TIMP-2 and IGFBP7 in human kidney biopsies in renal disease.

Background: Tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) are markers of tubular stress and urinary [TIMP-2]*[IGFBP7] is an established biomarker for risk assessment of acute kidney injury. There are no studies of expression profiles or localization of these markers in human renal tissue with confirmed renal disease. Methods: We analysed 37 kidney biopsies of patients with renal disease and 10 non-diseased control biopsies for TIMP-2 and IGFBP7 expression using immunohistochemistry. Changes in glomerular morphology were evaluated by a semi-quantitative glomerulosclerosis score (GSI) and tubular interstitial changes were graded by the tubular injury score (TSI) using periodic acid-Schiff-stained paraffin sections. Interstitial fibrosis and tubular atrophy (IF/TA) were graded according to the Banff classification. Urinary [TIMP-2]*[IGFBP7] was collected at the time of biopsy. Results: TIMP-2 and IGFBP7 had significantly greater expression in kidney biopsies from patients with renal disease compared with control tissue, especially in the tubular compartment. Here, IGFBP7 was detected in proximal and distal tubules while TIMP-2 was predominantly localized in the collecting ducts. Renal injury significantly correlated with staining intensity for TIMP-2 and IGFBP7: GSI weakly correlated with glomerular TIMP-2 (r = 0.36) and IGFBP7 (r = 0.35) and TSI correlated with tubular TIMP-2 (r = 0.41) and IGFBP7 (r = 0.43). Urinary [TIMP-2]*[IGFBP7] correlated weakly with the histopathological damage score but not with glomerular and tubular expression. Conclusion: Our findings underline the role of TIMP-2/IGFBP7 as an unspecific marker of renal injury that is already in use for early detection of acute kidney injury.

[Biomarkers in acute kidney injury - the search for the "renal troponin"]. / Biomarker bei akuter Nierenschädigung ­ die Suche nach dem "renalen Troponin".

The prognosis of acute kidney injury (AKI) is poor, partly due to significant limitations of the current functional marker-based definition, which results in too small therapeutic window to treat AKI. Therefore, AKI biomarkers are needed to detect AKI earlier. Classical filtration markers are serum creatinine and cystatin C, which, however, show clear limitations for AKI prediction. Early AKI markers are divided into damage markers and "stress" markers. The latter indicate a pre-injury phase with increased AKI risk. The one "renal troponin" will probably never be found because of heterogeneous renal structure and heterogeneous causes of AKI. However, AI-based models with inclusion of biomarkers could significantly improve AKI prediction and prognosis.

Under-recognition of Acute Kidney Injury after Cardiac Surgery in the ICU Impedes Early Detection and Prevention.

BACKGROUND: Acute kidney injury (AKI) is associated with high morbidity and mortality; therefore, prevention is important. The aim of this study was to systematically assess AKI incidence after cardiac surgery as documented in clinical routine compared to the real incidence because AKI may be under-recognized in clinical practice. Further, its postoperative management was compared to Kidney Disease: Improving Global Outcomes (KDIGO) recommendations because recognition and adequate treatment represent the fundamental cornerstone in the prevention and management of AKI. METHODS: This retrospective single-center study included n = 100 patients who underwent cardiac surgery with cardiopulmonary bypass. The coded incidence of postoperative AKI during intensive care unit stay after surgery was compared to the real AKI incidence. Furthermore, conformity of postoperative parameters with KDIGO recommendations for AKI prevention and management was reviewed. RESULTS: We found a considerable discrepancy between coded and real incidence, and conformity with KDIGO recommendations was found to be relatively low. The coded incidence was significantly lower (n = 12 vs. n = 52, p < 0.05), representing a coding rate of 23.1%. Regarding postoperative management, 90% of all patients had at least 1 episode with mean arterial pressure <65 mm Hg within the first 72 h. Furthermore, regarding other preventive parameters (avoiding hyperglycemia, stopping angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, avoiding contrast media, and nephrotoxic drugs), only 10 patients (20.8%) in the non-AKI group and in 5 (9.6%) subjects in the AKI group had none of all the above potential AKI-promoting factors. CONCLUSIONS: AKI recognition in everyday clinical routine seems to be low, especially in lower AKI stages, and the current postoperative management still offers potential for optimization. Possibly, higher AKI awareness and stricter postoperative management could already achieve significant effects in prevention and treatment of AKI.

Gender-Specific Differences of Renal Heat Tolerance in Older Adults during Heat Waves.

BACKGROUND: Heat waves are known to cause increased morbidity and mortality in susceptible populations like old and functionally impaired people. The objective of the study was to assess renal tubular stress, a predictor for development of acute kidney injury, during heat waves in Central Europe. As a marker of renal tubular stress tissue inhibitor of metalloproteinases-2 [TIMP-2]·insulin-like growth factor binding protein-7 [IGFBP7], a new FDA-cleared renal tubular stress biomarker, was used. MATERIALS AND METHODS: 68 residents from facilities of sheltered housing with urine samples collected at heat waves in 2015 and at control visits were included. Urinary [TIMP-2]·[IGFBP7] was compared between the heat waves and the control visits. Multivariate linear models were adjusted for age, frailty index, and functional comorbidity index. RESULTS: The median age was 82.0 years, 82.3% were women. The percentage of elevated levels of urinary [TIMP-2]·[IGFBP7] (>0.3 [ng/mL]2/1,000) in the total study population was higher at the heat waves than at the control visits (25.0% vs. 17.7%). The effect of the heat waves on urinary [TIMP-2]·[IGFBP7] was stronger in men than in women: The percentage of elevated levels was 75.0% in men and 14.3% in women. In the multivariate analysis, the mean urinary [TIMP-2]·[IGFBP7] was 0.48 (95% CI 0.25; 0.70) (ng/mL)2/1,000 higher in men than in women. Except gender, a number of additional variables did not show an association with urinary [TIMP-2]·[IGFBP7] at the heat waves or the control visits. CONCLUSIONS: At heat waves, urinary [TIMP-2]·[IGFBP7] was elevated and higher in men than in women. This suggests gender-specific differences in renal heat tolerance in older people.

Physician-guided, hybrid genetic testing exerts promising effects on health-related behavior without compromising quality of life.

Genetic risk analysis is increasingly in demand by participants. Hybrid genetic testing has the advantage over direct to consumer testing by involving a physician who guides the process and offers counseling after receiving the results. The objective of this study was to determine whether a structured physician moderated primary preventive, hybrid genetic risk assessment enhanced counseling program leads to improvement in lifestyle and does not impair quality of life. Risk genes for malignant, cardiovascular, coagulation, storage diseases and pharmacogenetics (> 100 genes) were tested. Screening, consultation and genetic counseling embedded in a primary/secondary prevention check-up program for executives of surrounding companies took place in a single center in Germany. Follow-up included established questionnaires for quality of life, nutrition and physical activity. Analysis included n = 244 participants. Median age at baseline was 49 years (interquartile range: 44-55), 93% were male, 3% (n = 7 of 136 responses) were smoker. Mean body mass index was 25.2 kg/m2. Follow-up response rate was 74% (n = 180), mean follow-up time was 6.8 months (standard deviation = 2.1). In 91 participants (37.8%, 91/241) at least one pathogenic variant was found, 60 thereof were clinically relevant (24.9%, 60/241). 238 participants (98%, 238/241) had > 1 pharmacogenetic variant, only 2 (0.8%, 2/241) took a correspondingly affected drug (56 participants took ≥ 1 drug/day). The energy expenditure significantly increased by ≈ 35% [median multiple of energy expenditure of 1.34 (confidence interval = 1.15-1.57, p < 0.001)] metabolic equivalents of task (MET)-min/week; participants spent on average 41 min (p < 0.001) less in sedentary activities per day and spent more time for lunch (≈ 2 additional minutes/day; p = 0.031). Indicators of the consumption of red meat and sweet pastries significantly decreased (both adjusted p = 0.049). Neither quality of life in general nor subgroup analysis of participants with at least one conspicuous genetic risk differed significantly over follow-up. Hybrid genetic testing and counseling exerted positive effects on health-related behavior and was not associated with major psychological adverse effects in the short-term follow-up. The approach seems to be feasible for use in preventive health care.

[Volume management: peri-operatively and peri-interventionally]. / Perioperatives und periinterventionelles Volumenmanagement.

Fluid therapy is one of the basic and most frequently performed medical therapies in everyday clinical practice. However, optimal volume management is a challenge: the application is simple, but the whole volume management is a complex process and physicians have to pay attention on underlying pathophysiology. Intravenous fluids should be prescribed like medications, i. e. the type of fluid and the amount must be adapted to each individual patient with his needs. Intravascular volume therapy is often used peri-operatively and peri-interventionally.Nowadays, crystalloid solutions are widely used and the standard is a balanced electrolyte solution. Only in selected situations 0,9 % sodium chloride solutions should be used, because they contain a high chloride concentration (154 mmol/l) and lead to increased risk of hyperchloremic metabolic acidosis.

Unravelling the pathophysiology of chronic kidney disease-associated pruritus.

For decades, itch related to chronic kidney disease (CKDaP) has been a clinical problem, but the aetiology and pathophysiology of CKDaP are still not yet fully understood-currently the underlying pathophysiological mechanisms are thought to be multifactorial. As new therapeutic targets have recently been identified and clinical trials have shown promising results, our current understanding of the interrelationships has expanded significantly. Here we review the pathophysiology and recent findings on modulation and sensitization of itch contributing to the development of CKDaP, covering hypothesis regarding immune system dysfunction, metabolic changes, uremic toxin deposition, peripheral neuropathy and imbalances in the endogenous opioid system.

[Infections-associated Glomerulonephritis]. / Infekt-assoziierte Glomerulonephritiden.

Glomerulonephritis, secondary to bacterial, or, more rarely, viral or parasitic infections, is called infection-associated. The epidemiology of infection-associated glomerulonephritis has changed in recent decades. For a long time, the classic form has been acute poststreptococcal glomerulonephritis (APGN), but in developed countries its incidence has declined sharply. However, there is an increase in staphylococcal associated glomerulonephritis (SAGN). The clinical manifestations of APGN and SAGN are different: APGN typically presents with a glomerulonephritis after an infectious latency period (post-infectious), while SAGN typically shows an immune complex glomerulonephritis concomitant with infection (para-infectious). SAGN often presents with an occult infections in older patients with multiple comorbidities.

Strong Associations Between Inflammation, Pruritus and Mental Health in Dialysis Patients.

Pruritus, impaired mental health and inflammation contribute to morbidity in end-stage renal disease. There are no studies on all 3 conditions. We therefore obtained inflammatory parameter data (C-reactive protein and interleukin-6), pruritus data and psychological test data (36-Item Short-Form Health Survey, "Allgemeine Depressionsskala" and Toronto Alexithymia Scale-20) for 19 dialysis patients with pruritus, 20 dialysis patients without pruritus and 15 healthy controls. Non-parametric hierarchical clustering revealed 3 clusters of parameters: one mainly driven by pruritus scores (chronic kidney disease-associated pruritus cluster), one by mental health scores (mental health cluster) and one by inflammatory parameters (inflammatory cluster). Factor analysis showed strong associations (mental health cluster/chronic kidney disease-associated pruritus cluster, r=-0.49; mental health cluster/inflammatory cluster, r=-0.52; inflammatory cluster/chronic kidney disease-associated pruritus cluster, r=0.48). For the first time, complete correlations between inflammation, mental health and pruritus in dialysis patients have been established. As all 3 conditions are associated with mortality, knowledge about their interdependence helps to understand end-stage renal disease pathophysiology.

Urinary [TIMP-2]·[IGFBP7]-guided randomized controlled intervention trial to prevent acute kidney injury in the emergency department.

BACKGROUND: Early detection and prevention of acute kidney injury (AKI) is important to reduce morbidity and mortality. Discovery of early-detection biomarkers has enabled early preventive approaches. There are no data on early biomarker-guided intervention with nephrological consultation in emergency departments (EDs). METHODS: In this prospective randomized controlled intervention trial, patients at high risk for AKI were screened with urinary [TIMP-2]·[IGFBP7] in the ED of Robert-Bosch-Hospital (Stuttgart, Germany). We screened 257 eligible patients of whom 100 met the inclusion criteria, with urinary [TIMP-2]·[IGFBP7] >0.3, and were included. The intervention group received immediate one-time nephrological consultation after randomization, implementing Kidney Disease: Improving Global Outcomes (KDIGO) 2012 recommendations on AKI. The primary outcome was the incidence of moderate to severe AKI within the first day after admission. Secondary outcomes were AKI occurrence within 3 days after admission, need for renal replacement therapy (RRT), length of hospital stay and death. RESULTS: The primary outcome did not differ significantly (P = 0.9) between the groups, neither within the first day nor within the first 3 days after admission. The intervention group had significantly (P < 0.05) lower serum creatinine (SCr) on Day 2 and lower maximum SCr and tended (P = 0.08) to have higher urine output (UOP) at Day 3 than the non-intervention group. No patient in the intervention group needed RRT (0 versus 3) during the hospital stay (P = 0.09). CONCLUSIONS: One-time routine nephrologist-guided application of the KDIGO bundle in ED patients with a risk for AKI cannot currently be recommended. However, due to the uniform trend of study endpoints in favour of intervention, further trials to investigate larger cohorts of more severely ill patients are warranted. TRIAL REGISTRATION: www.ClinicalTrials.gov, study number NCT02730637.

[Urine Examination - Step by Step]. / Urinuntersuchung ­ Schritt für Schritt.

The examination of the urine is the oldest and a very basic technique for every nephrologist. It helps to detect, diagnose and classify diseases of the kidneys and the urinary tract. Proteinuria is an important sign of kidney disease and an own factor in the pathophysiology of renal progression. Acanthocytes in the urine (> 5 %) have a high specifity (98 - 100 %) for diagnosing a glomerular hematuria.

Impact of an in-Hospital Patient Education Program on Choice of Renal Replacement Modality in Unplanned Dialysis Initiation.

BACKGROUND/AIMS: Up to 50% patients requiring dialysis receive an urgent, unplanned start (UPS) to renal replacement therapy (RRT). Most of these are initiated with an intravenous catheter and commenced and maintained on hemodialysis (HD). Although peritoneal dialysis (PD) could be an equipotent initial modality for RRT, it is used less frequently as long-term RRT in UPS patients. This multicenter-study aimed to evaluate the impact of a structured, in-hospital education program and factors influencing PD rates, especially in UPS patients. METHODS: Three German nephrology departments collaborated to implement an in-hospital education program. Retrospective analysis included 336 subjects and compared the rates of HD and PD in consecutive patients who started RRT 12 months prior (two centers) and for 12 months after (three centers) implementing the education program. RESULTS: PD rates increased significantly (p < 0.05) by 66% in all planned and unplanned dialysis starts after implementation of a structured, patient-centered education program. A highly significant (p < 0.0001) rise in utilization of PD was found, especially in UPS patients. In logistic regression analysis, PD modality choice was significantly influenced by age (p < 0.0001) and gender (p = 0.006). CONCLUSIONS: A structured, patient-centered in-hospital education program increases the frequency of PD in patients needing unplanned RRT. PD modality choice is significantly higher in young (p < 0.0001) and male (p = 0.006) patients.

Urinary TIMP2⋠IGFBP7 for the prediction of platinum-induced acute renal injury.

INTRODUCTION: Platinum-based chemotherapy (PBC) is a potent antineoplastic treatment, but cisplatin nephrotoxicity is often the limiting factor. Identifying the patients who are at risk for developing platinum-induced renal injury is an important issue. We tested urinary TIMP2·IGFBP7, a new US Food and Drug Administration (FDA)-cleared test to assess the risk of acute kidney injury (AKI), in a cohort of patients with malignant neoplastic disease receiving PBC. PATIENTS AND METHODS: A total of 58 patients with malignant neoplastic disease were enrolled in this study, of whom 32 patients had both urine samples and subsequent serum creatinine values available for detecting AKI within 72 hours. Urine samples were collected within 6 hours prior to PBC application and within 12 hours after the end of chemotherapy administration. We examined the predictive ability of TIMP2·IGFBP7 for the development of AKI as defined by KDIGO (Kidney Disease: Improving Global Outcomes) criteria within 72 hours after the administration of chemotherapy. Operating characteristics were determined for the previously validated TIMP2·IGFBP7 cutoff of 0.3 (ng/mL)2/1000. RESULTS: Four (12.5%) patients developed AKI within 72 hours. Primary disease was lymphoma in 13 patients (40.6%) and solid tumors in 19 patients (59.4%). Eight patients (25.0%) received carboplatin and 24 (75.0%) cisplatin. TIMP2·IGFBP7 after PBC administration discriminated for the risk of AKI with an area under the receiver operating characteristic curve (AUC; 95% confidence interval) of 0.92 (0.80-1.00). At the cutoff of 0.3 for TIMP2·IGFBP7, sensitivity was 50%, specificity was 87%, negative predictive value was 95% and positive predictive value was 25% for the prediction of AKI within 72 hours. CONCLUSION: Urinary TIMP2·IGFBP7 measured in specimens gathered after PBC may be a useful tool to early identify patients who are at risk for developing platinum-induced AKI.

Renal effects of metallothionein induction by zinc in vitro and in vivo.

BACKGROUND: Metallothionein (MTT) is an endogenous antioxidant that can be induced by both zinc (Zn) and ischemia. In kidneys, increased MTT expression exerts a putative protective role in diabetes and hypoxia. Our goal was to further investigate the behavior of MTT under the influence of Zn and hypoxia in vitro and in vivo. METHODS: MTT expression was measured in vitro in cell cultures of proximal tubular cells (LCC-PK1) by immune-histochemistry and real-time PCR after incubation with increasing concentrations of Zn under hypoxic and non-hypoxic conditions. In addition, in vivo studies were carried out in 54 patients to study MTT induction through Zn. This is a sub-study of a prospective, randomized, double-blind trial on prevention of contrast-media-induced nephropathy using Placebo, Zn and N-Acetylcysteine. Blood samples were obtained before and after 2 days p.o. treatment with or without Zn (60 mg). ELISA-based MTT level measurements were done to evaluate the effects of Zn administration. For in vivo analysis, we considered the ratio of MTT to baseline MTT (MTT1/MTT0) and the ratio of eGFR (eGFR1/eGFR0), correspondingly. RESULTS: In vitro quantitative immuno-histochemical analysis (IHC) and real-time PCR showed that at increasing levels of Zn (5, 10, and 15 µg/ml) led to a progressive increase of MTTs: Median (IQR) expression of IHC also increased progressively from 0.10 (0.09-0.12), 0.15 (0.12-0.18), 0.25 (0.25-0.27), 0.59 (0.48-0.70) (p < 0.0001). Median (IQR) expression of PCR: 0.59 (0.51-1.72), 1.62 (1.38-4.70), 3.58 (3.06-10.42) and 10.81 (9.24-31.47) (p < 0.0001). In contrast, hypoxia did not change MTT-levels in vitro (p > 0.05). In vivo no significant differences (p = 0.96) occurred in MTT-levels after 2 days of Zn administration compared with no Zn intake. Nevertheless, there was a significant correlation between MTT (MTT1/MTT0) and eGFR (eGFR1/eGFR0) in case of Zn administration (rho = -0.49; 95%-CI: -0.78 to -0.03; p = 0.04). CONCLUSIONS: We found that Zn did induce MTTs in vitro, whereas hypoxia had no significant impact. In contrast, no significant increase of MTTs was detected after in vivo administration of Zn. However, there was a significant negative correlation between MTT and eGFR in vivo in case of Zn administration, this could indicate a protective role of MTTs in a setting of reduced kidney function, which is possibly influenced by Zn. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00399256 . Retrospectively registered 11/13/2006.

Urinary [TIMP-2] × [IGFBP7] for risk prediction of acute kidney injury in decompensated heart failure.

BACKGROUND: In acute decompensated heart failure (ADHF) the risk of acute kidney injury (AKI) is high. Early detection of patients at risk for AKI is important. We tested urinary [TIMP-2] × [IGFBP7], a new US Food and Drug Administration-cleared test to assess AKI risk, in a cohort of hospitalized ADHF patients. HYPOTHESIS: In patients with ADHF, urinary [TIMP-2] × [IGFBP7] is associated with moderate to severe AKI and related to increased mortality. METHODS: We enrolled 400 patients in the emergency department at Robert-Bosch Hospital, Stuttgart, Germany. We examined the predictive ability of urinary [TIMP-2] × [IGFBP7] (units: [ng/mL]2 /1000) for development of AKI stage 2 or 3 within 24 hours of sample collection in patients with ADHF. Operating characteristics were determined for the validated cutoffs of 0.3 and 2.0. RESULTS: Forty patients had ADHF upon presentation and sufficient data for AKI staging. 27.5% developed AKI stage 2-3 within 7 days. Urinary [TIMP-2] × [IGFBP7] discriminated for AKI stage 2-3 over the first day with an area under the ROC curve of 0.84 (95% confidence interval: 0.72-0.93) and over 7 days with an AUC of 0.77 (95% confidence interval: 0.65-0.88). For the first day, sensitivity was 86% at the 0.3 cutoff and specificity was 95% at the 2.0 cutoff for prediction of AKI stage 2-3. There was a trend (P = 0.08) for higher mortality in patients with urinary [TIMP-2] × [IGFBP7] >2.0 and AKI 2-3. CONCLUSIONS: Urinary [TIMP-2] × [IGFBP7] is a promising marker for AKI risk assessment in patients with ADHF.

[Disorders of the acid-base balance and the anion gap]. / Störungen des Säure-Basen-Haushaltes und der Anionenlücke.

The regulation of the acid-base balance and pH is critical for the organism. The most important buffer system is CO2 / HCO3-. The kidney controls systemic bicarbonate and therefore the metabolic regulation and the lung is relevant for respiratory regulation by an effective CO2 elimination. There are four acid-base disorders with two metabolic and two respiratory disorders (acidosis and alkalosis). The anion gap enables a further workup of metabolic acidosis.

The Influence of Thyroid Function, Inflammation, and Obesity on Risk Prediction of Acute Kidney Injury by Cystatin C in the Emergency Department.

BACKGROUND/AIMS: There is a growing role for emergency departments (ED) in assessing acute kidney injury (AKI) for hospital admissions but there are few studies addressing acute kidney injury biomarkers and confounding factors in the ED. Cystatin C (CysC), a newer renal biomarker, is influenced by thyroid function, inflammation and obesity. This study aims to be the first study to address the impact of these parameters in the ED. METHODS: Admitted patients (n=397) were enrolled in the ED at Robert-Bosch-Hospital, Stuttgart, Germany. Daily serum creatinine (sCr) was recorded for AKI classification by Kidney Diseases Improves Global Outcome (KDIGO) criteria. CysC, thyroid stimulating hormone (TSH), thyroxine (T4), C-reactive protein (CRP) and body mass index (BMI) were registered at enrollment in the ED. Serum samples were collected at enrollment, after 6 hours and in the following mornings (day 1 to day 3). The correlation of CysC and sCr was studied on a two variable logistic regression model. A linear predictor was computed to predict minimal AKI stage and area under the curve (AUC) was calculated. RESULTS: Of 397 patients enrolled for classification by KDIGO AKI criteria, n=152 (38%) developed AKI, n=69 (17.4%) reached AKI stage I, n=70 (17.6%) AKI stage II, and n=13 (3%) AKI stage III. Although a correlation between CRP and CysC levels was shown (rho=0.376), this didn't affect the predictive ability for AKI according to our data. We compared receiver operating characteristic (ROC) curves (DeLong test) of CysC to ROC curves of CysC with the additional variables TSH, BMI, and CRP respectively. Our data shows that addition of CRP, TSH, or BMI does not improve prediction of AKI stage beyond prediction based solely on CysC levels. CONCLUSIONS: CysC is known to be influenced by thyroid function, inflammation and obesity, but in our large ED population there was no significant impact of these factors on the diagnostic accuracy of CysC to detect AKI in ED patients.

Urinary [TIMP-2]·[IGFBP7] - Novel Biomarkers to Predict Acute Kidney Injury.

BACKGROUND: Urine microscopy is an established technique to assess kidney disease, and can add valuable information about the mechanism of damage. However, it requires the time and expertise of an experienced nephrologist and, therefore, is typically used for a limited number of patients in practice. A rapid biomarker test that identifies patients from the emergency department (ED) who are likely to have positive urine microscopy findings would enable more efficient use of this technique. METHODS: Four hundred patients were enrolled in the ED; thereof 362 patients had available both tissue inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein 7 [TIMP-2]·[IGFBP7] and urine score (U-Score) data at enrollment. U-Score was assessed through urine microscopy as described previously. RESULTS: Fifteen (4%) of 362 patients had a U-Score >0. When patients were stratified into 3 groups using the validated [TIMP-2]·[IGFBP7] cutoffs of 0.3 and 2.0, the proportion of patients with a positive U-Score increased across the 3 strata from 1 to 6 to 24% (p < 0.001). At the 0.3 cutoff, [TIMP-2]·[IGFBP7] had a sensitivity of 87%, specificity of 62% and negative predictive value (NPV) of 99% for prediction of a positive U-Score. At the 2.0 cutoff, specificity increased to 95% and positive predictive value (PPV) increased to 24%. CONCLUSIONS: In ED patients, urinary [TIMP-2]·[IGFBP7] had a high NPV (99%) for ruling out a positive U-Score using the 0.3 cutoff and had a PPV of 24% (6-fold greater than the pre-test probability) using the 2.0 cutoff. As such, urinary [TIMP-2]·[IGFBP7] may enable more effective use of urine microscopy in these patients and thereby save time and personnel resources. SUMMARY: Urine microscopy is an established technique to assess acute kidney injury and can add valuable information about the mechanism of damage; however it requires the time and expertise of an experienced nephrologist and, therefore, is typically used for a limited number of patients in clinical practice. We have shown in ED patients, urinary [TIMP-2]·[IGFBP7] had a high NPV (99%) for ruling out a positive U-Score using the 0.3 cutoff and had a PPV of 24% (6-fold greater than the pre-test probability) using the 2.0 cutoff. As such, urinary [TIMP-2]·[IGFBP7] may enable more effective use of urine microscopy in these patients and thereby save time and personnel resources.

Association of Renal Stress/Damage and Filtration Biomarkers with Subsequent AKI during Hospitalization among Patients Presenting to the Emergency Department.

BACKGROUND AND OBJECTIVES: Emergency departments (EDs) have a growing role in hospital admissions, but few studies address AKI biomarkers in the ED. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients admitted to the internal medicine service were enrolled during initial workup in the ED at Robert-Bosch-Hospital, Stuttgart, Germany. Daily serum creatinine (sCr) and urine output (UO) were recorded for AKI classification by Kidney Disease Improving Global Outcomes (KDIGO) criteria. Cystatin C, kidney injury molecule-1, liver-type fatty acid-binding protein, and neutrophil gelatinase-associated lipocalin were measured in blood and urine, and IL-18, insulin-like growth factor-binding protein 7 (IGFBP7), tissue inhibitor of metalloproteinases-2 (TIMP-2) and [TIMP-2]⋅[IGFBP7] were measured in urine collected at enrollment, after 6 hours, and the following morning. Association between these biomarkers and the end point of moderate-severe AKI (KDIGO stage 2-3) occurring within 12 hours of each sample collection was examined using generalized estimating equation logistic regression. Performance for prediction of the AKI end point using two previously validated [TIMP-2]-[IGFBP7] cutoffs was also tested. RESULTS: Of 400 enrolled patients, 298 had sufficient sCr and UO data for classification by KDIGO AKI criteria: AKI stage 2 developed in 37 patients and AKI stage 3 in nine patients. All urinary biomarkers, sCr, and plasma cystatin C had statistically significant (P<0.05) odds ratios (ORs) for the AKI end point. In a multivariable model of the urine biomarkers and sCr, only [TIMP-2]⋅[IGFBP7] and sCr had statistically significant ORs. Compared with [TIMP-2]⋅[IGFBP7]<0.3 (ng/ml)(2)/1000, values between 0.3 and 2.0 (ng/ml)(2)/1000 indicated 2.5 (95% confidence interval [95% CI], 1.1 to 5.2) times the odds for the AKI end point and values >2.0 (ng/ml)(2)/1000 indicated 11.0 (95% CI, 4.4 to 26.9) times the odds. Addition of [TIMP-2]⋅[IGFBP7] to a clinical model significantly improved area under the receiver-operating characteristic curve from 0.67 (95% CI, 0.61 to 0.78) to 0.77 (95% CI, 0.72 to 0.86) (P<0.001); however, including both markers in the model was not significantly different from including either marker alone. CONCLUSIONS: Urinary [TIMP-2]⋅[IGFBP7] with pre-established cutoffs provides valuable information about risk for imminent AKI in the ED that is complementary to sCr and clinical risk factors.