent predictors of post-operative AKI were increasing age, male gender, lower baseline renal function and treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Timing of CM exposure did not affect risk of developing AKI, odds ratio 0.972 (95% confidence interval 0.935–1.010), P = 0.146. Conclusions For patients who have either just had or are soon to undergo general surgical procedures there appears to be no need to limit CT scan quality by avoiding the administration of CM. These patients may benefit from the increased diagnostic utility of contrast-enhanced CT scans without increasing their risk of perioperative AKI. [ABSTRACT FROM AUTHOR]

Background. Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis in the world, but there is little epidemiological data about possible changes in its presentation over the years. Available information about the influence of age on the form of clinical presentation is also scarce. Methods. The aim of the study was to analyse all renal biopsies performed between 1994 and 2013 and recorded in the Spanish Registry of Glomerulonephritis with a histological diagnosis of IgAN. The study was divided into five 4-year periods (1994-97, 1998-2001, 2002-05, 2006-09 and 2010-13) and patients were divided into four age groups: ≤16, 17-44, 45-64 and ≥65 years. Results. From 20.974 renal biopsies recorded, 2961 (14.1%) corresponded to IgAN. The prevalence of IgAN remained stable, but a significant increase in age [from 37.6 (SD 17.7) in 1994-97 to 44.9 (SD 16.8) years in 2010-13; P=0.001] and worse renal function at presentation [from serum creatinine (SCr) 1.9 (SD 1.9) in 1994-97 to 2.3 (SD 2.1) mg/dL in 2010-13; P=0.001] were observed over the years. Nephrotic-range proteinuria and acute kidney injury (AKI) as forms of presentation were significantly more common among patients≤65 years (17.7% and 43.2%, respectively) as compared with the other age groups [≥16 (11.4% and 13.1%, respectively), 17-44 (13.1% and 13%, respectively) and 45-64 (12.1% and 21.3%, respectively)]. Blood pressure, SCr and proteinuria were also significantly higher at presentation among elderly patients. Conclusions. Although the prevalence of IgAN in Spain has remained stable over the years, patients are significantly older and present with significantly worse renal function in the last years. The incidence of nephrotic-range proteinuria (17.7%) and AKI (43.2%) as forms of presentation is remarkable among patients #8805;65 years of age. [ABSTRACT FROM AUTHOR]

Goodpasture's or anti-glomerular basement membrane (GBM) disease is classically characterized by the presence of circulating autoantibodies directed against the non-collagenous domain of the a3 chain of type IV collagen, targeting glomerular and alveolar basement membranes, and associated with rapidly progressive crescentic glomerulonephritis, with alveolar haemorrhage in over half the patients. However, there are increasing examples of variants or atypical presentations of this disease, and novel therapeutic options have been proposed, which nephrologists should be aware of. The pathophysiology of this condition has been understood through molecular analysis of the antibody-antigen interactions and the use of human leucocyte antigen-transgenic animals, while the association of anti-GBM antibodies with antineutrophil cytoplasm antibodies and their combined impact on disease phenotype is increasingly recognized, providing some insights into the basis of glomerular damage and autoimmunity. [ABSTRACT FROM AUTHOR]

Background. Follistatin-like 3 (FSTL3) is a novel cytokine that regulates insulin sensitivity and counteracts activin/myostatin signalling. In the present study, regulation of FSTL3 in renal dysfunction was investigated in both human chronic kidney disease (CKD) and acute kidney dysfunction (AKD). Furthermore, mFSTL3 expression was analysed in insulin-sensitive tissues in a mousemodel of CKD. Methods. Circulating FSTL3 was quantified by enzyme-linked immunosorbent assay in 581 patients with CKD covering the whole spectrum of estimated glomerular filtration rate (eGFR) categories from G1 to G5. Furthermore, FSTL3 was measured in 61 patients before and within 30 h after elective unilateral nephrectomy, an established model of AKD. Moreover, mFSTL3 mRNA expression was investigated in an animal CKD model, that is, eNOS-/- db/db mice, and compared with littermate controls. Results. Median circulating FSTL3 levels significantly and continuously increased with deteriorating renal function (eGFR category G1: 6.1; G2: 8.2; G3: 12.7; G4: 18.5; G5: 32.1 mg/L; P<0.001). In both human CKD and AKD, renal dysfunction remained the strongest independent predictor of FSTL3 serum concentrations in multivariate analyses. FSTL3 was independently associated with an adverse cardiometabolic profile. In CKD mice, hepatic mFSTL3 mRNA expression was increased more than 6-fold as compared with controls. Conclusions. Circulating FSTL3 is significantly and independently associated with renal function in both patients with CKD and AKD. Hepatic mFSTL3 mRNA upregulation might contribute to increased FSTL3 levels in CKD. Our results are in agreement with the hypothesis that FSTL3 is eliminated by the kidneys and might counteract adverse activin/myostatin signalling observed in renal dysfunction. [ABSTRACT FROM AUTHOR]

I have been asked to comment on the pro and con opinions regarding high-volume plasma exchange. The authors of both positions have provided cogent arguments and a reasonable approach to choosing the exchange volume for any given therapeutic plasma exchange. The major issue of relevance in this discussion is the nature of the toxins targeted for removal. These parameters includemolecular weight, the apparent volume of distribution, the degree of protein binding, the biologic and chemical half-life, and the severity and rapidity of its toxicity. [ABSTRACT FROM AUTHOR]

Background. Early and accurate assessment of renal function is required for the successful detection and treatment of acute kidney injury (AKI). However, only retention parameters such as plasma urea and creatinine, and the indirect estimation of glomerular filtration rate are commonly available. Methods. Here, we measured the kinetics of plasma fluorescein isothiocyanate (FITC)-sinistrin excretion to detect alterations of renal function over time in a murine model of rhabdomyolysis-induced AKI. The half-life of FITC-sinistrin was evaluated using a transcutaneous device at different time points in conscious mice, from 4 days before renal damage up to 30 days after. Retention markers were also evaluated, in parallel. Results. Evaluation of the FITC-sinistrin half-life revealed early reduction of renal filtration, observed as early as 6 h after renal damage, and maintained up to 12 h following AKI. Plasma creatinine and urea levels correlated with the transcutaneous measurements of sinistrin excretion. Evaluation of sinistrin excretion also demonstrated that glycerol-treated animals did not develop AKI. Finally, histological analysis showed the presence of renal parenchymal lesions, which developed following the reduced renal filtration and persisted over time, highlighting the causative role of vascular dysfunction and myoglobin toxicity on the subsequent induction of tissue damage. Conclusions. Taken together, the results of this study provide important insights into the pathophysiology of kidney injury in rhabdomyolytic mice, and indicate that the transcutaneous measurement of FITC-sinistrin is an efficient and simple method to assess renal function precisely. This method also allows reduction of the required number of experimental animals by monitoring the samemouse over time. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) is an important health-care problem. Over the last decades, many innovative therapies and diagnostic approaches have been tried; however, none of these has been able to confirm consistently that they lead to improved outcomes. Much focus has been placed on intensive care unit (ICU)-associated AKI, whereas the bulk of AKI still concerns patients not in the ICU. Involvement of nephrologists in the care of AKI patients is necessary to further improve outcomes. It is unclear whether new technologies, such as biomarkers, are helpful and could replace nephrology consultation. [ABSTRACT FROM AUTHOR]

Patients with acute kidney injury (AKI) continue to pose challenges for clinicians worldwide. Our understanding of the pathophysiology, epidemiology and course of the disease has improved significantly; however, this has not translated into any significant improvement in outcomes. Multiple new biomarkers have been developed to characterize the course of the disease and have been evaluated in multiple trials. Unfortunately, the adoption of biomarkers into routine clinical care has not been as expected. Several factors contribute to the slow uptake and can be addressed. This article provides a framework for a patient-centered approach to utilize biomarkers to improve patient care and outcomes in AKI. [ABSTRACT FROM AUTHOR]

Background. Consensus guidelines for acute kidney injury (AKI) have recommended prompt treatment including attention to fluid balance, drug dosing and avoidance of nephrotoxins. These simple measures can be incorporated in a care bundle to facilitate early implementation. The objective of this study was to assess the effect of compliance with the AKI care bundle (AKI-CB) on in-hospital case-fatality and AKI progression. Methods. In this larger, propensity score-matched cohort of multifactorial AKI, we examined the impact of compliance with an AKI-CB in 3717 consecutive episodes of AKI in 3518 patients between 1 August 2013 and 31 January 2015. Propensity score matching was performed to match 939 AKI events where the AKI-CB was completed with 1823 AKI events where AKI-CB was not completed. Results. The AKI-CB was completed in 25.6% of patients within 24 h. The unadjusted case-fatality was higher when the AKICB was not completed versus when the AKI-CB was completed (24.4 versus 20.4%, P = 0.017). In multivariable analysis, AKICB completion within 24 h was associated with lower odds for in-hospital death [odds ratio (OR): 0.76; 95% confidence interval (95% CI): 0.62-0.92]. Increasing age (OR: 1.04; 95% CI: 1.03-1.05), hospital-acquired AKI (OR: 1.28; 95% CI: 1.04- 1.58), AKI stage 2 (OR: 1.91; 95% CI: 1.53-2.39) and increasing Charlson's comorbidity index (CCI) [OR: 3.31 (95% CI: 2.37- 4.64) for CCI of more than 5 compared with zero] had higher odds for death, whereas AKI during elective admission was associated with lower odds for death (OR: 0.29; 95% CI: 0.16-0.52). Progression to higher AKI stages was lower when the AKI-CB was completed (4.2 versus 6.7%, P = 0.02). Conclusions. Compliance with an AKI-CB was associated with lower mortality and reduced progression of AKI to higher stages. The AKI-CB is simple and inexpensive, and could therefore be applied in all healthcare settings to improve outcomes. [ABSTRACT FROM AUTHOR]

The tubular compartment of the kidney is the primary site of a wide range of insults that can result in acute kidney injury (AKI), a condition associated with high mortality and an increased risk to develop end-stage renal disease. Nevertheless, kidney function is often quickly recovered after tubular injury. How this happens has only partially been unveiled. Indeed, although it has clearly been demonstrated that regenerated epithelial cells arise from survived intratubular cells, the true entity, as well as the cellular source of this regenerative process, remains mostly unknown. Is whichever proximal tubular epithelial cell able to dedifferentiate and divide to replace neighboring lost tubular cells, thus suggesting an extreme regenerative ability of residual tubular epithelium, or is the regenerative potential of tubular epithelium limited, and mostly related to a preexisting population of intratubular scattered progenitor cells which are more resistant to death? Gaining insights on how this process takes place is essential for developing new therapeutic strategies to prevent AKI, as well as AKI-related chronic kidney disease. The aim of this review is to discuss why the answers to these questions are still open, and how further investigations are needed to understand which is the true regenerative potential of the tubule and who are the players that allow functional recovery after AKI. [ABSTRACT FROM AUTHOR]

Background. N-octanoyl dopamine (NOD) treatment improves renal function when applied to brain dead donors and in the setting of warm ischaemia-induced acute kidney injury (AKI). Because it also activates transient receptor potential vanilloid type 1 (TRPV1) channels, we first assessed if NOD conveys its renoprotective properties in warm ischaemia-induced AKI via TRPV1 and secondly, if renal transplant recipients also benefit from NOD treatment. Methods.We induced warmrenal ischaemia in Lewis, wild-type (WT) and TRPV1-/- Sprague-awley (sd) rats by clamping the left renal artery for 45 min. Transplantations were performed in allogeneic and syngeneic donor-ecipient combinations (Fisher to Lewis and Lewis to Lewis) with a cold ischaemia time of 20 h. Treatment was instituted directly after restoration of organ perfusion. Renal function, histology and perfusion were assessed by serum creatinine, microscopy and magnetic resonance imaging (MRI) using arterial spin labelling (ASL). Results. NOD treatment significantly improved renal function in Lewis rats afterwarm ischaemia-inducedAKI. Itwas, however, not effective after prolonged cold ischaemia. The renoprotective properties of NOD were only observed in Lewis or WT, but not in TRPV1-/- sd rats. Renal inflammation was significantly abrogated by NOD. MRI-ASL showed a significantly lower cortical perfusion in ischaemic when compared with non-ischaemic kidneys. No overall differences were observed in renal perfusion between NOD- and NaCl-treated rats. Conclusions. NOD treatment reduces renal injury in warm ischaemia, but is not effective in renal transplant in our experimental animal models. The salutary effect of NOD appears to be TPRV1-dependent, not involving large changes in renal perfusion. [ABSTRACT FROM AUTHOR]

Onco-nephrology is an evolving subspecialty that focuses on the complex relationships existing between kidney and cancer. In this opinion piece, we propose a 'decalogue of onco-nephrology', in order to highlight the areaswhere the nephrologist and oncologist should work closely over the ensuing years to provide cuttingedge care for patients afflicted with cancer and kidney disease. The 10 points we have highlighted include (1) acute kidney injury and chronic kidney disease in cancer patients; (2) nephrotoxic effects of anticancer therapy, either traditional chemotherapeutics or novel molecularly targeted agents; (3) paraneoplastic renal manifestations; (4) management of patients nephrectomized for a kidney cancer; (5) renal replacement therapy and active oncological treatments; (6) kidney transplantation in cancer survivors and cancer risk in ESRD patients; (7) oncological treatment in kidney transplant patients; (8) pain management in patients with cancer and kidney disease, (9) development of integrated guidelines for onco-nephrology patients and (10) clinical trials designed specifically for onco-nephrology. Following these points, a multidisciplinary onco-nephrology team will be key to providing outstanding, cutting-edge care in both the acute and chronic setting to these patients. [ABSTRACT FROM AUTHOR]

The administration of iodinated contrast medium (CM) has immediate negative impact on multiple levels of the nephron, including vasoconstriction, an increase in apoptotic pathways and oxidative stress. Therefore, contrast-induced acute kidney injury (CI-AKI) remains an important cause of sudden impairment of renal function. Far from being just a transient phenomenon, CI-AKI has consistently been shown to be associated with adverse outcomes. The phenomenon of chronic kidney disease (CKD) following AKI might explain why this entity portends a poor prognosis in the long run. While it is generally acknowledged that in individuals with normal renal function, the risk of CI-AKI is negligible, pre-existing renal disease is its greatest independent risk factor. Although several recent publications have challenged the dogma of CI-AKI as a stand-alone disease entity, these trials, despite careful propensity matching, are hampered by their retrospective nature. In this article, we concede that there is always a trade-off and that administration of CM may be justified if its diagnostic value is believed to outweigh its associated risks. However, we reason that despite considerable progress in the field, the risk of CI-AKI is still high in the modern era and that CM-based imaging should be employed with great restraint in patients with CKD. [ABSTRACT FROM AUTHOR]

Despite identification of several cellular mechanisms being thought to underlie the development of septic acute kidney injury (AKI), the pathophysiology of the occurrence of AKI is still poorly understood. It is clear, however, that instead of a single mechanism being responsible for its aetiology, an orchestra of cellular mechanisms failing is associated with AKI. The integrative physiological compartment where these mechanisms come together and exert their integrative deleterious action is the renal microcirculation (MC). This is why it is opportune to review the response of the renal MC to sepsis and discuss the determinants of its (dys)function and how it contributes to the pathogenesis of renal failure. A main determinant of adequate organ function is the adequate supply and utilization of oxygen at the microcirculatory and cellular level to perform organ function. The highly complex architecture of the renal microvasculature, the need to meet a high energy demand and the fact that the kidney is borderline ischaemic makes the kidney a highly vulnerable organ to hypoxaemic injury. Under normal, steady-state conditions, oxygen (O2) supply to the renal tissues is well regulated; however, under septic conditions the delicate balance of oxygen supply versus demand is disturbed due to renal microvasculature dysfunction. This dysfunction is largely due to the interaction of renal oxygen handling, nitric oxide metabolism and radical formation. Renal tissue oxygenation is highly heterogeneous not only between the cortex and medulla but also within these renal compartments. Integrative evaluation of the different determinants of tissue oxygen in sepsis models has identified the deterioration of microcirculatory oxygenation as a key component in the development AKI. It is becoming clear that resuscitation of the failing kidney needs to integratively correct the homeostasis between oxygen, and reactive oxygen and nitrogen species. Several experimental therapeutic modalities have been found to be effective in restoring microcirculatory oxygenation in parallel to improving renal function following septic AKI. However, these have to be verified in clinical studies. The development of clinical physiological biomarkers of AKI specifically aimed at the MC should form a valuable contribution to monitoring such new therapeutic modalities. [ABSTRACT FROM AUTHOR]

A goal for scientists studying septic acute kidney injury (AKI) should be to formulate a conceptual model of disease that is able to coherently reconcile the molecular and inflammatory consequences of sepsis with impaired epithelial tubular function, diminished glomerular filtration rate (GFR) and ultimately kidney failure. Recent evidence has shed light on how sepsis modulates the tubular regulation of ion, glucose, urea and water transport and acid–base homeostasis in the kidney. The present review summarizes recent discoveries on changes in epithelial transport under septic and endotoxemic conditions as well as the mechanisms that link inflammation with impaired tubular membrane transport. This paper also proposes that the tubular dysfunction that is mediated by inflammation in sepsis ultimately leads to increased sodium and chloride delivery to the distal tubule and macula densa, contributing to tubuloglomerular feedback and impaired GFR. We feel that this conceptual model resolves many of the physiologic and clinical paradoxes that septic AKI presents to practicing researchers and clinicians. [ABSTRACT FROM AUTHOR]

Dialy- and continuous renal replacement (CRRT) trauma are still un(der)recognized conditions that may be encountered during blood purification therapy. This particular form of trauma requires timely identification, a better understanding of pathophysiology and a definition of at-risk groups to prevent or correct any associated unwarranted effects. Among others, progress in the knowledge of antimicrobial pharmacokinetic/pharmacodynamic (PK/PD) behaviour during CRRT to obtain more efficient antimicrobial therapy with less side-effects is one key example of limiting CRRT trauma. Optimal anticipation and prevention of CRRT trauma will preserve the safe use of CRRT in haemodynamically unstable critically ill patients with acute kidney injury (AKI), especially in septic patients who are at the greatest risk. [ABSTRACT FROM PUBLISHER]

Background To determine the incidence and significance of acute kidney injury (AKI) after initiating highly active antiretroviral therapy (HAART). Methods A prospective cohort study of 271 consecutively treated HIV-infected patients, initiating first (75) or sequential HAART (196) from January 2008 to June 2011. AKI was diagnosed according to the Risk, Injury, Failure, Loss of kidney function, End-stage renal disease (RIFLE)/Acute Kidney Injury Network (AKIN) criteria, and the risk of progression to chronic kidney disease (CKD) was evaluated. Results A greater estimated glomerular filtration rate (eGFR) decrease after 1 year was observed for patients initiating a tenofovir disoproxil fumarate (TDF)-based regimen (−6.45 versus +0.98 mL/min/1.73 m2 when compared with patients without TDF; P < 0.01), both in the case of the first (−8.5 versus −2.27; P = 0.04) or successive regimens (−5.3 versus + 1.18 mL/min/1.73 m2; P < 0.01). AKI, as defined, was observed in 10% (28 cases, 6.98 episodes/100 patients-year), mostly stage I (27 cases), in a median time of 6 (3–16.5) months. Four cases (14%), having a worse baseline renal function progressed to CKD, whereas four recovered completely. In the multivariate analysis, AKI was associated with the concomitant use of cotrimoxazole prophylaxis and to low CD4+ count. CKD was diagnosed in 2% (six cases) of patients. Therefore, the overall rate of HAART-associated renal disorders was 11% (30 cases, 7.46 episodes/100 patients-year (95% confidence interval, 6.09–8.83). Conclusions The initiation of a tenofovir-based regimen is followed by a significant decline in eGFR, although it could be misinterpreted by the concomitant use of cotrimoxazole. A substantial proportion of patients develop AKI, but only a minority progress to CKD. Patients initiating HAART and developing AKI should be carefully monitored for progression of renal disease. [ABSTRACT FROM AUTHOR]

Background Cardiac surgery-related acute kidney injury (CS-AKI) results in increased morbidity and mortality. Different models have been developed to identify patients at risk of CS-AKI. While models that predict dialysis and CS-AKI defined by the RIFLE criteria are available, their predictive power and clinical applicability have not been compared head to head. Methods Of 1388 consecutive adult cardiac surgery patients operated with cardiopulmonary bypass, risk scores of eight prediction models were calculated. Four models were only applicable to a subgroup of patients. The area under the receiver operating curve (AUROC) was calculated for all levels of CS-AKI and for need for dialysis (AKI-D) for each risk model and compared for the models applicable to the largest subgroup (n = 1243). Results The incidence of AKI-D was 1.9% and for CS-AKI 9.3%. The models of Rahmanian, Palomba and Aronson could not be used for preoperative risk assessment as postoperative data are necessary. The three best AUROCs for AKI-D were of the model of Thakar: 0.93 [95% confidence interval (CI) 0.91–0.94], Fortescue: 0.88 (95% CI 0.87–0.90) and Wijeysundera: 0.87 (95% CI 0.85–0.89). The three best AUROCs for CS-AKI-risk were 0.75 (95% CI 0.73–0.78), 0.74 (95% CI 0.71–0.76) and 0.70 (95% CI 0.73–0.78), for Thakar, Mehta and both Fortescue and Wijeysundera, respectively. The model of Thakar performed significantly better compared with the models of Mehta, Rahmanian, Fortescue and Wijeysundera (all P-values <0.01) at different levels of severity of CS-AKI. Conclusions The Thakar model offers the best discriminative value to predict CS-AKI and is applicable in a preoperative setting and for all patients undergoing cardiac surgery. [ABSTRACT FROM AUTHOR]

Background Extracorporeal membrane oxygenation (ECMO) is increasingly used in the intensive care unit (ICU) setting to improve gas exchange in patients with acute respiratory distress syndrome as well as in patients pre- and post-heart and lung transplantation. In this clinical setting, acute kidney injury (AKI) is frequently observed. So far, it is unknown how AKI affects the survival of critically ill patients receiving ECMO support and whether veno-veno and veno-arterial ECMO have different effects on kidney function. Methods This is a retrospective analysis of patients undergoing ECMO treatment in medical and surgical ICUs in a tertiary care centre. We evaluated all patients undergoing ECMO treatment at our centre between 1 January 2005 and 31 December 2010. Data from all 200 patients (83F/117M), median age 45 (17–83) years, were obtained by chart review. Follow-up data were obtained for up to 3 months. Results Three-month survival of all patients was 31%. Of the 200 patients undergoing ECMO treatment, 60% (120/200) required renal replacement therapy (RRT) for AKI. While patients without RRT showed a 3-month survival of 53%, the survival of patients with AKI requiring RRT was 17% (P = 0.001). Longer duration of RRT was associated with a higher mortality. Conclusions AKI requiring RRT therapy in patients undergoing ECMO treatment increases mortality in ICU patients. Future studies have to clarify whether it is possible to identify patients who benefit from the combination of ECMO and RRT. [ABSTRACT FROM PUBLISHER]

This emergent strain of Shiga toxin-producing E.Coli differs in its clinical presentation in adults. (…) The efficacy of available and future treatments should therefore be evaluated by randomized clinical trials.Background May 22nd marks the beginning of a Shiga-toxin-producing Escherichia coli (STEC) O104:H4 outbreak in Northern Germany. By its end on 27 July, it had claimed 53 deaths among 2987 STEC and 855 confirmed haemolytic–uraemic syndrome (HUS) cases. Methods To describe short-term effectiveness of best supportive care (BSC), therapeutic plasma exchange (TPE) and TPE with eculizumab (TPE-Ecu) in 631 patients with suspected HUS treated in 84 hospitals in Germany, Sweden and the Netherlands using the web-based registry of the DGfN (online since 27 May). Results Of 631 entries, 491 fulfilled the definition of HUS (median age 46 years; 71% females). The median (inter-quartile range) hospital stay was 22 (14–31) days. Two hundred and eighty-one (57%) patients underwent dialysis and 114 (23%) mechanical ventilation. Fifty-seven patients received BSC, 241 TPE and 193 TPE-Ecu. Treatment strategy was dependent on disease severity (laboratory signs of haemolysis, thrombocytopenia, peak creatinine level, need for dialysis, neurological symptoms, frequency of seizures) which was lower in BSC than in TPE and TPE-Ecu patients. At study endpoint (hospital discharge or death), the median creatinine was lower in BSC [1.1 mg/dL (0.9–1.3)] than in TPE [1.2 mg/dL (1.0–1.5), P < 0.05] and TPE-Ecu [1.4 mg/dL (1.0–2.2), P < 0.001], while need for dialysis was not different between BSC (0.0%, n = 0), TPE (3.7%; n = 9) and TPE-Ecu (4.7%, n = 9). Seizures were absent in BSC and rare in TPE (0.4%; n = 1) and TPE-Ecu (2.6%; n = 5) patients. Total hospital mortality in HUS patients was 4.1% (n = 20) and did not differ significantly between the TPE and TPE-Ecu groups. Conclusions Despite frequent renal impairment, advanced neurological disorders and severe respiratory failure, short-term outcome was better than expected when compared with previous reports. Within the limitations of a retrospective registry analysis, our data do not support the notion of a short-term benefit of Ecu in comparison to TPE alone in the treatment of STEC-HUS. A randomized trial comparing BSC, TPE and Ecu seems to be prudent and necessary prior to establishing new treatment guidelines for STEC-HUS. [ABSTRACT FROM PUBLISHER]

Programmed cell death (PCD) had been widely used synonymously to caspase-mediated apoptosis until caspase-independent cell death was described. Identification of necrosis as a regulated process in ischaemic conditions has recently changed our understanding of PCD. At least three pathways of programmed necrosis (PN) have been identified. First, receptor-interacting protein kinase 3 (RIP3)-dependent necroptosis causes organ failure following stroke, myocardial infarction and renal ischaemia/reperfusion injury. Necroptosis can be mediated either by a large intracellular caspase-8-containing signalling complex called the ripoptosome or by the RIP1-/RIP3-containing necroptosome and is controlled by a caspase-8/FLICE inhibitory proteinlong heterodimer at least in the latter case. Second, mitochondrial permeability transition mediates apoptotic or necrotic stimuli and depends on the mitochondrial protein cyclophilin D. The third PN pathway involves the poly(ADP-ribose) polymerase-calpain axis that contributes to acute kidney injury (AKI). Preclinical interference with the PN pathways therefore raises expectations for the future treatment of ischaemic conditions. In this brief review, we aim to summarize the clinically relevant PCD pathways and to transfer the basic science data to settings of AKI. We conclude that pathologists were quite right to refer to ischaemic kidney injury as ‘acute tubular necrosis’. [ABSTRACT FROM PUBLISHER]

Background. Ischemia/reperfusion triggers acute kidney injury (AKI), mainly via aggravating hypoxia, oxidative stress, inflammation and renin–angiotensin system (RAS) activation. We investigated the role of angiotensin-converting enzyme (ACE) inhibition on the progression of AKI in a rat model of ischemia/reperfusion. Methods. Ninety-nine Sprague–Dawley rats were subjected to 1 h ischemia/reperfusion and/or left unilateral nephrectomy, with concurrent intraperitoneal implantation of Alzet pump. Via this pump, they were continuously infused with captopril 0.5 mg/kg/day, captopril 2 mg/kg/day or saline. The rats were sacrificed following 24, 48 or 168 h. Blood samples, 24-h urine collections and kidneys were allocated, to evaluate renal function, angiotensin-II, nitric oxide (NO), apoptosis, hypoxia, oxidative stress and inflammation. Results. Serum creatinine and cystatin-C significantly increased in ischemic rats, coinciding with histopathologic intrarenal damage, decreased NO, augmented angiotensin-II, interleukin (IL)-6, IL-10, transforming growth factor-beta. At the acute reperfusion stage, captopril prevented excessive angiotensin-II synthesis, ameliorated renal dysfunction, inhibited intrarenal inflammation and improved histopathologic findings. Most of the renoprotective effects of captopril were limited predominantly to acute reperfusion stage. Concurrently, captopril significantly decreased NO availability, exacerbated intrarenal hypoxia and augmented oxidative stress. Conclusions. At the acute stage of renal ischemia/reperfusion-induced AKI, ACE inhibition substantially contributed to the amelioration of acute injury by improving renal function, inhibiting systemic and intrarenal angiotensin-II, attenuating intrarenal inflammation and preserving renal tissue structure. Later on, at the post-reperfusion stage, most of the beneficial effects of captopril administration on the recuperating post-ischemic kidney were no longer evident. Concurrently, ACE inhibition exacerbated intrarenal hypoxia and accelerated oxidative stress, indicating that renal adaptation to some consequences of ischemia does require bioavailability of RAS components. [ABSTRACT FROM PUBLISHER]

Background. Recent research has shown cystatin C to predict mortality and cardiovascular morbidity independent of renal function. The aim of this study was to evaluate the prognostic value of cystatin C on mortality in adult general ICU patients with acute kidney injury (AKI). We later expanded the study and included patients without signs of AKI. [ABSTRACT FROM PUBLISHER]