Publications by authors named "Saban Elitok"

39 Publications

Osteoprotegerin is an independent risk factor predicting death in stable renal transplant recipients.

Clin Nephrol 2021 May 27. Epub 2021 May 27.

Background: Vascular calcification is common in chronic kidney disease and is associated with significant cardiovascular morbidity and mortality. One of the important factors regulating vascular calcification is osteoprotegerin (OPG). There are, however, limited data on the impact of OPG on all-cause mortality and graft loss in kidney transplant recipients so far. Given its impact on vascular calcification, the aim of our study is to analyze whether OPG was a risk factor of all-cause mortality and graft loss in 600 stable kidney transplant recipients.

Materials And Methods: 600 stable renal transplant recipients (367 women, 233 men) were followed for all-cause mortality and graft loss for 3 years. Blood and urine samples for analysis and clinical data were collected at study entry. We performed Kaplan-Meier survival analysis and Cox regression models considering confounding factors such as age, estimated glomerular filtration rate (eGFR), cold ischemia time, HbA1c, phosphorus, calcium, and albumin.

Results: 65 patients died, and 38 patients had graft loss during the observation period. The OPG baseline concentrations had no effect on graft loss, whereas Kaplan-Meier survival curve showed that baseline plasma OPG concentrations were associated with all-cause mortality in stable kidney transplant recipients (p < 0.0001, log-rank test). After multiple Cox regression analysis adjusting for age, eGFR, cold ischemia time, HbA1c, phosphorus, calcium, and albumin, plasma levels of OPG remained an independent predictor of all-cause mortality (HR, 1.181; 95%CI 1.035 - 1.347; p = 0.014).

Conclusion: Baseline plasma OPG is an independent risk factor for all-cause mortality but not graft loss in patients after kidney transplantation.
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http://dx.doi.org/10.5414/CN110470DOI Listing
May 2021

NGAL/hepcidin-25 ratio and AKI subtypes in patients following cardiac surgery: a prospective observational study.

J Nephrol 2021 May 24. Epub 2021 May 24.

Brandenburg Medical School Theodor Fontane, 16816, Neuruppin, Germany.

Background: Acute kidney injury (AKI) subtypes combining kidney functional parameters and injury biomarkers may have prognostic value. We aimed to determine whether neutrophil gelatinase-associated lipocalin (NGAL)/hepcidin-25 ratio (urinary concentrations of NGAL divided by that of hepcidin-25) defined subtypes are of prognostic relevance in cardiac surgery patients.

Methods: We studied 198 higher-risk cardiac surgery patients. We allocated patients to four groups: Kidney Disease Improving Global Outcomes (KDIGO)-AKI-negative and NGAL/hepcidin-25 ratio-negative (no AKI), KDIGO AKI-negative and NGAL/hepcidin-25 ratio-positive (subclinical AKI), KDIGO AKI-positive and NGAL/hepcidin-25 ratio-negative (clinical AKI), KDIGO AKI-positive and NGAL/hepcidin-25 ratio-positive (combined AKI). Outcomes included in-hospital mortality (primary) and long-term mortality (secondary).

Results: We identified 127 (61.6%) patients with no AKI, 13 (6.6%) with subclinical, 40 (20.2%) with clinical and 18 (9.1%) with combined AKI. Subclinical AKI patients had a 23-fold greater in-hospital mortality than no AKI patients. For combined AKI vs. no AKI or clinical AKI, findings were stronger (odds ratios (ORs): 126 and 39, respectively). After adjusting for EuroScore, volume of intraoperative packed red blood cells, and aortic cross-clamp time, subclinical and combined AKI remained associated with greater in-hospital mortality than no AKI and clinical AKI (adjusted ORs: 28.118, 95% CI 1.465-539.703; 3.737, 95% CI 1.746-7.998). Cox proportional hazard models found a significant association of biomarker-informed AKI subtypes with long-term survival compared with no AKI (adjusted ORs: pooled subclinical and clinical AKI: 1.885, 95% CI 1.003-3.542; combined AKI: 1.792, 95% CI 1.367-2.350).

Conclusions: In the presence or absence of KDIGO clinical criteria for AKI, the urinary NGAL/hepcidin-25-ratio appears to detect prognostically relevant AKI subtypes.

Trial Registration Number: NCT00672334, clinicaltrials.gov, date of registration: 6th May 2008, https://clinicaltrials.gov/ct2/show/NCT00672334 . Definition of AKI subtypes: subclinical AKI (KDIGO negative AND Ratio-positive), clinical AKI (KDIGO positive AND Ratio-negative) and combined AKI (KDIGO positive AND Ratio-positive) with urinary NGAL/hepcidin-25 ratio-positive cut-off at 85% specificity for in-hospital death. AKI, acute kidney injury. AUC, area under the curve. NGAL, neutrophil gelatinase-associated lipocalin. KDIGO, Kidney Disease Improving Global Outcomes Initiative AKI definition.
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http://dx.doi.org/10.1007/s40620-021-01063-5DOI Listing
May 2021

Relationship Between Vitamin D and Hormones Important for Human Fertility in Reproductive-Aged Women.

Front Endocrinol (Lausanne) 2021 14;12:666687. Epub 2021 Apr 14.

Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany.

Vitamin D deficiency is very common in women of reproductive age. Studies in animals suggests a link between vitamin D and reproductive hormone biosynthesis. A systematic analysis of the correlation of reproductive hormones in reproductive-aged women with both total and free vitamin D was, however, not done so far. This cross-sectional study was performed in 351 healthy reproductive age Caucasian women (median age, 28.0 years; interquartile ranges, 24.7-31.0 years). We measured serum levels of both total and free 25(OH)D, endocrinological, hematological and biochemical parameters. Spearman's rank correlations were performed to assess the correlation between 25(OH)D metabolites and selected parameters. Total vitamin D and free vitamin D measurements correlated well (rho=0.912, p < 0.0001). Both total 25(OH)D and free 25(OH)D showed significant negative correlation with FAI (rho=-0.229, p<0.0001 and rho=-0.195, p<0.0001 for total and free 25(OH)D, respectively); LH (rho=-0.177, p=0.001 and rho=-0.114, p=0.04 for total and free 25(OH)D, respectively), testosterone (rho=-0.174, p=0.001 and rho=-0.190, p<0.0001 for total and free 25(OH)D, respectively) and AMH (rho=-0.130, p=0.015 and rho=-0.107, p=0.047 for total and free 25(OH)D, respectively). Our study showed comparable correlations of both total and free 25(OH)D with endocrinological parameters, i.e. inverse correlations with free androgen index, luteinizing hormone, testosterone, LH/FSH ratio, androstenedione and anti-Müllerian hormone, and also with hematological and biochemical parameters, i.e. inverse correlations with erythrocytes, hsCRP and leukocytes count, and positive correlation with transferrin saturation, mean corpuscular hemoglobin and mean corpuscular volume in healthy reproductive age women.
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http://dx.doi.org/10.3389/fendo.2021.666687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081388PMC
April 2021

C-terminal and intact FGF23 in kidney transplant recipients and their associations with overall graft survival.

BMC Nephrol 2021 Apr 8;22(1):125. Epub 2021 Apr 8.

Fifth Department of Medicine (Nephrology/ Endocrinology/ Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany.

Background: Increased fibroblast growth factor 23 (FGF23) is a risk factor for mortality, cardiovascular disease, and progression of chronic kidney disease. Limited data exist comparing the association of either c-terminal FGF23 (cFGF23) or intact FGF23 (iFGF23) in kidney transplant recipients (KTRs) with overall (all-cause) graft loss.

Methods: We conducted a prospective observational cohort study in 562 stable kidney transplant recipients. Patients were followed for graft loss and all-cause mortality for a median follow-up of 48 months.

Results: During a median follow-up of 48 months, 94 patients had overall graft loss (primary graft loss or death with functioning graft). Both cFGF23 and iFGF23 concentrations were significantly higher in patients with overall graft loss than those without (24.59 [11.43-87.82] versus 10.67 [5.99-22.73] pg/ml; p < 0.0001 and 45.24 [18.63-159.00] versus 29.04 [15.23-60.65] pg/ml; p = 0.002 for cFGF23 and iFGF23, respectively). Time-dependent ROC analysis showed that cFGF23 concentrations had a better discriminatory ability than iFGF23 concentrations in predicting overall (all-cause) graft loss. Cox regression analyses adjusted for risk factors showed that cFGF23 (HR for one unit increase of log transformed cFGF23: 1.35; 95% CI, 1.01-1.79; p = 0.043) but not iFGF23 (HR for one unit increase of log transformed iFGF23: 0.97; 95% CI, 0.75-1.25; p = 0.794) was associated with the overall graft loss.

Conclusion: Elevated cFGF23 concentrations at baseline are independently associated with an increased risk of overall graft loss. iFGF23 measurements were not independently associated with overall graft loss. The cFGF23 ELISA might detect bioactive FGF23 fragments that are not detected by the iFGF23 ELISA.
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http://dx.doi.org/10.1186/s12882-021-02329-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033679PMC
April 2021

Predictive Value of Plasma NGAL:Hepcidin-25 for Major Adverse Kidney Events After Cardiac Surgery with Cardiopulmonary Bypass: A Pilot Study.

Ann Lab Med 2021 Jul;41(4):357-365

Department of Nephrology and Endocrinology, Klinikum Ernst von Bergmann, Potsdam, Germany.

Background: Neutrophil gelatinase-associated lipocalin (NGAL) and hepcidin-25 are involved in catalytic iron-related kidney injury after cardiac surgery with cardiopulmonary bypass. We explored the predictive value of plasma NGAL, plasma hepcidin-25, and the plasma NGAL:hepcidin-25 ratio for major adverse kidney events (MAKE) after cardiac surgery.

Methods: We compared the predictive value of plasma NGAL, hepcidin-25, and plasma NGAL:hepcidin-25 with that of serum creatinine (Cr) and urinary output and protein for primary-endpoint MAKE (acute kidney injury [AKI] stages 2 and 3, persistent AKI >48 hours, acute dialysis, and in-hospital mortality) and secondary-endpoint AKI in 100 cardiac surgery patients at intensive care unit (ICU) admission. We performed ROC curve, logistic regression, and reclassification analyses.

Results: At ICU admission, plasma NGAL, plasma NGAL:hepcidin-25, plasma interleukin-6, and Cr predicted MAKE (area under the ROC curve [AUC]: 0.77, 0.79, 0.74, and 0.74, respectively) and AKI (0.73, 0.89, 0.70, and 0.69). For AKI prediction, plasma NGAL:hepcidin-25 had a higher discriminatory power than Cr (AUC difference 0.26 [95% CI 0.00-0.53]). Urinary output and protein, plasma lactate, C-reactive protein, creatine kinase myocardial band, and brain natriuretic peptide did not predict MAKE or AKI (AUC <0.70). Only plasma NGAL:hepcidin-25 correctly reclassified patients according to their MAKE and AKI status (category-free net reclassification improvement: 0.82 [95% CI 0.12-1.52], 1.03 [0.29-1.77]). After adjustment to the Cleveland risk score, plasma NGAL:hepcidin-25 ≥0.9 independently predicted MAKE (adjusted odds ratio 16.34 [95% CI 1.77-150.49], =0.014).

Conclusions: Plasma NGAL:hepcidin-25 is a promising marker for predicting postoperative MAKE.
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http://dx.doi.org/10.3343/alm.2021.41.4.357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884201PMC
July 2021

Opposite correlation of 25-hydroxy-vitamin D- and 1,25-dihydroxy-vitamin D-metabolites with gestational age, bone- and lipid-biomarkers in pregnant women.

Sci Rep 2021 Jan 21;11(1):1923. Epub 2021 Jan 21.

Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany.

25-Hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D (1,25(OH)D) need to be bound to carrier proteins to be transported to their target cells. The majority of either 25OHD or 1,25(OH)D is bound to vitamin D-binding protein (DBP), a smaller fraction is bound to albumin and only very small amounts of 25OHD or 1,25(OH)D are free. Albumin-bound 25OHD or 1,25(OH)D is relatively easily available after dissociation from albumin. Thus, the sum of free and albumin-bound forms is called bioavailable 25OHD and bioavailable 1,25(OH)D. Total 25OHD and 1,25(OH)D are defined as the sum of free, albumin-bound and DBP-bound 25OHD and 1,25(OH)D, respectively. This cross-sectional study in 427 pregnant women compared the correlation of the six vitamin D compounds with biomarkers of bone health, lipid metabolism, kidney function, endocrine parameters, and group B water-soluble vitamins. Among the 25OHD metabolites analysed, total 1,25(OH)D showed clearly the best correlation with calcium, bone-specific alkaline phosphatase, adiponectin, LDL, HDL, urea, thyroxine, and group B water-soluble vitamins. When comparing the three 25OHD metabolites, both free 25OHD and bioavailable 25OHD showed overall good correlations with calcium, bone-specific alkaline phosphatase, adiponectin, LDL, HDL, urea, thyroxine, triiodothyronine, and group B water-soluble vitamins, The correlations of 1,25(OH)D and 25OHD metabolites went always in opposite directions. Only PTH correlates always inversely with all six vitamin D compounds. In conclusion, free 25(OH)D and bioavailable 25(OH)D are more precise determinants of the vitamin D status than total 25(OH)D in normal pregnancy, whereas total 1,25(OH)D is superior to free and bioavailable 1,25(OH)D. Except for PTH, correlations of 25(OH)D and 1,25(OH)D metabolites with typical clinical chemistry readouts go in opposite directions.
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http://dx.doi.org/10.1038/s41598-021-81452-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820257PMC
January 2021

Inferior vena cava-syndrome.

Vasa 2021 Jan 18:1-15. Epub 2021 Jan 18.

Diagnostic and Interventionel Radiology, Ernst von Bergmann Klinikum Potsdam, Potsdam, Germany.

Inferior vena cava syndrome (IVCS) is caused by agenesis, compression, invasion, or thrombosis of the IVC, or may be associated with Budd-Chiari syndrome. Its incidence and prevalence are unknown. Benign IVCS is separated from malignant IVCS. Both cover a wide clinical spectrum reaching from asymptomatic to highly symptomatic cases correlated to the underlying cause, the acuity, the extent of the venous obstruction, and the recruitment and development of venous collateral circuits. Imaging is necessary to determine the underlying cause of IVCS and to guide clinical decisions. Interventional therapy has changed the therapeutic approach in symptomatic patients. This article provides an overview over IVCS and focuses on interventional therapeutic methods and results.
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http://dx.doi.org/10.1024/0301-1526/a000919DOI Listing
January 2021

Superior vena cava syndrome.

Vasa 2020 Oct;49(6):437-448

Diagnostic and Interventional Radiology, Ernst von Bergmann Klinikum Potsdam, Potsdam, Germany.

The superior vena cava syndrome (SVCS) is caused by compression, invasion, and/or thrombosis of the superior vena cava and/or the brachiocephalic veins. Benign SVCS is separated from malignant SVCS. SVCS comprises a broad clinical spectrum reaching from asymptomatic cases to rare life-threatening emergencies with upper airway obstruction and increased intracranial pressure. Symptoms are correlated to the acuity and extent of the venous obstruction and inversely correlated to the development of the venous collateral circuits. Imaging is necessary to determine the exact underlying cause and to guide further interventions. Interventional therapy has widely changed the therapeutic approach in symptomatic patients. This article provides an overview over this complex syndrome and focuses on interventional therapeutic methods and results.
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http://dx.doi.org/10.1024/0301-1526/a000908DOI Listing
October 2020

A patient with chronic kidney disease, primary biliary cirrhosis and metabolic acidosis.

Clin Kidney J 2020 Jun 21;13(3):463-467. Epub 2019 Jun 21.

Institute of Physiology, University of Zurich, Zurich, Switzerland.

Autoimmune disorders such as rheumatoid arthritis or Sjögren's syndrome can be associated with impaired renal acid excretion. Only few cases of patients with primary biliary cirrhosis (PBC) and distal renal tubular acidosis (dRTA) have been described. Here, we present the case of a 60-year-old woman with PBC and dRTA. Her kidney biopsy showed an absence of markers of acid-secretory Type A intercalated cells (A-ICs) and expression of aquaporin-2, a marker of principal cells, in all cells lining the collecting duct. Moreover, the serum of the patient contained antibodies directed against a subset of cells of the collecting duct. Thus, PBC-related autoantibodies may target acid-secretory A-ICs and thereby impair urinary acidification.
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http://dx.doi.org/10.1093/ckj/sfz059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367120PMC
June 2020

ADAMTS13 and VWF activities guide individualized caplacizumab treatment in patients with aTTP.

Blood Adv 2020 07;4(13):3093-3101

Klinikum der Universität München-Medizinische Klinik und Poliklinik IV, Nephrologisches Zentrum, Munich, Germany.

Introduction of the nanobody caplacizumab was shown to be effective in the treatment of acquired thrombotic thrombocytopenic purpura (aTTP) in the acute setting. The official recommendations include plasma exchange (PEX), immunosuppression, and the use of caplacizumab for a minimum of 30 days after stopping daily PEX. This study was a retrospective, observational analysis of the use of caplacizumab in 60 patients from 29 medical centers in Germany. Immunosuppressive treatment led to a rapid normalization of ADAMTS13 activities (calculated median, 21 days). In 35 of 60 patients, ADAMTS13 activities started to normalize before day 30 after PEX; in 11 of 60 patients, the treatment was extended beyond day 30; and in 5 patients, it was extended even beyond day 58 due to persistent autoimmune activity. In 34 of 60 instances, caplacizumab was stopped before day 30 with a favorable outcome whenever ADAMTS13 activities were >10%. In contrast, 11 of 34 patients with ADAMTS13 activities <10% at the time of stopping caplacizumab treatment developed a nonfavorable outcome (disease exacerbation or relapse). In some cases, prolongation of the treatment interval to every other day was feasible and resulted in a sustained reduction of von Willebrand factor activity. ADAMTS13 activity measurements are central for a rapid diagnosis in the acute setting but also to tailor disease management. An ADAMTS13 activity-guided approach seems safe for identifying the individual time point when to stop caplacizumab to prevent overtreatment and undertreatment; this approach will result in significant cost savings without jeopardizing the well-being of patients. In addition, von Willebrand factor activity may serve as a biomarker for drug monitoring.
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http://dx.doi.org/10.1182/bloodadvances.2020001987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362349PMC
July 2020

Real-world data confirm the effectiveness of caplacizumab in acquired thrombotic thrombocytopenic purpura.

Blood Adv 2020 07;4(13):3085-3092

Klinikum der Universität München-Medizinische Klinik und Poliklinik IV, Nephrologisches Zentrum, Munich, Germany.

Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare but life-threatening condition. In 2018, the nanobody caplacizumab was approved for the treatment of adults experiencing an acute episode of aTTP, in conjunction with plasma exchange (PEX) and immunosuppression for a minimum of 30 days after stopping daily PEX. We performed a retrospective, observational analysis on the use of caplacizumab in 60 patients from 29 medical centers in Germany during acute disease management. Caplacizumab led to a rapid normalization of the platelet count (median, 3 days; mean 3.78 days). One patient died after late treatment initiation due to aTTP-associated complications. In 2 patients with initial disease presentation and in 4 additional patients with laboratory signs of an exacerbation or relapse after the initial therapy, PEX-free treatment regimens could be established with overall favorable outcome. Caplacizumab is efficacious in the treatment of aTTP independent of timing and ancillary treatment modalities. Based on this real-world experience and published literature, we propose to administer caplacizumab immediately to all patients with an acute episode of aTTP. Treatment decisions regarding the use of PEX should be based on the severity of the clinical presentation and known risk factors. PEX might be dispensable in some patients.
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http://dx.doi.org/10.1182/bloodadvances.2020001973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362370PMC
July 2020

The Effects of Intensive Versus Routine Treatment in Patients with Acute Kidney Injury.

Dtsch Arztebl Int 2020 04;117(17):289-296

Department of Cardiology, Brandenburg Heart Center, Immanuel Hospital, Bernau; Brandenburg Medical School Theodor Fontane; Institute of Social Medicine and Health Systems Research, Magdeburg University, Magdeburg; Department of Nephrology and Endocrinology, Ernst von Bergmann Hospital, Potsdam; Department of Urology and Pediatric Urology, Magdeburg University Hospital, Magdeburg; Department of Orthopedics and Trauma Surgery, Ameos Hospital, Schönebeck; Institute of Laboratory Medicine, Leipzig University Hospital, Leipzig; Diaverum Renal Care Center Am Neuen Garten, Potsdam; Faculty of Medicine, Otto-von-Guericke University of Magdeburg; Department of Nephrology, Essen University Hospital, Essen.

Background: In patients with acute kidney injury (AKI), specialized treatment-initiated in response to an early-warning system- may be beneficial compared with routine treatment.

Method: To explore effect estimators in a pilot trial (DRKS00010530), patients with AKI on regular wards of a university hospital were treated either in the usual way (control group) or more intensively (intervention group). The subjects were allotted randomly to the two treatment groups. The more intensive treatment consisted of an early warning system for a rise in the serum creatinine concentration, immediate consultation of a specialist, and the issuance of a patient kidney passport. The primary endpoint was recovery of renal function after AKI during the index hospitalization. Renal complications and process indicators were the secondary endpoints.

Results: The proportion of patients whose renal function returned to baseline after AKI was 50% in the intervention group (N = 26) and 42% in the control group (N = 26) (odds ratio 1.4, 95% confidence interval [0.5; 4.0], p = 0.58). The calculated glomerular filtration rate went down, from hospital admission to discharge, by 3 mL/min/1.73 m2 (1st-3rd quartile: [6; -20]) in the intervention group and by 13 mL/min/1.73 m2 in the control group (1st-3rd quartile: [0; -25]; p = 0.09). Complications of AKI such as hyperkalemia, pulmonary edema, and renal acidosis were rarer in the intervention group (15% versus 39%; p = 0.03). In the intervention group, compared with the control group, the cause of AKI was identified more frequently (27% versus 4%; p = 0.05); drugs with relevance to the kidney were discontinued more frequently (65% versus 31%; p = 0.01); and the diagnosis of AKI was more frequently documented in the patient's chart (58% versus 37%; p = 0.03).

Conclusion: Specialized consultations supported by an early warning system for AKI seem to be beneficial for patients. The findings of this pilot trial should be verified in larger-scale randomized controlled trials.
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http://dx.doi.org/10.3238/arztebl.2020.0289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297063PMC
April 2020

Endostatin Is an Independent Risk Factor of Graft Loss after Kidney Transplant.

Am J Nephrol 2020 22;51(5):373-380. Epub 2020 Apr 22.

Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany,

Background: Endostatin is a 20-kDa C-terminal fragment of collagen XVIII, known for its ability to inhibit the proliferation of capillary endothelial cells. Previous studies suggested that circulating endostatin independently predicts incident chronic kidney disease. However, the impact of endostatin on graft loss level in kidney transplant recipients (KTRs) remains unknown.

Methods: We conducted a prospective observational cohort study in 574 maintenance KTRs. Patients were followed for kidney graft loss and all-cause mortality during a median follow-up of 48 months. Serum-, and urine-samples and clinical data were collected at baseline. Serum Endostatin concentration was analyzed by an ELISA.

Results: Among 574 patients, 37 patients had graft loss and 62 patients died. For graft loss, the optimal cut-off value based on receiver operating characteristics analysis (area under the curve 0.79, 95% CI 0.71-0.86, p < 0.001) of endostatin was 147.3 pmol/L. Kaplan-Meier curves revealed that higher serum endostatin concentrations positively correlated with graft loss (p < 0.001). Multivariable Cox regression analyses showed that baseline endostatin concentrations were significantly associated with graft loss after adjusting for graft loss risk factors (adjusted hazard ratio [HR] 8.34; 95% CI 2.19-31.72; p = 0.002). The adjusted HRs for classical graft loss risk factors such as baseline estimated glomerular filtration rate and urinary protein excretion were lower (1.91 and 5.44, respectively). In contrast to graft loss, baseline endostatin concentrations were not associated with all-cause mortality.

Conclusion: Increased serum endostatin at baseline is independently associated with the risk of graft loss in KTRs.
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http://dx.doi.org/10.1159/000507824DOI Listing
May 2021

Impact of maternal smoking associated lyso-phosphatidylcholine 20:3 on offspring brain development.

J Steroid Biochem Mol Biol 2020 05 15;199:105591. Epub 2020 Jan 15.

Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Heidelberg, Germany; Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China; Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, China. Electronic address:

Maternal smoking during pregnancy affects fetal neurological development. Metabolomic studies in the general population suggest that smoking is associated with characteristic metabolic alterations. We investigated the association between the maternal smoking status, the fetal metabolome and head circumference at birth, as a surrogate parameter of brain development. 320 mother/newborn pairs of the Berlin Birth Cohort were investigated. Anthropometric parameters, including head circumference, of newborns of smoking mothers, former smoking mothers, and never smoking mothers were compared to assess the impact of maternal smoking behavior. Associations between maternal smoking behavior and 163 cord blood metabolites and associations between newborn head circumference and concentrations of smoking behavior related metabolites were analysed. Male newborns of smoking mothers had a reduced head circumference when compared with newborns from former smoking and never smoking mothers (p < 0.05). Using linear regression models corrected for established confounding factors, maternal smoking during pregnancy showed an independent association with head circumference (95% CI: -0.75~-0.41 cm, p = 2.45×10). In a stepwise linear regression model corrected for known confounding factors of brain growth lyso-phosphatidylcholine 20:3 (95% CI: 6.68~39.88 cm, p = 4.62×10) was associated with head circumference in male offspring only. None of the metabolites were associated with head circumference of female newborns. In conclusion, maternal smoking during pregnancy impacted on male offspring's development including brain development. The smoking related metabolite lyso-phosphatidylcholine 20:3 was associated with head circumference of male offspring.
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http://dx.doi.org/10.1016/j.jsbmb.2020.105591DOI Listing
May 2020

Free 25-Vitamin D Is Correlated with Cardiovascular Events in Prevalent Hemodialysis Patients but Not with Markers of Renal Mineral Bone Disease.

Kidney Blood Press Res 2019 14;44(3):344-353. Epub 2019 Jun 14.

Fifth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany.

Free vitamin D is the biologically active form of vitamin D. Vitamin D deficiency is associated with cardiovascular disease, the most common cause of mortality in hemodialysis patients. The goal of our current study was to investigate the relation between blood concentrations of free 25-hydroxyvitamin D with cardiovascular events in end-stage chronic kidney disease patients on hemodialysis, because this is unknown so far. We measured free vitamin D levels in 117 stable consecutive prevalent patients in September as a surrogate of vitamin D exposure during the past 6 months, and recorded the number of cardiovascular events during the previous 6 months defined as hospitalization due to heart failure, episodes of acute coronary syndrome, and stroke. Fourteen events occurred during the observation period. In patients without any cardiovascular events the free vitamin D levels were significantly higher as compared to those with cardiovascular events (patients without events: 5.68 [4.37-9.27] pg/mL; patients with events: 4.74 [3.46-5.37] pg/mL, p = 0.015). This finding remained stable after multiple regression analysis considering confounding factors such as age, time on dialysis, preexisting diabetes, hypertension, and coronary heart disease. In conclusion, our study shows that free vitamin D serum concentrations are independently associated with major cardiovascular events in chronic kidney disease patients on dialysis.
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http://dx.doi.org/10.1159/000499878DOI Listing
January 2020

[Treatment, clinical course, and cross-sectoral information transmission in patients with acute-on-chronic kidney injury].

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2019 Jun;62(6):773-781

MVZ Diaverum Am Neuen Garten, Potsdam, Deutschland.

Background: Delayed diagnosis and undertherapy of acute-on-chronic kidney injury (AKI-on-CKD) may trigger multiple organ injury and worsen clinical outcome.

Objectives: This study focused on description of in-hospital care and cross-sectoral information transmission of patients with AKI-on-CKD including subgroup analyses (under surgical vs. non-surgical and nephrology vs. non-nephrology care).

Materials And Methods: At a university clinic, we analysed clinical measures and documentation in patients with AKI-on-CKD. Cox regression was performed to identify independent risk factors for in-hospital-mortality and 180-day mortality.

Results: In 38 (25.3%) of 150 patients, progressing AKI-on-CKD was found. Nineteen patients (12.7%) received acute dialysis. Thirty patients (20.0%) died in hospital. Systemic hypotension (n = 76, 50.7%) and nephrotoxins (n = 26, 17.3%), both considered as causes for AKI-on-CKD, were treated in 36.8 and 19.2%, respectively, of affected patients. Fluid balance was documented in one third of patients. Nephrology referral was requested in 38 (25.3%) of patients (median 24.0 h after AKI-on-CKD start). Acute renal complications (n = 74, 49.3%) were an independent risk factor for in-hospital mortality (ExpB 6.5, p = 0.022) or 180-day mortality (ExpB 3.3, p = 0.034). Rarely, outpatient physicians were informed about AKI-on-CKD (n = 42, 28.0%) or renal function follow-up was recommended (n = 14, 11.7% of surviving patients).

Conclusions: Care gaps in therapy and cross-sectoral information transmission in patients with AKI-on-CKD were identified.
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http://dx.doi.org/10.1007/s00103-019-02926-wDOI Listing
June 2019

Urinary cGMP predicts major adverse renal events in patients with mild renal impairment and/or diabetes mellitus before exposure to contrast medium.

PLoS One 2018 12;13(4):e0195828. Epub 2018 Apr 12.

Institute for Nutritional Science, University of Potsdam, Potsdam, Germany.

Background: The use of iodine-based contrast agents entails the risk of contrast induced nephropathy (CIN). Radiocontrast agents elicit the third most common cause of nephropathy among hospitalized patients, accounting for 11-12% of cases. CIN is connected with clinically significant consequences, including increased morbidity, prolonged hospitalization, increased risk of complications, potential need for dialysis, and increased mortality rate. The number of in-hospital examinations using iodine-based contrast media has been significantly increasing over the last decade. In order to protect patients from possible complications of such examinations, new biomarkers are needed that are able to predict a risk of contrast-induced nephropathy. Urinary and plasma cyclic guanosine monophosphate (cGMP) concentrations are influenced by renal function. Urinary cGMP is primarily of renal cellular origin. Therefore, we assessed if urinary cGMP concentration may predict major adverse renal events (MARE) after contrast media exposure during coronary angiography.

Methods: Urine samples were prospectively collected from non-randomized consecutive patients with either diabetes or preexisting impaired kidney function receiving intra-arterial contrast medium (CM) for emergent or elective coronary angiography at the Charité Campus Mitte, University Hospital Berlin. Urinary cGMP concentration in spot urine was analyzed 24 hours after CM exposure. Patients were followed up over 90 days for occurrence of death, initiation of dialysis, doubling of plasma creatinine concentration or MARE.

Results: In total, 289 consecutive patients were included into the study. Urine cGMP/creatinine ratio 24 hours before CM exposure expressed as mean±SD was predictive for the need of dialysis (no dialysis: 89.77±92.85 μM/mM, n = 277; need for dialysis: 140.3±82.90 μM/mM, n = 12, p = 0.008), death (no death during follow-up: 90.60±92.50 μM/mM, n = 280; death during follow-up: 169.88±81.52 μM/mM, n = 9; p = 0.002), and the composite endpoint MARE (no MARE: 86.02±93.17 μM/mM, n = 271; MARE: 146.64±74.68 μM/mM, n = 18, p<0.001) during the follow-up of 90 days after contrast media application. cGMP/creatinine ratio stayed significantly increased at values exceeding 120 μM/mM in patients who developed MARE, required dialysis or died.

Conclusions: Urinary cGMP/creatinine ratio ≥ 120 μM/mM before CM exposure is a promising biomarker for the need of dialysis and all-cause mortality 90 days after CM exposure in patients with preexisting renal impairment or diabetes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0195828PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896998PMC
July 2018

Does NGAL reduce costs? A cost analysis of urine NGAL (uNGAL) & serum creatinine (sCr) for acute kidney injury (AKI) diagnosis.

PLoS One 2017 19;12(5):e0178091. Epub 2017 May 19.

Columbia University Medical Center, New York, New York, United States of America.

Introduction: Urine neutrophil gelatinase-associated lipocalin (uNGAL) is a sensitive and specific diagnostic test for acute kidney injury (AKI) in the Emergency Department (ED), but its economic impact has not been investigated. We hypothesized that uNGAL used in combination with serum creatinine (sCr) would reduce costs in the management of AKI in patients presenting to the ED in comparison to using sCr alone.

Materials And Methods: A cost simulation model was developed for clinical algorithms to diagnose AKI based on sCr alone vs. uNGAL plus sCr (uNGAL+sCr). A cost minimization analysis was performed to determine total expected costs for patients with AKI. uNGAL test characteristics were validated with eight-hundred forty-nine patients with sCr ≥1.5 from a completed study of 1635 patients recruited from EDs at two U.S. hospitals from 2007-8. Biomarker test, AKI work-up, and diagnostic imaging costs were incorporated.

Results: For a hypothetical cohort of 10,000 patients, the model predicted that the expected costs were $900 per patient (pp) in the sCr arm and $950 in the uNGAL+sCr arm. uNGAL+sCr resulted in 1,578 fewer patients with delayed diagnosis and treatment than sCr alone (2,013 vs. 436 pts) at center 1 and 1,973 fewer patients with delayed diagnosis and treatment than sCr alone at center 2 (2,227 vs. 254 patients). Although initial evaluation costs at each center were $50 pp higher in with uNGAL+sCr, total costs declined by $408 pp at Center 1 and by $522 pp at Center 2 due to expected reduced delays in diagnosis and treatment. Sensitivity analyses confirmed savings with uNGAL + sCr for a range of cost inputs.

Discussion: Using uNGAL with sCr as a clinical diagnostic test for AKI may improve patient management and reduce expected costs. Any cost savings would likely result from avoiding delays in diagnosis and treatment and from avoidance of unnecessary testing in patients given a false positive AKI diagnosis by use of sCr alone.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178091PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438176PMC
October 2017

Kaliopenic nephropathy revisited.

Clin Kidney J 2016 Aug 15;9(4):543-6. Epub 2016 Mar 15.

Division of Nephrology, Helios-Klinikum Berlin , and Experimental and Clinical Research Center, a joint cooperation of the Max-Delbrück Center for Molecular Medicine and the Charité Medical Faculty , Berlin-Buch , Germany.

In the 'older' literature, a definitive renal pathology was described in patients with long-standing hypokalaemia and depletion of the body's potassium reserves. The topic is relevant because possibly a quite cheaply reversible element in the course of chronic kidney disease progression could be addressed. Earlier, pathologists drew attention to vacuolar changes in renal tubular epithelium accompanied by inflammatory interstitial changes in patients with potassium losses. The diagnostic term 'kaliopenic nephropathy' was coined to describe such patients. Kaliopenic nephropathy now receives less emphasis than in earlier times. However, with eating disorders, laxative abuse and other potential causes, we suggest that the syndrome should be resurrected.
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http://dx.doi.org/10.1093/ckj/sfv154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4957711PMC
August 2016

Clinical effects of phosphodiesterase 3A mutations in inherited hypertension with brachydactyly.

Hypertension 2015 Oct 17;66(4):800-8. Epub 2015 Aug 17.

From the Children's' Hospital, Department of Pediatric Cardiology, Friedrich-Alexander University Erlangen, Erlangen, Germany (O.T.); Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany (J.T., J.J.); Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany (C.S., A.A., P.G.M., E.B.-K., I.H., A.M., Y.W.-N., J.S.-M., E.K., S.B., F.C.L.); Experimental and Clinical Research Center (ECRC), a joint co-operation between the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine (MDC), Berlin, Germany (A.A., P.G.M., E.B.-K., I.H., C.L., K.M., M.B., G.R., A.M., Y.W.-N., W.U., A.T., J.S.-M., S.B., F.C.L.); Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA (P.G.M.); Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, MA (P.G.M.); Department of Cardiology/Nephrology, Helios-Klinikum Berlin, Berlin, Germany (S.E., W.U., A.T., J.S.-M.); Department of Nephrology, Hannover University Medical School, Hannover, Germany (C.L.); Staatliche Technikerschule Berlin, Berlin, Germany (C.L.); Cardiology Section, VA Salt Lake City Health Care System, UT (M.A.M.); Departments of Internal Medicine and Pharmacology and Toxicology, University of Utah, Salt Lake City (M.A.M.); Blood Transfusion Center, Deutsches Rotes Kreuz, Oldenburg, Germany (T.M., A.D., S.G.); Division of Nephrology and Hypertension, Department of Medicine, Eastern Virginia Medical School, Norfolk, VA (H.R.T.); Hampton Veterans Affairs Medical Center, Hampton, VA (H.R.T); German Centre for Cardiovascular Research (DZHK), Berlin, Germany (E.K.); and Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN (F.C.L.).

Autosomal-dominant hypertension with brachydactyly is a salt-independent Mendelian syndrome caused by activating mutations in the gene encoding phosphodiesterase 3A. These mutations increase the protein kinase A-mediated phosphorylation of phosphodiesterase 3A resulting in enhanced cAMP-hydrolytic affinity and accelerated cell proliferation. The phosphorylated vasodilator-stimulated phosphoprotein is diminished, and parathyroid hormone-related peptide is dysregulated, potentially accounting for all phenotypic features. Untreated patients die prematurely of stroke; however, hypertension-induced target-organ damage is otherwise hardly apparent. We conducted clinical studies of vascular function, cardiac functional imaging, platelet function in affected and nonaffected persons, and cell-based assays. Large-vessel and cardiac functions indeed seem to be preserved. The platelet studies showed normal platelet function. Cell-based studies demonstrated that available phosphodiesterase 3A inhibitors suppress the mutant isoforms. However, increasing cGMP to indirectly inhibit the enzyme seemed to have particular use. Our results shed more light on phosphodiesterase 3A activation and could be relevant to the treatment of severe hypertension in the general population.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.115.06000DOI Listing
October 2015

G-protein coupled receptor auto-antibodies in thromboangiitis obliterans (Buerger's disease) and their removal by immunoadsorption.

Vasa 2014 Sep;43(5):347-52

Klinik für Kardiologie und Nephrologie, HELIOS Klinikum Berlin-Buch, Germany.

Background: Immunhistopathological and serological data favors an immunopathogenesis of thromboangiitis onliterans (TAO, Buerger's disease). Auto antbodies seem to play a major role. Immunoadsorption (IA) proved to be therapeutically effective. We focused on agonistic autoantibodies (agAAB) directed against G-protein coupled receptors (GPCR) and proved the hypothesis, that these agAAB might be present in TAO and that a five day course of IA might be able to eliminate these agAAB effectively.

Patients And Methods: Between December 2012 and May 2014 11 TAO-patients were treated by IA in a five day course. AgAAB-analysis was performed using specific ELISA techniques.

Results: AgAAB were detected in 9 out of 11 patients (81.8 %).Multiple agAAB were present in 7 patients (63.6 %). A clustering of agAAB directed against loop1 of the adrenergic α1-receptor and the endothelin-A-(ETA)receptor was identified, representing 72.7 % resp. 54.5 % of the patients. AgAAB directed against the angiotensin-1 (AT-1) epitope 1 or 2 were detected in 3 patients and agAAB directed against protease-activated receptor (PAR) loop1/2 were seen in 2 patients. AgAAB directed against ETA-receptor loop1 never appeared without agAAB directed against α1-receptor loop1. Immediately after a five day-course of IA agAAB were absent in 81.8 % of the total study group and in 77.8 % of all cases tested positive for agAAB before IA.

Conclusions: AgAAB directed against GPCR were identified in TAO patients with a clustering of agAAB directed against α-1-adrenergic receptor loop1 and ETA-receptor loop1. AgAA were eliminated by IA in the majority of cases. We suggest that these agAA play an important role in the pathogenesis of TAO and that their elimination might be responsible for the positive therapeutic effects reported in patients treated with IA.
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http://dx.doi.org/10.1024/0301-1526/a000372DOI Listing
September 2014

Peculiarly progressive tetraplegia.

Clin Kidney J 2013 Apr;6(2):231-2

Franz-Volhard Clinic , Helios-Klinikum-Berlin , Berlin , Germany.

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http://dx.doi.org/10.1093/ckj/sft023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4432457PMC
April 2013

A cardiorenal-pulmonary-cutaneous-muscle syndrome.

Clin Kidney J 2013 Apr;6(2):199-200

Charité Medical Faculty , Experimental and Clinical Research Center , Berlin , Germany.

Anti-synthetase syndrome is a relatively recently described auto-immune disease characterized by auto-antibodies to enzymes that acetylate transfer RNA (tRNA). Interstitial pulmonary disease and inflammatory myopathy are regular findings. Our patient also exhibited a lupus-like glomerulonephritis. An important clue was the presence of 'mechanics' hands. Nephrologists need to be aware of this syndrome.
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http://dx.doi.org/10.1093/ckj/sft017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4432453PMC
April 2013

A patient with a floating kidney and nephrotic syndrome.

Clin Nephrol 2014 Aug;82(2):128-32

Asymptomatic retroperitoneal fluid is rarely detected. We encountered a young man with known nephrotic syndrome who presented with left-sided abdominal pain. He had very little peripheral edema, but a massive fluid collection around a "floating" left kidney, as determined by three different imaging studies. Large amounts of fluid and a cyst surrounding the kidney were removed laparascopically and malignancy was excluded. The patient had a rare benign cystic mesothelioma together with focal-segmental glomerulosclerosis. Both diseases do not seem to be causally related. Complete surgical resection of the mesothelioma is the definitive treatment. If resection is incomplete, recurrence is frequent. Indeed, when our patient returned some years later for an elective hernia repair, the fluid collection had recurred.
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http://dx.doi.org/10.5414/CN107694DOI Listing
August 2014

Chronic hypokalaemia in a hypertensive patient.

Clin Kidney J 2012 Jun 18;5(3):223-4. Epub 2012 Apr 18.

Experimental and Clinical Research Center, Max-Delbrück Center, Berlin, Germany.

Hypokalaemia in hypertensive patients is a 'red flag' bringing to mind various classic secondary and genetic causes related to both hypokalaemia and hypertension. We encountered a patient who had an unusual cause for his disturbance that, to our knowledge, has not been described in hypertensive patients.
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http://dx.doi.org/10.1093/ckj/sfs041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400514PMC
June 2012

Diagnostic and prognostic stratification in the emergency department using urinary biomarkers of nephron damage: a multicenter prospective cohort study.

J Am Coll Cardiol 2012 Jan;59(3):246-55

Columbia University College of Physicians and Surgeons, New York, NY, USA.

Objectives: This study aimed to determine the diagnostic and prognostic value of urinary biomarkers of intrinsic acute kidney injury (AKI) when patients were triaged in the emergency department.

Background: Intrinsic AKI is associated with nephron injury and results in poor clinical outcomes. Several urinary biomarkers have been proposed to detect and measure intrinsic AKI.

Methods: In a multicenter prospective cohort study, 5 urinary biomarkers (urinary neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, urinary liver-type fatty acid binding protein, urinary interleukin-18, and cystatin C) were measured in 1,635 unselected emergency department patients at the time of hospital admission. We determined whether the biomarkers diagnosed intrinsic AKI and predicted adverse outcomes during hospitalization.

Results: All biomarkers were elevated in intrinsic AKI, but urinary neutrophil gelatinase-associated lipocalin was most useful (81% specificity, 68% sensitivity at a 104-ng/ml cutoff) and predictive of the severity and duration of AKI. Intrinsic AKI was strongly associated with adverse in-hospital outcomes. Urinary neutrophil gelatinase-associated lipocalin and urinary kidney injury molecule 1 predicted a composite outcome of dialysis initiation or death during hospitalization, and both improved the net risk classification compared with conventional assessments. These biomarkers also identified a substantial subpopulation with low serum creatinine at hospital admission, but who were at risk of adverse events.

Conclusions: Urinary biomarkers of nephron damage enable prospective diagnostic and prognostic stratification in the emergency department.
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http://dx.doi.org/10.1016/j.jacc.2011.10.854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3487165PMC
January 2012

Urinary neutrophil gelatinase-associated lipocalin distinguishes pre-renal from intrinsic renal failure and predicts outcomes.

Kidney Int 2011 Aug 16;80(4):405-14. Epub 2011 Mar 16.

Experimental and Clinical Research Center, a joint institution of the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Berlin, Germany.

In established acute kidney injury (AKI), serum creatinine poorly differentiates prerenal from intrinsic AKI. In this study, we tested whether urinary neutrophil gelatinase-associated lipocalin (NGAL) distinguishes between intrinsic and prerenal AKI, and tested its performance in predicting a composite outcome that included progression to a higher RIFLE (Risk, Injury, Failure, Loss of function, End stage renal disease) class, dialysis, or death. Urinary NGAL was measured using a standardized clinical platform in 161 hospitalized patients with established AKI. Sixteen patients were excluded because of postrenal obstruction or insufficient clinical information. Of the remaining 145 patients, 75 had intrinsic AKI, 32 had prerenal AKI, and 38 patients could not be classified. Urinary NGAL levels effectively discriminated between intrinsic and prerenal AKI (area under the receiver-operating characteristic curve 0.87). An NGAL level over 104 μg/l indicated intrinsic AKI (likelihood ratio 5.97), whereas an NGAL level <47 μg/l made intrinsic AKI unlikely (likelihood ratio 0.2). Patients experiencing the composite outcome had significantly higher median urinary NGAL levels on inclusion. In logistic regression analysis, NGAL independently predicted the composite outcome when corrected for demographics, comorbidities, creatinine, and RIFLE class. Hence, urinary NGAL is useful in classifying and stratifying patients with established AKI.
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http://dx.doi.org/10.1038/ki.2011.41DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870593PMC
August 2011

Recurrent metabolic acidosis in a dialysis patient.

Kidney Int 2010 Aug;78(4):425-6

HELIOS Klinikum Berlin, Experimental and Clinical Research Centre, Charité Medical Faculty and Max-Delbrück Centre for Molecular Medicine, Berlin, Germany.

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http://dx.doi.org/10.1038/ki.2010.180DOI Listing
August 2010

The case: the eyes have it!

Kidney Int 2009 Aug;76(4):465-6

Franz-Volhard Clinic Nephrology Section, HELIOS Klinkum Berlin, Berlin, Germany.

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http://dx.doi.org/10.1038/ki.2009.235DOI Listing
August 2009