Large Cohort Of Spanish Patients Research Articles

P516 Subcutaneous infliximab cut-off points in a large cohort of Spanish patients with inflammatory bowel disease and factors associated with long-term outcomes

Abstract Background Evidence suggests that subcutaneous formulation of biosimilar infliximab (CT-P13) (SC-IFX) is capable to maintain clinical remission safely and to increase drug levels with a good acceptance in patients with Crohn’s disease (CD) and ulcerative colitis (UC) patients. The aims of this study were to evaluate which are the adequate drug concentration thresholds to maintain remission, and the factors involved in the long-term outcomes. Methods Multicentre, descriptive, and observational study including CD and UC patients who were going to be switched from IV-IFX to SC-IFX on the ENEIDA registry (a large, prospectively maintained database of the Spanish Working Group in IBD–GETECCU). All patients were on clinical remission at least 24 weeks before changing. Clinical activity, C reactive protein (CRP) and fecal calprotectin (FC), as well as trough levels were collected at baseline, at 12, 24 and 56 weeks. Results Two hundred and twenty patients were included 74 UC (34%) and 146 (66%) CD. IV-IFX was mainly administered due to active disease (73%) and perianal disease (12%) and for 52.5 months [range 25-89]. Pre-switch, 106 (49%) were with intensified IV-IFX dose and 97 (44%) were on concomitant immunomodulatory therapy (IMM). Many patients (172, 78%) remained with standard dose. While that SC-IFX levels significantly increased following the switch from IV to SC-IFX, clinical indices, CRP levels and FC remained unchanged during the 52 weeks of follow-up (figure). SC-IFX levels were significantly higher between patients receiving the standard IV-IFX dose than those receiving the intensified IV-IFX dose, but CRP and CF were significantly lower at all observed points. IMM at baseline and perianal disease had no effect on IFX trough levels. However, the higher body mass index was associated with a decrease in IFX trough levels. Low levels before switching and high levels at week 24 were associated with better outcomes. SC-IFX levels of 16.6 μg/dl (11.4-21.6) at week 12 were significantly associated with deep remission (CRP<5 mg/L and FC <250 μg/g) (p=0.017). The suggested optimal SC-IFX cut-off concentration in all patients and in both UC and CD is shown in the table. During 1 year of follow-up, 29 (13%) patients discontinued IMM, 19 (8.6%) had adverse events, 5 (2.3%) were hospitalised, 12 (23.2%) required surgery and 14 (6%) withdrawn SC-IFX. Global drug persistence was high (92% at week 52), but outcomes were worse in CD than in UC. Conclusion Switching from IV IFX to SC IFX has been shown to safely maintain long-term remission in patients with CD and UC. Our cut-off point for deep remission was 12.22 μg/g at week 12 and 13.23 μg/g at week 56.

Impact of programming in a large cohort of implantable cardioverter-defibrillator patients with long-term follow-up: findings from the UMBRELLA study

Abstract Background Data about the penetration of current ICD programming recommendations in a real-life setting are lacking. Purpose To assess how modern-era ICD patients are programmed and to study the relationship between programming and ICD therapies in large cohort of Spanish patients. Methods UMBRELLA (NTC01561144) is a prospective, multicentre, nationwide study of ICD patients followed by remote monitoring. ICD programming was performed according to regular clinical practice at each site and it was automatically stored through the remote monitoring system. Arrhythmic events were also automatically stored and reviewed in a blinded process performed by a committee of experts. The study outcomes were appropriate ICD therapies and inappropriate shocks (IS). Results The study population consisted of 4296 patients implanted with an ICD from 2005 to 2017 (61.9±12.9 years, ischaemic cardiomyopathy in 50% and dilated cardiomyopathy in 22.7% of population). Primary prevention (PP) was the main indication (64.2%). At implant, 66.4% of patients had LVEF ≤35% and 18.9% had LVEF >50%. Majority of patients (52.4%) presented with narrow QRS (<120 ms), while QRS width was >150 ms in 26.7% of population. Single-chamber, dual-chamber and cardiac resynchronization therapy-defibrillator (CRT-D) devices were implanted in 47.2%, 22.6% and 30.2% of population, respectively. At first remote transmission, single zone detection programming was only enabled in 43.2% of population (52.6% among PP patients), while the remaining patients (56.8%) had a ventricular tachycardia zone enabled, despite the ventricular fibrillation (VF) zone (73.8% among secondary prevention patients). Delayed high-rate detection programming (detection interval <320 ms and NID ≥30/40 within the VF zone) was only enabled in 39.7% of population. Adherence to programming recommendations significantly increased through the study period (Table). During a mean follow-up of 46.6±27.3 months, 16,067 episodes of sustained ventricular arrhythmia (SVA) occurred. An appropriate ICD therapy was delivered to 85.7% (n=13,767) episodes of SVA in 1173 patients (event rate: 27.3%). In multivariate analysis, delayed high-rate detection in PP patients (HR: 0.76, 95% CI: 0.61–0.94) (Figure) and single-zone programming (HR: 0.69, 95% CI: 0.59–0.81) were associated to lower risk of appropriate ICD therapies. At follow-up, 257 patients (6% of population) experienced an IS. The incidence of IS did not differ according to type of device (6.4% vs. 6.2% vs. 5.2% for single-, dual-chamber, and CRT-D, respectively, p=0.321). In multivariate analysis single-zone programming (HR: 0.71, 95% CI: 0.51–0.97) was the only ICD setting independently related to a lower risk of IS. Conclusions Implementation of current programming recommendations is required in modern-era ICD patients. Funding Acknowledgement Type of funding sources: None. Figure 1Table 1

Relevance of gastrointestinal manifestations in a large Spanish cohort of patients with systemic lupus erythematosus: what do we know?

SLE can affect any part of the gastrointestinal (GI) tract. GI symptoms are reported to occur in >50% of SLE patients. To describe the GI manifestations of SLE in the RELESSER (Registry of SLE Patients of the Spanish Society of Rheumatology) cohort and to determine whether these are associated with a more severe disease, damage accrual and a worse prognosis. We conducted a nationwide, retrospective, multicentre, cross-sectional cohort study of 3658 SLE patients who fulfil ≥4 ACR-97 criteria. Data on demographics, disease characteristics, activity (SLEDAI-2K or BILAG), damage (SLICC/ACR/DI) and therapies were collected. Demographic and clinical characteristics were compared between lupus patients with and without GI damage to establish whether GI damage is associated with a more severe disease. From 3654 lupus patients, 3.7% developed GI damage. Patients in this group (group 1) were older, they had longer disease duration, and were more likely to have vasculitis, renal disease and serositis than patients without GI damage (group 2). Hospitalizations and mortality were significantly higher in group 1. Patients in group 1 had higher modified SDI (SLICC Damage Index). The presence of oral ulcers reduced the risk of developing damage in 33% of patients. Having GI damage is associated with a worse prognosis. Patients on a high dose of glucocorticoids are at higher risk of developing GI damage which reinforces the strategy of minimizing glucocorticoids. Oral ulcers appear to decrease the risk of GI damage.

Transforming growth factor beta-induced p.(L558P) variant is associated with autosomal dominant lattice corneal dystrophy type IV in a large cohort of Spanish patients.

Rare transforming growth factor beta-induced (TGFBI) gene variants are involved in autosomal dominant corneal dystrophies (CDs) with heterogeneous clinical features. The purpose of this study was to analyse TGFBI gene variants and genotype-phenotype correlations in a cohort affected by atypical stromal CD. Retrospective cohort study (from May 2014 to September 2017). Thirty-five individuals from 10 unrelated South European families presenting atypical lattice CD (LCD) were included. Corneal phenotypes were assessed by slit-lamp examination and optical coherence tomography (OCT). Contrast sensitivity was measured under mesopic conditions. Genomic DNA was obtained from blood samples, and all 17 TGFBI exons were screened for variants by Sanger sequencing. p.(L558P) variant of TGFBI gene. The p.(L558P) variant was identified in 22 members of the 10 families diagnosed with atypical LCD, characterized by late-onset and absence of recurrent erosion syndrome. OCT revealed punctiform deposits in the deep-mid stroma and normal anterior stroma. This variant was demonstrated to be transmitted with the disease according to autosomal dominant inheritance in most families. To the best of our knowledge, we describe a detailed clinical characterization of the largest CD cohort carrying the TGFBI p.(L558P) variant. We propose that the atypical phenotype of this recently reported alteration can be classified as a form of LCD type IV. The results show that OCT and anterior-posterior analysis of the stromal location of the opacities, along with a genetic analysis of TGFBI, are required to ensure accurate diagnosis and management of CDs.

Screening pulmonary arteriovenous malformations in a large cohort of Spanish patients with hemorrhagic hereditary telangiectasia

Background and objectivesBecause of the serious nature of potential complications, screening for pulmonary arteriovenous malformations is required in patients with hereditary hemorrhagic telangiectasia. The aim of this study was to evaluate the utility of contrast echocardiography and compare the performance of two contrast agents: agitated saline and Gelofusine. Material and methodsTwo hundred and five patients screened for PAVMs using TTCE and computed tomography (CT) performed with an interval of less than 180days. Contrast echocardiography studies were graded on a 4-point semiquantitative scale based on the amount of microbubbles seen in left heart chambers. ResultsPositive TTCE findings were seen in 137 (66.8%) patients, whereas CT confirmed PAVMs in 59 (43.1%). Two of 67 grade 1 patients; 18 of 42 grade 2; 17 of 22 grade 3 and all grade 4 had PAVMs on CT. Embolotherapy was feasible in 38.9% patients in grade 2 and 82.3% and 95.2% in grades 3–4. No patients in grade 1 were embolized. The mean cardiac cycle in which bubbles were first seen in the left heart in patients without and with PAVMs on CT was 6.1 and 3.9 (p<0.0001). Compared to saline, Gelofusine produced an overall increase in grade. ConclusionsNo grade 1 patients had treatable PAVMs. There is a need for improvement in the selection of patients for CT in grade 2, where less than half have PAVMs on CT. The cardiac cycle may help to differentiate between patients with and without PAVMs. Gelofusine was not better than saline for PAVM screening.

Clinical manifestations and long-term outcome of anti-Jo1 antisynthetase patients in a large cohort of Spanish patients from the GEAS-IIM group.

To evaluate the clinical manifestations, long-term clinical outcome and longitudinal pulmonary function in a large cohort of Spanish patients with anti-Jo1 antibodies. We retrospectively analyzed the clinical data and lung function parameters of 148 anti-Jo1 patients recruited from a multicentre registry including 18 Spanish hospitals. A composite endpoint was defined, comprising death due to respiratory failure directly related to antisynthetase syndrome (ASS), the need for long-term oxygen therapy or lung transplantation. Median follow-up was 78.3 months. Clinical presentation patterns at onset are as follows: isolated interstitial lung disease (ILD) (32.4%), isolated myositis (26.9%), concomitant myositis and ILD (22.8%), and isolated polyarthritis (17.9%). Myositis with ILD was the most frequent final clinical phenotype (67.6%). In most ASS patients, ILD was a non-progressive disease, tending to stabilize with therapy. The endpoint was reached in a significantly larger number of ILD patients with dyspnea at onset than those with paucisymptomatic or asymptomatic forms (p = 0.01). A steady FVC decrease was the hallmark of patients with end-stage lung disease. Estimated survival rates were 87.7% and 75.4% at 5 and 10 years, respectively. Cancer (p = 0.02) and advanced age at ASS diagnosis (p < 0.0001) were related to poorer survival. Mortality was significantly higher than in the general Spanish population, with a standardised mortality ratio (95% CI) of 4.03 (2.79-5.64). Anti-Jo1 ASS is a heterogeneous syndrome. ILD in ASS under immunosuppressive therapy is mainly a non-progressive disease. Dyspnea at ILD onset and a steady FVC decrease over time were related to a poorer respiratory prognosis.

Cardiovascular Events in Systemic Lupus Erythematosus: A Nationwide Study in Spain From the RELESSER Registry.

This article estimates the frequency of cardiovascular (CV) events that occurred after diagnosis in a large Spanish cohort of patients with systemic lupus erythematosus (SLE) and investigates the main risk factors for atherosclerosis.RELESSER is a nationwide multicenter, hospital-based registry of SLE patients. This is a cross-sectional study. Demographic and clinical variables, the presence of traditional risk factors, and CV events were collected. A CV event was defined as a myocardial infarction, angina, stroke, and/or peripheral artery disease. Multiple logistic regression analysis was performed to investigate the possible risk factors for atherosclerosis.From 2011 to 2012, 3658 SLE patients were enrolled. Of these, 374 (10.9%) patients suffered at least a CV event. In 269 (7.4%) patients, the CV events occurred after SLE diagnosis (86.2% women, median [interquartile range] age 54.9 years [43.2–66.1], and SLE duration of 212.0 months [120.8–289.0]). Strokes (5.7%) were the most frequent CV event, followed by ischemic heart disease (3.8%) and peripheral artery disease (2.2%). Multivariate analysis identified age (odds ratio [95% confidence interval], 1.03 [1.02–1.04]), hypertension (1.71 [1.20–2.44]), smoking (1.48 [1.06–2.07]), diabetes (2.2 [1.32–3.74]), dyslipidemia (2.18 [1.54–3.09]), neurolupus (2.42 [1.56–3.75]), valvulopathy (2.44 [1.34–4.26]), serositis (1.54 [1.09–2.18]), antiphospholipid antibodies (1.57 [1.13–2.17]), low complement (1.81 [1.12–2.93]), and azathioprine (1.47 [1.04–2.07]) as risk factors for CV events.We have confirmed that SLE patients suffer a high prevalence of premature CV disease. Both traditional and nontraditional risk factors contribute to this higher prevalence. Although it needs to be verified with future studies, our study also shows—for the first time—an association between diabetes and CV events in SLE patients.

How are we treating our systemic patients with primary Sjögren syndrome? Analysis of 1120 patients

ObjectiveTo describe how systemic disease is treated in a large cohort of Spanish patients with primary Sjögren syndrome (pSS) in daily practice, focusing on the adequacy of therapies for the level of systemic activity measured by ESSDAI score. Patients and methodsBy December 2014, our database included 1120 consecutive patients who fulfilled the 2002 classification criteria for SS. Therapeutic schedules were classified into 4 categories: no systemic therapies, hydroxychloroquine (HCQ) and/or low dose glucocorticoids (GCS) (<20mg/day), high dose GCS (>20mg/day) and use of second-line therapies (immunosuppressive agents, intravenous immunoglobulins [IVIG] and/or rituximab [RTX]). ResultsThere were 1048 (94%) women and 72 (6%) men , with a mean age at diagnosis of 54 years. The main drug-based therapeutic approaches for systemic pSS during follow-up were HCQ in 282 (25%) patients, GCS in 475 (42%, at doses >20mg/day in 255—23%), immunosuppressive agents in 148 (13%), IVIG in 25 (2%) and RTX in 35 (3%) patients. HCQ was associated with a lower risk of death (adjusted HR of 0.57, 95% 0.34–0.95). We classified 16 (7%) of the 255 patients treated with >20mg GCS and 21/148 (14%) treated with immunosuppressive agents as patients inadequately treated, mainly associated with articular involvement of low/moderate activity. ConclusionThe management of pSS should be organ-specific, using low dose GCS in patients with moderate systemic activity, limiting the use of high dose GCS and second-line therapies to refractory or potentially severe scenarios. The use of systemic therapies for dryness, chronic pain or fatigue is not warranted.

OP0213 The Degree of Activity Measured with the EULAR-SS Disease Activity Index (ESSDAI) Strongly Correlated with Death in Patients with Primary Sjogren Syndrome (GEAS-SS REGISTRY)

ObjectivesTo analyse the association between the new 2010 EULAR-SS disease activity index (ESSDAI) and death in a large cohort of Spanish patients with primary Sjogren syndrome (pSS)MethodsThe GEAS-SS multicenter registry...

THU0032 Fibromyalgia Prevalence and Related Factors in A Large Spanish Cohort of Patients with Systemic Lupus Erythematosus

BackgroundSystemic lupus erythematosus (SLE) is an autoimmune disease that may affect multiple organs. Fibromyalgia (FM) is a physical, mental and social impairing disease. FM has been observed in SLE patients....

SAT0288 Eosinophilic Granulomatosis with Poliangeitis (EGPA): Clinical Features and Outcome in A Large Serie of Spanish Patients

ObjectivesTo analyze the demographic, clinical, laboratory features and outcome of patients with EGPA in a large cohort of Spanish patients with AAVMethodsmulticenter retrospective-longitudinal study that included patients diagnosed with AAV...

AB0631 Anti-Rna Polymerase III and anti Pm/Scl Antibodies: Prevalence and Clinical Associations in A Large Cohort of Spanish Patients with Systemic Sclerosis

BackgroundSome authors postulate that systemic sclerosis's (SSc) heterogenic expression is mostly conditioned by the positivity to any of its specific auto-antibodies.ObjectivesTo assess the prevalence of anti-RNA-polymerase III (RNA-pol III) and...

OP0211 Association between Systemic Activity and Lymphoma in Primary Sjogren Syndrome: Baseline Essdai Predictors in 921 Spanish Patients (GEAS-SS Registry)

ObjectivesTo analyse the epidemiological, clinical and analytical features at diagnosis and the usefulness the new 2010 European activity index (ESSDAI) to predict the development of lymphoproliferative disease in a large...

Systemic involvement in primary Sjogren's syndrome evaluated by the EULAR-SS disease activity index: analysis of 921 Spanish patients (GEAS-SS Registry)

To evaluate systemic involvement in primary SS in a large cohort of Spanish patients using the EULAR-SS disease activity index (ESSDAI) definitions. Systemic involvement was characterized using ESSDAI definitions for the 10 clinical domains (constitutional, lymphadenopathy, glandular, articular, cutaneous, pulmonary, renal, peripheral nervous system, central nervous system and muscular). ESSDAI scores at diagnosis, during follow-up and cumulated at the last visit were calculated. The cohort consisted of 921 patients. After a mean follow-up of 75 months, 77 (8%) patients still had an ESSDAI score of zero at the last visit. Organ by organ, the percentage of patients who developed activity during the follow-up (ESSDAI score ≥ 1 at any time) ranged between 1.4% and 56%, with articular, pulmonary and peripheral neurological involvement being the most common. Logistic multivariate regression analysis showed the following features at diagnosis and had the closest association with systemic activity (statistically significant independent variables in at least two domains): cryoglobulinaemia in five domains; anaemia, lymphopenia and low C3 levels in three domains each and age <35 years in two domains. Sicca features, ANA and RF at diagnosis were not associated with a higher cumulated activity score in any clinical domain. Primary SS is undeniably a systemic disease, with the joints, lungs, skin and peripheral nerves being the most frequently involved organs. Cytopenias, hypocomplementaemia and cryoglobulinaemia at diagnosis strongly correlated with higher cumulated ESSDAI scores in the clinical domains. Clinically the ESSDAI provides a reliable picture of systemic involvement in primary SS.

THU0226 Clinical features and mortality causes in a large cohort of spanish patients with anca associated vasculitides

BackgroundAntineutrophil cytoplasmic autoantibody (ANCA) associated vasculitides (AAV) are uncommon chronic and relapsing diseases characterized by inflammatory cell infiltration and necrosis of blood vessel walls. They often have overlapping clinical and...

Claudin-19 Mutations and Clinical Phenotype in Spanish Patients with Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is an autosomal recessive tubular disorder characterized by excessive renal magnesium and calcium excretion and chronic kidney failure. This rare disease is caused by mutations in the CLDN16 and CLDN19 genes. These genes encode the tight junction proteins claudin-16 and claudin-19, respectively, which regulate the paracellular ion reabsortion in the kidney. Patients with mutations in the CLDN19 gene also present severe visual impairment. Our goals in this study were to examine the clinical characteristics of a large cohort of Spanish patients with this disorder and to identify the disease causing mutations. We included a total of 31 patients belonging to 27 unrelated families and studied renal and ocular manifestations. We then analyzed by direct DNA sequencing the coding regions of CLDN16 and CLDN19 genes in these patients. Bioinformatic tools were used to predict the consequences of mutations. Clinical evaluation showed ocular defects in 87% of patients, including mainly myopia, nystagmus and macular colobomata. Twenty two percent of patients underwent renal transplantation and impaired renal function was observed in another 61% of patients. Results of the genetic analysis revealed CLDN19 mutations in all patients confirming the clinical diagnosis. The majority of patients exhibited the previously described p.G20D mutation. Haplotype analysis using three microsatellite markers showed a founder effect for this recurrent mutation in our cohort. We also identified four new pathogenic mutations in CLDN19, p.G122R, p.I41T, p.G75C and p.G75S. A strategy based on microsequencing was designed to facilitate the genetic diagnosis of this disease. Our data indicate that patients with CLDN19 mutations have a high risk of progression to chronic renal disease.

Lack of association between the functional c-kit rs6554199 polymorphism and achalasia in a Spanish population

A functional polymorphism (rs6554199) located in the c-kit gene was associated with achalasia in a Turkish cohort. Our aim was to replicate this result in a large cohort of Spanish patients and controls. A case-control study was performed with 282 Spanish white unrelated patients and 687 healthy controls. All were genotyped for SNP rs6554199 using a TaqMan Assay. No association was found in our study (T allele frequency in patients and controls: 47.3% vs. 49.4%; OR=0.92, p=0.41). The finding that the T allele of the c-kit rs6554199 polymorphism could be associated with achalasia as reported in a Turkish population could not be replicated in a Spanish cohort. Although ethnic differences might explain these data, the sample size that compromised the statistical power in the Turkish cohort and is higher in our study, led us to suggest that the reported association seems to be a false positive.

Registry of the Spanish Network for Systemic Sclerosis: Clinical Pattern According to Cutaneous Subsets and Immunological Status

To investigate the incidence of clinical and immunological characteristics of a large cohort of Spanish patients with scleroderma (SSc) and identifying factors associated with particular organ manifestations assessed by a nationwide cross-sectional analysis. We classified SSc patients in 4 subsets using a modification of LeRoy and Medsger classification that included: "prescleroderma" (pre-SSc), limited cutaneous SSc (lcSSc), diffuse cutaneous SSc (dcSSc), and SSc sine scleroderma (ssSSc). Fourteen Spanish centers participated in patient recruitment. On January 2008, the database included 916 consecutive Spanish SSc patients, 801 women (87.4%) and 115 men (12.6%), all of whom fulfilled the classification criteria proposed by LeRoy and Medsger. Epidemiological, clinical, and laboratory data were collected according to a standard protocol. Mean age at diagnosis was 51.2 ± 15.1 years and mean age at disease onset was 44.9.0 ± 15.8 years. lcSSc was the most frequent subset (61.8%) followed by dcSSc (26.5%), ssSSc (7.5%), and preSSc (4%) subsets. Gender ratios were as follows: dcSSc subset, 200 women and 43 men (4.7:1); lcSSc subset, 503 women and 63 men (ratio 7.9:1), and ssSSc subset, 62 women and 7 men (ratio 8.9:1). Digital ulcers, interstitial lung disease (ILD), musculoeskeletal and esophageal involvement, and scleroderma renal crisis were more frequent in dcSSc than lcSSc and ssSSc subsets. The incidence of pulmonary arterial hypertension assessed by echocardiography was similar in all subsets but mean estimated systolic pulmonary arterial pressure was higher in ssSSc than in lcSSc subset (47.3 ± 23.9 mm Hg vs 39.6 ± 19.2 mm Hg; P < 0.03). Cardiac involvement was identified more frequently in ssSSc than in dcSSc and lcSSc subsets (49.3% vs 32.5% and 31.1%, respectively; P = 0.015 and P = 0.004 for both comparisons). Acro-osteolysis (8.2% vs 2.4%, P = 0.049), calcinosis (19.8% vs 7.2%, P < 0.05), and sicca syndrome (37.5% vs 14.5%, P < 0.0001) were more frequent in lcSSc than in ssSSc subsets. The frequency of clinical manifestations related to the presence of anticentromere antibodies or antitopoisomerase I antibodies was very similar to that identified in patients categorized to lcSSc and dcSSc, respectively. However, in multivariate studies, the ranking of the variables according to their overall explanatory effect on the model showed that the contributory effect of the antibody status was not greater than that of the clinical categorization into lcSSc and dcSSc for the majority of disease manifestations, but, in important manifestations, as ILD, absence of anticentromere antibodies was an independent predictor factor. The classification of SSc into dcSSc, lcSSc, and ssSSc subsets is the one that most closely reflects the natural history of the disease, as they presented clear clinical differences. The immunological profile helps to define important visceral alteration as ILD. Finally, to improve early diagnosis of SSc, patients with preSSc should be considered both to trace the true evolution of the disease and to define which patients could benefit from therapeutic measures able to prevent the appearance of visceral involvements.

Baseline characteristics of patients with chronic kidney disease stage 3 and stage 4 in spain: the MERENA observational cohort study

BackgroundTo obtain information on cardiovascular morbidity, hypertension control, anemia and mineral metabolism based on the analysis of the baseline characteristics of a large cohort of Spanish patients enrolled in an ongoing prospective, observational, multicenter study of patients with stages 3 and 4 chronic kidney diseases (CKD).MethodsMulticenter study from Spanish government hospital-based Nephrology outpatient clinics involving 1129 patients with CKD stages 3 (n = 434) and 4 (n = 695) defined by GFR calculated by the MDRD formula. Additional analysis was performed with GFR calculated using the CKD-EPI and Cockcroft-Gault formula.ResultsIn the cohort as a whole, median age 70.9 years, morbidity from all cardiovascular disease (CVD) was very high (39.1%). In CKD stage 4, CVD prevalence was higher than in stage 3 (42.2 vs 35.6% p < 0.024). Subdividing stage 3 in 3a and 3b and after adjusting for age, CVD increased with declining GFR with the hierarchy (stage 3a < stage 3b < stage 4) when calculated by CKD-EPI (31.8, 35.4, 42.1%, p 0.039) and Cockcroft-Gault formula (30.9, 35.6, 43.4%, p 0.010) and MDRD formula (32.5, 36.2, 42.2%,) but with the latter, it did not reach statistical significance (p 0.882). Hypertension was almost universal among those with stages 3 and 4 CKD (91.2% and 94.1%, respectively) despite the use of more than 3 anti-hypertensive agents including widespread use of RAS blockers. Proteinuria (> 300 mg/day) was present in more than 60% of patients and there was no significant differences between stages 3 and 4 CKD (1.2 ± 1.8 and 1.3 ± 1.8 g/day, respectively). A majority of the patients had hemoglobin levels greater than 11 g/dL (91.1 and 85.5% in stages 3 and 4 CKD respectively p < 0.001) while the use of erythropoiesis-stimulating agents (ESA) was limited to 16 and 34.1% in stages 3 and 4 CKD respectively. Intact parathyroid hormone (i-PTH) was elevated in stage 3 and stage 4 CKD patients (121 ± 99 and 166 ± 125 pg/mL p 0.001) despite good control of calcium-phosphorus levels.ConclusionThis study provides an overview of key clinical parameters in patients with CKD Stages 3 and 4 where delivery or care was largely by nephrologists working in a network of hospital-based clinics of the Spanish National Healthcare System.

Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia

BackgroundHereditary Spastic Paraplegias (HSP) are characterized by progressive spasticity and weakness of the lower limbs. At least 45 loci have been identified in families with autosomal dominant (AD), autosomal recessive (AR), or X-linked hereditary patterns. Mutations in the SPAST (SPG4) and ATL1 (SPG3A) genes would account for about 50% of the ADHSP cases.MethodsWe defined the SPAST and ATL1 mutational spectrum in a total of 370 unrelated HSP index cases from Spain (83% with a pure phenotype).ResultsWe found 50 SPAST mutations (including two large deletions) in 54 patients and 7 ATL1 mutations in 11 patients. A total of 33 of the SPAST and 3 of the ATL1 were new mutations. A total of 141 (31%) were familial cases, and we found a higher frequency of mutation carriers among these compared to apparently sporadic cases (38% vs. 5%). Five of the SPAST mutations were predicted to affect the pre-mRNA splicing, and in 4 of them we demonstrated this effect at the cDNA level. In addition to large deletions, splicing, frameshifting, and missense mutations, we also found a nucleotide change in the stop codon that would result in a larger ORF.ConclusionsIn a large cohort of Spanish patients with spastic paraplegia, SPAST and ATL1 mutations were found in 15% of the cases. These mutations were more frequent in familial cases (compared to sporadic), and were associated with heterogeneous clinical manifestations.