Association between branched-chain amino acids and renal function in the ELSA-Brasil study.

BACKGROUND & AIMS: Epidemiologic studies show high circulating Branched-chain amino acids (BCAA) are associated with excess body weight, impaired fasting glucose, insulin resistance, high blood pressure, and dyslipidemia. There is scarce data on the association between renal function and circulating levels of BCAA. Therefore, we aim to study this association in a sample of the Brazilian Longitudinal Study of Adults (ELSA-Brasil) METHODS: We analyzed participants who had at the baseline BCAA: valine, isoleucine, and leucine measured through nuclear magnetic resonance. The outcomes evaluated were estimated glomerular function (eGFR - CKD-EPI without race) and 12h-albumin-creatinine ratio (ACR). In addition, we built unadjusted and adjusted multivariable linear regression models to investigate the association between the BCAA (total and individual) and eGFR and ACR. RESULTS: We studied 4912 participants (age 51.7(±9.0) years, 53.4% women, 59.5% White (59.5%), 32.7% hypertension, and 18.2% diabetes). The mean BCAA level was 429.15 ± 87.15. The mean eGFR was 84.95 ± 15 ml/min/1.73 m2, and the median ACR was 6.5 (1.8-4920) mg/g. Descriptive analyses comparing eGFR stratified <60 ml/min/1.73 m2 and ACR≥30 mg/g demonstrate that BCAA levels are higher in patients with eGFR<60 and ACR ≥30. Regarding eGFR, an inverse association was detected with BCAA levels when adjusted for demographic variables, and it is not maintained after adjustments for other confounders. Also, a positive association was found for ACR≥30 mg/g, and BCAA levels, and this association is not confirmed after adjustments. CONCLUSIONS: BCAA levels were inversely associated with eGFR and positively associated with ACR. Further studies are necessary to allow the comprehension of those associations.

Potential Biomarkers of the Turnover, Mineralization, and Volume Classification: Results Using NMR Metabolomics in Hemodialysis Patients.

Bone biopsy is still the gold standard to assess bone turnover (T), mineralization (M), and volume (V) in CKD patients, and serum biomarkers are not able to replace histomorphometry. Recently, metabolomics has emerged as a new technique that could allow for the identification of new biomarkers useful for disease diagnosis or for the understanding of pathophysiologic mechanisms, but it has never been assessed in the chronic kidney disease-mineral and bone disorder (CKD-MBD) scenario. In this study, we investigated the association between serum metabolites and the bone TMV classification in patients with end-stage renal disease by using serum NMR spectroscopy and bone biopsy of 49 hemodialysis patients from a single center in Brazil. High T was identified in 21 patients and was associated with higher levels of dimethylsulfone, glycine, citrate, and N-acetylornithine. The receiver-operating characteristic curve for the combination of PTH and these metabolites provided an area under the receiver-operating characteristic curve (AUC) of 0.86 (0.76 to 0.97). Abnormal M was identified in 30 patients and was associated with lower ethanol. The AUC for age, diabetes mellitus, and ethanol was 0.83 (0.71 to 0.96). Low V was identified in 17 patients and was associated with lower carnitine. The association of age, phosphate, and carnitine provided an AUC of 0.83 (0.70 to 0.96). Although differences among the curves by adding selected metabolites to traditional models were not statistically significant, the accuracy of the diagnosis according to the TMV classification seemed to be improved. This is the first study to evaluate the TMV classification system in relation to the serum metabolome assessed by NMR spectroscopy, showing that selected metabolites may help in the evaluation of bone phenotypes in CKD-MBD. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Bisphosphonate utilization across the spectrum of eGFR.

Bisphosphonates are the most common treatment for osteoporosis but there are concerns regarding its use in CKD. We evaluated the frequency of BSP by eGFR categories among patients with osteoporosis from two healthcare systems. Our results show that 56% of patients were treated, with reduced odds in those with lower eGFR. INTRODUCTION: Osteoporosis is common in patients with chronic kidney disease (CKD). Bisphosphonates (BSP) are the most common treatment but there are concerns regarding its efficacy and toxicity in CKD. We evaluated the frequency of BSP use by level of estimated glomerular filtration rate (eGFR) in patients with osteoporosis. METHODS: We assessed BSP use in patients with incident osteoporosis from the SCREAM-Cohort, Stockholm-Sweden, and Geisinger Healthcare, PA, USA. Osteoporosis was defined as the first encountered ICD diagnosis, and BSP use was defined as the dispensation or prescription of any BSP from 6 months prior to 3 years after the diagnosis. Multinomial logistic regression was used to account for the competing risk of death. RESULTS: A total of 15,719 women and 3011 men in SCREAM and 17,325 women and 3568 men in Geisinger with incident osteoporosis were included. Overall, 56% of individuals used BSP in both studies, with a higher proportion in women. After adjustments, the odds of BSP was lower across lower eGFR in SCREAM, ranging from 0.90 (0.81-0.99) for eGFR 75-89 mL/min/1.73m2 to 0.56 (0.46-0.68) for eGFR 30-44 mL/min/1.73m2 in women and from 0.72 (0.54-0.97) for eGFR of 60-74 to 0.42 (0.25-0.70) for eGFR 30-44 mL/min/1.73m2 in men. In Geisinger, odds were lower for eGFR < 30 mL/min/1.73m2 in both sexes and the frequency of BSP use dropped over time. CONCLUSION: In the two healthcare systems, approximately half of the people diagnosed with osteoporosis received BSP. Practices of prescription in relation to eGFR varied, but those with lower eGFR were less likely to receive BSP.

Kidney Disease, Race, and GFR Estimation.

Assessment of GFR is central to clinical practice, research, and public health. Current Kidney Disease Improving Global Outcomes guidelines recommend measurement of serum creatinine to estimate GFR as the initial step in GFR evaluation. Serum creatinine is influenced by creatinine metabolism as well as GFR; hence, all equations to estimate GFR from serum creatinine include surrogates for muscle mass, such as age, sex, race, height, or weight. The guideline-recommended equation in adults (the 2009 Chronic Kidney Disease Epidemiology Collaboration creatinine equation) includes a term for race (specified as black versus nonblack), which improves the accuracy of GFR estimation by accounting for differences in non-GFR determinants of serum creatinine by race in the study populations used to develop the equation. In that study, blacks had a 16% higher average measured GFR compared with nonblacks with the same age, sex, and serum creatinine. The reasons for this difference are only partly understood, and the use of race in GFR estimation has limitations. Some have proposed eliminating the race coefficient, but this would induce a systematic underestimation of measured GFR in blacks, with potential unintended consequences at the individual and population levels. We propose a more cautious approach that maintains and improves accuracy of GFR estimates and avoids disadvantaging any racial group. We suggest full disclosure of use of race in GFR estimation, accommodation of those who decline to identify their race, and shared decision making between health care providers and patients. We also suggest mindful use of cystatin C as a confirmatory test as well as clearance measurements. It would be preferable to avoid specification of race in GFR estimation if there was a superior, evidence-based substitute. The goal of future research should be to develop more accurate methods for GFR estimation that do not require use of race or other demographic characteristics.

Metabolomics biomarkers and the risk of overall mortality and ESRD in CKD: Results from the Progredir Cohort.

INTRODUCTION: Studies on metabolomics and CKD have primarily addressed CKD incidence defined as a decline on eGFR or appearance of albuminuria in the general population, with very few evaluating hard outcomes. In the present study, we investigated the association between metabolites and mortality and ESRD in a CKD cohort. SETTING AND METHODS: Data on 454 participants of the Progredir Cohort Study, Sao Paulo, Brazil were used. Metabolomics was performed by GC-MS (Agilent MassHunter) and metabolites were identified using Agilent Fiehn GC/MS and NIST libraries. After excluding metabolites present in <50% of participants, 293 metabolites were analyzed. An FDR q value <0.05 criteria was applied in Cox models on the composite outcome (mortality or incident renal replacement therapy) adjusted for batch effect, resulting in 34 metabolites associated with the outcome. Multivariable-adjusted Cox models were then built for the composite outcome, death, and ESRD incident events. Competing risk analysis was also performed for ESRD. RESULTS: Mean age was 68±12y, mean eGFR-CKDEPI was 38.4±14.6 ml/min/1.73m2 and 57% were diabetic. After adjustments (GC-MS batch, sex, age, DM and eGFR), 18 metabolites remained significantly associated with the composite outcome. Nine metabolites were independently associated with death: D-malic acid (HR 1.84, 95%CI 1.32-2.56, p = 0.0003), acetohydroxamic acid (HR 1.90, 95%CI 1.30-2.78, p = 0.0008), butanoic acid (HR 1.59, 95%CI 1.17-2.15, p = 0.003), and docosahexaenoic acid (HR 0.58, 95%CI 0.39-0.88, p = 0.009), among the top associations. Lactose (SHR 1.49, 95%CI 1.04-2.12, p = 0.03), 2-O-glycerol-α-D-galactopyranoside (SHR 1.76, 95%CI 1.06-2.92, p = 0.03), and tyrosine (SHR 0.52, 95%CI 0.31-0.88, p = 0.02) were associated to ESRD risk, while D-threitol, mannitol and myo-inositol presented strong borderline associations. CONCLUSION: Our results identify specific metabolites related to hard outcomes in a CKD population. These findings point to the need of further exploration of these metabolites as biomarkers in CKD and the understanding of the underlying biological mechanisms related to the observed associations.

1,5-Anhydroglucitol predicts CKD progression in macroalbuminuric diabetic kidney disease: results from non-targeted metabolomics.

INTRODUCTION: Metabolomics allows exploration of novel biomarkers and provides insights on metabolic pathways associated with disease. To date, metabolomics studies on CKD have been largely limited to Caucasian populations and have mostly examined surrogate end points. OBJECTIVE: In this study, we evaluated the role of metabolites in predicting a primary outcome defined as dialysis need, doubling of serum creatinine or death in Brazilian macroalbuminuric DKD patients. METHODS: Non-targeted metabolomics was performed on plasma from 56 DKD patients. Technical triplicates were done. Metabolites were identified using Agilent Fiehn GC/MS Metabolomics and NIST libraries (Agilent MassHunter Work-station Quantitative Analysis, version B.06.00). After data cleaning, 186 metabolites were left for analyses. RESULTS: During a median follow-up time of 2.5 years, the PO occurred in 17 patients (30.3%). In non-parametric testing, 13 metabolites were associated with the PO. In univariate Cox regression, only 1,5-anhydroglucitol (HR 0.10; 95% CI 0.01-0.63, p = .01), norvaline and L-aspartic acid were associated with the PO. After adjustment for baseline renal function, 1,5-anhydroglucitol (HR 0.10; 95% CI 0.02-0.63, p = .01), norvaline (HR 0.01; 95% CI 0.001-0.4, p = .01) and aspartic acid (HR 0.12; 95% CI 0.02-0.64, p = .01) remained significantly and inversely associated with the PO. CONCLUSION: Our results show that lower levels of 1,5-anhydroglucitol, norvaline and L-aspartic acid are associated with progression of macroalbuminuric DKD. While norvaline and L-aspartic acid point to interesting metabolic pathways, 1,5-anhydroglucitol is of particular interest since it has been previously shown to be associated with incident CKD. This inverse biomarker of hyperglycemia should be further explored as a new tool in DKD.

GlycA, a marker of protein glycosylation, is related to albuminuria and estimated glomerular filtration rate: the ELSA-Brasil study.

BACKGROUND: Systemic inflammation has been implicated in several chronic diseases. GlycA is a new nuclear mass resonance (NMR) spectroscopy-derived biomarker of systemic inflammation that reflects protein glycosylation. We evaluated the association of GlycA with albuminuria and eGFR in the ELSA-Brasil Study. METHODS: The cross-sectional association between GlycA (automated NMR LipoProfile(®) test spectra, LabCorp, Raleigh, NC), and overnight 12 h-albuminuria and CKD-EPI eGFR was evaluated among 5050 participants. RESULTS: GlycA was higher among older, women, smokers, alcohol abstemious, obese and in those with diabetes, hypertension or dyslipidemia. In addition, both eGFR and albuminuria were associated to GlycA. In linear regression, GlycA was independently associated with log albuminuria (B 0.03; 95%CI 0.02-0.04, P < 0.0001, per 1sd increase) and inversely related to eGFR (B -0.53; 95%CI -0.99 - -0.07, P < 0.02), even after adjustments including hsCRP. In logistic regression, GlycA was independently related to the risk of A2 or A3 albuminuria (OR 1.42, 95%CI 1.27-1.57, p < 0.0001, per 1sd increase), of having an eGFR < 60 ml/min/1.73m2 (OR 1.26, 95%CI 1.12-1.41, p = 0.0003, per 1 sd) or of a combined diagnosis of both conditions (OR 1.35, 95%CI 1.23-1.46, p < 0.0001, per 1 sd). In the ROC curve, GlycA had a higher AUC in comparison to hsCRP (AUC 0.67 vs. 0.62, p = 0.06) for the association with albuminuria A2 or A3. CONCLUSIONS: The present study demonstrates that GlycA is associated with albuminuria and eGFR, independently of major risk factors for CKD progression, including (and with a stronger association than) hsCRP. GlycA should be further evaluated in CKD progression.

Management of diabetes mellitus in individuals with chronic kidney disease: therapeutic perspectives and glycemic control.

The purpose of this study was to evaluate the therapeutic options for diabetes treatment and their potential side effects, in addition to analyzing the risks and benefits of tight glycemic control in patients with diabetic kidney disease. For this review, a search was performed using several pre-defined keyword combinations and their equivalents: "diabetes kidney disease" and "renal failure" in combination with "diabetes treatment" and "oral antidiabetic drugs" or "oral hypoglycemic agents." The search was performed in PubMed, Endocrine Abstracts and the Cochrane Library from January 1980 up to January 2015. Diabetes treatment in patients with diabetic kidney disease is challenging, in part because of progression of renal failure-related changes in insulin signaling, glucose transport and metabolism, favoring both hyperglycemic peaks and hypoglycemia. Additionally, the decline in renal function impairs the clearance and metabolism of antidiabetic agents and insulin, frequently requiring reassessment of prescriptions. The management of hyperglycemia in patients with diabetic kidney disease is even more difficult, requiring adjustment of antidiabetic agents and insulin doses. The health team responsible for the follow-up of these patients should be vigilant and prepared to make such changes; however, unfortunately, there are few guidelines addressing the nuances of the management of this specific population.

Management of diabetes mellitus in individuals with chronic kidney disease: therapeutic perspectives and glycemic control

The purpose of this study was to evaluate the therapeutic options for diabetes treatment and their potential side effects, in addition to analyzing the risks and benefits of tight glycemic control in patients with diabetic kidney disease. For this review, a search was performed using several pre-defined keyword combinations and their equivalents: “diabetes kidney disease” and “renal failure” in combination with “diabetes treatment” and “oral antidiabetic drugs” or “oral hypoglycemic agents.” The search was performed in PubMed, Endocrine Abstracts and the Cochrane Library from January 1980 up to January 2015. Diabetes treatment in patients with diabetic kidney disease is challenging, in part because of progression of renal failure-related changes in insulin signaling, glucose transport and metabolism, favoring both hyperglycemic peaks and hypoglycemia. Additionally, the decline in renal function impairs the clearance and metabolism of antidiabetic agents and insulin, frequently requiring reassessment of prescriptions. The management of hyperglycemia in patients with diabetic kidney disease is even more difficult, requiring adjustment of antidiabetic agents and insulin doses. The health team responsible for the follow-up of these patients should be vigilant and prepared to make such changes; however, unfortunately, there are few guidelines addressing the nuances of the management of this specific population.

FGF-23 as a predictor of renal outcome in diabetic nephropathy.

BACKGROUND AND OBJECTIVES: Fibroblast growth factor 23 (FGF-23) has emerged as a new factor in mineral metabolism in chronic kidney disease (CKD). An important regulator of phosphorus homeostasis, FGF-23 has been shown to independently predict CKD progression in nondiabetic renal disease. We analyzed the relation between FGF-23 and renal outcome in diabetic nephropathy (DN). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: DN patients participating in a clinical trial (enalapril+placebo versus enalapril+losartan) had baseline data collected and were followed until June 2009 or until the primary outcome was reached. Four patients were lost to follow-up. The composite primary outcome was defined as death, doubling of serum creatinine, and/or dialysis need. RESULTS: At baseline, serum FGF-23 showed a significant association with serum creatinine, intact parathyroid hormone, proteinuria, urinary fractional excretion of phosphate, male sex, and race. Interestingly, FGF-23 was not related to calcium, phosphorus, 25OH-vitamin D, or 24-hour urinary phosphorus. Mean follow-up time was 30.7±10 months. Cox regression showed that FGF-23 was an independent predictor of the primary outcome, even after adjustment for creatinine clearance and intact parathyroid hormone (10 pg/ml FGF-23 increase = hazard ratio, 1.09; 95% CI, 1.01 to 1.16, P=0.02). Finally, Kaplan-Meier analysis showed a significantly higher risk of the primary outcome in patients with FGF-23 values of >70 pg/ml. CONCLUSIONS: FGF-23 is a significant independent predictor of renal outcome in patients with macroalbuminuric DN. Further studies should clarify whether this relation is causal and whether FGF-23 should be a new therapeutic target for CKD prevention.

Case report: a rare cause of metabolic alkalosis.

A case of a 66-year-old white man with recent onset of oedema, hypertension, metabolic alkalosis and profound hypokalaemia is described. The initial laboratorial workup showed that urinary chloride concentration and potassium excretion were increased, suggesting a state of hyperaldosteronism. Nonetheless, renin activity was low and aldosterone levels were normal. The metabolic alkalosis seen in this case was due to a rare cause, the ectopic adrenocorticotropic hormone syndrome. A literature review in the subject is presented.

Vitamin D status in a sunny country: where has the sun gone?

BACKGROUND & AIMS: Hypovitaminosis D [serum 25 vitamin D<30 ng/ml] is related to the development of metabolic bone disease and greater risk of chronic illnesses. However, it is frequently under-diagnosed, mainly in countries where UV radiation is abundant. We prospectively determined the prevalence and the predictors of serum 25 vitamin D (s25(OH)D) in a healthy Brazilian population after the winter and after the summer. METHODS: 603 (118M and 485F) healthy Brazilian volunteers aged 18-90 years from a universitary hospital were selected after the winter of 2006. From the initial sample, 209 volunteers (31M and 178F) accepted to participate in a second health check after the subsequent summer. RESULTS: After the winter, median s25(OH)D was 21.4 ng/mL and 77.4% of the population presented hypovitaminosis D. s25(OH)D was significantly related to age, BMI, PTH and race. In multivariate linear regression analysis, s25(OH)D was significantly and independently dependent on age, glycemia and skin color. Significant increase in s25(OH)D was verified after summer [10.6 (3.7-19.3 ng/ml); p<0.001] and this improvement was dependent on age. We also observed a significant decrease in hyperparathyroidism prevalence (20.8% vs. 4.9%; P<0.0001). CONCLUSION: In São Paulo, at the end of winter, we observed a high prevalence of hypovitaminosis D and secondary hyperparathyroidism in healthy adults. s25(OH)D was dependent on age and skin color. After summer, we observed a decrease in the prevalence of hypovitaminosis D. This unexpected finding emphasizes the need for a strong recommendation to monitor s25(OH)D, even in a sunny country such as Brazil.

Tuberculosis-associated collapsing glomerulopathy: remission after treatment.

Collapsing glomerulopathy (CG) is a severe form of nephrotic syndrome and has been mostly associated with human immunodeficiency virus (HIV) infection. Treatment response is poor, and the disease frequently leads to end-stage renal disease. More recently, CG has been described in association with other conditions, such as drug exposure and other infections, but renal prognosis remains unfavorable. This paper reports an interesting case of an HIV-negative patient with tuberculosis-related CG who needed dialysis for five months but presented full renal recovery after tuberculosis (TB) treatment and corticotherapy.

Initial thyroid status and cardiovascular risk factors: the EPIC-Norfolk prospective population study.

CONTEXT: Thyroid status affects several aspects of cardiovascular risk profile, including lipid levels and blood pressure. Whether thyroid status affects the risk of coronary heart disease (CHD) and all-cause mortality remains controversial. DESIGN: The EPIC-Norfolk prospective population study. Mean follow-up was 10.6 years. PATIENTS: Study participants were 11 554 men and women aged 45-79 years, who were living in Norfolk, UK. MEASUREMENTS: Baseline cardiovascular risk factors were recorded and concentrations of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were measured in baseline samples. Regression analyses were performed to assess the association between thyroid hormone levels and cardiovascular risk factors. A proportional hazards model was used to estimate the risk of CHD and all-cause mortality by baseline thyroid status. No information was available on thyroid treatment during follow-up. RESULTS: Thyroid abnormalities were common, particularly among women. Thyroid abnormalities were associated with an altered cardiovascular risk profile. Even within the normal range, thyroid hormone levels, TSH more strongly than FT4, were associated with lipid levels and blood pressure among both men and women. We did not observe a significant association between subclinical thyroid abnormalities and risk of CHD or all-cause mortality. CONCLUSIONS: Despite the association between thyroid hormone levels and cardiovascular risk factors, thyroid status was not statistically significantly associated with the risk of future CHD or all-cause mortality in this large cohort.

Pressäo arterial e doença coronária: um desafio aos estudos epidemiológicos / Blood pressure and coronary heart disease: a challange for epidemiologic studies

A hipertensão arterial continua sendo um dos principais fatores de risco para doenças cardiovasculares e, como tal, é um dos pontos fundamentais na prevenção primária e secundária dessas doenças. No entanto, ainda se discute qual seria o nível ideal de redução da pressão arterial, principalmente naquele indivíduo que já é portador de doença coronária. Alguns autores, defensores da denominada cruva em "J", argumentam que a partir de certo ponto de redução da pressão arterial, estaríamos proporcionando aumento no risco de mortalidade. Outros autores que a relação entre pressão arterial e mortalidade é puramente linear e que não há aumento do risco de mortalidade. Neste texto, objetivamos revisar os principais artigos relacionados a esse tema. Apesar de ainda não haver consenso sobre qual o nível ideal de redução da pressão arterial, também é claro que tratar esse paciente a níveis subótimos, ou seja, mantê-lo com pressão arterial acima de 140x90 mmHg, significa aumentar seu risco de morte cardiovascular.

Prevençäo secundária da doença coronária em pacientes hipertensos / Secondary prevention of coronary heart disease in hypertensive patients

A prevenção secundária do indivíduo com doença coronária consiste em uma série de medidas farmacológicas e não-farmacológicas que visam a evitar ou minimizar um novo evento cardiovascular: Resultam, portanto, em melhor qualidade de vida, diminuição da taxa de mortalidade cardiovascular e redução do ônus tratamento de tais pacientes. Neste texto, são discutidos os elementos-chave na prevenção secundária: as medidas não-farmacológicas, como dieta, obesidade, tabagismo, atividade física e controle lipídico, assim como as farmacológicas, como o uso de aspirina, betabloqueadores, antagonistas de canais de cálcio, inibidores da enzima conversora de angiotensiva e terapia de reposição hormonal.