Inflammaging and Blood Pressure Profiles in Late Life: The Screening for CKD among Older People across Europe (SCOPE) Study.

The neutrophil-to-lymphocyte ratio (NLR) is a marker for systemic inflammation. Since inflammation plays a relevant role in vascular aging, the aim of this study was to investigate whether NLR is associated with blood pressure profiles in older adults. This study was performed within the framework of the SCOPE study including 2461 outpatients aged 75 years and over. Mean blood pressure values, namely systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP) were investigated across tertiles of NLR. Change in blood pressure levels in 2 years of follow-up were compared across categories of baseline NLR. Data of 2397 individuals were used, of which 1854 individuals had hypertension. Mean values of blood pressure did not differ across categories of baseline NLR in individuals without hypertension. Individuals with hypertension with a high-range NLR had lower SBP and PP when compared to those in low-range NLR (mean difference SBP -2.94 mmHg, p = 0.032 and PP -2.55 mmHg, p = 0.030). Mean change in blood pressure in 2 years did only slightly differ in non-clinically relevant ranges, when compared across tertiles of baseline NLR. NLR as a marker of inflammaging was not associated with unfavorable blood pressure profiles in older individuals with or without hypertension.

The relevance of geriatric assessments on the association between chronic kidney disease stages and mortality among older people: a secondary analysis of a multicentre cohort study.

BACKGROUND: age-adapted definition of chronic kidney disease (CKD) does not take individual risk factors into account. We aimed at investigating whether functional impairments influence CKD stage at which mortality increases among older people. METHODS: our series consisted of 2,372 outpatients aged 75 years or more enrolled in a multicentre international prospective cohort study. The study outcome was 24-month mortality. Kidney function was assessed by estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR). Geriatric assessments included handgrip strength, short physical performance battery (SPPB), cognitive impairment, dependency in basic activities of daily living (BADL) and risk of malnutrition. Analysis was carried out by Cox regression, before and after stratification by individual functional impairments. Survival trees including kidney function and functional impairments were also investigated, and their predictivity assessed by C-index. RESULTS: overall, mortality was found to increase starting from eGFR = 30-44.9 ml/min/1.73 m2 (hazard ratio [HR] = 3.28, 95% confidence interval [CI] = 1.81-5.95) to ACR = 30-300 mg/g (HR = 1.96, 95%CI = 1.23-3.10). However, in survival trees, an increased risk of mortality was observed among patients with impaired handgrip and eGFR = 45-59.9 ml/min/1.73 m2, as well as patients with ACR < 30 mg/g and impaired handgrip and SPPB. Survival tree leaf node membership had greater predictive accuracy (C-index = 0.81, 95%CI = 0.78-0.84 for the eGFR survival tree and C-index = 0.77, 95%CI = 0.71-0.81 for the ACR survival tree) in comparison with that of individual measures of kidney function. CONCLUSIONS: physical performance helps to identify a proportion of patients at an increased risk of mortality despite a mild-moderate impairment in kidney function and improves predictive accuracy of individual measures of kidney function.

Diabetes, sarcopenia and chronic kidney disease; the Screening for CKD among Older People across Europe (SCOPE) study.

BACKGROUND: Sarcopenia may be more present in older adults with diabetes (DM). Accordingly, we evaluated the prevalence of sarcopenia and its associated risk factors among community-dwelling older adults with DM. METHODS: A cross-sectional analysis of older people living in the community was carried out. Participants (aged 75 years and more) came from an European multicenter prospective cohort (SCOPE study). Global geriatric assessment including short physical performance battery, handgrip strength test and bioelectrical impedance analysis was performed. Sarcopenia was defined by the updated criteria of the European Working Group on Sarcopenia in Older People (EWGSOP2). Estimated glomerular filtration rate (eGFR) was calculated using Berlin Initiative Study (BIS) to define the stages of chronic kidney disease (CKD). Previous known DM was defined as physician-diagnosed DM registered in the patient's medical record or the use of DM-related medications. Hemoglobin A1c levels and specific DM therapies administered were collected. Time elapsed from the first diagnosis of DM was not collected and, therefore, was not included in the analyses. RESULTS: A total of 1,420 subjects were evaluated with a median age of 79.0 (6.0) years, of which 804 (56.6%) were women and 615 (43.3%) men; 315 (22.2%) participants had prior DM diagnosis, with a median age of 80.0 (6.0), 146 (46.3%) were women. Using EWGSOP2 definition, 150 (10.6%) participants in the SCOPE study met diagnostic criteria for sarcopenia. Participants without diabetes had more often normal results in the 3 sarcopenia components than participants with diabetes [887 (80.31%) vs. 227 (72.1%), p = 0.002], highlighting higher percentages of severe sarcopenia in participants with diabetes [27 (8.6%) vs. 58 (5.2%), p = 0.028]. Confirmed or severe sarcopenia was detected in 41 (13%) participants with diabetes and 109 (9.8%) participants without diabetes (p = 0.108). According to BIS equation, sarcopenia was not significantly more prevalent in the more advanced stages of CKD (p = 0.845). In multivariate analyses, older age (odds ratios [OR], 1.17; 95% confidence interval [CI], 1.08-1.27), and lower body mass index (OR, 0.79; 95% CI, 0.71-0.89 were associated with the presence of sarcopenia. CONCLUSIONS: One tenth of all older community-dwelling subjects have sarcopenia. Older age and being thinner, but not worse renal function, were associated with higher prevalence of sarcopenia in older older adults with diabetes.

[Clinical implications of the estimated glomerular filtration rate]. / Klinische Implikationen der geschätzten glomerulären Filtrationsrate.

A correct determination of the glomerular filtration rate (GFR) is necessary and at the same time difficult. Using gold standard methods, such as measurement of inulin clearance, are not feasible in clinical practice raising the need for methods to estimate GFR using easy to measure endogenous biomarkers. Plasma concentrations of the filtration markers creatinine and cystatin C alone are not adequate to easily calculate kidney function. This is mainly due to a non-linear relationship between plasma concentrations and GFR and GFR-independent factors influencing the plasma concentrations. Therefore, formulae have been developed to estimate GFR using easily available variables. Currently, the most useful formulae are those developed by the modification of diet in renal disease (MDRD) study and more recently by the chronic kidney disease epidemiology (CKD-EPI) collaboration. For older individuals some specifically validated formulae were developed some years ago, among them the Berlin initiative study 1 (BIS-1) and BIS­2 formulae. The accuracy of the estimated filtration rate (eGFR) with respect to the true GFR depends on various factors. The accuracy of the formula is especially low in the GFR range above 60 ml/min · 1.73 m2, during recent or rapid changes of GFR and in the case of extreme physical traits, especially a very high or low muscle mass. In older individuals an eGFR around 60 ml/min · 1.73 m2 alone is not sufficient to discriminate between age-related and disease-related decline in GFR. Nonetheless dosing of medications with predominantly renal excretion should be made according to the eGFR.

Chronic kidney disease in the context of multimorbidity patterns: the role of physical performance : The screening for CKD among older people across Europe (SCOPE) study.

BACKGROUND: Chronic kidney disease (CKD) is known to be associated with several co-occurring conditions. We aimed at exploring multimorbidity patterns associated with CKD, as well as the impact of physical performance and CKD severity on them in a population of older outpatients. METHODS: Our series consisted of 2252 patients enrolled in the Screening of CKD among Older People across Europe multicenter observational study. Hypertension, stroke, transient ischemic attack, cancer, hip fracture, osteoporosis, Parkinson's disease, asthma, chronic obstructive pulmonary disease, congestive heart failure, angina, myocardial infarction, atrial fibrillation, anemia, CKD (defined as GFR < 60, < 45 or < 30 ml/min/1.73 m2), cognitive impairment, depression, hearing impairment and vision impairment were included in the analyses. Physical performance was assessed by the Short Physical Performance Battery (SPPB) and used as stratification variable. Pairs of co-occurring diseases were analyzed by logistic regression. Patterns of multimorbidity were investigated by hierarchical cluster analysis. RESULTS: CKD was among the most frequently observed conditions and it was rarely observed without any other co-occurring disease. CKD was significantly associated with hypertension, anemia, heart failure, atrial fibrillation, myocardial infarction and hip fracture. When stratifying by SPPB, CKD was also significantly associated with vision impairment in SPPB = 5-8 group, and hearing impairment in SPPB = 0-4 group. Cluster analysis individuated two main clusters, one including CKD, hypertension and sensory impairments, and the second including all other conditions. Stratifying by SPPB, CKD contribute to a cluster including diabetes, anemia, osteoporosis, hypertension and sensory impairments in the SPPB = 0-4 group. When defining CKD as eGFR< 45 or 30 ml/min/1.73 m2, the strength of the association of CKD with hypertension, sensory impairments, osteoporosis, anemia and CHF increased together with CKD severity in pairs analysis. Severe CKD (eGFR< 30 ml/min/1.73 m2) contributed to a wide cluster including cardiovascular, respiratory and neurologic diseases, as well as osteoporosis, hip fracture and cancer. CONCLUSIONS: CKD and its severity may contribute significantly to specific multimorbidity patterns, at least based on the cluster analysis. Physical performance as assessed by SPPB may be associated with not negligible changes in both co-occurring pairs and multimorbidity clusters. TRIAL REGISTRATION: The SCOPE study is registered at clinicaltrials.gov ( NCT02691546 ).

Clinical Implications of Estimating Glomerular Filtration Rate with Three Different Equations Among Older People. Preliminary Results of the Project "Screening for Chronic Kidney Disease among Older People across Europe (SCOPE)".

We aimed at investigating to what extent CKD may be staged interchangeably by three different eGFR equations in older people, and evaluating the source of discrepancies among equations in a population of 2257 patients older than 75 years enrolled in a multicenter observational study. eGFR was calculated by CKD-EPI, BIS and FAS equations. Statistical analysis was carried out by Bland-Altman analysis. κ statistic was used to quantify the agreement between equations in classifying CKD stages. The impact of selected variables on the difference among equations was graphically explored. The average difference between BIS and FAS was -0.24 (95% limits of agreement (95%LA = -4.64-4.14) mL/min/1.73 m2. The difference between CKD-EPI and BIS and between CKD-EPI and FAS was 8.97 (95%LA = -2.90-20.84) and 8.72 (95%LA = -2.11-19.56) mL/min/1.73 m2, respectively. As regards CKD stage classification, κ value was 0.47 for both CKD-EPI vs. FAS and CKD-EPI vs. BIS, while BIS and FAS had similar classificatory properties (κ = 0.90). Muscle mass was found related to the difference between CKD-EPI and BIS (R2 = 0.11) or FAS (R2 = 0.14), but not to the difference between BIS and FAS. In conclusion, CKD-EPI and BIS/FAS equations are not interchangeable to assess eGFR among older people. Muscle mass may represent a relevant source of discrepancy among eGFR equations.

The role of wrist monitors to measure blood pressure in older adults.

BACKGROUND: Arterial hypertension is a common condition in older adults with increasing data about blood pressure (BP) targets and antihypertensive treatment in this population. Recent studies have opened new discussions about the different usual and unusual methods of blood pressure monitoring. However, there are no evidence-based recommendations whether BP should be measured at upper arms or at wrist, which seems to be more comfortable in older and frail people. AIMS: The purpose of this study was to test the quality of wrist BP monitors as diagnostic method in older adults. METHODS: BP measurements at both upper arms and at both wrists were compared under standardized conditions in 605 patients ≥ 75 years. Differences in wrist and upper arm BP were, furthermore, correlated with various diagnoses and parameters including ankle-brachial-index (ABI). RESULTS: In patients of 75-80 years, there were no differences in BP measurements at upper arms compared to wrists whereas in patients > 80 years, BP measurements at wrists were significantly lower than at upper arms. In both age groups BP measured at wrist was significantly lower in patients with ABI < 0.9. CONCLUSIONS: BP wrist monitors could be considered as a serious alternative in adults of 75-80 years or in older persons with normal ABI values.

Design and methodology of the screening for CKD among older patients across Europe (SCOPE) study: a multicenter cohort observational study.

BACKGROUND: Decline of renal function is common in older persons and the prevalence of chronic kidney disease (CKD) is rising with ageing. CKD affects different outcomes relevant to older persons, additionally to morbidity and mortality which makes CKD a relevant health burden in this population. Still, accurate laboratory measurement of kidney function is under debate, since current creatinine-based equations have a certain degree of inaccuracy when used in the older population. The aims of the study are as follows: to assess kidney function in a cohort of 75+ older persons using existing methodologies for CKD screening; to investigate existing and innovative biomarkers of CKD in this cohort, and to align laboratory and biomarker results with medical and functional data obtained from this cohort. The study was registered at ClinicalTrials.gov, identifier NCT02691546, February 25th 2016. METHODS/DESIGN: An observational, multinational, multicenter, prospective cohort study in community dwelling persons aged 75 years and over, visiting the outpatient clinics of participating institutions. The study will enroll 2450 participants and is carried out in Austria, Germany, Israel, Italy, the Netherlands, Poland and Spain. Participants will undergo clinical and laboratory evaluations at baseline and after 12 and 24 months- follow-up. Clinical evaluation also includes a comprehensive geriatric assessment (CGA). Local laboratory will be used for 'basic' parameters (including serum creatinine and albumin-to-creatinine ratio), whereas biomarker assessment will be conducted centrally. An intermediate telephone follow-up will be carried out at 6 and 18 months. DISCUSSION: Combining the use of CGA and the investigation of novel and existing independent biomarkers within the SCOPE study will help to provide evidence in the development of European guidelines and recommendations in the screening and management of CKD in older people. TRIAL REGISTRATION: This study was registered prospectively on the 25th February 2016 at clinicaltrials.gov ( NCT02691546 ).

Estimated glomerular filtration rate and functional status among older people: A systematic review.

BACKGROUND: The association between chronic kidney disease (CKD) and functional status may change as a function of the equation used to estimate glomerular filtration rate (eGFR). We reviewed the predictive value of different eGFR equations in regard to frailty and disability outcomes. METHODS: We searched Pubmed from inception to March 2018 for studies investigating the association between eGFR and self-reported and/or objective measures of frailty or disability. Cross-sectional and longitudinal studies were separately analysed. RESULTS: We included 16 studies, one of which reporting both cross-sectional and longitudinal data. Three out of 7 cross-sectional studies compared different eGFR equations in regard to their association with functional status: two studies showed that cystatin C-based, but not creatinine-based eGFR may be associated with hand-grip strength or frailty; another study showed that two different creatinine-based eGFR equations may be similarly associated with disability. Four out of 10 longitudinal studies provided comparative data: two studies reported similar association with disability for different creatinine-based eGFR equations; one study showed that creatinine-based eGFR was not associated with frailty, but a not significant trend for association was observed with cystatin C-based eGFR; one study showed that cystatin C-based but not creatinine-based eGFR may predict incident mobility disability, while both methods may predict gait speed decline. High heterogeneity was observed in regard to confounders included in reviewed studies. None of them included the most recently published equations. CONCLUSION: Available data do not support the superiority of one of the eGFR equations in terms of measuring or predicting functional decline.

Comparison of Coagulation Parameters, Anticoagulation, and Need for Transfusion in Patients on Interventional Lung Assist or Veno-Venous Extracorporeal Membrane Oxygenation.

Clinical data on anticoagulation needs of modern extracorporeal membrane oxygenation (ECMO) and its impact on coagulation are scarce. Therefore, we analyzed coagulation-related parameters, need for transfusion, and management of anticoagulation in adult patients with severe acute respiratory failure during treatment with either pumpless interventional lung assist (iLA) or veno-venous ECMO (vv-ECMO). Sixty-three patients treated with iLA and 192 patients treated with vv-ECMO at Regensburg University Hospital between January 2005 and May 2011 were analyzed. Data related to anticoagulation, transfusion, and coagulation parameters were collected prospectively by the Regensburg ECMO registry. Except for a higher, sequential organ failure assessment (SOFA) score in the ECMO group (12 [9-15] vs. 11 [7-14], P = 0.007), a better oxygenation, and a lower dosage of vasopressors in the iLA patients, both groups had similar baseline characteristics. No difference was noted in terms of outcome and overall transfusion requirements. Factors of the plasmatic coagulation system were only marginally altered over time and did not differ between groups. Platelet counts in ECMO-treated patients, but not in those treated with iLA, dropped significantly during extracorporeal support. A more intense systemic anticoagulation with a mean activated partial thromboplastin time (aPTT) > 53 s led to a higher need for transfusions compared with the group with a mean aPTT < 53 s, whereas the average durability of membrane oxygenators was not affected. Need for red blood cell (RBC) transfusion was highest in patients with extrapulmonary sepsis (257 mL/day), and was significantly lower in primary pulmonary adult respiratory distress syndrome (ARDS) (102 mL/day). Overall, 110 (0-274) mL RBC was transfused in the ECMO group versus 146 (41-227) mL in the iLA group per day on support. The impact of modern iLA and ECMO systems on coagulation allows comparatively safe long-term treatment of adult patients with acute respiratory failure. A moderate systemic anticoagulation seems to be sufficient. Importantly, platelets are more affected by vv-ECMO compared with pumpless iLA.

Lipoxygenase products in the urine correlate with renal function and body temperature but not with acute transplant rejection.

Acute transplant rejection is the leading cause of graft loss in the first months after kidney transplantation. Lipoxygenase products mediate pro- and anti-inflammatory actions and thus we aimed to correlate the histological reports of renal transplant biopsies with urinary lipoxygenase products concentrations to evaluate their role as a diagnostic marker. This study included a total of 34 kidney transplant recipients: 17 with an acute transplant rejection and 17 controls. LTE4, LTB4, 12-HETE and 15-HETE concentrations were measured by enzyme immunoassay. Urinary lipoxygenase product concentrations were not significantly changed during an acute allograft rejection. Nevertheless, LTB4 concentrations correlated significantly with the body temperature (P ≤ 0.05) 3 months after transplantation, and 12- and 15-HETE concentrations correlated significantly with renal function (P ≤ 0.05) 2 weeks after transplantation. In conclusion, our data show a correlation for LTB4 with the body temperature 3 months after transplantation and urinary 12- and 15-HETE concentrations correlate positively with elevated serum creatinine concentrations but do not predict acute allograft rejection.

Elevated urinary sVCAM-1, IL6, sIL6R and TNFR1 concentrations indicate acute kidney transplant rejection in the first 2 weeks after transplantation.

We tested the hypothesis that increased urinary cytokine concentrations may indicate an acute kidney transplant rejection. Eight patients with an early rejection in their protocol biopsy about 14days after transplantation (group A), 9 patients with a biopsy proven rejection 2-3months after transplantation (group B) and 18 patients without acute rejection in their protocol biopsies both at 14days and 3months (group C, represents the control group) were chosen for this study. At the time of biopsy, the mean urinary concentration of interleukin 6 (IL6), soluble IL6 receptor (sIL6R), tumor necrosis factor receptor 1 (TNFR1), and soluble vascular cell adhesion molecule -1 (sVCAM-1) were significantly higher in patients with an early acute transplant rejection, i.e. in group A compared to patients in the control group (p<0.01). Additionally we found already 14days after transplantation significantly higher concentrations of urinary sIL6R and sVCAM-1 in group B patients who suffered of late acute rejection compared to patients with no acute rejection (group C, p<0.05). No significant correlation could be shown for interleukin 1 receptor antagonist (IL1ra), TNF, and TNFR2. In conclusion, elevated urinary concentrations of IL6, sIL6R, TNFR1 and sVCAM-1 clearly indicate an early acute transplant rejection. Especially sVCAM-1 may also serve as an early marker of an upcoming late rejection. However, further studies are warranted to verify the value of individual cytokine profiles to predict acute rejection episodes.

Traditional and nontraditional cardiovascular risk factors and estimated risk for coronary artery disease in renal transplant recipients: a single-center experience.

BACKGROUND/AIMS: The prevalence of cardiovascular disease in renal transplant recipients is markedly higher than in the general population due to the high prevalence of traditional cardiovascular risk factors, renal transplant function impairment and treatment with immunosuppressive drugs that affect blood pressure, cholesterol and blood glucose levels. METHODS: Cross-sectional analysis using our renal transplant clinic cohort investigating (1) the cardiovascular risk factors present in this cohort, and (2) estimating their impact on the risk of coronary artery disease (CAD) by using the Framingham algorithm. RESULTS: Control of modifiable cardiovascular risk factors in 231 renal transplant recipients is suboptimal, i.e. 47.2% of patients are hypertensive, 10.3% actively smoke, 39.4% have serum cholesterol concentrations >200 mg/dl, and 19.7% have diabetes mellitus. Blood pressure, age, hyperlipidemia, smoking and diabetes modulate the estimated CAD risk in males and females. Furthermore, a short time period (less than 1 year) since transplantation and increased serum creatinine levels negatively influenced the CAD risk in this patient population. CONCLUSION: According to current guidelines, the control of modifiable cardiovascular risk factors in renal transplant recipients is suboptimal. The decreasing CAD risk over time after transplantation may be due to the reduction of immunosuppressive drugs with time and survival bias.

Absence of gadolinium deposits in the peritoneal membrane of patients with encapsulating peritoneal sclerosis.

UNLABELLED: Background. Encapsulating peritoneal sclerosis (EPS) is a severe complication of long-term peritoneal dialysis (PD) characterized by the development of an extensive fibrosis of the visceral peritoneum that may eventually lead to intestinal constriction. Its cause remains elusive. Nephrogenic systemic fibrosis (NSF), a disabling disease that can follow gadolinium-based contrast injection during magnetic resonance imaging, is characterized by systemic fibrosis of the skin, joints, liver, heart and vessels. Affected tissues are infiltrated by CD34+ and CD68+ fibroblasts. In the present study, we tested the hypothesis that EPS could have been triggered by a previous gadolinium injection. Methods. We performed histopathological analysis of the peritoneal membrane of two EPS and two control patients all exposed to long-term PD, including immunostaining with CD34 and CD68. The presence of gadolinium and other metals was also assessed by conventional and energy-filtered transmission electron microscopy. RESULTS: Numerous CD34+ and CD68+ cells were found in both the EPS and control patients within the vascular endothelium and in macrophages, respectively, but not in interstitial fibrocytes, as it could be expected in NSF. No trace of gadolinium deposits could be found in the four peritoneal samples; dispersed tiny iron inclusions were evidenced in the connective tissue of both EPS patients. CONCLUSIONS: These findings argue against the implication of gadolinium in the development of EPS in long-term PD patients.

Dose dependent effects of platelet derived chondroitinsulfate A on the binding of CCL5 to endothelial cells.

BACKGROUND: Chemokines immobilized on endothelial cells play a central role in the induced firm adhesion and transendothelial migration of leukocytes. Activation of platelets at sites of vascular injury is considered to support leukocyte adhesion and extravasation. However, activated platelets also secrete soluble glycosaminoglycans that can interfere with immobilization of chemokines. We therefore analyzed the impact of platelet derived glycosaminoglycans on the immobilization of the chemokine CCL5 (RANTES) on human microvascular endothelial cells and their influence on CCL5-CCR5 interactions. RESULTS: We confirm that undiluted serum in contrast to plasma decreases binding of CCL5 to endothelial cells. However, when lower concentrations of serum were used, CCL5-presentation on endothelial cells was markedly enhanced. This enhancement was neutralized if serum was digested with chondroinitase ABC. Using different chondroitinsulfate-subtypes we demonstrate that chondroitinsulfate A mediates the enhanced presentation of CCL5 on endothelial cells, whereas chondroitinsulfate B/C even at low concentrations block CCL5 binding. CCR5 downregulation on CCR5-transfected CHO cells or human monocytes is increased by preincubation of CCL5 with serum or chondroitinsulfate A. CONCLUSION: We show that chondroitinsulfate A released from platelets increases the binding of chemokines to endothelial cells and supports receptor internalization in a dose dependent manner. These data help to understand the proinflammatory effects of activated platelets.

Ultrastructural evidence of dermal gadolinium deposits in a patient with nephrogenic systemic fibrosis and end-stage renal disease.

BACKGROUND AND OBJECTIVES: The pathogenesis of acquired nephrogenic systemic fibrosis recently described for patients with renal insufficiency and a history of exposition to gadolinium-based magnetic resonance contrast agents is not completely understood. A role for circulating fibroblasts in the fibrosing tissue is hypothetical, and the mechanism of the assumed trigger function of gadolinium remains elusive. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A skin lesion on a 76-yr-old man with symptoms of nephrogenic systemic fibrosis lasting 5 mo was studied at the ultrastructural level. After confirmation of he diagnosis by histopathologic methods, the presence and distribution of gadolinium, iron, calcium, and magnesium by energy filtering transmission electron microscopy was also examined. RESULTS: The performed electron spectroscopic imaging and electron energy loss spectroscopic analyses on deparaffinized samples revealed deposition of gadolinium in irregular small aggregates that adhered to cell profiles and collagen fibers of the connective tissue, forming a perivascular "gadolinium-deposit zone" in the skin. Traces of iron signal were demonstrated in singular gadolinium-positive deposits, and iron presence was found in adjacent connective tissue. The ultrastructural cell analysis of the lesion showed among numerous poorly differentiated fibrocytes also higher differentiated cells with myofibroblastic characteristics, including bundles of intermediate filaments and attachment plaques in the cell periphery, indicating an ability of lesional fibroblasts to differentiate into myofibroblastic cells. CONCLUSIONS: These findings support the pivotal role of gadolinium chelates in the development of nephrogenic systemic fibrosis.

Selective binding and presentation of CCL5 by discrete tissue microenvironments during renal inflammation.

T cells are differentially recruited to the tubulointerstitium during renal inflammation. The selective presentation of chemokines by surface structures may in part underlie this phenomenon. In an attempt to better characterize the presentation of chemokines by tissue environments an exemplary chemokine with a well-defined structure was selected, and a binding assay for the protein on fixed archival tissue sections was developed. This article describes the selective binding of the chemokine CCL5 to renal structures. CCL5 was shown to bind to endothelial regions, interstitial extracellular matrix, tubular epithelial cells, and tubular basement membranes but rarely to glomerular structures in well-preserved kidneys. In contrast, binding of CCL5 to glomerular components was seen in renal biopsies with acute allograft glomerulitis (in which T cells accumulate in glomeruli). The N terminus mediates receptor binding, whereas two clusters of basic amino acid residues ((44)RKNR(47) and (55)KKWVR(59)) are involved in the presentation of CCL5 by extracellular structures. Mutation of either loop abrogated CCL5 binding to tissue sections. Variations of the N terminus and a mutation that prevents higher order oligomerization did not change the binding pattern. The data suggest that renal compartments differ in their capacity to present chemokines, which may help explain the differential recruitment of leukocytes during allograft injury. Both clusters of basic residues in CCL5 are necessary for sufficient binding of CCL5 to tissue sections.