Background:Chronic kidney disease (CKD) contributes to global mortality and morbidity, also due to infectious complications resulting from immune system dysregulation. Recently, respiratory syncytial virus (RSV) vaccines based on the prefusion F (preF) glycoprotein have been licensed for prevention of severe disease in elderly and in patients with comorbidities, but data on immunogenicity in patients with CKD are scarce. Methods:We characterized humoral and cellular immunogenicity of 75 patients with CKD stages G3a to G5d both before and 14 days (IQR 2) after vaccination with an adjuvanted protein-based RSVpreF3-vaccine using ELISA and flow cytometry. Data on adverse events were collected through a self-reported questionnaire. Results:Vaccination led to a significant induction of RSV-specific CD4 T cells (P < .0001) and the increase did not differ between the CKD stages. CD8 T cells were not specifically induced. Despite high seroprevalence prior to vaccination, quantitative levels of RSV-specific immunoglobulins IgG and F protein-specific IgG were significantly induced on vaccination (both P < .0001), with a less pronounced increase in patients with advanced CKD. Urinary albumin-creatinine-ratio (UACR) was shown to be predictive of vaccine response in a multivariate regression model using age, serum creatinine and urea as covariates (P = .035). The vaccine was well tolerated with mostly transient adverse events at the injection site. Conclusions:RSV-vaccination led to a robust CD4 T-cell and humoral response in patients with CKD with less pronounced effects in those with high-grade proteinuria. Long-term data on immunogenicity and correlation with clinical outcomes are warranted to define optimal vaccination strategies.

Maintenance immunosuppression is a cornerstone of long-term allograft survival in kidney transplant recipients and typically involves calcineurin-inhibitors such as tacrolimus, mycophenolate mofetil, and corticosteroids. Tacrolimus has a narrow therapeutic index and is subject to drug-drug interactions mediated by the cytochrome P450 (CYP) system. We report a case of tacrolimus intoxication following itraconazole therapy that was successfully managed by CYP3A4 induction using rifampicin.A 65-year-old man with diabetic kidney disease underwent deceased-donor kidney transplantation and developed severe tacrolimus intoxication in the early postoperative period after recent oral itraconazole therapy for treatment of tinea pedis. Tacrolimus trough levels increased up to 45.9 ng/ml and were associated with anuric, dialysis dependent allograft dysfunction, neurotoxicity, and hemodynamic instability requiring intensive care management. Tacrolimus was discontinued, and induction of CYP3A4 metabolism was leveraged for increased tacrolimus elimination using intravenous rifampicin. Hemodialysis combined with CytoSorb hemoadsorption was performed to enhance protein-bound itraconazole removal suggesting toxic itraconazole levels and to decrease acute inflammation. Itraconazole plasma concentrations were not elevated and remained unchanged during hemoadsorption. Tacrolimus levels declined markedly within 72 hours after initiation of rifampicin. Kidney function recovered, and the patient was discharged with stable graft function.Clinically relevant drug-drug interactions in transplant recipients are frequent yet often underrecognized. This case demonstrates that CYP3A4 induction using rifampicin may represent an effective therapeutic strategy to increase tacrolimus clearance, underscoring the need for improved awareness and development of standardized treatment approaches for acute tacrolimus intoxication.

Background. Cytomegalovirus-specific immunoglobulins (CMV-IVIg) can contribute to viral control after transplantation. Apart from neutralizing antiviral activity, knowledge on their potential indirect effects on the restoration of virus-specific T-cell immunity is limited. Therefore, we tested whether CMV-IVIg may affect cytokine induction and proliferation of CMV-specific T cells in vitro. Methods. Blood samples of 38 individuals (23 kidney transplant recipients and 15 immunocompetent controls) were stimulated using CMV antigens in saturating and low antigen concentration, or with the polyclonal stimulus Staphylococcus aureus enterotoxin B in the presence or absence of CMV-IVIg. CD4 and CD8 T-cell effector function, including the induction of cytokines interferon-gamma, tumor necrosis factor, and interleukin-2, was characterized after 6 h, and specific proliferation was quantified after 5 d using flow cytometry. Results. Irrespective of antigen concentration, the presence or absence of CMV-IVIg had no effect on the percentage of CMV-specific CD4 and CD8 T cells producing interferon-gamma, tumor necrosis factor, or interleukin-2. However, proliferation of CMV-specific CD3 T cells, including CD4 and CD8 T-cell subpopulations, was significantly higher in the presence of CMV-IVIg at both saturating (P = 0.007) and low antigen concentrations (P = 0.022). In contrast, a lower percentage of both cytokine-producing T cells (P < 0.0001) and proliferating T cells (P < 0.0001) was observed in the presence of CMV-IVIg after polyclonal stimulation. Conclusions. CMV-IVIg did not have any effect on immediate T-cell effector function. However, the marked effect of CMV-IVIg on increasing the proliferation of CMV-specific T cells while concomitantly reducing polyclonal T-cell function may have implications for the therapeutic use of immunoglobulins to restore CMV-specific T cells in patients with active CMV infection without increasing the alloreactive burden.

Respiratory syncytial virus (RSV) prefusion F-based vaccines have recently been approved for immunosuppressed individuals, but data in solid organ transplant (SOT) recipients remain limited. This observational study assessed natural RSV immunity among 52 controls and 197 patients with immunodeficiencies, of which 46 kidney transplant recipients, 30 lung transplant (LuTx) recipients, and 19 patients with chronic kidney disease subsequently received a single dose of a protein-based RSV vaccine to quantify and characterize RSV-specific antibodies and T cells pre- and postvaccination using enzyme-linked immunosorbent assay and flow cytometry. Reactogenicity was self-reported. Over 90% had natural pan-RSV-specific immunoglobulin G, and 30% to 58% had RSV-specific CD4 T cells. Vaccination was well tolerated and led to a significant increase in antibodies and polyfunctional CD4 T cells (P < .0001), with similar T cell levels to both RSV-subtypes A and B. CD4 T cell responses were comparable between kidney transplant and patients with chronic kidney disease, but significantly lower in LuTx recipients (P = .023) and in SOT recipients within the first year posttransplant (P = .005). The vaccine did not induce any CD8 T cells. In conclusion, a single RSV vaccine dose induced strong immunoglobulin G and CD4 T cell responses with RSV-A/B cross-reactivity. However, LuTx and early posttransplant SOT recipients showed reduced T cell responses. Alternative strategies may be required to improve immunogenicity in heavily immunosuppressed SOT recipients.

ABSTRACT To date, no drugs are approved for BK polyomavirus (BKPyV) reactivation, a major cause of nephropathy after kidney transplantation. Recently, tumor necrosis factor‐α (TNF‐α) blockade has been proposed as a promising therapy, however, the effect of TNF‐α on the clinically most common archetype (ww) BKPyV remained unclear. Assays in primary renal proximal tubule epithelial cells (RPTEC) allowed efficient replication only of BKPyV strains with rearranged (rr) non‐coding control regions (NCCR), which may develop at later disease stages, but not of ww‐BKPyV. Here, we optimized culture conditions allowing robust replication of patient‐derived ww‐BKPyV, while efficiently preserving their ww‐NCCR. TNF‐α promoted rr‐BKPyV replication, while the T H 1 cytokine IFN‐γ suppressed it, also in the presence of TNF‐α. Surprisingly, TNF‐α alone was sufficient to suppress all ww‐BKPyV strains tested. Comprehensive analysis using siRNAs, and chimeric or mutated BKPyV‐strains revealed that the response to TNF‐α depends on the NCCR type, and that the NF‐κB p65 pathway but not the conserved NF‐κB binding site is essential for the TNF‐α‐induced enhancement of rr‐BKPyV replication. Our data suggest that in immunosuppressed patients with archetype‐dominated infections, TNF‐α blockade could interfere with natural TNF‐α‐mediated anti‐BKPyviral control, and this could be detrimental when IFN‐γ‐driven T H 1 responses are impaired. Ongoing inflammation, however, could lead to the selection of rearrangements responding to NCCR‐activating pathways downstream of NF‐κB p65 signaling, that may overcome the initial TNF‐α‐mediated suppression. Our findings also highlight the importance of using clinically relevant BKPyV isolates for drug testing and discovery, for which this new assay paves the way.

BACKGROUND:Childhood-onset chronic kidney disease is a progressive condition that can have a major effect on life expectancy and quality. We evaluated the usefulness of the kidney tubular cell stress marker urinary Dickkopf-related protein 3 (DKK3) in determining the short-term risk of chronic kidney disease progression in children and identifying those who will benefit from specific nephroprotective interventions. METHODS:In this observational cohort study, we assessed the association between urinary DKK3 and the combined kidney endpoint (ie, the composite of 50% reduction of the estimated glomerular filtration rate [eGFR] or progression to end-stage kidney disease) or the risk of kidney replacement therapy (ie, dialysis or transplantation), and the interaction of the combined kidney endpoint with intensified blood pressure reduction in the randomised controlled ESCAPE trial. Moreover, urinary DKK3 and eGFR were quantified in children aged 3-18 years with chronic kidney disease and urine samples available enrolled in the prospective multicentre ESCAPE (NCT00221845; derivation cohort) and 4C (NCT01046448; validation cohort) studies at baseline and at 6-monthly follow-up visits. Analyses were adjusted for age, sex, hypertension, systolic blood pressure SD score (SDS), BMI SDS, albuminuria, and eGFR. FINDINGS:659 children were included in the analysis (231 from ESCAPE and 428 from 4C), with 1173 half-year blocks in ESCAPE and 2762 in 4C. In both cohorts, urinary DKK3 above the median (ie, >1689 pg/mg creatinine) was associated with significantly greater 6-month eGFR decline than with urinary DKK3 at or below the median (-5·6% [95% CI -8·6 to -2·7] vs 1·0% [-1·9 to 3·9], p<0·0001, in ESCAPE; -6·2% [-7·3 to -5·0] vs -1·5% [-2·9 to -0·1], p<0·0001, in 4C), independently of diagnosis, eGFR, and albuminuria. In ESCAPE, the beneficial effect of intensified blood pressure control was limited to children with urinary DKK3 higher than 1689 pg/mg creatinine, in terms of the combined kidney endpoint (HR 0·27 [95% CI 0·14 to 0·55], p=0·0003, number needed to treat 4·0 [95% CI 3·7 to 4·4] vs 250·0 [66·9 to ∞]) and the need for kidney replacement therapy (HR 0·33 [0·13 to 0·85], p=0·021, number needed to treat 6·7 [6·1 to 7·2] vs 31·0 [27·4 to 35·9]). In 4C, inhibition of the renin-angiotensin-aldosterone system resulted in significantly lower urinary DKK3 concentrations (least-squares mean 12 235 pg/mg creatinine [95% CI 10 036 to 14 433] in patients not on angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers vs 6861 pg/mg creatinine [5616 to 8106] in those taking angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers, p<0·0001). INTERPRETATION:Urinary DKK3 indicates short-term risk of declining kidney function in children with chronic kidney disease and might allow a personalised medicine approach by identifying those who benefit from pharmacological nephroprotection, such as intensified blood pressure lowering. FUNDING:None.

Background: Cardiovascular diseases and chronic kidney disease (CKD) are highly prevalent, aggravate each other, and account for substantial mortality. Both conditions are characterized by activation of the innate immune system. The alarmin interleukin-1α (IL-1α) is expressed in a variety of cell types promoting (sterile) systemic inflammation. The aim of the present study was to examine the role of IL-1α in mediating inflammation in the setting of acute myocardial infarction (AMI) and CKD. Methods: We assessed the expression of IL-1α on the surface of monocytes from patients with AMI and patients with CKD and determined its association with atherosclerotic cardiovascular disease events during follow-up in an explorative clinical study. Furthermore, we assessed the inflammatory effects of IL-1α in several organ injury models in Il1a −/ − and Il1b −/ − mice and investigated the underlying mechanisms in vitro in monocytes and endothelial cells. Results: IL-1α is strongly expressed on the surface of monocytes from patients with AMI and CKD compared with healthy controls. Higher IL-1α surface expression on monocytes from patients with AMI and CKD was associated with a higher risk for atherosclerotic cardiovascular disease events, which underlines the clinical relevance of IL-1α. In mice, IL-1α, but not IL-1β, mediates leukocyte-endothelial adhesion as determined by intravital microscopy. IL-1α promotes accumulation of macrophages and neutrophils in inflamed tissue in vivo. Furthermore, IL-1α on monocytes stimulates their homing at sites of vascular injury. A variety of stimuli such as free fatty acids or oxalate crystals induce IL-1α surface expression and release by monocytes, which then mediates their adhesion to the endothelium via IL-1 receptor-1. IL-1α also promotes expression of the VCAM-1 (vascular cell adhesion molecule-1) on endothelial cells, thereby fostering the adhesion of circulating leukocytes. IL-1α induces inflammatory injury after experimental AMI, and abrogation of IL-1α prevents the development of CKD in oxalate or adenine-fed mice. Conclusions: IL-1α represents a key mediator of leukocyte-endothelial adhesion and inflammation in AMI and CKD. Inhibition of IL-1α may serve as a novel anti-inflammatory treatment strategy.

Chronic kidney disease (CKD) represents a global public health problem with high disease related morbidity and mortality. Since CKD etiology is heterogeneous, early recognition of patients at risk for progressive kidney injury is important. Here, we evaluated the tubular epithelial derived glycoprotein dickkopf-3 (DKK3) as a urinary marker for the identification of progressive kidney injury in a non-CKD cohort of patients with chronic obstructive pulmonary disease (COPD) and in an experimental model. In COSYCONET, a prospective multicenter trial comprising 2,314 patients with stable COPD (follow-up 37.1 months), baseline urinary DKK3, proteinuria and estimated glomerular filtration rate (eGFR) were tested for their association with the risk of declining eGFR and the COPD marker, forced expiratory volume in one second. Baseline urinary DKK3 but not proteinuria or eGFR identified patients with a significantly higher risk for over a 10% (odds ratio: 1.54, 95% confidence interval: 1.13-2.08) and over a 20% (2.59: 1.28-5.25) decline of eGFR during follow-up. In particular, DKK3 was associated with a significantly higher risk for declining eGFR in patients with eGFR over 90 ml/min/1.73m2 and proteinuria under 30 mg/g. DKK3 was also associated with declining COPD marker (2.90: 1.70-4.68). The impact of DKK3 was further explored in wild-type and Dkk3-/- mice subjected to cigarette smoke-induced lung injury combined with a CKD model. In this model, genetic abrogation of DKK3 resulted in reduced pulmonary inflammation and preserved kidney function. Thus, our data highlight urinary DKK3 as a possible marker for early identification of patients with silent progressive CKD and for adverse outcomes in patients with COPD.

Aims Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown. Methods and results We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality. Conclusion The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.

Abstract Background and Aims Chronic kidney disease (CKD) represents one of the strongest cardiovascular risk factors. Recently, we have shown that activation of the NOD-like receptor protein-3 (NLRP3) inflammasome mediates progression of kidney injury and CKD-associated vascular disease (Zewinger et al. Nat Immunol 2013). Components of the NLRP3 inflammasome pathway such as interleukin-1β (IL-1β) can therapeutically be targeted. Associations of genetically determined life-long inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown. Method We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 3,061 patients enrolled in the LURIC study undergoing coronary angiography in a gene-centric approach. Functional relevance of the rs10754555 NLRP3 variant was studied in freshly isolated human monocytes. Findings were validated in 39,755 participants from eight independent studies (CV risk populations) as well as in 483,258 participants of the UKBiobank study (general population). Results Genetic analyses identified the highly prevalent (MAF 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Expression of NLRP3 mRNA and inflammasome-dependent effector responses of isolated human monocytes from rs10754555 carriers were significantly higher as compared to non-carriers. In homozygous rs10754555 carriers, the prevalence of coronary artery disease (CAD) was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age in LURIC and in UKBiobank. Importantly, in LURIC and in UKBiobank, homozygous rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up (HR 1.37, 95%-CI 1.08-1.74 and HR 1.13, 95%-CI 1.02-1.25, respectively). Consistently, rs10754555 was associated with higher cardiovascular mortality (HR 1.11, 95%-CI 1.05-1.16; P<0.001) in an additive model in patients with prevalent CAD. Conclusion The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent CAD and mortality. This study provides evidence for a substantial role of life-long, genetically-driven systemic inflammation in cardiovascular disease and highlights the NLRP3 inflammasome as a therapeutic target in the general population and particular in patients with CKD.

Abstract Background and Aims Chronic kidney disease (CKD) and chronic obstructive pulmonary disease (COPD) represent a global public health problem worldwide. As such, both conditions are associated with high disease-related morbidity and mortality. However, it is unclear whether the presence of CKD aggravates the clinical course of COPD and vice versa. Method In a novel murine model of cigarette smoke (CS)-induced lung injury combined with an adenine nephropathy model, kidney and lung inflammation, and fibrosis were studied. Moreover, in 2,314 patients with stable COPD enrolled in the prospective, multi-centre COSYCONET study, urinary Dickkopf-3 (DKK3), a biomarker of kidney injury and CKD progression was quantified. The association between urinary DKK3 and trajectories of forced expiratory pressure in 1 second (FEV1) and estimated glomerular filtration rate (eGFR) during a median follow-up of 37.1 months, exercise capacity, risk of exacerbation, and mortality was determined. Results In the CKD-COPD animal model, the presence of kidney injury was associated with increased systemic and pulmonary inflammation, impaired pulmonary function, as well as more severe damage of the lung architecture. Moreover, CS enhanced kidney fibrosis. Accordingly, in the COPD patients from the COSYCONET study, higher urinary DKK3 was associated with declining FEV1 during follow-up (OR 3.36, 95% CI 2.22-5.08). Moreover, high urinary DKK3 was associated with higher risk for exacerbation (OR 1.24, 95% CI 1.03-1.50), lower 6-minute walking distance, and higher all-cause mortality (HR 1.49, 95% CI 1.08-2.05). Importantly, high urinary DKK3 was associated with declining eGFR during follow-up (OR 2.23, 95% CI 1.22-4.07) independently from baseline kidney function and proteinuria, which was confirmed by a machine learning approach. Conclusion These data uncover a novel pathophysiological link between CKD and COPD. Patient with COPD and concomitant CKD are at high risk for worsening pulmonary function and adverse outcomes. Elevated urinary DKK3 allows identification of COPD patients with progressive CKD. Measurement of urinary DKK3 in patients with COPD may therefore represent a novel tool for risk stratification and the identification of patients, who might in particular benefit from preventive therapeutic strategies to prevent progression of COPD and CKD as well.

Chronic kidney disease (CKD) is associated with a substantially increased risk for the development of atherosclerotic cardiovascular (CV) disease. Accordingly, CV mortality is increased even in the earliest stages of CKD. In the general population and in CKD patients, high plasma levels of low-density lipoprotein cholesterol (LDL-C) are crucially involved in the initiation and progression of atherosclerotic vascular lesions. Lowering LDL-C by use of statins and/or ezetimibe represents the gold standard of lipid-lowering therapy, with a great body of evidence from several large clinical trials. Statin therapy reduces CV events in patients with normal and impaired kidney function alike, while the evidence for patients on maintenance haemodialysis is weaker. The inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) serine protease represents a novel lipid-lowering tool. Currently the monoclonal antibodies evolocumab and alirocumab are the approved PCSK9 inhibitors. Despite maximum-tolerated statin therapy, they efficiently further reduce LDL-C plasma levels without any major adverse effects. Moreover, in large clinical outcome trials, both antibodies have been proven to lower CV events. Notably, the LDL-lowering capacity was independent of baseline kidney function and also efficient in patients with moderate CKD. However, patients with severely impaired kidney function, that is, the population at the highest CV risk, have been excluded from those trials. The relevance of the LDL-independent effects of PCSK9 inhibitors, such as lowering lipoprotein(a) or ameliorating dyslipidaemia in patients with nephrotic syndrome, has to be determined. Therefore further specific studies assessing the effects and outcomes of PCSK9-inhibiting treatment in CKD patients are warranted.

NLRP3-inflammasome-driven inflammation is involved in the pathogenesis of a variety of diseases. Identification of endogenous inflammasome activators is essential for the development of new anti-inflammatory treatment strategies. Here, we identified that apolipoprotein C3 (ApoC3) activates the NLRP3 inflammasome in human monocytes by inducing an alternative NLRP3 inflammasome via caspase-8 and dimerization of Toll-like receptors 2 and 4. Alternative inflammasome activation in human monocytes is mediated by the Toll-like receptor adapter protein SCIMP. This triggers Lyn/Syk-dependent calcium entry and the production of reactive oxygen species, leading to activation of caspase-8. In humanized mouse models, ApoC3 activated human monocytes in vivo to impede endothelial regeneration and promote kidney injury in an NLRP3- and caspase-8-dependent manner. These data provide new insights into the regulation of the NLRP3 inflammasome and the pathophysiological role of triglyceride-rich lipoproteins containing ApoC3. Targeting ApoC3 might prevent organ damage and provide an anti-inflammatory treatment for vascular and kidney diseases.

BACKGROUND: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. METHODS: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. FINDINGS: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). INTERPRETATION: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. FUNDING:No study funding.

Background The individual course of CKD may vary, and improved methods for identifying which patients will experience short-term eGFR loss are needed. Assessing urinary Dickkopf-3 (DKK3), a stress-induced tubular epithelia-derived profibrotic glycoprotein, may provide information about ongoing tubulointerstitial fibrosis and short-term eGFR loss. Methods To investigate urinary DKK3's potential as a biomarker of short-term eGFR loss (over 12 months), we prospectively assessed eGFR and urinary DKK3 levels in patients with CKD of various etiologies at baseline and annual follow-ups. We also measured urinary DKK3 in a general population sample and patients with diagnostic kidney biopsies or IgA nephropathy under treatment. Results Median urinary DKK3-to-creatinine concentration at baseline was significantly higher in patients with CKD than the general population sample (431 versus 33 pg/mg). In the CKD cohort, having a urinary DKK3-to-creatinine level >4000 pg/mg was independently and significantly associated after multiple adjustments with mean annual decline in eGFR of 7.6% over 12 months. Urinary DKK3 significantly improved prediction of kidney function decline compared with eGFR or albuminuria alone. Urinary DKK3-to-creatinine levels were related to the extent of tubulointerstitial fibrosis in kidney biopsies. In patients with IgA nephropathy, a rise in urinary DKK3 was associated with significant eGFR decline within 6 months, whereas stable or decreasing urinary DKK3 indicated a more favorable course. Conclusions Urinary DKK3 levels identify patients at high risk for eGFR decline over the next 12 months regardless of the cause of kidney injury and beyond established biomarkers, potentially providing a tool to monitor CKD progression and assess effects of interventions.