Silvia Maria de Oliveira Titan

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.

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.

Obstetric Outcome in Pregnant Women on Long-term Dialysis: A Case Series

BACKGROUND Although still uncommon, pregnancy frequency in women on maintenance hemodialysis therapy has increased in the past 20 years. Most published reports suggest that intensified hemodialysis regimens result in better pregnancy outcomes. The small number of patients investigated in all reported series is the main limitation of the available studies. STUDY DESIGN Retrospective case series. SETTING & PARTICIPANTS Data for all pregnancies that occurred in 1988-2008 in women undergoing maintenance hemodialysis (52 pregnancies) at the São Paulo University Medical School (São Paulo, Brazil). OUTCOMES & MEASUREMENTS We analyzed maternal and fetal outcomes of 52 pregnancies, as well as their relationship with various clinical, laboratory, and hemodialysis parameters, such as pre-eclampsia, pregnancy before or after dialysis therapy, hemodialysis dose, polyhydramnios, anemia, and predialysis serum urea level. In addition, logistic regression models for a composite adverse fetal outcome (perinatal death or extremely premature delivery) and linear regression models for birth weight were built. RESULTS 87% overall rate of successful delivery, with a mean gestational age of 32.7 +/- 3.1 weeks. Pre-eclampsia was associated with a poor prognosis compared with pregnancies without pre-eclampsia: a successful delivery rate of 60% versus 92.9% (P = 0.02), extremely premature delivery rate of 77.8% versus 3.3% (P < 0.001), lower gestational age (P < 0.001), and birth weight (P < 0.001). Patients with an adverse composite fetal outcome had a higher frequency of pre-eclampsia (P < 0.001), lower frequency of polyhydramnios (P = 0.03), lower third-trimester hematocrit (P = 0.03), and higher predialysis serum urea level (P = 0.03). The same results were seen for birth weight. LIMITATIONS Retrospective data analysis. The absence of creatinine clearance measurements did not allow evaluation of the impact of residual renal function on fetal outcome. CONCLUSIONS Outcomes of pregnancy in women undergoing hemodialysis often are good. Pre-eclampsia, third-trimester hematocrit, polyhydramnios, and predialysis serum urea level are important variables associated with fetal outcome and birth weight.

Urinary MCP-1 and RBP: independent predictors of renal outcome in macroalbuminuric diabetic nephropathy.

BACKGROUND Albuminuria has been considered a sine qua non condition for the diagnosis of diabetic nephropathy (DN) and has been widely used as a surrogate outcome of chronic kidney disease (CKD). However, recent data suggest that albuminuria may fail as a biomarker in a subset of patients, and the search for novel markers is intense. METHODS We analyzed the role of urinary RBP and of serum and urinary cytokines (TGF-beta, MCP-1 and VEGF) as predictors of the risk of dialysis, doubling of serum creatinine or death (primary outcome, PO) in 56 type 2 diabetic patients with macroalbuminuric DN. RESULTS Mean follow-up time was 30.7±10 months. Urinary RBP and MCP-1 were significantly higher in patients presenting the PO, whereas no difference was shown for TGF-β or VEGF. In the Cox regression, urinary RBP, MCP-1 and VEGF were positively associated and serum VEGF was inversely related to the risk of the PO. However, after adjustments for creatinine clearance, proteinuria, and blood pressure only urinary RBP (OR 11.6; 95% CI 2.7-49.2, p=0.001 for log RBP) and urinary MCP-1 (OR 11.0; 95% CI 1.6-76.4, p=0.02 for log MCP-1) remained as significant independent predictors of the PO. CONCLUSION Urinary RBP and MCP-1 are independently related to the risk of CKD progression in patients with macroalbuminuric DN. Whether these biomarkers have a role in the setting of normoalbuminuria and microalbuminuria in DN should be further investigated.

Phosphorus Is Associated with Coronary Artery Disease in Patients with Preserved Renal Function

High serum phosphorus levels have been associated with mortality and cardiovascular events in patients with chronic kidney disease and in the general population. In addition, high phosphorus levels have been shown to induce vascular calcification and endothelial dysfunction in vitro. The aim of this study was to evaluate the relation of phosphorus and coronary calcification and atherosclerosis in the setting of normal renal function. This was a cross-sectional study involving 290 patients with suspected coronary artery disease and undergoing elective coronary angiography, with a creatinine clearance >60 ml/min/1.73 m2. Coronary artery obstruction was assessed by the Friesinger score and coronary artery calcification by multislice computed tomography. Serum phosphorus was higher in patients with an Agatston score >10 than in those with an Agatston score ≤10 (3.63±0.55 versus 3.49±0.52 mg/dl; p = 0.02). In the patients with Friesinger scores >4, serum phosphorus was higher (3.6±0.5 versus 3.5±0.6 mg/dl, p = 0.04) and median intact fibroblast growth factor 23 was lower (40.3 pg/ml versus 45.7 pg/ml, p = 0.01). Each 0.1-mg/dl higher serum phosphate was associated with a 7.4% higher odds of having a Friesinger score >4 (p = 0.03) and a 6.1% greater risk of having an Agatston score >10 (p = 0.01). Fibroblast growth factor 23 was a negative predictor of Friesinger score (p = 0.002). In conclusion, phosphorus is positively associated with coronary artery calcification and obstruction in patients with suspected coronary artery disease and preserved renal function.

Parathyroidectomy Improves Survival In Patients with Severe Hyperparathyroidism: A Comparative Study

Background and objectives Secondary hyperparathyroidism (SHPT) in CKD is associated with an increased risk for mortality, but definitive data showing that parathormone control decreases mortality is still lacking. This study aimed to compare the mortality of patients with severe SHPT submitted to parathyroidectomy(PTX) with those who did not have access to surgery. Methods This is a retrospective study in a cohort of 251 CKD patients with severe SHPT who were referred to a CKD-MBD Center for PTX from 2005 until 2012. Results Most of our patients had indication of PTX, but only 49% of them had access to this surgical procedure. After a mean follow-up of 23 months, 72 patients had died. Non-survivors were older; more often had diabetes, lower serum 25 vitamin D and mostly had not been submitted to surgery. The relative risk of death was lower in the PTX patients (0.428; 95% CI, 0.28 to 0.67; p<0.0001). After adjustments, mortality risk was dependent on age (1.04; 95% CI, 1.01 to 1.07; p = 0.002), 25 vitamin D (0.43; 95% CI, 0.24 to 0.81; p = 0.006) and no access to PTX (4.13; 95% CI, 2.16 to 7.88; p<0.0001). Results remained the same in a second model using the PTX date as the study start date for the PTX group. Conclusions Our data confirms the benefit of PTX on mortality in patients with severe SHPT. The high mortality encountered in our population is significant and urges the need to better treat these patients.

Validação de questionário para diagnóstico de cefaléia em ambulatório de hospital universitário

Headache is a common complaint with a high prevalence in ambulatory settings. The physical and neurological examinations are frequently normal. The use of questionnaires as a screening method for patients with primary headache could facilitate the diagnosis in non specialized medical centers. In the present study, we used a questionnaire , based on the IHS criteria and modified by the authors, applied to 204 patients from the outpatient clinic of the Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo. Half of the patients were submitted to a clinical interview. We compared the results of the questionnaire with the results of the medical interview (gold standard). Most of the headaches we studied were primary headaches (89.6%). The questionnaire revealed a sensitivity of 90.2% and specificity of 57.9% for migraine detection with a chance corrected agreement {kappa) of 0.47 and a positive predictive (PPV) value of 65.7% and a negative predictive value (NPV) de 86.8%. The sensitivity for tension-type headache detection was 60.8% and the specificity 87.1 % with a kappa value of 0.49 and a PPV of 77.8% and a NPV of 75.9%. We conclude that this questionnaire can be used as a screening method for diagnosing headache and that it can be applied by non-medical personnel. This questionnaire could also be used for population studies.Headache is a common complaint with a high prevalence in ambulatory settings. The physical and neurological examinations are frequently normal. The use of questionnaires as a screening methods for patients with primary headache could facilitate the diagnosis in non-specialized medical centers. In the present study, we used a questionnaire, based on the IHS criteria and modified by the authors, applied to 204 patients from the outpatient clinic of the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Half of the patients were submitted to a clinical interview. We compared the results of the questionnaire with the results of the medical interview (gold standard). Most of the headaches we studied were primary headaches (89.6%). The questionnaire revealed a sensitivity of 90.2% and specificity of 57.9% for migraine detection with a chance corrected agreement (kappa) of 0.47 and a positive predictive (PPV) value of 65.7% and a negative predictive value (NPV) de 86.8%. The sensitivity for tension-type headache detection was 60.8% and the specificity 87.1% with a kappa value of 0.49 and a PPV of 77.8% and a NPV of 75.9%. We conclude that this questionnaire can be used as a screening method for diagnosing headache and that it can be applied by non-medical personnel. This questionnaire could also be used for population studies.

Hipertensão arterial sistêmica e morbidade psiquiátrica em ambulatório de hospital terciário

Arterial hypertension is one of the most important risk factor for cardiovascular disease, the main cause of death in Brazil. Hypertensive patients that have treated in tertiary care hospitals have shown elevated co-morbidity including psychiatric disturbances. Our objective is to study psychiatric co-morbidity among severe hypertensive patients. This study was performed in an out-patient clinic of tertiary medical care setting. Forty-one patients were enrolled in this research (26 women, 15 men). They were submitted to a clinical interview and answering the PRIME-MD, a specific questionnaire for diagnosis of psychiatric disturbances (by a general practitioner). Frequencies of psychiatric disturbances were different in men and women: 63.4% of the women in this study showed some type of psychiatric disturbance versus 36.6% of men (p=0.012). The majority of the diagnosis were mood disturbances, mainly depression associated or not with anxious disturbances. Mean age of psychiatric disturbance patients was 47.1 years versus 59.3 years in the patients without psychiatric disturbances (p=0.0049), showing the presence of psychiatric disturbances in younger patients. Other factors as systolic arterial blood pressure, diastolic arterial blood pressure and body mass index did not show any differences associated with psychiatric disturbance. We conclude that there is a great co-morbidity between high complexity hospitals hypertensive patients and that this type of disturbance is more frequent in women and in younger patients.A hipertensao arterial sistemica representa um dos principais fatores de risco para as doencas cardiovasculares que sao a principal causa de morte em nosso meio. Hipertensos que frequentam hospital terciario apresentam elevada co-morbidade incluindo disturbios psiquiatricos. O objetivo deste estudo e avaliar a morbidade psiquiatrica em hipertensos graves. Este estudo foi realizado em ambulatorio geral de hospital terciario: 41 pacientes (26 mulheres e 15 homens) foram submetidos a consulta medica com aplicacao do PRIME-MD, um questionario especifico para diagnostico de alteracoes psiquiatricas a ser realizado pelo clinico. A frequencia de disturbios psiquiatricos diferiu em homens e mulheres: 63,4% das mulheres na pesquisa apresentavam algum tipo de disturbio contra 36,6% dos homens (p=0,012). A maior parte dos diagnosticos foi de disturbios do humor representados pela depressao associada ou nao a disturbios ansiosos. A media de idade dos pacientes com disturbio psiquiatrico foi 47,1 anos contra 59,3 anos dos pacientes sem disturbio psiquiatrico (p=0,0049), mostrando a presenca dos disturbios psiquiatricos em pacientes mais jovens. Outros fatores pesquisados, como a pressao arterial sistolica, a pressao arterial diastolica e indice de massa corporea nao apresentaram diferencas em funcao dos disturbios psiquiatricos apresentados. Concluimos que ha grande co-morbidade psiquiatrica em hipertensos que frequentam ambulatorios de hospital terciario e que esses disturbios sao mais frequentes em mulheres e em pacientes jovens.Arterial hypertension is one of the most important risk factor for cardiovascular disease, the main cause of death in Brazil. Hypertensive patients that have treated in tertiary care hospitals have shown elevated co-morbidity including psychiatric disturbances. Our objective is to study psychiatric co-morbidity among severe hypertensive patients. This study was performed in an out-patient clinic of tertiary medical care setting. Forty-one patients were enrolled in this research (26 women, 15 men). They were submitted to a clinical interview and answering the PRIME-MD, a specific questionnaire for diagnosis of psychiatric disturbances (by a general practitioner). Frequencies of psychiatric disturbances were different in men and women: 63.4% of the women in this study showed some type of psychiatric disturbance versus 36.6% of men (p = 0.012). The majority of the diagnosis were mood disturbances, mainly depression associated or not with anxious disturbances. Mean age of psychiatric disturbance patients was 47.1 years versus 59.3 years in the patients without psychiatric disturbances (p = 0.0049), showing the presence of psychiatric disturbances in younger patients. Other factors as systolic arterial blood pressure, diastolic arterial blood pressure and body mass index did not show any differences associated with psychiatric disturbance. We conclude that there is a great co-morbidity between high complexity hospitals hypertensive patients and that this type of disturbance is more frequent in women and in younger patients.

MYH9 and APOL1 Gene Polymorphisms and the Risk of CKD in Patients with Lupus Nephritis from an Admixture Population

MYH9 polymorphisms have been described to be associated with the risk of CKD in non-diabetic nephropathy, HIV nephropathy and FSGS. Predominating in black descendants, MHY9 genetic variants could partially explain the excess risk of CKD associated with African ancestry. However, recent data suggests that APOL1 gene co-segregate with MYH9, and could be the gene truly associated with CKD risk. In this study, we evaluated the role of MYH9 and APOL1 gene polymorphisms in the risk of CKD in Brazilian patients with lupus nephritis (LN). A retrospective analysis of 196 LN patients was done. MYH9 rs4821480, rs2032487, rs4821481 and rs3752462, APOL 1rs73885319, rs16996616, rs60910145, rs71785313, and APOL3 rs11089781 gene polymorphisms were determined. Genetic ancestry was ascertained both by autossomal ancestry and mitochondrial haplogroup. Primary outcome was defined as doubling of serum creatinine (DC) or end stage renal disease (ESRD). Sixty-two patients presented the PO. In our population, MYH9 and APOL1 were not in LD. None APOL polymorphism was associated with the PO, whereas rs3752462 MYH9 polymorphism showed a positive association (HR3.72, 95%CI 1.47–9.38, p = 0.005). When we analyzed the MYH9 E1 haplotype, the GCCT carriers (1 or 2 alelles present in 29.7% in the PO group vs. 18.5% in controls) showed a significant association to the risk of PO, even after adjustments for baseline estimated creatinine clearance and autossomal ancestry (HR 2.0, 95%CI 1.2–3.4, p = 0.01). Our results show that in our population MYH9, but not APOL1, gene polymorphisms confer an increased risk of CKD in LN patients, independently of race.

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.