Cystatin C and creatinine-based eGFR levels and their correlation to long-term morbidity and mortality in older adults.

BACKGROUND: The prevailing diagnostic criteria for CKD are age-independent, but have been challenged in light of the eGFR decline associated with normal aging. The stages of CKD communicate magnitude of risk of ESRD, cardiovascular morbidity, and mortality. AIMS: This study aims to provide more insight into the morbidity and mortality associated with eGFR levels corresponding to the current CKD stages in older adults. METHODS: The 2931 older adults in the Good Aging in Skåne study were randomized from the general population. The exposure variable used was eGFR level (CKD-EPI based on creatinine and cystatin C) with eGFR 60-89 mL/min/1.73 m2 as a reference; the outcomes were mortality, acute cardiovascular disease, congestive heart failure, and rapid kidney function decline (RKFD; defined as a decline in eGFR by 3 mL/min/1.73 m2 per year or more). RESULTS: The mean age at baseline was 73 (SD 11) and mean follow-up time 11 (SD 5) years. Mortality was higher at lower eGFR levels with adjusted HR (95% CI) being 1.58 (1.34-1.88), 1.22 (1.05-1.41), 1 (reference), and 0.90 (0.67-1.21) for eGFR < 45, 45-59, 60-89 and ≥ 90 mL/min/1.73 m2, respectively. For acute CVD the adjusted HR (95% CI) were 1.23 (0.81-1.87), 1.21 (0.87-1.69), 1 (reference), and 0.53 (0.28-1.00) for the same eGFR levels. CONCLUSIONS: This study confirms that mortality in older adults increases with decreasing eGFR at eGFR levels below today's threshold for CKD. The correlation was less certain for lower eGFR and incident cardiovascular disease.

Prevalence and determinants of differences in cystatin C and creatinine-based estimated glomerular filtration rate in community-dwelling older adults: a cross-sectional study.

BACKGROUND: Differences in cystatin C and creatinine-based estimated glomerular filtration rate (eGFR) can lead to clinical uncertainty. Existing eGFR equations perform poorly in a subset of individuals. This study aims to describe the prevalence of differences between cystatin C-based (eGFRcys) and creatinine-based (eGFRcreat) eGFR in older adults and to explore which subsets of individuals may be most affected by differing estimations. METHODS: In this cross-sectional study, participants from a cohort of community-dwelling older adults were examined at a baseline visit in 2001-2004 as part of the larger "Good Aging in Skåne" study. Exposure variables were obtained from questionnaires, interviews, examinations, and medical records. Blood samples were taken during the baseline visit, cryopreserved, and analyzed at a later time for biomarkers. The CKD-EPI equations were used to estimate GFR. Initial descriptive analyses were performed on 2931 individuals. A total of 2532 participants were included in the final multiple linear regression. RESULTS: Nearly two-thirds of participants had eGFR differences exceeding 10%, with nearly 20 % of participants having eGFR differences exceeding 30%. Smoking, age, body mass index (BMI), C-reactive protein (CRP), glucocorticoid use, and mean eGFR were correlated with differences between eGFRcreat and eGFRcys. CONCLUSIONS: Differences between eGFRcreat and eGFRcys are common and often of large magnitude in this community-dwelling population of older adults. The finding of multiple non-GFR determinants correlated to differences in GFR estimations can help direct future research to improve eGFR equations for subgroups prone to conflicting GFR estimations or to guide choice of biomarker for GFR estimation in these subgroups.

Male sex and vascular risk factors affect cystatin C-derived renal function in older people without diabetes or overt vascular disease.

BACKGROUND/OBJECTIVES: to explore the effect of ageing on renal function with cystatin C as the marker of glomerular filtration rate (GFR) in the general population without vascular disease or diabetes. DESIGN: a cross-sectional analysis of a healthy subset from the Good Aging in Skåne-cohort study representative of the Swedish general population. SUBJECTS: 1252 participants without vascular disease and diabetes (43.9% men) of whom 203 were over 80 years old were included from the original cohort of 2931. METHODS: plasma cystatin C and plasma creatinine were used as markers for GFR. Estimated GFR (eGFR) was calculated with three chronic kidney disease epidemiology collaboration (CKD-EPI) formulas involving cystatin C, creatinine or both. RESULTS: the median for plasma cystatin C was 0.93 mg/l (60-69 years old), 1.04 (70-79 years old) and 1.24 (80+ years old). The difference in mg/l between the 5th and 95th percentile was 0.46, 0.62 and 0.90 for these age groups. Male sex increased the age effect on plasma cystatin C levels with 0.004 mg/l/year (P = 0.03), adjusted for vascular risk factors. Smoking, lower HDL and higher diastolic blood pressure were associated with higher cystatin C levels. 54.7% (CKD-EPI creatinine) to 73.9% (CKD-EPI cystatin C) of the 80+ had an eGFR < 60 ml/min/1.73 m2. CONCLUSION: non-diabetics without overt vascular disease exhibit an age related but heterogeneous decline in renal function. The ageing effect is more pronounced in men. At least half of healthy 80+ years old could be expected to have at least CKD Stage 3 with eGFR < 60 ml/min/1.73 m2.

In vitro Analysis of the Intradiscal Pressure of the Thoracic Spine.

The hydrostatic pressure of the nucleus pulposus represents an important parameter in the characterization of spinal biomechanics, affecting the segmental stability as well as the stress distribution across the anulus fibrosus and the endplates. For the development of experimental setups and the validation of numerical models of the spine, intradiscal pressure (IDP) values under defined boundary conditions are therefore essential. Due to the lack of data regarding the thoracic spine, the purpose of this in vitro study was to quantify the IDP of human thoracic spinal motion segments under pure moment loading. Thirty fresh-frozen functional spinal units from 19 donors, aged between 43 and 75 years, including all segmental levels from T1-T2 to T11-T12, were loaded up to 7.5 Nm in flexion/extension, lateral bending, and axial rotation. During loading, the IDP was measured using a flexible sensor tube, which was inserted into the nucleus pulposus under x-ray control. Pressure values were evaluated from third full loading cycles at 0.0, 2.5, 5.0, and 7.5 Nm in each motion direction. Highest IDP increase was found in flexion, being significantly (p < 0.05) increased compared to extension IDP. Median pressure values were lowest in lateral bending while exhibiting a large variation range. Flexion IDP was significantly increased in the upper compared to the mid- and lower thoracic spine, whereas extension IDP was significantly higher in the lower compared to the upper thoracic spine, both showing significant (p < 0.01) linear correlation with the segmental level at 7.5 Nm (flexion: r = -0.629, extension: r = 0.500). No significant effects of sex or age were detected, however trends toward higher IDP in specimens from female donors and decreasing IDP with increasing age, potentially caused by fibrotic degenerative changes in the nucleus pulposus tissue. Sagittal and transversal cuttings after testing revealed possible relationships between nucleus pulposus quality and pressure moment characteristics, overall leading to low or negative intrinsic IDP and non-linear pressure-moment behavior in case of fibrotic tissue alterations. In conclusion, this study provides insights into thoracic spinal IDP and offers a large dataset for the validation of numerical models of the thoracic spine.

[Structured Career Pathways in the University Medicine - From Promotion to Clinician Scientist Programs]. / Strukturierte Karrierewege in der Universitätsmedizin.

Scientifically active medical doctors are required for successful translation of novel basic findings into the clinic. However, there is an increasing tendency of young medical doctors to primarily follow a more clinically and not scientifically orientated career pathway. Therefore, the establishment of novel career education structures and career perspectives in university medicine are important to stop this development. Here, we will discuss the current situation and ongoing attempts to design novel structural programs that allow a better combination of clinical and scientific work by highlighting also current developments at the Faculty of Medicine at the University of Freiburg.

In vitro analysis of the segmental flexibility of the thoracic spine.

Basic knowledge about the thoracic spinal flexibility is limited and to the authors' knowledge, no in vitro studies have examined the flexibility of every thoracic spinal segment under standardized experimental conditions using pure moments. In our in vitro study, 68 human thoracic functional spinal units including the costovertebral joints (at least n = 6 functional spinal units per segment from T1-T2 to T11-T12) were loaded with pure moments of ±7.5 Nm in flexion/extension, lateral bending, and axial rotation in a custom-built spine tester to analyze range of motion (ROM) and neutral zone (NZ). ROM and NZ showed symmetric motion behavior in all loading planes. In each loading direction, the segment T1-T2 exhibited the highest ROM. In flexion/extension, the whole thoracic region, with exception of T1-T2 (14°), had an average ROM between 6° and 8°. In lateral bending, the upper thoracic region (T1-T7) was, with an average ROM between 10° and 12°, more flexible than the lower thoracic region (T7-T12) with an average ROM between 8° and 9°. In axial rotation, the thoracic region offered the highest overall flexibility with an average ROM between 10° and 12° in the upper and middle thoracic spine (T1-T10) and between 7° and 8° in the lower thoracic spine (T10-T12), while a trend of continuous decrease of ROM could be observed in the lower thoracic region (T7-T12). Comparing these ROM values with those in literature, they agree that ROM is lowest in flexion/extension and highest in axial rotation, as well as decreasing in the lower segments in axial rotation. Differences were found in flexion/extension and lateral bending in the lower segments, where, in contrast to the literature, no increase of the ROM from superior to inferior segments was found. The data of this in vitro study could be used for the validation of numerical models and the design of further in vitro studies of the thoracic spine without the rib cage, the verification of animal models, as well as the interpretation of already published human in vitro data.

Combining Cystatin C and Creatinine Yields a Reliable Glomerular Filtration Rate Estimation in Older Adults in Contrast to ß-Trace Protein and ß2-Microglobulin.

BACKGROUND: The glomerular filtration rate (GFR) is the most important measure of kidney function and chronic kidney disease (CKD). This study aims to validate commonly used equations for estimated GFR (eGFR) based on creatinine (cr), cystatin C (cys), ß-trace protein (BTP), and ß2-microglobulin (B2M) in older adults. METHOD: We conducted a validation study with 126 participants aged between 72 and 98 with a mean measured GFR (mGFR) by iohexol clearance of 54 mL/min/1.73 m2. The eGFR equations (CKD-Epidemiology collaboration [CKD-EPI], Berlin Initiative Study [BIS], Full Age Spectrum [FAS], Modification of Diet in Renal Disease [MDRD]cr, Caucasian-Asian-Pediatric-Adult [CAPA]cys, Lund-Malmö Revised [LM-REV]cr, and MEAN-LM-CAPAcr-cys), were assessed in terms of bias (median difference: eGFR-mGFR), precision (interquartile range of the differences), and accuracy (P30: percentage of estimates ±30% of mGFR). The equations were compared to a benchmark equation: CKD-EPIcr-cys. RESULTS: All cystatin C-based equations underestimated the GFR compared to mGFR, whereas bias was mixed for the equations based only on creatinine. Accuracy was the highest for CKD-EPIcr-cys (98%) and lowest for MDRD (82%). Below mGFR 45 mL/min/1.73 m2 only equations incorporating cystatin C reached P30 accuracy >90%. CKD-EPIcr-cys was not significantly more accurate than the other cystatin C-based equations. In contrast, CKD-EPIcr-cys was significantly more accurate than all creatinine-based equations except LM-REVcr. CONCLUSION: This study confirms that it is reasonable to use equations incorporating cystatin C and creatinine in older patients across a wide spectrum of GFR. However, the results call into question the use of creatinine alone below mGFR 45 mL/min/1.73 m2. B2M and BTP do not demonstrate additional value in eGFR determination in older adults.

[Stem cell network North Rhine-Westphalia]. / Kompetenznetzwerk Stammzellforschung NRW.

The Stem Cell Network NRW is an initiative of the North Rhine Westphalian Ministry of Science and Research. A statewide organization involving research facilities in Aachen, Bielefeld, Bochum, Bonn, Cologne, Düsseldorf, Essen and Münster, it covers virtually the whole spectrum of scientific issues in the field of adult and embryonic stem cell research. The Network consists of two working groups. One focuses on biomedical, the other on ethical, legal and sociological issues. In these groups, top scientists, doctors, philosophers, theologians, sociologists and legal experts combine their expertise with a view to making stem cell research responsible and transparent. The Stem Cell Network NRW is a model example of the North Rhine Westphalian government's strategy of identifying, promoting and creating a common platform for the research disciplines of the future--for the benefit of science, business and above all society at large.

Thiel-fixation preserves the non-linear load-deformation characteristic of spinal motion segments, but increases their flexibility.

Human cadaveric specimens are recommended as the best option for in-vitro tests. However, fresh human spine specimens are often difficult to obtain. Further problems are the potential risk of infection and they can only be used over a limited test period. Therefore, the use of embalmed specimens is often discussed. The most common method is formalin fixation. However, this type of embalming can result in failure, because the biomechanical properties of the tissue is partially influenced. In recent years the development of the new method, the fixation according to Thiel, could provide an alternative to fresh or formalin-fixed specimens. The aim of the present study is to compare the biomechanical properties between fresh and Thiel-fixed spine specimens, and to compare the data to previous data of a test with formalin fixation. For the study, six L1-L2 spinal segments from 16-week-old calves were biomechanically tested. The parameters, range of motion and neutral zone, were determined in flexion/extension, right/left lateral bending and left/right axial rotation. The results showed that the specimens kept their non-linear load-deformation-characteristic after Thiel fixation. The range of motion of Thiel-fixed specimens increased relative to the unembalmed state by approximately 22% in flexion-extension, 23% in lateral bending (p<0.05) and 45% in axial rotation (p<0.05). In conclusion, the results still suggest a preference for fresh cadaveric spine specimens for quantitative biomechanical in-vitro testing, because they provide the best physiological conditions. However, for preliminary tests, which may only be used for orientation, embalmed specimens using the Thiel fixation method might serve as an alternative. Compared to formalin-fixated specimens which become approximately 5 times stiffer and completely lose their non-linear load-deformation-characteristic, as found in a previous study; the Thiel fixation maintains the non-linear load-deformation-characteristic but increases the range of motion.

Fracture models in the lumbar sheep spine: a biomechanical investigation.

The purpose of this study was to find out if a limited resection of the cranial vertebral body leaving the posterior wall intact is a sufficient model for AO type 3 fractures, or if additional resection of the posterior wall is necessary. In six, fresh-frozen, lumbar sheep spine specimens, the segmental stability was tested in three motion planes in a spine tester. First, the intact specimens were tested. Then, partial resection of the intervertebral disc L3/4 and resection of the cranial vertebral body of L4 was performed, leaving the posterior wall intact. This defect was tested without instrumentation and with a ventral monosegmental interlocking plate mounted. Then, the defect was extended to a total cranial resection, including the posterior wall, and the tests were subsequently repeated. The stability of both types of defects under the different conditions was compared. Without instrumentation, the total cranial resection showed significantly more ROM in flexion/extension and axial rotation than partial cranial resection. With the ventral interlocking plate mounted, the instability in total cranial resection was significantly higher in flexion/extension, with the relative relation even being increased. In axial rotation and lateral bending, the differences were equalized by the mounted plate. From a biomechanical point of view, total cranial resection including the posterior wall should be preferred as a sheep spine fracture model for AO type 3 fractures.

Validity and interobserver agreement of a new radiographic grading system for intervertebral disc degeneration: Part I. Lumbar spine.

Many different radiographic grading systems for disc degeneration are described in literature. However, only a few of them are tested for interobserver agreement and none for validity. Furthermore, most of them are based on a subjective terminology. The aim of this study, therefore, is to combine these systems to a new one in which all subjective terms are replaced by more objective ones and to test this new system for validity and interobserver agreement. Since lumbar and cervical discs need to be graded differently, this study was divided into the present Part I for the lumbar and a Part II for the cervical spine. The new radiographic grading system covers the three variables "Height Loss", "Osteophyte Formation" and "Diffuse Sclerosis". On lateral and postero-anterior radiographs, each of these three variables first has to be graded individually. Then, the "Overall Degree of Degeneration" is assigned on a four-point scale from 0 (no degeneration) to 3 (severe degeneration). For validation, the radiographic degrees of degeneration of 44 lumbar discs were compared to the respective macroscopic ones, which were defined as "real" degrees of degeneration. The agreement between observers with different levels of experience was determined using the radiographs of 84 lumbar discs. Agreement was quantified using quadratic weighted Kappa coefficients (Kappa) with 95% confidence limits (95% CL). The validation of the new radiographic grading system revealed a substantial agreement between the radiographic and the "real" macroscopic overall degree of degeneration (Kappa=0.714, 95% CL: 0.587-0.841). The radiographic grades, however, tended to be slightly lower than the "real" ones. The interobserver agreement was substantial for all the three variables and for the overall degree of degeneration (Kappa=0.787, 95% CL: 0.702-0.872). However, the inexperienced observer tended to assign slightly lower degrees of degeneration than the experienced one. In conclusion, we believe that the new radiographic grading system is an almost objective, valid and reliable tool to quantify the degree of degeneration of individual lumbar intervertebral discs. However, the user should always remember that the "real" degree of degeneration tends to be underestimated and that slight differences between the ratings of observers with different levels of experience have to be expected.

Biomechanical evaluation of a new total posterior-element replacement system.

STUDY DESIGN: In vitro study to characterize the flexibility of a new total posterior-element system when instrumented to L4-L5 segments. OBJECTIVE: The goal of this in vitro study was to investigate whether an optimized version of the TOPS implant (Impliant Ltd., Ramat Poleg, Israel) is capable to restore the physiologic motion characteristic of a spinal segment after facetectomy. SUMMARY OF BACKGROUND DATA: The TOPS implant is designed to replace the posterior elements of a functional spinal unit, to provide flexible restabilization and spinal alignment, while maintaining the intervertebral disc. The implant is composed of bilateral pedicle screws, connected with 2 crossbars in the transversal plane. The crossbars are joined together by an elastic element capable of transmitting tensile and compressive loads, as well as shear forces. METHODS: Six human cadaver specimens (L3-S1) (median age 61 years: minimum 47 and maximum 74 years) were used for this in vitro experiment. The specimens were loaded with pure moments of +/-7.5 Nm in flexion/extension, lateral bending, and axial rotation. The following states were investigated: (1) intact; (2) after bilateral laminectomy, including facetectomy of the lower facet joints, of the upper vertebra L4; and (3) after device implantation. The range of motion (ROM), neutral zone, and intradiscal pressure were determined from a third cycle. In a second step, the ROM in axial rotation was determined as a function of different flexion/extension postures. RESULTS: In the neutral position, the laminectomy and facetectomy increased the median values of the ROM in flexion plus extension, lateral bending right plus left, and significantly in axial rotation left plus right from: 8.2 degrees, 7.6 degrees, 3.6 degrees to 12.1 degrees, 8.5 degrees, and 8.5 degrees (Wilcoxon signed rank test; P < 0.05). After fixation of the implant, the ROM was again reduced to 6.8 degrees, 7.8 degrees, and 3.8 degrees. In a flexed posture, the ROM in axial rotation was slightly increased compared to the neutral position. With increasing extension, the axial rotation decreased linearly from 3.7 degrees in neutral position to 2.3 degrees in 4 degrees extension in the segment L4-L5. The characteristic of the intradiscal pressure versus load with the implant was similar to that of the intact specimen. CONCLUSION: The TOPS implant almost ideally restored the ROM in lateral bending and axial rotation compared to that of the intact specimen. In the sagittal plane, 85% of the intact ROM could be obtained. The ROM in axial rotation as a function of flexion and extension angle also mimics the biomechanical behavior of the posterior complex of a lumbar spine. This relationship between ROM and posture emphasizes the importance of a proper implantation.

Validity and interobserver agreement of a new radiographic grading system for intervertebral disc degeneration: Part II. Cervical spine.

A new radiographic grading system for a more objective assessment of lumbar intervertebral disc degeneration has been described and tested in Part I of this study. The aim of the present Part II of the study was to adapt this system to the cervical spine, and to test it for validity and interobserver agreement. Some modifications of the grading system described in Part I were necessary to make it applicable to the cervical spine. Its basic structure, however, stayed untouched. The three variables "Height Loss", "Osteophyte Formation" and "Diffuse Sclerosis" first have to be graded individually. Then, the "Overall Degree of Degeneration" is assigned on a four-point scale from 0 (no degeneration) to 3 (severe degeneration). For validation, the radiographic degrees of degeneration of 28 cervical discs were compared to the respective macroscopic ones, which were defined as "real" degrees of degeneration. The interobserver agreement was determined between one experienced and one unexperienced observer using the radiographs of 57 cervical discs. Quadratic weighted Kappa coefficients (kappa) with 95% confidence limits (95% CL) were used for statistical evaluation. The validation of the new version of the radiographic grading system showed a moderate agreement with the "real", macroscopic overall degree of degeneration (kappa=0.599, 95% CL 0.421-0.786). In 64% of all discs the "real" overall degree of degeneration was underestimated but never overestimated. This underestimation, however, was much less pronounced and the Kappa coefficients were significantly higher for the three variables: Height Loss, Osteophyte Formation, and Diffuse Sclerosis separately. The agreement between the radiographic ratings of the experienced and the unexperienced observer was substantial for the overall degree of degeneration (kappa=0.688, 95% CL 0.580-0.796), almost perfect for the variable, Height Loss, moderate for Osteophyte Formation and fair for Diffuse Sclerosis. In conclusion, we believe that the new version of the radiographic grading system is a sufficiently valid and reliable tool to quantify the degree of degeneration of individual cervical intervertebral discs. In comparison to the version for the lumbar spine described in Part I, however, a slightly higher tendency to underestimate the "real" overall degree of degeneration and somewhat higher interobserver differences have to be expected.