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The WNT–β-catenin system is an evolutionary conserved signalling pathway that is of particular importance for morphogenesis and cell organization during embryogenesis. The system is usually suppressed in adulthood; however, it can be re-activated in organ injury and regeneration. WNT-deficient mice display severe kidney defects at birth. Transient WNT–β-catenin activation stimulates tissue regeneration after acute kidney injury, whereas sustained (uncontrolled) WNT–β-catenin signalling promotes kidney fibrosis in chronic kidney disease (CKD), podocyte injury and proteinuria, persistent tissue damage during acute kidney injury and cystic kidney diseases. Additionally, WNT–β-catenin signalling is involved in CKD-associated vascular calcification and mineral bone disease. The WNT–β-catenin pathway is tightly regulated, for example, by proteins of the Dickkopf (DKK) family. In particular, DKK3 is released by ‘stressed’ tubular epithelial cells; DKK3 drives kidney fibrosis and is associated with short-term risk of CKD progression and acute kidney injury. Thus, targeting the WNT–β-catenin pathway might represent a promising therapeutic strategy in kidney injury and associated complications.This Review discusses advances in the understanding of WNT–β-catenin signalling and its regulation during kidney injury, along with its potential diagnostic and therapeutic implications.

Early detection is a key strategy to prevent kidney disease, its progression and related complications, but numerous studies show that awareness of kidney disease at the population level is low. Therefore, increasing knowledge and implementing sustainable solutions for early detection of kidney disease are public health priorities. Economic and epidemiological data underscore why kidney disease should be placed on the global public health agenda — kidney disease prevalence is increasing globally and it is now the seventh leading risk factor for mortality worldwide. Moreover, demographic trends, the obesity epidemic and the sequelae of climate change are all likely to increase kidney disease prevalence further, with serious implications for survival, quality of life and health care spending worldwide. Importantly, the burden of kidney disease is highest among historically disadvantaged populations that often have limited access to optimal kidney disease therapies, which greatly contributes to current socioeconomic disparities in health outcomes. This joint statement from the International Society of Nephrology, European Renal Association and American Society of Nephrology, supported by three other regional nephrology societies, advocates for the inclusion of kidney disease in the current WHO statement on major non-communicable disease drivers of premature mortality.Addressing the burden of non-communicable diseases is a global public health priority. In this joint Consensus Statement, the American Society of Nephrology, the European Renal Association and the International Society of Nephrology highlight the need to recognize kidney disease as a key driver of premature mortality, in addition to other non-communicable diseases already prioritized by the World Health Organization.

Patients with chronic kidney failure—defined as a glomerular filtration rate persistently below 15 mL/min per 1·73 m2—have an unacceptably high mortality rate. In developing countries, mortality results primarily from an absence of access to renal replacement therapy. Additionally, cardiovascular and non-cardiovascular mortality are several times higher in patients on dialysis or post-renal transplantation than in the general population. Mortality of patients on renal replacement therapy is affected by a combination of socioeconomic factors, pre-existing medical disorders, renal replacement treatment modalities, and kidney failure itself. Characterisation of the key pathophysiological contributors to increased mortality and cardiorenal risk staging systems are needed for the rational design of clinical trials aimed at decreasing mortality. Policy changes to improve access to renal replacement therapy should be combined with research into low-cost renal replacement therapy and optimum clinical care, which should include multifaceted approaches simultaneously targeting several of the putative contributors to increased mortality.

Cardiac surgery is associated with a high risk of postoperative acute kidney injury (AKI) and subsequent loss of kidney function. We explored the clinical utility of urinary dickkopf-3 (DKK3), a renal tubular stress marker, for preoperative identification of patients at risk for AKI and subsequent kidney function loss. This observational cohort study included patients who had cardiac surgery in a derivation cohort and those who had cardiac surgery in a validation cohort (RenalRIP trial). The study comprised consecutive patients who had elective cardiac surgery at the Saarland University Medical Centre (Homburg, Germany; derivation cohort) and those undergoing elective cardiac surgery (selected on the basis of a Cleveland Clinical Foundation score of 6 or higher) who were enrolled in the prospective RenalRIP multicentre trial (validation cohort) and who were randomly assigned to remote ischaemic preconditioning or a sham procedure. The association between the ratio of preoperative urinary concentrations of DKK3 to creatinine (DKK3:creatinine) and postoperative AKI, defined according to the Kidney Disease Improving Global Outcomes criteria, and subsequent kidney function loss, as determined by estimated glomerular filtration rate, was assessed. In the 733 patient in the derivation cohort, urinary concentrations of DKK3 to creatinine that were higher than 471 pg/mg were associated with significantly increased risk for AKI (odds ratio [OR] 1·65, 95% CI 1·10–2·47, p=0·015), independent of baseline kidney function. Compared with clinical and other laboratory measurements, urinary concentrations of DKK3:creatinine significantly improved AKI prediction (net reclassification improvement 0·32, 95% CI 0·23–0·42, p<0·0001). High urinary DKK3:creatinine concentrations were independently associated with significantly lower kidney function at hospital discharge and after a median follow-up of 820 days (IQR 733–910). In the RenalRIP trial, preoperative urinary DKK3:creatinine concentrations higher than 471 pg/mg were associated with a significantly higher risk for AKI (OR 1·94, 95% CI 1·08–3·47, p=0·026), persistent renal dysfunction (OR 6·67, 1·67–26·61, p=0·0072), and dialysis dependency (OR 13·57, 1·50–122·77, p=0·020) after 90 days compared with DKK3:creatinine concentrations of 471 pg/mg or less. Urinary DKK3:creatinine concentrations higher than 471 pg/mg were associated with significantly higher risk for AKI (OR 2·79, 95% CI 1·45–5·37) and persistent renal dysfunction (OR 3·82, 1·32–11·05) only in patients having a sham procedure, but not remote ischaemic preconditioning (AKI OR 1·35, 0·76–2·39 and persistent renal dysfunction OR 1·05, 0·12–9·45). Preoperative urinary DKK3 is an independent predictor for postoperative AKI and for subsequent loss of kidney function. Urinary DKK3 might aid in the identification of patients in whom preventive treatment strategies are effective. No study funding.

Plasma exchange (PE) and immunoadsorption (IA) are standard therapeutic options of immune-mediated neurological disorders. This study evaluates the relation of the relative quantity of applied dose of PE and/ or IA and its achieved therapeutic effectiveness within the treated underlying neurological disorders. In a retrospective study, we evaluated data from PE and IA carried out 09/2009-06/2014 in neurological patients at the University-Hospital of Saarland, Germany. Apheresis dose was defined as the ratio of the extracorporeal treated plasma volume to the patient’s plasma volume. Effectiveness was assessed through disease-specific tests and scores by the attending neurologist(s); results were classified into response or no response. 1101 apheresis (PE:238, IA:863), in 153 hospital-stays were carried out, averaged, 7.0 treatments per patients, 82% responded, 18% not. Mean applied apheresis dose per treatment was 0.91 with mean doses of 1.16 for PE and 0.81 for IA. The totally applied mean dose per stay was 5.6 (PE:5.01, IA:5.81). No correlation was seen between apheresis dosing and treatment effectiveness (PE:R2 = 0.074, IA:R2 = 0.0023). PE and IA in therapy-refractory immune-mediated neurological disorders majorly achieved a measurable severity improvement – without correlation to the applied dose. Moreover, our data rather suggest, that effectiveness may be given with volumes below currently recommended volumes.

Background As of 2009, anticoagulation with citrate was standard practice in continuous renal replacement therapy (CRRT) for critically ill patients at the University Medical Centre of Saarland, Germany. Partial hepatic metabolism of citrate means accumulation may occur during CRRT in critically ill patients with impaired liver function. The aim of this study was to evaluate the actual influence of hepatic function on citrate-associated complications during long-term CRRT. Methods In a retrospective study conducted between January 2009 and November 2012, all cases of dialysis therapy performed in the interdisciplinary surgical intensive care unit were analysed. Inclusion criteria were CRRT and regional anticoagulation with citrate, pronounced liver dysfunction, and pathologically reduced indocyanine green plasma disappearance rate (ICG-PDR). Results A total of 1339 CRRTs were performed in 69 critically ill patients with liver failure. At admission, the mean Model for End-stage Liver Disease score was 19.2, and the mean ICG-PDR was 9.8%. Eight patients were treated with liver replacement therapy, and 30 underwent transplants. The mortality rate was 40%. The mean duration of dialysis was 19.4 days, and the circuit patency was 62.2 h. Accumulation of citrate was detected indirectly by total serum calcium/ionised serum calcium (tCa/iCa) ratio > 2.4. This was noted in 16 patients (23.2%). Dialysis had not to be discontinued for metabolic disorder or accumulation of citrate in any case. In 26% of cases, metabolic alkalosis occurred with pH > 7.5. Interestingly, no correlation between citrate accumulation and liver function parameters was detected. Moreover, most standard laboratory liver function parameters showed poor predictive capabilities for accumulation of citrate. Conclusions Our findings indicate that extra-hepatic metabolism of citrate seems to exist, avoiding in most cases citrate accumulation in critically ill patients despite impaired liver function. Because the citric acid cycle is oxygen-dependent, disturbed microcirculation would result in inadequate citrate metabolism. Raising the tCa/iCa ratio would therefore be an indicator of severity of illness and mortality rather than of liver failure. However, further studies are warranted for confirmation.

Renal ischemia-reperfusion (I/R) injury is a major cause of acute kidney injury (AKI). Non-coding RNAs are crucially involved in its pathophysiology. We identified hypoxia-induced long non-coding RNA Malat1 (Metastasis Associated Lung Adenocarcinoma Transcript 1) to be upregulated in renal I/R injury. We here elucidated the functional role of Malat1 in vitro and its potential contribution to kidney injury in vivo . Malat1 was upregulated in kidney biopsies and plasma of patients with AKI, in murine hypoxic kidney tissue as well as in cultured and ex vivo sorted hypoxic endothelial cells and tubular epithelial cells. Malat1 was transcriptionally activated by hypoxia-inducible factor 1-α. In vitro , Malat1 inhibition reduced proliferation and the number of endothelial cells in the S-phase of the cell cycle. In vivo , Malat1 knockout and wildtype mice showed similar degrees of outer medullary tubular epithelial injury, proliferation, capillary rarefaction, inflammation and fibrosis, survival and kidney function. Small-RNA sequencing and whole genome expression analysis revealed only minor changes between ischemic Malat1 knockout and wildtype mice. Contrary to previous studies, which suggested a prominent role of Malat1 in the induction of disease, we did not confirm an in vivo role of Malat1 concerning renal I/R-injury.

Peritonitis is a common complication of peritoneal dialysis (PD). Our root cause analysis allowed to attribute some cases to leakage of the PD catheter. Accordingly, a clinically based stress test study on potential material damage issues of PD catheters was performed, focusing on material damage caused by cleaning, de- and attachment procedures during dialysate changes and on the individual storage methods of PD catheters between dialysate changes. PD catheters were exposed to both chemical stress by repeating dialysate-flow and physical stress simulating de- and connecting, fixation, pressure, flexing, folding etc.—simulating standard clinical daily routine of 8–10 years PD catheter usage. Potentially by normal usage caused damages should be then detected by intraluminal pressure, light- and electron microscopy. The multi-step visual control showed no obvious damages on PD catheters nor any leakage or barrier indulgence. Our tests simulating daily routine usage of PD catheters for several years could not detect any material defects under chemical or physical stress. Hence, we presume that most PD catheter damages, as identified cause for peritonitis in some of our patients, may be due to accidental, unnoticed external damage (e.g. through scissors, while changing dressings) or neglecting PD catheter handling specifications.

Fibroblast growth factor (FGF)-23 is a recently discovered regulator of calcium–phosphate metabolism. Whereas other known FGFs mainly act in a paracrine manner, FGF-23 has significant systemic effects. Together with its cofactor Klotho, FGF-23 enhances renal phosphate excretion in order to maintain serum phosphate levels within the normal range. In patients with chronic kidney disease (CKD), FGF-23 levels rise in parallel with declining renal function long before a significant increase in serum phosphate concentration can be detected. However, in cross-sectional studies increased FGF-23 levels in patients with CKD were found to be associated not only with therapy-resistant secondary hyperparathyroidism but were also independently related to myocardial hypertrophy and endothelial dysfunction after adjustment for traditional markers of calcium–phosphate metabolism. Finally, in prospective studies high serum FGF-23 concentrations predicted faster disease progression in CKD patients not on dialysis, and increased mortality in patients receiving maintenance hemodialysis. FGF-23 may therefore prove to be an important therapeutic target in the management of CKD.

Several microRNAs (miRNAs) have been linked to chronic kidney disease (CKD) mortality, cardiovascular (CV) complications and kidney disease progression. However, their association with clinical outcomes remains poorly evaluated. We used real-time qPCR to measure serum levels of miR-126 and miR-223 in a large cohort of 601 CKD patients (CKD stage G1 to G5 patients or on renal replacement therapy – CKD G5D) from Ghent University Hospital and 31 healthy controls. All-cause mortality and cardiovascular and renal events were registered as endpoints over a 6 year follow-up period. miR-126 levels were significantly lower from CKD stage G2 on, compared to controls. The serum levels of miR-223 were significantly lower from CKD stage G3B on. When considering overall mortality, patients with levels of either miR-126 or miR-223 below the median had a lower survival rate. Similar results were observed for CV and renal events. The observed link between the two miRNAs’ seric levels and mortality, cardiovascular events or renal events in CKD appears to depend on eGFR. However, this does not preclude their potential role in the pathophysiology of CKD. In conclusion, CKD is associated with a decrease in circulating miR-223 and miR-126 levels