Calcitriol and FGF-23, but neither PTH nor sclerostin, are associated with calciuria in CKD.

PURPOSE: The recent observation that urinary calcium excretion (UCE) drops considerably with CKD and that this effect may occur beyond compensation for reduced intestinal calcium absorption suggests that CKD per se is a state of sustained positive calcium balance, a mechanism likely to contribute to vascular calcification and CVD in CKD. However, the determinants of UCE reduction in CKD are not well understood and there is a lack of clinical studies, particularly in the CKD population. Therefore, in this study, we aimed to evaluate variables associated with UCE in a CKD cohort. METHODS: Baseline data on 356 participants of the Progredir Study, Sao Paulo, Brazil, essentially composed of CKD G3a-G4, were analyzed according to UCE (24 h urine collection). RESULTS: Median 24 h UCE was 38 mg/day (IQR 21-68 mg/day) and 0.48 mg/kg/day (IQR 0.28-0.82 mg/kg/day). In univariate analysis, UCE was inversely related to age, phosphorus, 1-84 PTH, FGF-23 and sclerostin, and positively associated with eGFR, DBP, 1,25(OH)2-vitamin D, calcium, bicarbonate, total calorie intake and spironolactone use. After adjustments for age, sex and eGFR, only 1,25(OH)2-vitamin D, calcium, FGF-23, bicarbonate and total calorie intake remained associated with it, but not PTH nor sclerostin. Lastly, in a multivariable model, eGFR, serum 1,25(OH)2-vitamin D, calcium, and FGF-23 remained associated with UCE. Similar results were observed when calcium fractional excretion was used instead of UCE, with eGFR, 1-25-vitamin D and FGF-23 remaining as independent associations. CONCLUSION: Our results showed that CKD is associated with very low levels of UCE and that 1,25(OH)2-vitamin D, serum calcium and FGF-23 were independently associated with UCE in this population, raising the question whether these factors are modulators of the tubular handling of calcium in CKD.

Metabolites related to eGFR: Evaluation of candidate molecules for GFR estimation using untargeted metabolomics.

BACKGROUND: Metabolomics can be used to identify novel metabolites related to renal function and that could therefore be used for estimating GFR. We evaluated metabolites replicated and related to eGFR in 3 studies (CKD and general population). METHODS: Metabolomics was performed by GC-MS. The Progredir Cohort (n = 454, class 3 and 4 CKD) was used as the derivation study and adjusted linear regression models on eGFR-CKDEPI were built. Bonferroni correction was applied for selecting metabolites to be independently validated in the Diabetic Nephropathy Study (n = 56, macroalbuminuric DN) and in the Baependi Heart Study (BHS, n = 1145, general population). RESULTS: In the Progredir Cohort, 72 metabolites where associated with eGFR. Of those, 11 were also significantly associated to eGFR in the DN Study and 8 in the BHS. Four metabolites were replicated and significantly associated to eGFR in all 3 studies: d-threitol, myo-inositol, 4-deoxierythronic acid and galacturonic acid. In addition, pseudouridine was strongly correlated to eGFR only in the 2 CKD populations. CONCLUSIONS: Our results demonstrate metabolites that are potential biomarkers of renal function: d-threitol, myo-inositol, 4-deoxierythronic acid, galacturonic acid and pseudouridine. Further investigation is needed to determine their performance against otherwise gold-standard methods, most notably among those with normal eGFR.

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-ß 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.

Lupus nephritis is more severe in children and adolescents than in older adults.

OBJECTIVE: To evaluate clinicopathological features and treatment response in patients with lupus nephritis (LN), comparing the childhood- and late-onset forms of the disease. METHODS: We retrospectively analyzed clinical presentation, treatment and evolution in patients diagnosed with LN by renal biopsy between 1999 and 2008. Patients were grouped by age-≤18 years (n = 23); and ≥50 years (n = 13)-and were followed for the first year of treatment. RESULTS: The baseline features of the childhood- and late-onset groups, respectively, were as follows: mean age, 15 ± 2 and 54 ± 5 years; female gender, 87% and 92%; hypertension, 87% and 77%; Systemic Lupus Erythematosus Disease Activity Index, 29 ± 9 and 17 ± 7 (p = 0.002); estimated glomerular filtration rate (eGFR), 86 ± 66 and 70 ± 18 ml/min; concurrent SLE/LN diagnosis, 90% and 15% (p < 0.001); crescents on biopsy, 74% and 30% (p = 0.02); activity index on biopsy, 4.8 ± 2.6 and 3.3 ± 1.9 (p = 0.10); and interstitial fibrosis (>10%), 39% and 61% (p = 0.08). Treatment consisted mainly of methylprednisolone, prednisone and intravenous cyclophosphamide, average cumulative doses being similar between the groups. After 12 months of treatment, the eGFR in the younger and older patients was 116 ± 62 and 78 ± 20 ml/min, respectively (p = 0.005). Three of the younger patients progressed to dialysis at 12 months, compared with none of the older patients. CONCLUSION: Childhood-onset LN seems to be more severe than is late-onset LN.

ACEI and ARB combination therapy in patients with macroalbuminuric diabetic nephropathy and low socioeconomic level: a double-blind randomized clinical trial.

OBJECTIVE: The combination of an ACE inhibitor (ACEI) and an angiotensin II receptor blocker (ARB) has been proposed for the treatment of diabetic nephropathy (DN), but doubts remain about its efficacy and safety. We compared the effects of combination therapy and ACEI monotherapy on proteinuria and on three urinary inflammatory cytokines (MCP-1, TGF-beta and VEGF). DESIGN AND PATIENTS: 56 patients with macroalbuminuric DN received 40 mg/d enalapril for 4 months, followed by add-on 100 mg/day losartan or placebo for another 4 months. The primary and secondary endpoints were reduction of proteinuria and cytokine levels, respectively. RESULTS: Proteinuria did not fall in either group. Repeated measures ANOVA revealed no difference between groups. A high side effect rate was observed (28.5%). Finally, unadjusted logistic regression showed no difference between groups, but after adjustments the risk of worsening proteinuria was higher in the combination therapy group (p = 0.04). The same pattern was observed for urinary MCP- 1. CONCLUSION: These results suggest that 1) in advanced DN with severe proteinuria and poor metabolic control, angiotensin II blockade may be less effective than in other groups of CKD patients. 2) In such patients, combination therapy may not afford superior renoprotection compared to enalapril. 3) Urinary MCP-1 is a promising biomarker for the response to ACEI and/or ARB treatment and for the risk of associated unwanted effects.

Worse renal outcome of lupus nephritis in male patients: a case-control study.

BACKGROUND: Progression and long-term renal outcome of lupus nephritis (LN) in male patients is a controversial subject in the literature. The aim of this study was to evaluate the influence of male gender on the renal outcome of LN. METHODS: All male (M) LN patients who fulfilled American College of Rheumatology lupus criteria and who were referred for a kidney biopsy from 1999 to 2009 were enrolled in the study. Subjects with end-stage renal disease at baseline, or follow-up time below 6 months, were excluded. Cases were randomly matched to female (F) patients according to the class of LN, baseline estimated glomerular filtration rate (eGFR, Modification of Diet in Renal Disease simplified formula) and follow-up time. Treatment was decided by the clinical staff based on usual literature protocols. The primary endpoint was doubling of serum creatinine and/or end-stage renal disease. The secondary endpoint was defined as a variation of glomerular filtration rate (GFR) per year (ΔGFR/y index), calculated as the difference between final and initial eGFR adjusted by follow-up time for each patient. RESULTS: We included 93 patients (31 M : 62 F). At baseline, M and F patients were not statistically different regarding WHO LN class (II 9.7%, IV 71%, V 19.3%), eGFR (M 62.4 ± 36.4 ml/min/1.73 m2 versus F 59.9 ± 32.7 ml/min/1.73 m2), follow-up time (M 44.2 ± 27.3 months versus F 39.9 ± 27.9 months), and 24-hour proteinuria (M 5.3 ± 4.6 g/day versus F 5.2 ± 3.0 g/day), as well as age, albumin, C3, antinuclear antibody, anti-DNA antibody and haematuria. There was no difference in the primary outcome (M 19% versus F 13%, log-rank p = 0.62). However, male gender was significantly associated with a worse renal function progression, as measured by ΔGFR/y index (ß coefficient for male gender -12.4, 95% confidence interval -22.8 to -2.1, p = 0.02). The multivariate linear regression model showed that male gender remained statistically associated with a worse renal outcome even after adjustment for eGFR, proteinuria, albumin and C3 complement at baseline. CONCLUSION: In our study, male gender presented a worse evolution of LN (measured by an under GFR recovering) when compared with female patients with similar baseline features and treatment. Factors that influence the progression of LN in men and sex-specific treatment protocols should be further addressed in new studies.

Acute renal failure and hypercalcemia in an athletic young man.

Hypercalcemia is a life-threatening disorder and is related primarily to neoplastic diseases and primary and secondary hyperparathyroidism. The association of hypercalcemia and renal failure is frequent in the medical literature, although pathogenetic mechanisms remain to be elucidated. In this article, we present a case of hypercalcemia and acute renal failure secondary to vitamin D and vitamin A intoxication, after an over-the-counter intramuscular use by a young man starting an athletic performance program. A discussion of clinical picture, diagnosis and treatment is made, and we highlight the risk of pathological conditions triggered by inadvertent use of supplementation products and formulas available in health and fitness commercial centers.

Frequency of eating and concentrations of serum cholesterol in the Norfolk population of the European prospective investigation into cancer (EPIC-Norfolk): cross sectional study.

OBJECTIVES: To examine the relation between self reported eating frequency and serum lipid concentrations in a free living population. DESIGN: Cross sectional population based study. SETTING: Norfolk, England. PARTICIPANTS: 14 666 men and women aged 45-75 years from the Norfolk cohort of the European prospective investigation into cancer (EPIC-Norfolk). MAIN OUTCOME MEASURES: Concentrations of blood lipids. RESULTS: Mean concentrations of total cholesterol and low density lipoprotein cholesterol decreased in a continuous relation with increasing daily frequency of eating in men and women. No consistent relation was observed for high density lipoprotein cholesterol, body mass index, waist to hip ratio, or blood pressure. Mean cholesterol concentrations differed by about 0.25 mmol/l between people eating more than six times a day and those eating once or twice daily; this difference was reduced to 0.15 mmol/l after adjustment for possible confounding variables, including age, obesity, cigarette smoking, physical activity, and intake of energy and nutrients (alcohol, fat, fatty acids, protein, and carbohydrate). CONCLUSIONS: Concentrations of total cholesterol and low density lipoprotein cholesterol are negatively and consistently associated with frequency of eating in a general population. The effects of eating frequency on lipid concentrations induced in short term trials in animals and human volunteers under controlled laboratory conditions can be observed in a free living general population. We need to consider not just what we eat but how often we eat.

Chronic effect of parathyroid hormone on NHE3 expression in rat renal proximal tubules.

BACKGROUND: The most abundant Na+/H+ exchanger in the apical membrane of proximal tubules is the type 3 isoform (NHE3), and its activity is acutely inhibited by parathyroid hormone (PTH). In the present study, we investigate whether changes in protein abundance as well as in mRNA levels play a significant role in the long-term modulation of NHE3 by PTH. METHODS: Three groups of animals were compared: (1) HP: animals submitted to hyperparathyroidism by subcutaneous implantation of PTH pellets, providing threefold basal levels of this hormone (2.1 U. h-1); (2) control: sham-operated rats in which placebo pellets were implanted; (3) PTX: animals submitted to hypoparathyroidism by thyroparathyroidectomy followed by subcutaneous implantation of thyroxin pellets, which provided basal levels of thyroid hormone. After eight days, we measured bicarbonate reabsorption in renal proximal tubules by in vivo microperfusion. NHE3 activity was also measured in brush border membrane (BBM) vesicles by proton dependent uptake of 22Na. NHE3 expression was evaluated by Northern blot, Western blot and immunohistochemistry. RESULTS: Bicarbonate reabsorption in renal proximal tubules was significantly decreased in HP rats. Na+/H+ exchange activity in isolated BBM vesicles was 6400 +/- 840, 9225 +/- 505, and 12205 +/- 690 cpm. mg-1. 15 s-1 in HP, sham, and PTX groups, respectively. BBM NHE3 protein abundance decreased 39.3 +/- 8.2% in HP rats and increased 54.6 +/- 7.8% in PTX rats. Immunohistochemistry showed that expression of NHE3 protein in apical BBM was decreased in HP rats and was increased in PTX rats. Northern blot analysis of total kidney RNA showed that the abundance of NHE3 mRNA was 20.3 +/- 1.3% decreased in HP rats and 27. 7 +/- 2.1% increased in PTX. CONCLUSIONS: Our results indicate that the chronic inhibitory effect of PTH on the renal proximal tubule NHE3 is associated with changes in the expression of NHE3 mRNA levels and protein abundance.

[Systemic arterial hypertension and psychiatric morbidity in the outpatient care setting of a tertiary hospital]. / 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.