Significance of Basal Cell Carcinomas Exhibiting Intravascular Invasion.

ABSTRACT: Intravascular invasion of tumor cells can be associated with metastasis in many cancers. Basal cell carcinomas (BCCs), however, rarely metastasize; therefore, the clinical impact of intravascularly invasive BCC (IVBCC) is currently unclear. Because of these facts and the rarity of IVBCC, questions have arisen on whether IVBCC truly exists. We present 4 cases of IVBCC: one case with obvious tumor islands within immunolabeled blood vessels in the context of advanced disease and 3 cases found incidentally during Mohs micrographic surgery. We discuss the difficulty in studying IVBCC, the idea that it could be due to artifact, and the lack of direct clinical-pathological correlation. Given these challenges, we propose diagnostic criteria for IVBCC to decrease ambiguity for pathological diagnosis. Such criteria may facilitate further studies on the clinical significance of IVBCC.

Primary Cutaneous Gamma-Delta T-cell Lymphoma: A Case Report and Review of Literature.

Primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL) is a rare type of lymphoma, representing less than 1% of all cutaneous T-cell lymphomas. It is typically aggressive and chemotherapy-refractory. Hence, most institutions tend to employ intensive chemotherapy followed by stem cell transplantation although there is no standard of care established. We report a case of PCGD-TCL and discuss the challenges associated with the diagnosis and management of PCGD-TCL.

MOC-31 Antibody Immunolabeling During Mohs Surgery.

BACKGROUND: Ber-EP4 is an antibody that labels basal cell carcinoma (BCC) by targeting epithelial cell adhesion molecule (Ep-CAM). MOC-31, a monoclonal mouse antibody, also targets Ep-CAM and is currently used to differentiate several extracutaneous epithelial tumors. However, the utility of MOC-31 has not been fully described in cutaneous tumors and in Mohs micrographic surgery (MMS). OBJECTIVE: To evaluate MOC-31 labeling in BCC and other cutaneous tumors and to compare immunolabeling intensity of MOC-31 and Ber-EP4 in BCCs. MATERIALS AND METHODS: Nineteen permanently fixed and 29 frozen BCC specimens and 23 other cutaneous tumors were labeled with MOC-31; labeling intensity of tumors, epidermis, and adnexal structures were recorded. In a separate study, a blinded dermatopathologist compared labeling intensities of 8 BCC specimens, each labeled with MOC-31 and Ber-EP4.4. RESULTS: MOC-31 labeled all BCCs. Eccrine coils and follicular bulbs did label variably, although this did not detract utility of MOC-31. Five of thirteen cutaneous squamous cell carcinomas and one of two Merkel cell carcinomas demonstrated MOC-31 positivity. MOC-31 and Ber-EP4 labeled BCCs similarly. CONCLUSION: MOC-31, an antibody directed against Ep-CAM, is sensitive for BCCs in frozen specimens encountered in MMS and permanently fixed specimen. In addition, MOC-31 demonstrated comparable immunolabeling characteristics with Ber-EP4 for BCCs.

Peritumoral matrilin-2 staining may be useful in distinguishing basal cell carcinoma from folliculocentric basaloid proliferation.

BACKGROUND: Folliculocentric basaloid proliferation (FBP) is a benign and reactive proliferation which can histopathologically mimic basal cell carcinomas (BCCs). The incidental presence of FBP during the excision of a BCC can occasionally lead to excessive tissue removal. One distinguishing feature of BCCs is that they invade the stroma, whereas FBPs generally do not. METHODS: Matrilin-2 is an extracellular matrix protein associated with tumor invasion, and we compared the expression of matrilin-2 in peritumoral cells of BCC and FBP. RESULTS: We found increased matrilin-2 expression within the peritumoral stroma of 41 of 42 BCCs (97.7%), with strong expression in all (100%) cases of infiltrative subtypes and in 21 of 25 (84%) nodular subtypes of BCC. We found no expression of peritumoral matrilin-2 in any of the seven cases of FBP. CONCLUSION: Our results suggest that immunolabeling with the matrilin-2 antibody may help distinguish BCCs from FBPs.

NANS-mediated synthesis of sialic acid is required for brain and skeletal development.

We identified biallelic mutations in NANS, the gene encoding the synthase for N-acetylneuraminic acid (NeuNAc; sialic acid), in nine individuals with infantile-onset severe developmental delay and skeletal dysplasia. Patient body fluids showed an elevation in N-acetyl-D-mannosamine levels, and patient-derived fibroblasts had reduced NANS activity and were unable to incorporate sialic acid precursors into sialylated glycoproteins. Knockdown of nansa in zebrafish embryos resulted in abnormal skeletal development, and exogenously added sialic acid partially rescued the skeletal phenotype. Thus, NANS-mediated synthesis of sialic acid is required for early brain development and skeletal growth. Normal sialylation of plasma proteins was observed in spite of NANS deficiency. Exploration of endogenous synthesis, nutritional absorption, and rescue pathways for sialic acid in different tissues and developmental phases is warranted to design therapeutic strategies to counteract NANS deficiency and to shed light on sialic acid metabolism and its implications for human nutrition.

Progression of Hip Dysplasia in Mucopolysaccharidosis Type I Hurler After Successful Hematopoietic Stem Cell Transplantation.

BACKGROUND: Dysostosis multiplex contributes substantially to morbidity in patients with Hurler syndrome (mucopolysaccharidosis type I Hurler phenotype [MPS I-H]), even after successful hematopoietic stem cell transplantation (HSCT). One of the hallmarks of dysostosis multiplex in MPS I-H is hip dysplasia, which often requires surgical intervention. We sought to describe in detail the course of hip dysplasia in this group of patients, as assessed by radiographic analysis, and to identify potential outcome predictors. METHODS: Longitudinal data were obtained from digitally scored pelvic radiographs of patients with MPS I-H using OrthoGon software for parameters including, but not limited to, the acetabular index, migration percentage, Smith ratio, and neck-shaft angle. Scoring was performed independently by two blinded observers. Additional information on genotype, enzyme replacement therapy pre-HSCT, donor chimerism, and enzyme activity post-HSCT were obtained. General trends and potential correlations were calculated with mixed-model statistics. RESULTS: Fifty-two patients (192 radiographs) were included in this analysis. Intraobserver and interobserver variation analysis showed an intraclass correlation coefficient ranging from 0.78 to 1.00. Among the twenty-one patients with follow-up beyond the age of five years, the acetabular index was in the range of severe hip dysplasia in up to 86% of the patients. Severe coxa valga was seen in 91% of the patients. Lateral and superior femoral displacement were highly prevalent, with the migration percentage outside the reference range in up to 96% of the patients. Finally, anterior pelvic tilt increased with age (p = 0.001). No correlations were identified between clinical parameters and radiographic findings. CONCLUSIONS: Our study shows that progressive acetabular dysplasia as well as coxa valga and hip displacement are highly prevalent and progressive over time in patients with MPS I-H, despite successful HSCT. These data may provide essential natural history determinations for the assessment of efficacy of new therapeutic strategies aimed at improving skeletal outcomes in patients with MPS I-H.

Drug-associated skin lesions in a patient with myelofibrosis receiving ruxolitinib.

Ruxolitinib, a small molecule JAK-1/2 inhibitor, was approved by the U.S. Food and Drug Administration (FDA) in November 2011, as the first therapeutic for the treatment of intermediate and high-risk myelofibrosis. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is one of the most well-studied intracellular signaling networks. Recent advances in our understanding of the complexities of signal activation and regulation of gene expression has provided opportunities for targeted therapeutic interventions. Although numerous inhibitors of the JAK/STAT pathway are currently being evaluated in clinical trials, ruxolitinib represents the first FDA approved in-class JAK inhibitor. We report a drug eruption associated with ruxolitinib.

Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency.

BACKGROUND & AIMS: Lysosomal acid lipase deficiency is an autosomal recessive enzyme deficiency resulting in lysosomal accumulation of cholesteryl esters and triglycerides. LAL-CL04, an ongoing extension study, investigates the long-term effects of sebelipase alfa, a recombinant human lysosomal acid lipase. METHODS: Sebelipase alfa (1mg/kg or 3mg/kg) was infused every-other-week to eligible subjects. Safety and tolerability assessments, including liver function, lipid profiles and liver volume assessment, were carried out at regular intervals. RESULTS: 216 infusions were administered to eight adult subjects through week 52 during LAL-CL04. At week 52, mean alanine aminotransferase and aspartate aminotransferase levels were normal with mean change from baseline of -58% and -40%. Mean changes for low-density lipoprotein, total cholesterol, triglyceride and high-density lipoprotein were -60%, -39%, -36%, and +29%, respectively. Mean liver volume by magnetic resonance imaging and hepatic proton density fat fraction decreased (12% and 55%, respectively). Adverse events were mainly mild and unrelated to sebelipase alfa. Infusion-related reactions were uncommon: three events of moderate severity were reported in two subjects; one patient's event was suggestive of a hypersensitivity-like reaction, but additional testing did not confirm this, and the subject has successfully re-started sebelipase alfa. Of samples tested to date, no anti-drug antibodies have been detected. CONCLUSIONS: Long-term dosing with sebelipase alfa in lysosomal acid lipase-deficient patients is well tolerated and produces sustained reductions in transaminases, improvements in serum lipid profile and reduction in the hepatic fat fraction. A randomized, placebo-controlled phase 3 trial in children and adults is underway (ARISE: NCT01757184).

Design and methods of a postmarketing pharmacoepidemiology study assessing long-term safety of Prolia® (denosumab) for the treatment of postmenopausal osteoporosis.

PURPOSE: To describe the rationale and methods for a prospective, open-cohort study assessing the long-term safety of Prolia(®) for treatment of postmenopausal osteoporosis (PMO) in postmarketing settings. METHODS: Data will be derived from United States Medicare, United Healthcare, and Nordic (Denmark, Sweden, Norway) national registries. Observation will begin on the date of first Prolia(®) regulatory approval (May 26, 2010) and continue for 10 years. Women with PMO will be identified by postmenopausal age, osteoporosis diagnosis, osteoporotic fracture, or osteoporosis treatment. Exposure to Prolia(®) and bisphosphonates will be updated during follow-up; exposure cohorts will be defined based on patient-years during which patients are on- or post-treatment. Nine adverse events (AEs) will be assessed based on diagnosis codes: osteonecrosis of the jaw (ONJ), atypical femoral fracture (AFF), fracture healing complications, hypocalcemia, infection, dermatologic AEs, acute pancreatitis, hypersensitivity, and new primary malignancy. Medical review will confirm selected potential cases of ONJ and AFF. Incidence rates (IRs) of AEs will be described overall and for exposure cohorts; multivariate Cox proportional hazard regression models will compare IRs of AEs across exposure cohorts. Utilization patterns of Prolia(®) for approved, and unapproved indications will be described. CONCLUSION: This study is based on comprehensive preliminary research and considers methodological challenges specific to the study population. The integrated data systems used in this regulatory committed program can serve as a powerful data resource to assess diverse and rare AEs over time.

Effects of denosumab on fracture and bone mineral density by level of kidney function.

The incidences of osteoporosis and chronic kidney disease (CKD) both increase with increasing age, yet there is a paucity of data on treatments for osteoporosis in the setting of impaired kidney function. We examined the efficacy and safety of denosumab (DMAb) among subjects participating in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) Study. We estimated creatinine clearance (eGFR) using Cockcroft-Gault and classified levels of kidney function using the modified National Kidney Foundation classification of CKD. We examined incident fracture rates; changes in bone mineral density (BMD), serum calcium, and creatinine; and the incidence of adverse events after 36 months of follow-up in subjects receiving DMAb or placebo, stratified by level of kidney function. We used a subgroup interaction term to determine if there were differences in treatment effect by eGFR. Most (93%) women were white, and the mean age was 72.3 ± 5.2 years; 73 women had an eGFR of 15 to 29 mL/min; 2817, between 30 to 59 mL/min; 4069, between 60 to 89 mL/min, and 842 had an eGFR of 90 mL/min or greater. None had stage 5 CKD. Fracture risk reduction and changes in BMD at all sites were in favor of DMAb. The test for treatment by subgroup interaction was not statistically significant, indicating that treatment efficacy did not differ by kidney function. Changes in creatinine and calcium and the incidence of adverse events were similar between groups and did not differ by level of kidney function. It is concluded that DMAb is effective at reducing fracture risk and is not associated with an increase in adverse events among patients with impaired kidney function.

Chronic kidney disease and the risk of end-stage renal disease versus death.

BACKGROUND: Among older adults with chronic kidney disease (CKD), the comparative event rates of end-stage renal disease (ESRD) and cause-specific death are unknown. OBJECTIVE: To compare the rates of ESRD, cardiovascular and non-cardiovascular death and examine risk factors for ESRD and all-cause mortality in Cardiovascular Health Study (CHS) participants. DESIGN: The CHS is a longitudinal cohort study of community-dwelling adults aged 65 years and older. PARTICIPANTS: 1,268 participants with an estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m(2) were followed until the time of first event (ESRD, cardiovascular or non-cardiovascular death) or until March 31, 2003. MAIN MEASURES: The outcomes were ESRD, cardiovascular- and non-cardiovascular death. Rates of each event were calculated, and a Cox Proportional Hazards Model with a competing risk framework was used to examine risk factors for ESRD as compared with death. Predictors included age, gender, race, BMI, hypertension, diabetes, cardiovascular disease, heart failure, tobacco use, eGFR, and total cholesterol. KEY RESULTS: During 9.7 years of follow-up, 5% of the cohort progressed to ESRD, and 61% of the cohort died. The rate (per 100 person-years) was 0.5 for ESRD and 6.8 for all-cause mortality (3.0 for cardiovascular and 3.8 for non-cardiovascular mortality). In the competing risk framework, lower eGFR, male gender, African-American race, and higher BMI were associated with an increased risk of ESRD. CONCLUSIONS: Older adults with CKD are 13-fold more likely to die from any cause than progress to ESRD and are 6-fold more likely to die from cardiovascular causes than develop ESRD.

The utility of the DNA microarray scanner to simplify the immunofluorescence evaluation of autoimmune bullous diseases.

A DNA microarray scanner was used as a digital fluorescence microscope to simplify the diagnosis of autoimmune bullous diseases. Frozen sections of skin biopsies were taken from 3 patients with bullous pemphigoid and 1 patient each with lichen planus pemphigoides, linear immunoglobulin (Ig) A disease, and dermatitis herpetiformis. After incubation with cyanine-labeled antibodies, the tissues were scanned at 5-mum resolution using an instrument originally designed to study gene expression. The microarray scanner's large field of view, unlike that of fluorescence microscopy, allowed a view of the entire specimen, considerably easing the orientation of tissue. All images were diagnostic and included a linear pattern along the basement membrane zone (BMZ) using anti-IgG and anti-C3 in all cases of bullous pemphigoid, a linear pattern of IgG along the BMZ in lichen planus pemphigoides, and a linear pattern of IgA along the BMZ in linear IgA dermatosis. IgA deposition along dermal papillary tips was seen in dermatitis herpetiformis, but a granular pattern was indiscernible at the 5-mum resolution. The advantages of the microarray scanner over standard fluorescence microscopy include speed, technical ease, large field of view, potential for visualizing multiple antibodies simultaneously in a tissue, and convenience of digital image archiving.

Effect of darbepoetin alfa administered once monthly on maintaining hemoglobin levels in older patients with chronic kidney disease.

BACKGROUND: The anemia of chronic kidney disease (CKD) is associated with increased hospitalizations, increased cardiovascular morbidity and mortality, and diminished quality of life in the elderly. Darbepoetin alfa is an erythropoiesis-stimulating agent that has been shown to be effective in treating anemia in patients with CKD (but not on dialysis) when administered using extended-dosing regimens. OBJECTIVE: The purpose of this post hoc analysis was to examine the efficacy and safety profile of once-monthly (QM) darbepoetin alfa in study patients stratified according to age (ie, <65, 65-74, and > or =75 years). METHODS: Patients with CKD but not on dialysis, receiving darbepoetin alfa every other week (Q2W), and with stable hemoglobin (Hb) levels between 11 and 13 g/dL, inclusive, were enrolled in this 33-week, multicenter, open-label, single-arm study. The study was carried out at 36 US centers and consisted of a 24-week QM darbepoetin alfa dose-titration period followed by an 8-week evaluation period. Hb levels were measured Q2W. Study results were stratified according to patient age (<65, 65-74, and > or =75 years). RESULTS: A total of 152 patients (79 women, 73 men) were enrolled; 55 patients (36%) were <65 years of age, 46 (30%) were 65 to 74 years of age, and 51 (34%) were > or =75 years of age. In patients who received > or =1 dose of darbepoetin alfa, Hb levels > or =11 g/dL were maintained in 76%, 80%, and 71% of patients aged <65, 65 to 74, and > or =75 years, respectively. For patients who completed the study, the proportions who maintained Hb levels > or =11 g/dL were 83%, 88%, and 85%, respectively, for the 3 age groups. The safety profile of QM darbepoetin alfa in this study was consistent with that expected in patients with CKD not receiving dialysis. CONCLUSIONS: Darbepoetin alfa administered QM maintained Hb levels > or =11 g/dL in patients with CKD (not on dialysis) aged <65, 65 to 74, and > or =75 years. This treatment regimen may help optimize anemia management for older community-dwelling and long-term care patients.

Greater epoetin alfa responsiveness is associated with improved survival in hemodialysis patients.

BACKGROUND AND OBJECTIVES: Among hemodialysis patients, achieved hemoglobin is associated with Epoetin alfa dose and erythropoietin responsiveness. A prospective erythropoietin responsiveness measure was developed and its association with mortality evaluated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data from 321 participants were used and randomized to the hematocrit normalization arm of the Normal Hematocrit Cardiac Trial. Subjects were to receive a 50% Epoetin alfa dose increase at randomization. The prospective erythropoietin responsiveness measure was defined as the ratio of weekly hematocrit change (over the 3 wk after randomization) per Epoetin alfa dose increase (1000 IU/wk) corresponding to the mandated 50% dose increase at randomization. The distribution of responsiveness was divided into quartiles. Over a 1-yr follow-up, Cox proportional hazard modeling evaluated associations between this responsiveness measure and mortality. RESULTS: Erythropoietin responsiveness values ranged from -2.1% to 2.4% per week per 1000 IU. Although subjects were similar across response quartiles, mortality ranged between 14% and 34% among subjects in the highest and lowest response quartiles (P = 0.0004), respectively. After adjusting for baseline prognostic indicators, highest versus lowest responsiveness was associated with a hazard ratio of 0.41 (95% confidence interval, 0.20 to 0.87). CONCLUSION: Lower erythropoietin responsiveness is a strong, independent predictor of mortality risk and should be considered when evaluating associations between clinical outcomes and potential prognostic indicators, such as Epoetin alfa dose and achieved hemoglobin values.

Differences in kidney function and incident hypertension: the multi-ethnic study of atherosclerosis.

BACKGROUND: Kidney disease and hypertension commonly coexist, yet the direction of their association is still debated. OBJECTIVE: To evaluate whether early kidney dysfunction, measured by serum cystatin C levels and urinary albumin excretion, predates hypertension in adults without clinically recognized kidney or cardiovascular disease. DESIGN: Observational cohort study using data from 2000 to 2005. SETTING: The MESA (Multi-Ethnic Study of Atherosclerosis), a community-based study of subclinical cardiovascular disease in adults age 45 to 84 years. PARTICIPANTS: 2767 MESA participants without prevalent hypertension, cardiovascular disease, or clinically recognized kidney disease (an estimated glomerular filtration rate <60 mL/min per 1.73 m2 or microalbuminuria). MEASUREMENTS: Cystatin C was measured by using a nephelometer, and urinary albumin and creatinine were measured from a spot morning collection. The primary outcome was incident hypertension, defined as systolic blood pressure of at least 140 mm Hg, diastolic blood pressure of at least 90 mm Hg, or use of an antihypertensive medication. RESULTS: During a median follow-up of 3.1 years, 19.7% of the cohort (545 participants) developed hypertension. After adjustment for established hypertension risk factors, each 15-nmol/L increase in cystatin C was associated with a statistically significant 15% greater incidence of hypertension (P = 0.017). The highest sex-specific quartile of urinary albumin-creatinine ratio was associated with a statistically insignificant 16% greater incidence of hypertension (P = 0.192) compared with the lowest quartile. No statistical evidence suggested a multiplicative interaction. LIMITATIONS: Unmeasured characteristics may have confounded observed associations of kidney markers with hypertension. Follow-up was relatively short. Hypertension that may have occurred between study visits or hypertension that was not captured by standard cuff measurements may have been missed. CONCLUSION: Differences in kidney function, indicated by cystatin C levels, are associated with incident hypertension among individuals without clinical kidney or cardiovascular disease. These population-based findings complement experimental work implicating early kidney damage in the pathogenesis of essential hypertension.

Cardiovascular risk factors and incident acute renal failure in older adults: the cardiovascular health study.

BACKGROUND AND OBJECTIVES: Although the elderly are at increased risk for acute renal failure, few prospective studies have identified risk factors for acute renal failure in the elderly. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The associations of cardiovascular disease risk factors, subclinical cardiovascular disease, and clinical coronary heart disease with the risk for development of acute renal failure were examined in older adults in the Cardiovascular Health Study, a prospective cohort study of community-dwelling older adults. Incident hospitalized cases of acute renal failure were identified through hospital discharge International Classification of Diseases, Ninth Revision codes and confirmed through physician diagnoses of acute renal failure in discharge summaries. RESULTS: Acute renal failure developed in 225 (3.9%) of the 5731 patients during a median follow-up period of 10.2 yr. In multivariate analyses, diabetes, current smoking, hypertension, C-reactive protein, and fibrinogen were associated with acute renal failure. Prevalent coronary heart disease was associated with incident acute renal failure, and among patients without prevalent coronary heart disease, subclinical vascular disease measures were also associated with acute renal failure: Low ankle-arm index (< or =0.9), common carotid intima-media thickness, and internal carotid intima-media thickness. CONCLUSIONS: In this large, population-based, prospective cohort study, cardiovascular risk factors and both subclinical and clinical vascular disease were associated with incident acute renal failure in the elderly.

Association of mild to moderate kidney dysfunction and coronary calcification.

Coronary artery calcification (CAC) is prevalent and predicts mortality among patients with ESRD, but whether less severe kidney dysfunction is associated with CAC is uncertain. To address this question, 6749 participants of the Multi-Ethnic Study of Atherosclerosis, who were middle-aged and without known cardiovascular disease, were evaluated. Renal function was categorized by cystatin C quartiles and estimated GFR (eGFR; < to >60 ml/min per 1.73 m(2)), and CAC was evaluated by computed tomography (CT). Fifty percent of participants had CAC, mean cystatin C was 0.90 mg/L, and 10% had eGFR <60 ml/min per 1.73 m(2). In unadjusted analysis, kidney dysfunction by either measure was strongly associated with CAC; however, the associations were lost after adjustment for age, gender, race, hypertension, and IL-6 (relative risk 1.04 [95% confidence interval 0.97 to 1.11] for the highest cystatin C quartile compared with the lowest, and relative risk 1.03 [95% confidence interval 0.98 to 1.08] for eGFR below compared with above 60 m/min per 1.73 m(2)). Similarly, neither higher cystatin C nor eGFR <60 was associated with severity of CAC. These results suggest that a higher burden of CAC is unlikely to explain the association between mild to moderate kidney dysfunction and cardiovascular mortality.

Chronic kidney disease increases risk for venous thromboembolism.

Chronic kidney disease (CKD) is associated with increased risk for cardiovascular disease morbidity and mortality, but its association with incident venous thromboembolism (VTE) in non-dialysis-dependent patients has not been evaluated in a community-based population. With the use of data from the Longitudinal Investigation of Thromboembolism Etiology (LITE) study, 19,073 middle-aged and elderly adults were categorized on the basis of estimated GFR, and cystatin C (available in 4734 participants) was divided into quintiles. During a mean follow-up time of 11.8 yr, 413 participants developed VTE. Compared with participants with normal kidney function, relative risk for VTE was 1.28 (95% confidence interval [CI] 1.02 to 1.59) for those with mildly decreased kidney function and 2.09 (95% CI 1.47 to 2.96) for those with stage 3/4 CKD, when adjusted for age, gender, race, and center. After additional adjustment for cardiovascular disease risk factors, an increased risk for VTE was still observed in participants with stage 3/4 CKD, with a multivariable adjusted relative risk of 1.71 (95% CI 1.18 to 2.49). There was no significant association between cystatin C and VTE. In conclusion, middle-aged and elderly patients with CKD (stages 3 through 4) are at increased risk for incident VTE, suggesting that VTE prophylaxis may be particularly important in this population.