Low Phase Angle Values Are Associated with Malnutrition according to the Global Leadership Initiative on Malnutrition Criteria in Kidney Transplant Candidates: Preliminary Assessment of Diagnostic Accuracy in the FRAILMar Study.

Malnutrition has a negative impact on patients with chronic diseases and its early identification is a priority. The primary objective of this diagnostic accuracy study was to assess the performance of the phase angle (PhA), a bioimpedance analysis (BIA)-derived parameter, for malnutrition screening using the Global Leadership Initiative for Malnutrition (GLIM) criteria as the reference standard in patients with advanced chronic kidney disease (CKD) waiting for kidney transplantation (KT); criteria associated with low PhA in this population were also analyzed. Sensitivity, specificity, accuracy, positive and negative likelihood ratios, predictive values, and area under the receiver operating characteristic curve were calculated for PhA (index test) and compared with GLIM criteria (reference standard). Of 63 patients (62.9 years old; 76.2% men), 22 (34.9%) had malnutrition. The PhA threshold with the highest accuracy was ≤4.85° (sensitivity 72.7%, specificity 65.9%, and positive and negative likelihood ratios 2.13 and 0.41, respectively). A PhA ≤ 4.85° was associated with a 3.5-fold higher malnutrition risk (OR = 3.53 (CI95% 1.0-12.1)). Considering the GLIM criteria as the reference standard, a PhA ≤ 4.85° showed only fair validity for detecting malnutrition, and thus cannot be recommended as a stand-alone screening tool in this population.

Alloimmune risk assessment for antibody-mediated rejection in kidney transplantation: A practical proposal.

Kidney transplantation is the treatment of choice for patients with end-stage renal disease. Although an improvement in graft survival has been observed in the last decades with the use of different immunosuppressive drugs, this is still limited in time with antibody-mediated rejection being a main cause of graft-loss. Immune monitoring and risk assessment of antibody-mediated rejection before and after kidney transplantation with useful biomarkers is key to tailoring treatments to achieve the best outcomes. Here, we provide a review of the rationale and several accessible tools for immune monitoring, from the most classic to the modern ones. Finally, we end up discussing a practical proposal for alloimmune risk assessment in kidney transplantation, including histocompatibility leukocyte antigen (HLA) and non-HLA antibodies, HLA molecular mismatch analysis and characterization of peripheral blood immune cells.

Changes in acute headache medication use and health care resource utilization: Results from a randomized, double-blind, placebo-controlled clinical trial evaluating galcanezumab in adults with treatment-resistant migraine (CONQUER).

BACKGROUND: Patients with migraine, particularly with multiple prior preventive treatment failures, often have high rates of acute headache medication use and are at risk for overuse (acute or symptomatic headache medication use between 10 and 15 days per month [depending on the medication] for > 3 months). Furthermore, these patients have greater health care resource utilization (HCRU). OBJECTIVE: To examine acute headache medication use and HCRU with galcanezumab compared with placebo in a population with multiple prior migraine preventive treatment failures. METHODS: In the 3-month double-blind phase, patients with episodic or chronic migraine and treatment failures to 2 to 4 standard-of-care migraine preventive categories (lack of effectiveness or safety/tolerability) received galcanezumab 120 mg/month (following a 240-mg loading dose) or placebo; an optional 3 month open-label phase followed. Acute headache medication use (monthly days with acute headache medication utilization) was self-reported daily. The change from baseline in monthly days with acute headache medication used a mixed-model repeated measures analysis. HCRU was reported at baseline (for the previous 6 months) and at monthly visits. Migraine-related HCRU rates were evaluated in the total population per 100 patient-years. RESULTS: Of the 462 patients (galcanezumab n=232, placebo n=230), baseline mean days/month of acute headache medication was 12.3; 44.8% had acute headache medication overuse. Across months 1-3, least squares (LS) mean reductions in acute headache medication use were greater for the galcanezumab group (4.2) compared with placebo (0.9); the LS mean difference was 3.4 (95% CI = 2.7-4.1; P < 0.0001). Greater reductions in the galcanezumab group were observed as early as month 1; statistical separation continued at months 2 and 3 (all P < 0.0001). During the open-label phase, reductions from baseline ranged from 4.7 to 5.3 days and were similar in patients who transitioned from placebo to patients continuing galcanezumab. Reductions from baseline of migraine-specific health care visits (double-blind phase) were numerically greater with galcanezumab than placebo (215.5 vs 155.3). Patients switching to galcanezumab had reductions (212.9 days) similar to patients continuing galcanezumab (222.6 days). Migraine-specific emergency department visits decreased by two-thirds at month 3 in the galcanezumab group compared with nearly no reduction in the placebo group that experienced a similar reduction during the open-label phase. For both groups, migraine-specific hospitalizations were less than 2 per 100 patient-years. CONCLUSIONS: These results demonstrate that galcanezumab has the potential to reduce acute headache medication use and overuse and HCRU in patients with prior migraine preventive treatment failures. DISCLOSURES: Data were presented in part as a poster presentation at the 14th European Headache Congress (European Headache Federation), Virtual Meeting, July 3-5, 2020. Dr Ambrosini is on the advisory board for Eli Lilly and Company and received honorarium from Teva, Novartis, and Eli Lilly and Company. Dr Estemalik is on the advisory boards for Eli Lilly and Company, Lundbeck, and Allergan and the speakers' bureau for Teva, Lundbeck, Eli Lilly and Company, Allergan, and Biohaven. He received consulting fees from Eli Lilly and Company, Teva, Lundbeck, and Allergan and support for attending meetings and/or travel from Eli Lilly and Company, Allergan, Biohaven, Teva, and Lundbeck. Dr Pascual received research support from Instituto de Salud Carlos III, Ministry of Economy, Spain. He was also on advisory boards for Allergan, Amgen-Novartis, Eli Lilly and Company, and Stendhal and received consulting fees or honoraria from Allegan, Eli Lilly and Company, Novartis-Amgen, and Teva. Dr Rettiganti is an employee of Eli Lilly and Company and/or one of its subsidiaries, Indianapolis, IN. She is also a minor stock and restricted stockholder of Eli Lilly and Company. Mr. Stroud and Ms. Day are employees of Eli Lilly and Company and/or one of its subsidiaries, Indianapolis, IN. Dr Ford is an employee of and holds stock of Eli Lilly and Company and/or one of its subsidiaries, Indianapolis, IN. She also received support for attending meetings and/or travel from Eli Lilly and Company.

Low-value care practice in headache: a Spanish mixed methods research study.

BACKGROUND: Headache is one of the most prevalent diseases. The Global Burden of Disease Study ranks it as the seventh most common disease overall and the second largest neurological cause of disability in the world. The "Do Not Do" recommendations are a strategy for increasing the quality of care and reducing the cost of care for headache. This study aimed to identify specific low-value practices in headache care, determine their frequency, and estimate the cost overrun that they represent, in order to establish "Do not Do" recommendations specifically for headache by consensus and according to scientific evidence. METHODS: This was a mixed methods research study that combined qualitative consensus-building techniques, involving a multidisciplinary panel of experts to define the "Do Not Do" recommendations in headache care, and a retrospective observational study with review of a randomized set of patient records from the past 6 months in four hospitals, to quantify the frequency of these "Do Not Do" practices. We calculated the sum of direct costs of medical consultations, medicines, and unnecessary diagnostic tests. RESULTS: Seven "Do Not Do" recommendations were established for headache. In total, 3507 medical records were randomly reviewed. Low-value practices had a highly variable occurrence, depending on the hospital and type of headache. Overall, 34.1% of low-value practices were related to treatment, 21% were related to overuse of imaging in consultation, and 19% were related to emergency care. The estimated cost of low-value practices in the four hospitals was 203,520.47 euros per 1000 patients. CONCLUSIONS: This study identified low-value headache practices that need to be eradicated and provided data on their frequency and cost overruns.

Luminex screening first vs. direct single antigen bead assays: Different strategies for HLA antibody monitoring after kidney transplantation.

MAIN PROBLEM: Luminex panel and single antigen beads (SAB) are used for screening and DSA specificity determination respectively. The cost of SAB may limit its general use, so some labs perform SAB tests only after positive screening. METHODS: We compared both strategies: 1) SAB only if positive screening with kits from manufacturer A, and 2) direct SAB from manufacturer B, and correlate their sensitivity with histological findings. RESULTS: We selected 118 kidney transplant recipients with a normal biopsy (n = 19), histological antibody-mediated damage (ABMR, n = 52) or interstitial fibrosis/tubular atrophy (IFTA, n = 47) following Banff 2015 and 2017 classification. Direct SAB detected DSA in 13 patients missed by screening. Strategy 1 detected DSA in 0% normal, 61.5% ABMR and 8.5% IFTA patients; percentages with strategy 2 were 5.2%, 78.8% and 14.8% (p=0.004). Strategy 2 identified DSA allowing full ABMR diagnosis in 17% cases missed by strategy 1. Thereafter, direct SAB from manufacturer A confirmed DSA in 46% DSA-positive cases with strategy 2 (55.5% ABMR cases). CONCLUSIONS: Luminex screening failed to identify clinically relevant HLA antibodies, hampering DSA detection in patients with possible ABMR. Direct SAB testing should be the chosen strategy for post-transplantation monitoring, albeit direct SAB from the two existing manufacturers may diverge in as much as 50% of cases.

Optimization of tacrolimus in kidney transplantation: New pharmacokinetic perspectives.

Tacrolimus is the cornerstone of immunosuppressive therapy after kidney transplantation (KT), but its use is complicated by a narrow therapeutic index and high inter- and intra-patient pharmacokinetic variability. There are three available oral formulations of tacrolimus: immediate-release tacrolimus (IR-Tac), extended-release tacrolimus (ER-Tac) and a MeltDose® (LCPT) formulation, the latter favoring a prolonged drug release and increased bioavailability. The time-concentration curves of these formulations are different. Compared with IR-Tac and ER-Tac, LCPT has a relatively flat pharmacokinetic profile with less fluctuation between trough and peak exposures, and a delayed peak concentration. This translates to a more stable delivery of tacrolimus and may alleviate the risk of underexposure and allograft rejection or overexposure and toxicity. The once-daily formulation of both ER-TAC and LCPT may also offer a potential advantage on patient adherence. Fast metabolizers of tacrolimus, the elderly, and human leukocyte antigen-sensitized patients are at risk of poorer outcomes after KT, possibly associated with a different exhibited pharmacokinetics of tacrolimus or different requirements in terms of exposure. Simple, practical strategies are needed to identify patients at risk of suboptimal KT outcomes and those who would benefit from a more proactively personalized approach to tacrolimus treatment. This review aims to increase awareness of the link between the pharmacokinetics of oral tacrolimus formulations and the clinical needs of patients after KT, particularly among those who have clinically significant pharmacokinetic variation of tacrolimus.

Access to kidney transplantation in European adults aged 75-84 years and related outcomes: an analysis of the European Renal Association-European Dialysis and Transplant Association Registry.

To what extent access to, and allocation of kidney transplants and survival outcomes in patients aged ≥75 years have changed over time in Europe is unclear. We included patients aged ≥75-84 years (termed older adults) receiving renal replacement therapy in thirteen European countries between 2005 and 2014. Country differences and time trends in access to, and allocation of kidney transplants were examined. Survival outcomes were determined by Cox regression analyses. Between 2005 and 2014, 1392 older adult patients received 1406 transplants. Access to kidney transplantation varied from ~0% (Slovenia, Greece and Denmark) to ~4% (Norway and various Spanish regions) of all older adult dialysis patients, and overall increased from 0.3% (2005) to 0.9% (2014). Allocation of kidney transplants to older adults overall increased from 0.8% (2005) to 3.2% (2014). Seven-year unadjusted patient and graft survival probabilities were 49.1% (95% confidence interval, 95% CI: 43.6; 54.4) and 41.7% (95% CI: 36.5; 46.8), respectively, with a temporal trend towards improved survival outcomes. In conclusion, in the European dialysis population aged ≥75-84 years access to kidney transplantation is low, and allocation of kidney transplants remains a rare event. Though both are increasing with time and vary considerably between countries. The trend towards improved survival outcomes is encouraging. This information can aid informed decision-making regarding treatment options.

Advances in the evaluation of bone health in kidney transplant patients. / Avances en la valoración de la salud ósea en el trasplantado renal.

Bone disease related to chronic kidney disease and, particularly, to kidney transplant patients is a common cause or morbidity and mortality, especially due to a higher risk of osteoporotic fractures. Despite the fact that this has been known for decades, to date, an appropriate diagnostic strategy has yet to be established. Apart from bone biopsy, which is invasive and scarcely used, no other technique is available to accurately establish the risk of fracture in kidney patients. Techniques applied to the general population, such as bone densitometry, have not been subjected to sufficient external validation and their use is not systematic. This means that the identification of patients at risk of fracture and therefore those who are candidates for preventive strategies is an unmet need. Bone strength, defined as the ability of the bone to resist fracture, is determined by bone mineral density (measured by bone densitometry), trabecular architecture and bone tissue quality. The trabecular bone score estimates bone microarchitecture, and low values have been described as an independent predictor of increased fracture risk. Bone microindentation is a minimally invasive technique that measures resistance of the bone to micro-cracks (microscopic separation of mineralised collagen fibres), and therefore bone tissue biomechanical properties. The superiority over bone densitometry of the correlation between the parameters measured by trabecular bone score and microindentation with the risk of fracture in diverse populations led us to test its feasibility in chronic kidney disease and kidney transplant patients.

Strategies for an Expanded Use of Kidneys From Elderly Donors.

The old-for-old allocation policy used for kidney transplantation (KT) has confirmed the survival benefit compared to remaining listed on dialysis. Shortage of standard donors has stimulated the development of strategies aimed to expand acceptance criteria, particularly of kidneys from elderly donors. We have systematically reviewed the literature on those different strategies. In addition to the review of outcomes of expanded criteria donor or advanced age kidneys, we assessed the value of the Kidney Donor Profile Index policy, preimplantation biopsy, dual KT, machine perfusion and special immunosuppressive protocols. Survival and functional outcomes achieved with expanded criteria donor, high Kidney Donor Profile Index or advanced age kidneys are poorer than those with standard ones. Outcomes using advanced age brain-dead or cardiac-dead donor kidneys are similar. Preimplantation biopsies and related scores have been useful to predict function, but their applicability to transplant or refuse a kidney graft has probably been overestimated. Machine perfusion techniques have decreased delayed graft function and could improve graft survival. Investing 2 kidneys in 1 recipient does not make sense when a single KT would be enough, particularly in elderly recipients. Tailored immunosuppression when transplanting an old kidney may be useful, but no formal trials are available.Old donors constitute an enormous source of useful kidneys, but their retrieval in many countries is infrequent. The assumption of limited but precious functional expectancy for an old kidney and substantial reduction of discard rates should be generalized to mitigate these limitations.

Renal volume and cardiovascular risk assessment in normotensive autosomal dominant polycystic kidney disease patients.

Cardiovascular disease, closely related to an early appearance of hypertension, is the most common mortality cause among autosomal dominant polycystic kidney disease patients (ADPKD). The development of hypertension is related to an increase in renal volume. Whether the increasing in the renal volume before the onset of hypertension leads to a major cardiovascular risk in ADPKD patients remains unknown.Observational and cross-sectional study of 62 normotensive ADPKD patients with normal renal function and a group of 28 healthy controls. Renal volume, blood pressure, and renal (urinary albumin excretion), blood vessels (carotid intima media thickness and carotid-femoral pulse wave velocity), and cardiac (left ventricular mass index and diastolic dysfunction parameters) asymptomatic organ damage were determined and were considered as continuous variables. Correlations between renal volume and the other parameters were studied in the ADPKD population, and results were compared with the control group. Blood pressure values and asymptomatic organ damage were used to assess the cardiovascular risk according to renal volume tertiles.Even though in the normotensive range, ADPKD patients show higher blood pressure and major asymptomatic organ damage than healthy controls. Asymptomatic organ damage is not only related to blood pressure level but also to renal volume. Multivariate regression analysis shows that microalbuminuria is only associated with height adjusted renal volume (htTKV). An htTKV above 480 mL/m represents a 10 times higher prevalence of microalbuminuria (4.8% vs 50%, P < 0.001). Normotensive ADPKD patients from the 2nd tertile renal volume group (htTKV > 336 mL/m) show higher urinary albumin excretion, but the 3rd tertile htTKV (htTKV > 469 mL/m) group shows the worst cardiovascular risk profile.Normotensive ADPKD patients show in the early stages of the disease with slight increase in renal volume, higher cardiovascular risk than healthy controls. An htTKV above 468 mL/m is associated with the greatest increase in cardiovascular risk of normotensive ADPKD patients with normal renal function. Early strategies to slow the progression of the cardiovascular risk of these patients might be beneficial in their long-term cardiovascular survival.

Strategies to increase the donor pool and access to kidney transplantation: an international perspective.

In this position article, DESCARTES (Developing Education Science and Care for Renal Transplantation in European States) board members describe the current strategies aimed at expanding living and deceased donor kidney pools. The article focuses on the recent progress in desensitization and kidney paired exchange programmes and on the expanded criteria for the use of donor kidneys and organs from donors after circulatory death. It also highlights differences in policies and practices across different regions with special regard to European Union countries. Living donor kidney paired exchange, the deceased donor Acceptable Mismatch Programme and kidneys from donors after circulatory death are probably the most promising innovations for expanding kidney transplantation in Europe over the coming decade. To maximize success, an effort is needed to standardize transplant strategies, policies and legislation across European countries.

[Something's moving in chronic migraine]. / Algo se mueve en la migraña crónica.

TITLE: Algo se mueve en la migraña cronica.

[Rizatriptan: experience after 15 years of clinical use]. / Rizatriptan: experiencia tras 15 años de uso clinico.

We review the development of rizatriptan, one of the seven 5-HT1B/1D agonists available for the symptomatic treatment of migraine, emphasizing the most relevant contributions carried out from our country. Rizatriptan has shown the quickest onset of action, both in controlled studies and in the different metaanalyses, which translates in high efficacy levels at two hours. Its tolerability and safety profile is similar to that of the other compounds in this pharmacological group. Postlaunching studies have shown that its high efficacy leads to pharmacoeconomic savings and to a robust preference and satisfaction by the patient for this triptan. Its efficacy is improved with an early use within migraine attacks and recent data have shown also efficacy in adolescents. This global profile places rizatriptan as a triptan of first choice for any kind of migraine attacks.

TITLE: Rizatriptan: experiencia tras 15 años de uso clinico.En este trabajo se pasa revista al desarrollo del rizatriptan, uno de los siete agonistas 5-HT1B/1D disponibles para el tratamiento sintomatico de la migraña, prestando especial atencion a las aportaciones mas relevantes llevadas a cabo desde España. El rizatriptan ha demostrado ser el triptan con inicio de accion mas rapido, tanto en estudios comparativos controlados como en diversos metaanalisis, lo que se ha traducido en elevados niveles de eficacia a las dos horas. El perfil de seguridad y tolerabilidad de este triptan es similar al del resto de los compuestos de este grupo farmacologico. Los estudios poscomercializacion han evidenciado que su eficacia se traduce en ahorro farmacoeconomico y preferencia y satisfaccion del paciente con este triptan. Su eficacia mejora con su uso precoz dentro de la crisis de migraña, y datos recientes indican que el rizatriptan es util tambien en preadolescentes. Este perfil global posiciona al rizatriptan como un triptan de eleccion para cualquier tipo de crisis de migraña.

Responsiveness of migraine-ACT and MIDAS questionnaires for assessing migraine therapy.

BACKGROUND: Migraine is frequently undertreated. The 4-item Migraine Assessment of Current Therapy (Migraine-ACT) questionnaire is a simple and reliable tool to identify patients requiring a change in current acute migraine treatment. OBJECTIVE: To investigate the responsiveness of the Migraine-ACT tool, and compare it with that of the Migraine Disability Assessment (MIDAS) questionnaire, for patients with migraine at 1100 primary care sites in Spain. METHODS: Patients eligible for this open-label, 2-visit prospective study reported migraine for >1 year and >or=1 migraine attack per month and were new to the clinic or on follow-up care for <6 months. Validated Spanish versions of the Migraine-ACT and MIDAS questionnaires were administered, and patient satisfaction with treatment was recorded, at baseline and at 3 months. RESULTS: A total of 3272 patients, 78% female, were enrolled, and 2877 (88%) returned for the 3-month visit. Investigators changed baseline migraine treatment for 72% of returning patients; 85% and 80% of these patients had improved Migraine-ACT and MIDAS scores at 3 months, respectively. Patients who reported being completely or very satisfied with migraine treatment numbered 492 (15%) at baseline and 1406 (49%) at 3 months. Migraine-ACT and MIDAS score agreement for improvement at 3 months was poor (kappa = 0.339). Both the mean MIDAS score and the distribution of Migraine-ACT scores improved over the course of 3 months; however, Migraine-ACT scores were significantly (P < .001) more sensitive (83% vs 75%) and specific (72% vs 58%) than MIDAS scores. The area under the curve in the receiver-operating characteristic analysis was significantly (P < .0001) greater for Migraine-ACT (0.82) as compared with the MIDAS (0.70) questionnaire. CONCLUSIONS: These results suggest that the Migraine-ACT questionnaire can be used more reliably than the MIDAS questionnaire for detecting improvements in treatment of new and follow-up patients with migraine.