[SGLT2 inhibitors, also in frail older adults?] / SGLT2-remmers, ook bij kwetsbare ouderen?

Sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors) have gained prominence in the treatment of diabetes mellitus type 2, heart failure, and chronic kidney disease. However, concerns arise for frail older adults, given their underrepresentation in trials and heightened susceptibility to adverse drug events. This review summarizes the clinical effects of SGLT2 inhibitors in older adults with frailty. SGLT2 inhibitors seem to exhibit consistent cardiovascular benefits irrespective of age. As such, these drugs can be beneficial for older adults with 'cardiovascular frailty': in other words, cardiovascular multimorbidity. However, in the current data there is a lack of focus on the broader definition of frailty, which also includes functional status and self-dependence. Also, some research suggest that adverse events, such as volume depletion and genitourinary infections, are more common in the frail older population. Therefore, until more data is available, SGLT2 inhibitors should be prescribed with caution in older adults living with frailty.

The impact of cardiovascular diagnostics and treatments on fall risk in older adults: a scoping review and evidence map.

BACKGROUND: We aimed to summarize the published evidence on the fall risk reducing potential of cardiovascular diagnostics and treatments in older adults. METHODS: Design: scoping review and evidence map. DATA SOURCES: Medline and Embase. ELIGIBILITY CRITERIA: all available published evidence; Key search concepts: "older adults," "cardiovascular evaluation," "cardiovascular intervention," and "falls." Studies reporting on fall risk reducing effect of the diagnostic/treatment were included in the evidence map. Studies that investigated cardiovascular diagnostics or treatments within the context of falls, but without reporting a fall-related outcome, were included in the scoping review for qualitative synthesis. RESULTS: Two articles on cardiovascular diagnostics and eight articles on cardiovascular treatments were included in the evidence map. Six out of ten studies concerned pacemaker intervention of which one meta-analyses that included randomized controlled trials with contradictory results. A combined cardiovascular assessment/evaluation (one study) and pharmacotherapy in orthostatic hypotension (one study) showed fall reducing potential. The scoping review contained 40 articles on cardiovascular diagnostics and one on cardiovascular treatments. It provides an extensive overview of several diagnostics (e.g., orthostatic blood pressure measurements, heart rhythm assessment) useful in fall prevention. Also, diagnostics were identified, that could potentially provide added value in fall prevention (e.g., blood pressure variability and head turning). CONCLUSION: Although the majority of studies showed a reduction in falls after the intervention, the total amount of evidence regarding the effect of cardiovascular diagnostics/treatments on falls is small. Our findings can be used to optimize fall prevention strategies and develop an evidence-based fall prevention care pathway. Adhering to the World guidelines on fall prevention recommendations, it is crucial to undertake a standardized assessment of cardiovascular risk factors, followed by supplementary testing and corresponding interventions, as effective components of fall prevention strategies. In addition, accompanying diagnostics such as blood pressure variability and head turning can be of added value.

Therapeutic dilemmas: cognitive enhancers and risk of falling in older adults-a clinical review.

PURPOSE: Cognitive enhancers are the primary pharmacological therapy prescribed to those with dementia, comprising of memantine and the acetylcholinesterase inhibitors (AChEIs). The long-term cognitive and behavioural benefits of these medications, as well as their potential contribution to falls is currently debated, with recent Delphi studies being unable to reach consensus on whether these medications should be deprescribed. In this narrative clinical review, as part of a series on deprescribing in people at risk of falls, we explore the potential falls-related side effects experienced in people taking cognitive enhancers, alongside situations where deprescribing may be appropriate. METHODS: We undertook a literature search of PubMed and Google Scholar, using terms capturing falls and cognitive enhancers, as well as consulting the British National Formulary and published Summary of Medicinal Product Characteristics. These searches informed the subsequent clinical review. RESULTS: Cognitive enhancers should be subject to regular review, including confirmation of appropriate treatment indication, and occurrence of side effects in the context of falls. AChEIs, in particular, are associated with a broad range of side effects that can contribute to increased falls risk. These include bradycardia, syncope and neuromuscular effects. Where these have been identified, deprescribing should be considered, as well as alternative treatment options. Deprescribing studies have shown mixed results, likely due to considerable methodological heterogeneity. Several suggested guidelines exist to aid deprescribing decisions, many of which are highlighted in this review. CONCLUSIONS: The use of cognitive enhancers should be regularly reviewed and decisions to deprescribe made on a case-by-case basis, considering both the risks and benefits of stopping these medications.

European position paper on polypharmacy and fall-risk-increasing drugs recommendations in the World Guidelines for Falls Prevention and Management: implications and implementation.

Falls prevention and management in older adults is a critical global challenge. One of the key risk factors for falls is the use of certain medications. Therefore, to prevent medication-related falls, the following is recommended in the recent World Guidelines for Falls Prevention and Management: (1) assess for fall history and the risk of falls before prescribing potential fall-risk-increasing drugs (FRIDs), (2) use a validated, structured screening and assessment tool to identify FRIDs when performing a medication review, (3) include medication review and appropriate deprescribing of FRIDs as a part of the multifactorial falls prevention intervention, and (4) in long-term care residents, if multifactorial intervention cannot be conducted due to limited resources, the falls prevention strategy should still always include deprescribing of FRIDs.In the present statement paper, the working group on medication-related falls of the World Guidelines for Falls Prevention and Management, in collaboration with the European Geriatric Medicine Society (EuGMS) Task and Finish group on FRIDs, outlines its position on how to implement and execute these recommendations in clinical practice.Preferably, the medication review should be conducted as part of a comprehensive geriatric assessment to produce a personalized and patient-centered assessment. Furthermore, the major pitfall of the published intervention studies so far is the suboptimal implementation of medication review and deprescribing. For the future, it is important to focus on gaining which elements determine successful implementation and apply the concepts of implementation science to decrease the gap between research and practice.

Applying systems thinking to unravel the mechanisms underlying orthostatic hypotension related fall risk.

Orthostatic hypotension (OH) is an established and common cardiovascular risk factor for falls. An in-depth understanding of the various interacting pathophysiological pathways contributing to OH-related falls is essential to guide improvements in diagnostic and treatment opportunities. We applied systems thinking to multidisciplinary map out causal mechanisms and risk factors. For this, we used group model building (GMB) to develop a causal loop diagram (CLD). The GMB was based on the input of experts from multiple domains related to OH and falls and all proposed mechanisms were supported by scientific literature. Our CLD is a conceptual representation of factors involved in OH-related falls, and their interrelatedness. Network analysis and feedback loops were applied to analyze and interpret the CLD, and quantitatively summarize the function and relative importance of the variables. Our CLD contains 50 variables distributed over three intrinsic domains (cerebral, cardiovascular, and musculoskeletal), and an extrinsic domain (e.g., medications). Between the variables, 181 connections and 65 feedback loops were identified. Decreased cerebral blood flow, low blood pressure, impaired baroreflex activity, and physical inactivity were identified as key factors involved in OH-related falls, based on their high centralities. Our CLD reflects the multifactorial pathophysiology of OH-related falls. It enables us to identify key elements, suggesting their potential for new diagnostic and treatment approaches in fall prevention. The interactive online CLD renders it suitable for both research and educational purposes and this CLD is the first step in the development of a computational model for simulating the effects of risk factors on falls.

Diuretics, SGLT2 inhibitors and falls in older heart failure patients: to prescribe or to deprescribe? A clinical review.

PURPOSE: Both heart failure and its treatment with diuretics or SGLT2 inhibitors increase fall risk in older adults. Therefore, decisions to continue or deprescribe diuretics or SGLT2 inhibitors in older heart failure patients who have fallen are generally highly complex and challenging for clinicians. However, a comprehensive overview of information required for rationale and safe decision-making is lacking. The aim of this clinical review was to assist clinicians in safe (de)prescribing of these drug classes in older heart failure patients. METHODS: We comprehensively searched and summarized published literature and international guidelines on the efficacy, fall-related safety issues, and deprescribing of the commonly prescribed diuretics and SGLT2 inhibitors in older adults. RESULTS: Both diuretics and SGLT2 inhibitors potentially cause various fall-related adverse effects. Their fall-related side effect profiles partly overlap (e.g., tendency to cause hypotension), but there are also important differences; based on the currently available evidence of this relatively new drug class, SGLT2 inhibitors seem to have a favorable fall-related adverse effect profile compared to diuretics (e.g., low/absent tendency to cause hyperglycemia or electrolyte abnormalities, low risk of worsening chronic kidney disease). In addition, SGLT2 inhibitors have potential beneficial effects (e.g., disease-modifying effects in heart failure, renoprotective effects), whereas diuretic effects are merely symptomatic. CONCLUSION: (De)prescribing diuretics and SGLT2 inhibitors in older heart failure patients who have fallen is often highly challenging, but this clinical review paper assists clinicians in individualized and patient-centered rational clinical decision-making: we provide a summary of available literature on efficacy and (subclass-specific) safety profiles of diuretics and SGLT2 inhibitors, and practical guidance on safe (de)prescribing of these drugs (e.g. a clinical decision tree for deprescribing diuretics in older adults who have fallen).

Deprescribing practices, habits and attitudes of geriatricians and geriatricians-in-training across Europe: a large web-based survey.

PURPOSE: To provide an overview of the current deprescribing attitudes, practices, and approaches of geriatricians and geriatricians-in-training across Europe. METHODS: An online survey was disseminated among European geriatricians and geriatricians-in-training. The survey comprised Likert scale and multiple-choice questions on deprescribing approaches and practices, deprescribing education and knowledge, and facilitators/barriers of deprescribing. Responses to the survey questions and participant characteristics were quantified and differences evaluated between geriatricians and geriatricians-in-training and between European regions. RESULTS: The 964 respondents (median age 42 years old; 64% female; 21% geriatricians-in-training) were generally willing to deprescribe (98%) and felt confident about deprescribing (85%). Despite differences across European regions, the most commonly reported reasons for deprescribing were functional impairment and occurrence of adverse drug reactions. The most important barriers for deprescribing were patients' unwillingness, fear of negative consequences, lack of time, and poor communication between multiple prescribers. Perceived risk of adverse drug reactions was highest for psychotropic drugs, nonsteroidal anti-inflammatory drugs, cardiovascular drugs, and opioid analgesics. Only one in four respondents (23% of geriatricians and 37% of geriatricians-in-training) think education in medical school had sufficiently prepared them for deprescribing in clinical practice. They reported that their future deprescribing activities would probably increase with improved information sharing between various prescribers, deprescribing recommendations in guidelines, and increased education and training. Approximately 90% think that a paradigm shift is required for prescribers and patients, increasing focus on the possible benefits of deprescribing (potentially) inappropriate medications. CONCLUSIONS: Based on the outcomes of this survey, we recommend investing in improved inter-professional communication, better education and evidence-based recommendations to improve future patient-centered deprescribing practices.

Medication reviews and deprescribing as a single intervention in falls prevention: a systematic review and meta-analysis.

BACKGROUND: our aim was to assess the effectiveness of medication review and deprescribing interventions as a single intervention in falls prevention. DESIGN: systematic review and meta-analysis. DATA SOURCES: Medline, Embase, Cochrane CENTRAL, PsycINFO until 28 March 2022. ELIGIBILITY CRITERIA: randomised controlled trials of older participants comparing any medication review or deprescribing intervention with usual care and reporting falls as an outcome. STUDY RECORDS: title/abstract and full-text screening by two reviewers. RISK OF BIAS: Cochrane Collaboration revised tool. DATA SYNTHESIS: results reported separately for different settings and sufficiently comparable studies meta-analysed. RESULTS: forty-nine heterogeneous studies were included. COMMUNITY: meta-analyses of medication reviews resulted in a risk ratio (RR) of 1.05 (95% confidence interval, 0.85-1.29, I2 = 0%, 3 studies(s)) for number of fallers, in an RR = 0.95 (0.70-1.27, I2 = 37%, 3 s) for number of injurious fallers and in a rate ratio (RaR) of 0.89 (0.69-1.14, I2 = 0%, 2 s) for injurious falls. HOSPITAL: meta-analyses assessing medication reviews resulted in an RR = 0.97 (0.74-1.28, I2 = 15%, 2 s) and in an RR = 0.50 (0.07-3.50, I2 = 72% %, 2 s) for number of fallers after and during admission, respectively. LONG-TERM CARE: meta-analyses investigating medication reviews or deprescribing plans resulted in an RR = 0.86 (0.72-1.02, I2 = 0%, 5 s) for number of fallers and in an RaR = 0.93 (0.64-1.35, I2 = 92%, 7 s) for number of falls. CONCLUSIONS: the heterogeneity of the interventions precluded us to estimate the exact effect of medication review and deprescribing as a single intervention. For future studies, more comparability is warranted. These interventions should not be implemented as a stand-alone strategy in falls prevention but included in multimodal strategies due to the multifactorial nature of falls.PROSPERO registration number: CRD42020218231.

Impact of cardiovascular evaluations and interventions on fall risk in older adults: a protocol for a scoping review and evidence map.

INTRODUCTION: Cardiovascular disorders are increasingly recognised as important fall risk factors in older adults. Falls are a major public health problem in older adults, and therefore, effective interventions for reducing falls are essential for this population. Cardiovascular disease is a clinically relevant (but often overlooked) and potentially modifiable risk factor for falls. Literature describing the effects of cardiovascular assessments and treatments on fall prevention has generally focused on only one specific test or treatment. A comprehensive, comparative overview surrounding the effectiveness of available assessments and treatments on cardiovascular related fall risk is currently lacking. METHODS AND ANALYSIS: A scoping review and evidence map will be conducted to summarise the available evidence regarding the (comparative) effectiveness of cardiovascular assessments and therapeutic interventions on reducing fall risk in older individuals. A systematic and comprehensive literature search will be performed in MEDLINE and Embase using the key components 'older adults', 'cardiovascular evaluation', 'cardiovascular intervention' and 'falls'. Furthermore, we will create an evidence map to summarise the quantity and quality of currently available evidence identified in the scoping review. The evidence map will consider, but will not be limited to, observational studies, randomised controlled trials and reviews evaluating cardiovascular tests and treatments (vs controls) on fall risk in older adults. ETHICS AND DISSEMINATION: The scoping review and evidence map will only include data that are publicly available and, therefore, ethical approval is not required. The results will be submitted for publication in a peer-reviewed journal and presented at scientific conferences.

Opioids and Falls Risk in Older Adults: A Narrative Review.

Pain treatment is important in older adults but may result in adverse events such as falls. Opioids are effective for nociceptive pain but the evidence for neuropathic pain is weak. Nevertheless, both pain and opioids may increase the risk of falls. This narrative literature review aims to summarize the existing knowledge on the opioid-related fall risk in older adults, including the pharmacokinetics and pharmacodynamics, and assist clinicians in prescribing and deprescribing opioids in older persons. We systematically searched relevant literature on opioid-related fall risk in older adults in PubMed and Scopus in December 2020. We reviewed the literature and evaluated fall-related adverse effects of opioids, explaining how to optimally approach deprescribing of opioids in older adults. Opioid use increases fall risk through drowsiness, (orthostatic) hypotension and also through hyponatremia caused by weak opioids. When prescribing, opioids should be started with low dosages if possible, keeping in mind their metabolic genetic variation. Falls are clinically significant adverse effects of all opioids, and the risk may be dose dependent and highest with strong opioids. The risk is most prominent in older adults prone to falls. To reduce the risk of falls, both pain and the need for opioids should be assessed on a regular basis, and deprescribing or changing to a lower dosage or safer alternative should be considered if the clinical condition allows. Deprescribing should be done by reducing the dosage gradually and by assessing and monitoring the pain and withdrawal symptoms at the same time. Weighing the risks and benefits is necessary before prescribing opioids, especially to older persons at high risk of falls. Clinical decision tools assist prescribers in clinical decisions regarding (de-) prescribing.

[Whether or not to use gabapentinoids in adults with chronic neuropathic pain]. / Wel of geen gabapentinoïden bij volwassenen met chronische neuropathische pijn?

CASE DESCRIPTION: A frail 85-year-old woman with chronic neuropathic pain after hip surgery, not responding to treatment with acetaminophen and morphine patches. Should she be prescribed a gabapentinoid? DISCUSSION: Gabapentinoids and antidepressants are considered first-line therapies. They achieve clinically relevant (i.e. ≥ 50%) pain reduction in approximately one-third of patients with postherpetic neuralgia and peripheral diabetic neuropathy. Evidence for other types of neuropathic pain is limited. Adverse events occur frequently and are mostly mild in nature; serious adverse effects are rare. Prescription of gabapentinoids in specific patient groups (e.g. elderly patients and patients with a history of depression or substance abuse) deserves careful consideration, because the risk/benefit ratio in those groups may be altered. In order to reduce the risk of withdrawal symptoms, slow tapering is recommended. CONCLUSION: Chronic neuropathic pain often has a negative impact on the quality of life and is difficult to treat. In general, treatment with a gabapentinoid is a possible first-line treatment option. However, they may be relatively contraindicated in vulnerable patients.

Characterization of immune cell, endothelial, and renal responses upon experimental human endotoxemia.

INTRODUCTION: Although the effects of relatively high concentrations of endotoxin on endothelial activation/dysfunction and kidney markers has been described in literature, detailed insight in the LPS concentration-effect relationship, the magnitude, variability and timing of the response, and potential effects of endotoxemia on the kidneys is lacking. A study was performed to assess the effects of low- to moderate dose (0.5, 1 or 2ng/kg) endotoxemia on the endothelium and kidneys as measured by a panel of novel highly sensitive kidney injury markers. METHODS: This was a randomized, double-blind, placebo-controlled study with single ascending doses of LPS (0.5, 1 or 2ng/kg) administered to healthy male volunteers (3 cohorts of 8 subjects, LPS:placebo 6:2). Endothelial measures included selectins, cell adhesion molecules, and thrombomodulin. Renal measures included novel, sensitive and specific biomarkers of acute kidney injury. RESULTS: Endotoxin exposure resulted in consistent LPS dose-dependent responses in inflammatory markers, E- and P- Selectin, VCAM1, ICAM1, and thrombomodulin. The observed biological responses were transient, reaching a level of significance of at least <0.01 in the highest dose group and with an effect size which was dependent on the administered LPS dose. LPS-induced inflammatory and endothelial effects did not translate into a change in renal damage biomarkers, although at 2ng/kg LPS, subtle and transient biomarker changes were observed that may relate to (subclinical) tubular damage. DISCUSSION: We demonstrated that administration of a single LPS dose of 2ng/kg to healthy volunteers results in significant inflammatory and endothelial responses, without inducing clinically relevant signs of kidney injury. These findings support the application of the human endotoxemia model in future clinical pharmacology studies.

Antisense-mediated reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9): a first-in-human randomized, placebo-controlled trial.

AIMS: LDL-receptor expression is inhibited by the protease proprotein convertase subtilisin/kexin type 9 (PCSK9), which is considered a pharmacological target to reduce LDL-C concentrations in hypercholesterolaemic patients. We performed a first-in-human trial with SPC5001, a locked nucleic acid antisense inhibitor of PCSK9. METHODS: In this randomized, placebo-controlled trial, 24 healthy volunteers received three weekly subcutaneous administrations of SPC5001 (0.5, 1.5 or 5 mg kg(-1)) or placebo (SPC5001 : placebo ratio 6 : 2). End points were safety/tolerability, pharmacokinetics and efficacy of SPC5001. RESULTS: SPC5001 plasma exposure (AUC(0,24 h)) increased more than dose-proportionally. At 5 mg kg(-1), SPC5001 decreased target protein PCSK9 (day 15 to day 35: -49% vs. placebo, P < 0.0001), resulting in a reduction in LDL-C concentrations (maximal estimated difference at day 28 compared with placebo -0.72 mmol l(-1), 95% confidence interval - 1.24, -0.16 mmol l(-1); P < 0.01). SPC5001 treatment (5 mg kg(-1)) also decreased ApoB (P = 0.04) and increased ApoA1 (P = 0.05). SPC5001 administration dose-dependently induced mild to moderate injection site reactions in 44% of the subjects, and transient increases in serum creatinine of ≥20 µmol l(-1) (15%) over baseline with signs of renal tubular toxicity in four out of six subjects at the highest dose level. One subject developed biopsy-proven acute tubular necrosis. CONCLUSIONS: SPC5001 treatment dose-dependently inhibited PCSK9 and decreased LDL-C concentrations, demonstrating human proof-of-pharmacology. However, SPC5001 caused mild to moderate injection site reactions and renal tubular toxicity, and clinical development of SPC5001 was terminated. Our findings underline the need for better understanding of the molecular mechanisms behind the side effects of compounds such as SPC5001, and for sensitive and relevant renal toxicity monitoring in future oligonucleotide studies.

Acute kidney injury during therapy with an antisense oligonucleotide directed against PCSK9.

Antisense oligonucleotides have been explored widely in clinical trials and generally are considered to be nontoxic for the kidney, even at high concentrations. We report a case of toxic acute tubular injury in a healthy 56-year-old female volunteer after a pharmacologically active dose of a locked nucleic acid antisense oligonucleotide was administered. The patient received 3 weekly subcutaneous doses of experimental drug SPC5001, an antisense oligonucleotide directed against PCSK9 (proprotein convertase subtilisin/kexin type 9) that is under investigation as an agent to reduce low-density lipoprotein cholesterol levels. Five days after the last dose, the patient's serum creatinine level increased from 0.81 mg/dL at baseline (corresponding to an estimated glomerular filtration rate [eGFR] of 78 mL/min/1.73 m(2)) to 2.67 mg/dL (eGFR, 20 mL/min/1.73 m(2)), and this increase coincided with the presence of white blood cells, granular casts, and minimal hematuria on urine microscopy. The patient's serum creatinine level peaked at 3.81 mg/dL (eGFR, 13 mL/min/1.73 m(2)) 1 week after the last oligonucleotide dose. Kidney biopsy showed multifocal tubular necrosis and signs of oligonucleotide accumulation. Upon conservative treatment, the patient's serum creatinine level gradually decreased and reached her baseline level 44 days after the last oligonucleotide was administered. The patient recovered fully and kidney function was normal at every follow-up visit.

Bramwell-Hill modeling for local aortic pulse wave velocity estimation: a validation study with velocity-encoded cardiovascular magnetic resonance and invasive pressure assessment.

BACKGROUND: The Bramwell-Hill model describes the relation between vascular wall stiffness expressed in aortic distensibility and the pulse wave velocity (PWV), which is the propagation speed of the systolic pressure wave through the aorta. The main objective of this study was to test the validity of this model locally in the aorta by using PWV-assessments based on in-plane velocity-encoded cardiovascular magnetic resonance (CMR), with invasive pressure measurements serving as the gold standard. METHODS: Seventeen patients (14 male, 3 female, mean age ± standard deviation = 57 ± 9 years) awaiting cardiac catheterization were prospectively included. During catheterization, intra-arterial pressure measurements were obtained in the aorta at multiple locations 5.8 cm apart. PWV was determined regionally over the aortic arch and locally in the proximal descending aorta. Subsequently, patients underwent a CMR examination to measure aortic PWV and aortic distention. Distensibility was determined locally from the aortic distension at the proximal descending aorta and the pulse pressure measured invasively during catheterization and non-invasively from brachial cuff-assessment. PWV was determined regionally in the aortic arch using through-plane and in-plane velocity-encoded CMR, and locally at the proximal descending aorta using in-plane velocity-encoded CMR. Validity of the Bramwell-Hill model was tested by evaluating associations between distensibility and PWV. Also, theoretical PWV was calculated from distensibility measurements and compared with pressure-assessed PWV. RESULTS: In-plane velocity-encoded CMR provides stronger correlation (p = 0.02) between CMR and pressure-assessed PWV than through-plane velocity-encoded CMR (r = 0.69 versus r = 0.26), with a non-significant mean error of 0.2 ± 1.6 m/s for in-plane versus a significant (p = 0.006) error of 1.3 ± 1.7 m/s for through-plane velocity-encoded CMR. The Bramwell-Hill model shows a significantly (p = 0.01) stronger association between distensibility and PWV for local assessment (r = 0.8) than for regional assessment (r = 0.7), both for CMR and for pressure-assessed PWV. Theoretical PWV is strongly correlated (r = 0.8) with pressure-assessed PWV, with a statistically significant (p = 0.04) mean underestimation of 0.6 ± 1.1 m/s. This theoretical PWV-estimation is more accurate when invasively-assessed pulse pressure is used instead of brachial cuff-assessment (p = 0.03). CONCLUSIONS: CMR with in-plane velocity-encoding is the optimal approach for studying Bramwell-Hill associations between local PWV and aortic distensibility. This approach enables non-invasive estimation of local pulse pressure and distensibility.

Endothelial cell chimerism occurs more often and earlier in female than in male recipients of kidney transplants.

BACKGROUND: Endothelial chimerism occurs in renal transplants, but factors involved in its development and its impact on outcome, are unknown. Most studies on chimerism are restricted to gender-mismatched combinations of female donor organs into male recipients. By using blood group antigen mismatches to detect chimeric cells, we circumvented this restriction. We determined which factors predispose for the development of endothelial chimerism, and how it influences graft survival. METHODS: We studied 85 renal transplant biopsies of 24 patients with either blood group A or B, who received a blood group O kidney. Biopsies were scored according to BANFF '97. Blood group antigens were stained by immunohistochemistry. Semiquantitative scoring was performed by four independent observers. RESULTS: Endothelial chimerism was found in 27/85 biopsies from 16/24 patients. All female recipients, but only half of the male recipients, had endothelial chimerism in their grafts (P < 0.025). In female recipients, endothelial chimerism occurred significantly earlier than in male recipients (P < 0.02). The presence of endothelial chimerism was not associated with: rejection, outcome, original renal disease, previous transplantations, age, warm/cold ischemia time, pretransplantation blood urea levels, or erythropoietin therapy. CONCLUSION: We are the first to report that endothelial chimerism occurs significantly more often in female than in male recipients of renal transplants. Endothelial chimerism had no influence on graft outcome. We hypothesize that hormonal factors may influence the development of endothelial chimerism, in parallel with differences in endothelial function between males and females in cardiovascular disease.