Timm H. Westhoff

Urinary Tissue Inhibitor of Metalloproteinase-2 (TIMP-2) • Insulin-Like Growth Factor-Binding Protein 7 (IGFBP7) Predicts Adverse Outcome in Pediatric Acute Kidney Injury

Background The G1 cell cycle inhibitors tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) have been identified as promising biomarkers for the prediction of adverse outcomes including renal replacement therapy (RRT) and mortality in critically ill adult patients who develop acute kidney injury (AKI). However, the prognostic value of urinary TIMP-2 and IGFBP7 in neonatal and pediatric AKI for adverse outcome has not been investigated yet. Methods The product of the urinary concentration of TIMP-2 and IGFBP7 ([TIMP-2]•[IGFBP7]) was assessed by a commercially available immunoassay (NephroCheck™) in a prospective cohort study in 133 subjects aged 0–18 years including 46 patients with established AKI according to pRIFLE criteria, 27 patients without AKI (non-AKI group I) and 60 apparently healthy neonates and children (non-AKI group II). AKI etiologies were: dehydration/hypovolemia (n = 7), hemodynamic instability (n = 7), perinatal asphyxia (n = 9), septic shock (n = 7), typical hemolytic-uremic syndrome (HUS; n = 5), interstitial nephritis (n = 5), vasculitis (n = 4), nephrotoxic injury (n = 1) and renal vein thrombosis (n = 1). Results When AKI patients were classified into pRIFLE criteria, 6/46 (13%) patients fulfilled the criteria for the category “Risk”, 13/46 (28%) for “Injury”, 26/46 (57%) for “Failure” and 1/46 (2%) for “Loss”. Patients in the “Failure” stage had a median 3.7-fold higher urinary [TIMP-2]•[IGFBP7] compared to non-AKI subjects (P<0.001). When analyzed for AKI etiology, highest [TIMP-2]•[IGFBP7] values were found in patients with septic shock (P<0.001 vs. non-AKI I+II). Receiver operating characteristic (ROC) curve analyses in the AKI group revealed good performance of [TIMP-2]•[IGFBP7] in predicting 30-day (area under the curve (AUC) 0.79; 95% CI, 0.61–0.97) and 3-month mortality (AUC 0.84; 95% CI, 0.67–0.99) and moderate performance in predicting RRT (AUC 0.67; 95% CI, 0.50–0.84). Conclusions This study shows that urinary [TIMP-2]•[IGFBP7] has a good diagnostic performance in predicting adverse outcomes in neonatal and pediatric AKI of heterogeneous etiology.

Urinary calprotectin and posttransplant renal allograft injury

Objective Current methods do not predict the acute renal allograft injury immediately after kidney transplantation. We evaluated the diagnostic performance of urinary calprotectin for predicting immediate posttransplant allograft injury. Methods In a multicenter, prospective-cohort study of 144 incipient renal transplant recipients, we postoperatively measured urinary calprotectin using an enzyme-linked immunosorbent assay and estimated glomerular filtration rate (eGFR) after 4 weeks, 6 months, and 12 months. Results We observed a significant inverse association of urinary calprotectin concentrations and eGFR 4 weeks after transplantation (Spearman ru200a=u200a−0.33; P<0.001). Compared to the lowest quartile, patients in the highest quartile of urinary calprotectin had an increased risk for an eGFR less than 30 mL/min/1.73 m2 four weeks after transplantation (relative risk, 4.3; P<0.001; sensitivity, 0.92; 95% CI, 0.77 to 0.98; specificity, 0.48; 95% CI, 0.31 to 0.66). Higher urinary calprotectin concentrations predicted impaired kidney function 4 weeks after transplantation, as well as 6 months and 12 months after transplantation. When data were analyzed using the urinary calprotectin/creatinine-ratio similar results were obtained. Urinary calprotectin was superior to current use of absolute change of plasma creatinine to predict allograft function 12 months after transplantation. Urinary calprotectin predicted an increased risk both in transplants from living and deceased donors. Multivariate linear regression showed that higher urinary calprotectin concentrations and older donor age predicted lower eGFR four weeks, 6 months, and 12 months after transplantation. Conclusions Urinary calprotectin is an early, noninvasive predictor of immediate renal allograft injury after kidney transplantation.

Urinary calprotectin, kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin for the prediction of adverse outcome in pediatric acute kidney injury

AbstractEarly identification of patients with acute kidney injury (AKI) being at high risk for adverse outcome can influence medical treatment. This study compares urinary calprotectin, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) for their performance in predicting mortality and need for renal replacement therapy (RRT) in pediatric AKI patients. Urinary biomarker concentrations were assessed prospectively in 141 subjects aged 0–18xa0years including 55 patients with established AKI according to pediatric Risk, Injury, Failure, Loss, and End-stage kidney disease (pRIFLE) criteria, 27 patients without AKI, and 59 healthy children. Within the AKI group, receiver operating characteristic (ROC) curve analysis revealed moderate to poor performance of calprotectin and KIM-1 in the prediction of 30-day mortality (calprotectin area under the curve (AUC) 0.55; KIM-1 AUC 0.55) and 3-month mortality (calprotectin AUC 0.61; KIM-1 AUC 0.60) and fair performance in the prediction of RRT requirement (calprotectin AUC 0.72; KIM-1 AUC 0.71). Urinary NGAL showed good performance in predicting 30-day (AUC 0.79) and 3-month (AUC 0.81) mortality and moderate performance in predicting RRT (AUC 0.61).n Conclusions: Whereas urinary calprotectin and KIM-1 can be useful for the prediction of RRT, urinary NGAL has a good diagnostic performance in predicting mortality in pediatric patients with AKI of heterogeneous etiology.What is known:• There is increasing evidence that urinary biomarkers like neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) are valuable for the prediction of adverse outcome in adult acute kidney injury (AKI), whereas data on pediatric AKI is scarce.What is new:• Urinary calprotectin and KIM-1 do not predict mortality in our heterogeneous pediatric AKI cohort, but they show moderate performance in the prediction of dialysis.• Urinary NGAL is a good predictor of mortality performing better than pRIFLE stage, eGFR, or creatinine, but it shows moderate performance in the prediction of dialysis.

Urinary biomarkers for the differentiation of prerenal and intrinsic pediatric acute kidney injury

BackgroundUrinary calprotectin and neutrophil gelatinase-associated lipocalin (NGAL) have recently been identified as promising biomarkers for the differentiation of prerenal and intrinsic acute kidney injury (AKI) in adults. In the study reported here we examined the diagnostic accuracy of calprotectin, NGAL, and kidney injury molecule 1 (KIM-1) in pediatric patients.MethodsUrinary calprotectin, NGAL, and KIM-1 concentrations were assessed in a study population of 139 pediatric subjects including 39 patients with intrinsic AKI, 14 with prerenal AKI, and 86 non-AKI subjects.ResultsMedian urinary calprotectin and NGAL concentrations were higher in patients with intrinsic AKI than in those with prerenal AKI (calprotectin by 22-fold, NGAL by 9-fold). Receiver operating characteristic (ROC) curve analyses for the differentiation of intrinsic and prerenal AKI resulted in an area under the curve (AUC) of 0.90 [95xa0% confidence interval (CI) 0.81–0.98] for calprotectin and 0.73 (95xa0% CI 0.58–0.87) for NGAL. Median urinary KIM-1 concentrations were not significantly different between patients with prerenal AKI and those with intrinsic disease (Pu2009=u20090.98; AUC 0.50, 95xa0% CI, 0.35–0.65). The AUC for the fractional excretion of sodium (FENa) and proteinuria was 0.78 (95xa0% CI 0.63–0.92) and 0.77 (CI 0.65–0.90), respectively.ConclusionsUrinary calprotectin outperforms NGAL, KIM-1, FENa, and proteinuria as a biomarker for the differentiation of prerenal and intrinsic AKI in pediatric patients with a high diagnostic accuracy.

Effects of Treatment of Asymptomatic Hyperuricemia on Graft Survival and Mortality in Kidney Transplant Recipients.

BACKGROUND Hyperuricemia is very common after renal transplantation. It is associated with an increased risk of cardiovascular events and graft loss. To date, however, treatment is only recommended in symptomatic disease. MATERIAL AND METHODS We included 503 adult patients who underwent kidney transplantation at the Charité-Universitätsmedizin Berlin in this retrospective study. Patients were followed up for up to 120 months. All-cause mortality, graft survival, changes in level of serum uric acid (SUA), and estimated glomerular filtration rate (eGFR) were analyzed. RESULTS At 12 months post-transplantation, 225 patients had a serum uric acid (SUA) level >7 mg/dl: 52 patients were treated with allopurinol, 37 with benzbromarone, and 136 patients received no medication for hyperuricemia (control). At 12 months, eGFR did not differ between groups (p=0.15) but treated patients had higher SUA levels (p<0.001) compared to the control group. SUA-lowering treatment was associated with a lower risk of all-cause mortality (p=0.013) and graft loss (p=0.014) compared to controls. At 120 months, patients in the treatment group had lower SUA levels (p=0.001) and higher eGFR (p<0.001) compared to the control group. CONCLUSIONS Treatment of asymptomatic hyperuricemia was associated with a substantial benefit in patient and graft survival.

Differential T cell response against BK virus regulatory and structural antigens: A viral dynamics modelling approach

BK virus (BKV) associated nephropathy affects 1–10% of kidney transplant recipients, leading to graft failure in about 50% of cases. Immune responses against different BKV antigens have been shown to have a prognostic value for disease development. Data currently suggest that the structural antigens and regulatory antigens of BKV might each trigger a different mode of action of the immune response. To study the influence of different modes of action of the cellular immune response on BKV clearance dynamics, we have analysed the kinetics of BKV plasma load and anti-BKV T cell response (Elispot) in six patients with BKV associated nephropathy using ODE modelling. The results show that only a small number of hypotheses on the mode of action are compatible with the empirical data. The hypothesis with the highest empirical support is that structural antigens trigger blocking of virus production from infected cells, whereas regulatory antigens trigger an acceleration of death of infected cells. These differential modes of action could be important for our understanding of BKV resolution, as according to the hypothesis, only regulatory antigens would trigger a fast and continuous clearance of the viral load. Other hypotheses showed a lower degree of empirical support, but could potentially explain the clearing mechanisms of individual patients. Our results highlight the heterogeneity of the dynamics, including the delay between immune response against structural versus regulatory antigens, and its relevance for BKV clearance. Our modelling approach is the first that studies the process of BKV clearance by bringing together viral and immune kinetics and can provide a framework for personalised hypotheses generation on the interrelations between cellular immunity and viral dynamics.

Aortic Valve Replacement as a Trigger of Atypical Hemolytic Uremic Syndrome

Mechanical hemolysis is a frequent but usually harmless complication of aortic valve replacement. The most common reason is valvular leakage. This report presents atypical hemolytic uremic syndrome (aHUS) as an alternative cause of mechanical hemolysis after this procedure. aHUS is a complement-mediated disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. It necessitates immediate specific treatment including plasma exchange or complement inhibition to avoid an adverse outcome. The present case identifies aortic valve replacement as a trigger of aHUS and shows that this disease must be taken into account in the differential diagnosis of hemolysis after valve surgery.

Response to Does Atrial Fibrillation Affect the Automated Oscillometric Blood Pressure Measurement

We thank Stergiou and coworkers for their interest in our study.1 The authors criticize that we did not use a validation protocol. The present study examines the impact of one single parameter (atrial fibrillation, AF) on the accuracy of oscillometry. It is not a validation study. The performance of a device in a validation procedure is determined by a broad variety of parameters. Bland–Altman analysis—as used in our study—is the statistical gold standard to assess the accuracy of a measurement technique and allows to analyze the impact of a single parameter like AF by statistical comparison of the resulting biases.2 Furthermore, the …

BKV, CMV, and EBV Interactions and their Effect on Graft Function One Year Post-Renal Transplantation: Results from a Large Multi-Centre Study

Background BK virus (BKV), Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivations are common after kidney transplantation and associated with increased morbidity and mortality. Although CMV might be a risk factor for BKV and EBV, the effects of combined reactivations remain unknown. The purpose of this study is to ascertain the interaction and effects on graft function of these reactivations. Methods 3715 serum samples from 540 kidney transplant recipients were analysed for viral load by qPCR. Measurements were performed throughout eight visits during the first post-transplantation year. Clinical characteristics, including graft function (GFR), were collected in parallel. Findings BKV had the highest prevalence and viral loads. BKV or CMV viral loads over 10,000 copies·mL−1 led to significant GFR impairment. 57 patients had BKV-CMV combined reactivation, both reactivations were significantly associated (pu202f=u202f0.005). Combined reactivation was associated with a significant GFR reduction one year post-transplantation of 11.7u202fmL·min−1·1.73u202fm−2 (pu202f=u202f0.02) at relatively low thresholds (BKVu202f>u202f1000 and CMVu202f>u202f4000 copies·mL−1). For EBV, a significant association was found with CMV reactivation (pu202f=u202f0.02), but no GFR reduction was found. Long cold ischaemia times were a further risk factor for high CMV load. Interpretation BKV-CMV combined reactivation has a deep impact on renal function one year post-transplantation and therefore most likely on long-term allograft function, even at low viral loads. Frequent viral monitoring and subsequent interventions for low BKV and/or CMV viraemia levels and/or long cold ischaemia time are recommended. Fund Investigator Initiated Trial; financial support by German Federal Ministry of Education and Research (BMBF).

Unbeobachtete automatisierte Blutdruckmessung

Die SPRINT-Studie hat die Diskussion darüber entfacht, wie der Blutdruck am besten zu bestimmen sei. Soll in der Praxis unbeobachtet gemessen werden oder bleibt die bislang übliche Messung durch Praxispersonal der Goldstandard?