Comparison Between Twenty-Four-Hour Collection and Single Spot Urines for the Detection of Biogenic Amines by High-Performance Liquid Chromatography Tandem Mass Spectrometry.

Background: Pheochromocytomas and paragangliomas (PPGL) are neuroendocrine tumors that originate from adrenal medulla or extra-adrenal chromaffin cells, respectively. They produce an excess of catecholamines and their metabolites. Abnormal levels of these biomolecules have been also found in pediatric patients with neuroblastoma (NB). Due to the diurnal fluctuation, the laboratory practice recommends the determination of biogenic amines in acidified 24-h urine samples. However, the collection and acidification of specimens cannot be performed easily, especially for children. Spot urines represent an attractive alternative for the detection of catecholamines and corresponding metabolites. Methods: In our study, we enrolled 50 patients with symptoms related to PPGL and we determined the concentration values for both spot and 24-h urine samples using high-performance liquid chromatography tandem mass spectrometry (HPLC/MS-MS). Since day variations of the urinary concentration are due to fluctuations in renal excretion rather than in production, we normalized the concentration of biogenic amines in spot urine and in 24-h urine collection to urinary creatinine concentration. A correlation study between the normalized levels of biogenic amines was performed using a linear regression analysis model and Pearson's correlation coefficients. Results: We obtained a good correlation of values which suggests an interchangeability of the 24-h and random urine samples. Only for epinephrine a weak correlation was determined. Conclusions: Our findings suggest that the sample collection as single spot urine may replace 24-h collection for the detection of urinary biogenic amines by HPLC/MS-MS.

Spot urinary sodium in CKD patients: correlation with 24h-excretion and evaluation of commonly used prediction equations.

BACKGROUND: Salt intake in CKD patients can affect cardiovascular risk and kidney disease progression. Twenty-four hour (24h) urine collections are often used to investigate salt metabolism but are cumbersome to perform. We assessed urinary sodium (U-Na) concentration in spot urine samples and investigated the correlation with 24h U-Na excretion and concentration in CKD patients under nephrological care. Further, we studied the role of CKD stage and diuretics and evaluated the performance of commonly used formulas for the prediction of 24h U-Na excretion from spot urine samples. METHODS: One hundred eight patients of the German Chronic Kidney Disease (GCKD) study were included. Each participant collected a 24h urine and two spot urine samples within the same period. The first spot urine sample (AM) was part of the second morning urine. The second urine sample was collected before dinner (PM). Patients were advised to take their medication as usual without changing dietary habits. U-Na concentrations in the two spot urine samples and their average ((AM + PM)/2) were correlated with U-Na concentration and total Na excretion in the 24h urine collections. Correlations were subsequently studied after stratification by CKD stage and diuretic intake. The usefulness of three commonly applied equations to estimate 24h U-Na excretion from spot urine samples (Kawasaki, Tanaka and Intersalt) was determined using Bland-Altman plots, analyses of sensitivity, specificity, as well as positive (PPV) and negative predictive values (NPV). RESULTS: Participants (42 women, 66 men) were on average (± SD) 62.2 (± 11.9) years old, with a mean serum creatinine of 1.6 (± 0.5) mg/dl. 95% had arterial hypertension, 37% diabetes mellitus and 55% were on diuretics. The best correlation with 24h U-Na total excretion was found for the PM spot U-Na sample. We also found strong correlations when comparing spot and 24h urine U-Na concentration. Correction of spot U-Na for U-creatinine did not improve strength of correlations. Neither CKD stage, nor intake of diuretics had significant impact on these correlations. All examined formulas revealed a significant mean bias. The lowest mean bias and the strongest correlation between estimated and measured U-Na excretion in 24h were obtained using the Tanaka-formula. Also, application of the Tanaka-formula with PM U-Na provided best sensitivity, specificity, PPV and NPV to estimate U-Na excretion > 4g/d corresponding to a salt consumption > 10g/d. CONCLUSION: U-Na concentration of spot urine samples correlated with 24h U-Na excretion especially when PM spot U-Na was used. However, correlation coefficients were relatively low. Neither CKD stage nor intake of diuretics appeared to have an influence on these correlations. There was a significant bias for all tested formulas with the Tanaka-formula providing the strongest correlation with measured 24h U-Na excretion. In summary, using spot urine samples together with the Tanaka-formula in epidemiological studies appears feasible to determine associations between approximate salt intake and outcomes in CKD patients. However, the usefulness of spot-urine samples to guide and monitor salt consumption in individual patients remains limited.

Association between spot urinary sodium-to-potassium ratio and blood pressure among Chinese adults aged 18-69 years: the SMASH study.

Background: Excessive sodium and low potassium intake are involved in the development of hypertension. Growing evidence showed that the sodium-to-potassium ratio (Na/K) was significantly associated with blood pressure (BP). However, studies on the dose-response relationship of spot urinary Na/K ratio with hypertension and BP in the general population are scarce, especially in the Chinese population. Materials and methods: Data from the post-intervention survey of the Shandong Ministry of Health Action on Salt and Hypertension (SMASH) project was analyzed. Associations between Na/K molar ratio and hypertension prevalence and between Na/K molar ratio and BP indices were analyzed using multivariable logistic and linear regression, respectively, followed by subgroup analysis and interaction analysis. The restricted cubic spline model was used to explore the dose-response relationship. Informed by existing literature, we adjusted for potential confounding factors, including temperature and renal function, to assess the association and dose-response relationship. Results: There was a non-linear positive association between Na/K and hypertension (OR:1.09, 95%CI: 1.08-1.11) and a linear positive association between Na/K and systolic BP, diastolic BP, and mean arterial pressure (ß 0.53, 95%CI: 0.45-0.60; ß 0.36, 95%CI: 0.31-0.41; and ß 0.42, 95%CI: 0.36-0.47, respectively). The association was stronger in individuals with hypertension, female patients, those in the 50-59-year age group, and those who were obese. Environmental temperatures had little impact on associations. Conclusion: Our findings provide further evidence that the spot urinary Na/K ratio is a simple, useful, and convenient indicator for monitoring salt reduction and potassium increase, which could be used in clinical and public health practices.

Assessing Sodium Intake in Middle-Aged and Older Adults with Elevated Blood Pressure: Validation of Spot Urine Excretion and Dietary Survey-Derived Estimates.

This cross-sectional study evaluated the validity of three alternative methods compared to the gold standard 24-h urine collection for estimating dietary sodium intake, a modifiable risk factor for hypertension, among middle-aged and older adults with elevated blood pressure. These included spot urine collection (using Kawasaki, Tanaka, and INTERSALT equations), 24-h dietary recall, and food frequency questionnaire responses, compared to 24-h urine collection in a subset of 65 participants (aged 50-75 years, 58.5% women, 61.6% hypertensive) from the DePEC-Nutrition trial. The validity of the methods was assessed using bias, the Spearman correlation coefficient (SCC), the intraclass correlation coefficient (ICC), and Bland-Altman analysis. Among the alternative methods, spot urine collection using the Kawasaki equation showed the strongest correlation (SCC 0.238; ICC 0.119, 95% CI -0.079 to 0.323), but it exhibited a significant bias (1414 mg/day, p-value < 0.001) relative to 24-h urine collection. Conversely, dietary surveys had a smaller bias but wider limits of agreement. These findings underscore the complexities of accurately estimating dietary sodium intake using spot urine collection or dietary surveys in this specific population, suggesting that a combination or the refinement of existing methodologies might improve accuracy. Further research with larger samples is necessary to develop more reliable methods for assessing sodium intake in this high-risk group.

No change in 24-h sodium intake estimated from spot urine in Norwegian adults from 2006 to 2019: the population-based Trøndelag Health Study (HUNT).

OBJECTIVE: Monitoring time trends in salt consumption is important for evaluating the impact of salt reduction initiatives on public health outcomes. There has so far not been available data to indicate if salt consumption in Norway has changed during the previous decade. We aimed to assess whether average 24-h salt intake estimated from spot urine samples in the adult population of mid-Norway changed from 2006-2008 to 2017-2019 and to describe variations by sex, age and educational level. DESIGN: Repeated cross-sectional studies. SETTING: The population-based Trøndelag Health Study (HUNT). PARTICIPANTS: In each of two consecutive waves (HUNT3: 2006-2008 and HUNT4: 2017-2019), spot urine samples were collected from 500 men and women aged 25-64 years, in addition to 250 men and women aged 70-79 years in HUNT4. Based on spot urine concentrations of Na, K and creatinine and age, sex and BMI, we estimated 24-h Na intake using the International Cooperative Study on Salt and Blood Pressure (INTERSALT) equation for the Northern European region. RESULTS: Mean (95 % CI) estimated 24-h salt intakes in men were 11·1 (95 % CI 10·8, 11·3) g in HUNT3 and 10·9 (95 % CI 10·6, 11·1) g in HUNT4, P = 0·25. Corresponding values in women were 7·7 (95 % CI 7·5, 7·9) g and 7·7 (95 % CI 7·5, 7·9) g, P = 0·88. Mean estimated salt intake in HUNT4 decreased with increasing age in women, but not in men, and it did not differ significantly across educational level in either sex. CONCLUSIONS: Estimated 24-h salt intake in adult men and women in mid-Norway did not change from 2006-2008 to 2017-2019.

Evaluation of three prediction formulas of 24-hour urinary sodium excretion in Chinese residents: a systematic review and meta-analysis.

OBJECTIVE: To determine the appropriateness of three widely used formulas estimating 24-h urinary Na (24hUNa) from spot urine samples in the Chinese population. DESIGN: Systematic review and meta-analysis. SETTING: Literature review was conducted to identify studies for estimating 24hUNa using the Kawasaki, Tanaka and INTERSALT formulas simultaneously in PubMed, Embase and the Cochrane library databases. The mean difference (MD) and correlation coefficients (r) between measures and estimates from different formulas were assessed. PARTICIPANTS: Information extraction and quality assessment were performed in thirteen studies involving 8369 subjects. RESULTS: Two studies which affected the overall robustness were excluded in the 'leave-one-out' sensitivity analyses. Within the final meta-analysis included eleven studies and 7197 participants, 36·07 mmol/d (95 %CI 16·89, 55·25) of MD was observed in the Kawasaki formula, and -19·62 mmol/d (95 %CI -37·37, -1·87) in the Tanaka formula and -35·78 mmol/d (95 %CI -50·76, -20·80) in the INTERSALT formula; a pooled r-Fisher's Z of 0·39 (95 %CI 0·32, 0·45) in the Kawasaki formula, 0·43 (95 %CI 0·37, 0·49) in the Tanaka formula and 0·36 (95 %CI 0·31, 0·42) in the INTERSALT formula. Subgroup analyses were conducted to explore the possible factors affecting the accuracy of the formula estimation from three mainly aspects: population types, Na intake levels and urine specimen types. CONCLUSIONS: The meta-analysis suggested that the Tanaka formula performed a more accurate estimate in Chinese population. Time of collecting spot urine specimens and Na intake level of the sample population might be the main factors affecting the accuracy of the formula estimation.

Comparison of body iodine pool assessment methods before radioiodine therapy.

INTRODUCTION AND OBJECTIVES: Radioactive iodine therapy (RAIT) is recommended to reduce the risk of recurrence and metastasis in patients with intermediate-high risk differentiated thyroid cancer (DTC). In preparation for RAIT, stimulation of thyroid-stimulating hormone and reduction of body iodine pool are important for treatment success. For this purpose, patients are asked to reduce their iodine intake before RAIT, and the body iodine pool can be evaluated by measuring iodine excretion in urine before treatment. The aim of our study is to compare the methods used to measure the body iodine pool in the evaluation of the restricted iodine diet (RID) effectiveness applied in the RAIT preparation. PATIENTS AND METHODS: Eighty DTC patients discontinued levothyroxine three weeks before RAIT and followed up with a RID two weeks before treatment. After two weeks of RID, all patients collected their 24-h urine the day before the RAIT date. Patients completed 24-h urine samples on the morning of the RAIT date and also provided a spot urine sample. The estimated 24-h creatinine excretion of the patients was calculated. Estimated 24-h urinary iodine excretion (UIE) was calculated using the spot urine iodine/creatinine (I/C) ratio of the patients. 24-h UIE, iodine concentration in spot urine, I/C ratios in spot urine and estimated 24-h UIE of the patients were analyzed by comparing with each other. RESULTS: In 99% of the patients, RID efficiency was sufficient according to 24-h UIE before RAIT. The mean 24-h UIE was 48.81 micrograms/day (mcg/day) in 24-h urine samples taken from the patients to evaluate the body iodine pool. The patients' iodine concentrations in spot urine, I/C ratios in spot urine, and estimated 24-h UIE were all statistically significantly lower than actual 24-h UIE, which was the reference method (p: 0.026 vs <0.001 vs 0.041). Moderate positive correlation between 24-h UIE and iodine concentration in spot urine (r: 0.440), I/C ratio in spot urine (r: 0.493), and estimated 24-h UIE (r: 0.560) found. The strongest correlation was obtained with the estimated 24-h UIE. CONCLUSION: The estimated 24-h UIE obtained by using the I/C ratio in spot urine can be used practically and safely as an alternative to UIE in 24-h urine, which is the gold standard method for evaluating body iodine pool.

Associations between estimation of salt intake and salt-restriction spoons and hypertension status in patients with poorly controlled hypertension: a community-based study from Huzhou City, Eastern China.

BACKGROUND: As the prevalence of hypertension increases in China, it is advised to use salt-restriction spoons (SRS) as a lifestyle modification. This study aimed to examine the associations between estimated salt consumption, SRS usage, and the hypertension status in individuals with poorly controlled hypertension. METHODS: Data was collected in Huzhou City, Zhejiang Province, in 2021 using convenience sampling. The analysis involved ordinal logistic regression and restricted cubic splines to assess the relevant factors. RESULTS: The study found that 73.34% of the 1215 patients had uncontrolled blood pressure (BP). Urinary excretion was assessed through the utilization of the Kawasaki, INTERSALT, and Tanaka formulas. The outcomes of these three methodologies revealed average daily sodium excretion values of 208.70 (65.65), 154.78 (33.91), and 162.61 (40.87) mmol, respectively. The prevalence of utilizing SRS was found to be 37.78% in this study. Despite the acknowledgment among SRS users of the potential hazards associated with excessive salt consumption, there exists a contradictory pattern of attitudes and behaviors concerning salt reduction. Among individuals with different levels of salt intake (quartiles 1-4, Q1 vs Q4), there was a positive association between limiting salt and hypertension status when controlling for other variables (Kawasaki adjusted OR = 0.58, 95% CI = 0.43-0.79; INTERSALT adjusted OR = 0.62, 95% CI = 0.41-0.92; Tanaka adjusted OR = 0.61, 95% CI = 0.45-0.92, p < 0.05). Our research also revealed that using or used SRS was a protective factor for blood BP control (adjusted OR = 0.79, 95% CI = 0.64-0.99, P < 0.05). The restricted cubic spline plots illustrated a monotonic upward relationship between estimated 24-h urinary Na and BP (P-overall association < 0.05; P-non-linear association > 0.05). CONCLUSIONS: The use of dietary SRS could result in decrease in daily salt intake for BP control in patients with poorly controlled hypertension. To reduce the impact of high BP in China, additional studies are required to create interventions that can enhance the results for patients.

Association between sodium-to-potassium ratio in spot urine and hospitalization due to heart failure in high-risk Japanese patients.

Background: In Japanese cardiovascular (CV) high-risk patients, the ESPRIT (Evaluation of Sodium Intake for the Prediction of Cardiovascular Events in Japanese High-risk Patients) study showed that high sodium excretion (≥4.0 g/day) was associated with a composite CV events of heart failure (HF) hospitalization, acute coronary syndrome, cerebrovascular events, and CV deaths. In this context, the sodium-to-creatinine (Na/Cr) ratio in spot urine was found to be significantly associated with HF hospitalizations. Since a stable potassium balance plays a particularly relevant role for CV patients, this post-hoc study was designed to investigate the extent to which consideration of the sodium-to-potassium (Na/K) ratio represents a better predictor of HF hospitalizations in the ESPRIT study population. Methods: This is a post-hoc analysis of a previously reported ESPRIT study (n = 520, 60 HF hospitalizations). Results: Receiver operating curve analysis yielded optimal Na/K ratio cut-off value of 2.9 for detecting HF hospitalization. Kaplan-Meier curve showed that high Na/K ratio in spot urine was associated with increased HF hospitalization (p < 0.001). Cox proportional hazards model analysis revealed that high Na/K ratio was associated with HF hospitalization with a hazard ratio of 2.97 (confidence interval: 1.67-5.61). An association between high Na/K ratio and HF hospitalization remained after adjustments for Na/Cr ratio in spot urine or the use of diuretics. Conclusion: The Na/K ratio in spot urine is associated with HF hospitalization in high-risk Japanese patients.

Mid-Trimester Spot Urinary Albumin/Creatinine Ratio as a Screening Tool in Prediction of Pre-eclampsia.

Aims and Objectives: To determine utilization of spot urinary albumin/creatinine ratio (UACR) to predict subsequent development of preeclampsia, measured between 17 and 24 weeks of gestational age in asymptomatic antenatal woman and determine their maternal and neonatal outcomes. Introduction: In preeclampsia the basic pathology is generalized endothelial dysfunction. It causes glomerular endotheliosis which leads to proteinuria, decreased glomerular filtration rate and renal blood flow. Thus microalbuminuria is an early marker which can measured to predict preeclampsia. Materials and Methods: It is a prospective observational study, carried out for one year in a cohort of asymptomatic antenatal women at 17-24 weeks of gestational age, attending hospital for routine antenatal check-up with a singleton pregnancy and no associated complications. Urine albumin and creatinine ratio (UACR) is measured at first visit, and women were followed till delivery and the maternal and foetal outcomes were recorded. Results: Out of 81 pregnant women enrolled in the study, 58% belonged to 18-25 years, 54.3% belonged to lower middle class. There was a significant difference in mean UACR among women who developed preeclampsia (PE) and gestational diabetes mellitus (GDM) with p value < 0.05. In the study there was significant association between severe PE, PE and GDM with UACR at 22 as cut-off, with p value < 0.05. In the study among those with UACR > 22, 2.5% had IUFD, 12.5% had LBW, and 7.5% were admitted to NICU. Conclusion: With the measurement of spot UACR in mid-trimester we can predict the development of preeclampsia before the onset of clinical manifestations. UACR > = 171 mg/g predicted preeclampsia well before the onset of clinical manifestations with high sensitivity of 83.3% and specificity of 98.6%. Supplementary Information: The online version contains supplementary material available at 10.1007/s13224-023-01862-9.

Valores basales de creatinina en orina puntual en escolares del Municipio San Diego: Carabobo-Venezuela / Spot urine creatinine referential levels in school children from San Diego county: Carabobo-Venezuela

Los valores referenciales de creatinina, están establecidos solo para adultos. Pocos países y organismos internacionales han adoptado niveles referenciales de creatinina en orina puntual en una población infantil. en ausencia de reglamentación para estos niveles en niños, son utilizados como referencia los establecidos por países con características diferentes a la de niños venezolanos. Esto motivó a los autores a determinar valores basales de creatinina en orina puntual en escolares, del municipio San Diego del Estado Carabobo, en el 2006. El estudio fue descriptivo de corte transversal, se determinaron niveles de creatinina en orina puntual a 123 niños entre 6-12 años de edad de ambos géneros. El método utilizado fue el de Jaffe modificado. La media del Valor basal fue de 0,96 ± 0,44 g/L. Sin diferencias estadísticas significativas, al compararlas por género y edad. El 98,4% de la población presentó concentraciones de valores basales entre 0,3-3,0 g/L. Estos resultados de valores medios de creatinina en orina en escolares, proponen hacer un aporte preliminar que sirva como base a proximos estudios que puedan establecer rangos referenciales del valor basal puntual en niños

The reference values of urinary creatinine found in the literature are for adults. Few countries and international organisms have adopted spot urine creatinine referential levels in children. In obsence of a specific regulation established to these levels in children population, the urinary creatinine values used like reference have been established in countries with geographical and culture characteristics, body composition and diet habits different from Venezuela children. This approach motivated to the autors of this study determine baseline values of spot urinary creatinine in schoolchildren related to age and gender in San Diego county in the years 2006. The study was a descriptive cross-sectional, where we determined the baseline levels in 123 children in age range between 6 to 12 years old of both genders. The analysis was realized by the Jaffé modified method. The baseline average was 0,96 ± 0,44 g/L. There was not significant statistical difference between the values of different and gender. The 98.4% of the studied population showed baseline concentrations between 0.3-3.0 g/L. Results will become a base for future studies that will set spot baseline reference ranges for children

Spot urine porphyrins/creatinine ratio profile of healthy Brazilian individuals adjusted for personal habits

Changes in urinary porphyrin excretion may be the result of hereditary causes and/or from environmental or occupational exposure. The objective of this study was to measure the amount of some porphyrins in spot urine samples obtained from volunteers randomly selected from a healthy adult population of São Paulo with a sensitive HPLC method and to estimate normal ranges for a non-exposed population. Spot urine samples were collected from 126 subjects (both genders, 18 to 65 years old) not occupationally exposed to porphyrinogenic agents. Porphyrin fractions were separated on RP-18 HPLC column eluted with a methanol/ammonium acetate buffer gradient, pH 4.0, and measured fluorometrically (excitation 405 nm/emission 620 nm). The amount of porphyrins was corrected for urinary creatinine excretion. Only 8-carboxyl (uro) and 4-carboxyl (copro) porphyrins were quantified as µg/g creatinine. Data regarding age, gender, occupational activities, smoking and drinking habits were analyzed by Mann-Whitney and Kruskal-Wallis tests. Uroporphyrin results did not differ significantly between the subgroups studied. Copro and uro + copro porphyrins were significantly different for smokers (P = 0.008) and occupational activities (P = 0.004). With respect to alcohol consumption, only men drinking >20 g/week showed significant differences in the levels of copro (P = 0.022) and uro + copro porphyrins (P = 0.012). The 2.5-97.5th percentile limit values, excluding those for subjects with an alcohol drinking habit >20 g/week, were 0-20.8, 11.7-93.1, and 15.9-102.9 µg/g creatinine for uro, copro and uro + copro porphyrins, respectively. These percentile limit values can be proposed as a first attempt to provide urinary porphyrin reference values for our population, serving for an early diagnosis of porphyrinopathies or as biomarkers of exposure to porphyrinogenic agents.

Assessing albuminuria in spot morning samples from diabetic patients / Avaliação de albuminúria em amostra matinal em pacientes diabéticos

Microalbuminuria assessment is essential for diagnosing incipient nephropathy in diabetic patients. The present study aim to evaluate whether urinary albumin concentration (UAC) and urinary albumin-to-creatinine ratio (UACR) agree with 24 h urine collection in screening for albuminuria > 30 mg/24 h in type 1 and 2 diabetics. In this cross-sectional study were evaluated 293 diabetic patients (117 type 1 and 176 type 2). Albuminuria was determinated by turbidimetric immunoassay. The best discriminator value was 22 mg/l (sensitivity 82.5 percent, specificity 74.0 percent) for UAC and 27.3 mg/g creatinine (sensitivity 83.3 percent, specificity 80.9 percent) for UACR. Areas under ROC curves were 0.868 and 0.878, respectively (p = 0.53). Lower discriminators as 10 mg/l (sensitivity 94.2 percent, specificity 48.6 percent) and 10 mg/g creatinine (sensitivity 96.7 percent, specificity 49.1 percent) attained high sensitivities. UAC and UACR from spot morning urine had similar accuracy in screening microalbuminuria. The simplicity and lower cost of UAC justifies its preferential clinical use.

Pesquisar microalbuminúria é essencial para o diagnóstico de nefropatia incipiente diabética. Este estudo objetiva avaliar concordância entre concentração de albumina urinária (CAU) e relação albuminúria-creatinúria (RAC) com coleta urinária de 24 h para pesquisa de albuminúria > 30 mg/24 h em diabéticos tipos 1 e 2. Estudou-se transversalmente 293 pacientes diabéticos (117 tipo 1 e 176 tipo 2). A albuminúria foi determinada por imunoensaio turbidimétrico. O melhor discriminador para CAU foi 22 mg/l (sensibilidade 82,5 por cento, especificidade 74 por cento) e para RAC 27,3 mg/g de creatinina (sensibilidade 83,3 por cento, especificidade 80,9 por cento). Áreas sob as curvas ROC foram 0,868 e 0,878, respectivamente (p = 0,53). Menores discriminadores como 10 mg/l (sensibilidade 94,2 por cento, especificidade 48,6 por cento) e 10 mg/g de creatinina (sensibilidade 96,7 por cento, especificidade 49,1 por cento) resultaram sensibilidades maiores. CAU e RAC de amostras urinárias isoladas matinais apresentaram acurácia semelhante para pesquisa de microalbuminúria. Simplicidade e baixo custo da CAU justificam seu uso clínico preferencial.