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Cholecalciferol Supplementation in Hemodialysis Patients: Effects on Mineral Metabolism, Inflammation, and Cardiac Dimension Parameters

BACKGROUND AND OBJECTIVES Vitamin D deficiency is highly prevalent in chronic kidney disease. The aim of this study was to evaluate the effects of oral cholecalciferol supplementation on mineral metabolism, inflammation, and cardiac dimension parameters in long-term hemodialysis (HD) patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This 1-year prospective study included 158 HD patients. Serum levels of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)(2)D], intact parathyroid hormone, and plasma brain natriuretic peptide as well as circulating bone metabolism and inflammation parameters were measured before and after supplementation. Baseline 25(OH)D and 1,25(OH)(2)D levels were measured twice (end of winter and of summer, respectively). Therapy with paricalcitol, sevelamer, and darbepoietin was evaluated. RESULTS There was an increase in serum 25(OH)D and 1,25(OH)(2)D levels after supplementation. Conversely, serum calcium, phosphorus, and intact parathyroid hormone were decreased. There was a reduction in the dosage and in the number of patients who were treated with paricalcitol and sevelamer. Darbepoietin use was also reduced, with no modification of hemoglobin values. Serum albumin increased and C-reactive protein decreased during the study. Brain natriuretic peptide levels and left ventricular mass index were significantly reduced at the end of the supplementation. CONCLUSIONS Oral cholecalciferol supplementation in HD patients seems to be an easy and cost-effective therapeutic measure. It allows reduction of vitamin D deficiency, better control of mineral metabolism with less use of active vitamin D, attenuation of inflammation, reduced dosing of erythropoiesis-stimulating agents, and possibly improvement of cardiac dysfunction.

25-Hydroxyvitamin D3, arterial calcifications and cardiovascular risk markers in haemodialysis patients

BACKGROUND Decreased vitamin D serum levels have been recently related to arterial stiffening and vascular calcifications in haemodialysis (HD) patients, but the pathophysiology of this association is not yet clear. The aim of this study was to evaluate the relationship between vascular calcifications, cardiovascular risk factors [including brain natriuretic peptide (BNP), pulse pressure (PP) and left ventricular mass index] and 25-hydroxyvitamin D3 (25(OH)D3) and 1,25-dihydroxyvitamin D3 [1,25(OH)(2)D3] serum levels. METHODS We performed a cross-sectional study with 223 prevalent HD patients, 48% females, 27% diabetics, with the mean age of 62.7 +/- 15.3 years and the mean HD time of 42.9 +/- 39.3 months. Forty-seven percent of the patients were taking active forms of vitamin D. RESULTS Serum levels of [25(OH)D3] were low (21.6 +/- 12.2 ng/mL) and negatively correlated with age (r = -0.31, P < 0.001), diabetes mellitus (DM) (r = -0.20, P = 0.004), C-reactive protein (r = -0.25, P < 0.001), log(10) BNP (r = -0.22, P = 0.002), PP > 65 mmHg (r = -0.21, P = 0.003) and vascular calcifications (r = -0.26, P < 0.001). Levels of [25(OH)D3] were positively correlated with [1,25(OH)(2)D3] (r = 0.25, P < 0.001) and albumin (r = 0.23, P = 0.001). On multivariate analysis, levels of [25(OH)D3] were independently associated with DM (P < 0.001), lower albumin levels (P = 0.003), higher BNP values (P = 0.005), PP > 65 mmHg (P = 0.006) and a higher vascular calcification score (>or= 3) (P = 0.002). CONCLUSIONS These results suggest that lower levels of [25(OH)D3] are a cardiovascular risk marker in HD patients, since they are strongly associated with higher BNP levels, increased PP and with the presence of vascular calcifications. The exact role of [25(OH)D3] deficiency on cardiovascular morbi-mortality needs to be clarified in large randomized controlled trials.

Lower Serum Magnesium Is Associated with Cardiovascular Risk Factors and Mortality in Haemodialysis Patients

Background: Hypomagnesaemia is a cardiovascular (CV) risk factor in the general population. The aim of this study was to evaluate the relationship between pre-dialysis magnesium (Mg) and CV risk markers, [including pulse pressure (PP), left ventricular mass index (LVMI) and vascular calcifications (VC)], and mortality in haemodialysis (HD) patients. Methods: We performed a 48-month prospective study in 206 patients under pre-dilution haemodiafiltration with a dialysate Mg concentration of 1 mmol/l. Results: Lower Mg concentrations were predictors of an increased PP (≥65 mm Hg) (p = 0.002) and LVMI (≥140 g/m2) (p = 0.03) and of a higher VC score (≥3) (p = 0.01). Patients with Mg <1.15 mmol/l had a lower survival at the end of the study (p = 0.01). Serum Mg <1.15 mmol/l was an independent predictor of all-cause (p = 0.01) and CV mortality (p = 0.02) when adjusted for multiple CV risk factors. Conclusions: Lower Mg levels seem to be associated with increased CV risk markers, like PP, LVMI and VC, and with higher mortality in HD patients.

Treatment of Hepatitis C Virus Infection in Kidney Transplant Recipients: Case Report

Chronic hepatitis C virus (HCV) infection exists in a large proportion of patients undergoing renal transplantation. Nowadays it is not considered to be an absolute contraindication to transplantation; however, it is associated with an increased risk for the patient and accounts for a shorter half-life of the renal allograft. We present three transplant recipients who displayed serious hepatic dysfunction after renal transplantation due to an HCV infection. In two of these cases, the liver biopsies established the diagnosis of FCH. In the third case, the liver biopsy was compatible with the early stages of FCH. All patients were started on peg-interferon alfa 2-b and ribavirin with subsequent normalization of hepatic function and early complete viral responses.

Determination of the Renal Threshold for Glucose Excretion in Familial Renal Glucosuria

Background/Aims: Familial Renal Glucosuria (FRG) is characterized by the presence of persistent isolated glucosuria in the absence of hyperglycemia. Mutations in SLC5A2, the gene coding for the sodium-glucose co-transporter 2 (SGLT2), are responsible for FRG. Phenotype/genotype correlations in FRG have mostly relied on the quantification of Urinary Glucose Excretion (UGE), which is dependent on both the filtered glucose load and the renal glucose reabsorptive capacity. In the current work, the renal threshold for glucose excretion (RTG) was determined in an FRG cohort, with the purpose of characterizing the impact of SGLT2 mutations on renal glucose transport. Methods: From January to December of 2013, eight FRG individuals with identified SLC5A2 mutations were enrolled. Patients were given a Mixed-Meal Tolerance Test during which blood glucose and UGE were measured over a 4 h period and the data was used to calculate RTG, according to a recently validated protocol. Results: In patients with homozygous mutations, RTG values were very low, with a mean (SD) of 0.95 (1.17) mmol/l, compared to commonly reported values of approximately 10-11.1 mmol/l in healthy subjects. In subjects with heterozygous mutations, mean (SD) RTG values were 4.91 (1.23) mmol/l, which are approximately one-half of the values in subjects without mutations. Conclusions: In FRG, mutations in SLC5A2 lead to reductions in RTG and increases in UGE. Because determination of RTG is not influenced by the filtered glucose load, the calculated RTG values provide a more refined measure of the impact of mutations on renal glucose transport than can be obtained from UGE alone.

Sirolimus-Induced Drug Fever in a Renal Transplant Patient: A Case Report

Herein we have described the case of a male renal transplant recipient who developed drug fever apparently related to sirolimus. He had been stable under an immunosuppressive regimen of tacrolimus and mycophenolate mofetil, but developed acute cellular rejection at 5 years after transplantation due to noncompliance. Renal biopsy showed marked interstitial fibrosis, and immunosuppression was switched from mycophenolate to sirolimus, maintaining low tacrolimus levels. One month later he was admitted to our hospital for investigation of intermittently high fever, fatigue, myalgias, and diarrhea. Physical examination was unremarkable and drug levels were not increased. Lactic dehydrogenase and C-reactive protein were increased. The blood cell count and chest radiographic findings were normal. After extensive cultures, he was started on broad-spectrum antibiotics. Inflammatory markers and fever worsened, but diarrhea resolved. All serologic and imaging tests excluded infection, immune-mediated diseases, and malignancy. After 12 days antibiotics were stopped as no clinical improvement was achieved. Drug fever was suspected; sirolimus was replaced by mycophenolate mofetil. Fever and other symptoms disappeared after 24 hours; inflammatory markers normalized in a few days. After 1 month the patient was in good health with stable renal function. Although infrequent, the recognition of drug fever as a potential side effect of sirolimus may avoid unnecessary invasive diagnostic procedures. Nevertheless, exclusion of other common causes of fever is essential.

Calcium Acetate/Magnesium Carbonate and Cardiovascular Risk Factors in Chronic Hemodialysis Patients

Background/Aim: Calcium acetate/magnesium carbonate (CaMg) is a recent phosphate binder that has been shown to have protective cardiovascular (CV) effects in animal models. The aim of this study was to evaluate the relationship between CaMg therapy and CV risk markers like pulse pressure (PP), left ventricular mass index (LVMI) and valvular calcifications compared to sevelamer or no phosphate binder (NPB) therapy in chronic hemodialysis (HD) patients. Methods: We performed a 48-month prospective study in 138 HD patients under hemodiafiltration with a dialysate Mg concentration of 0.5 mmol/l. Patients underwent treatment with CaMg or sevelamer for at least 36 months or NPB therapy. Demographic, clinical, biochemical and echocardiographic parameters were evaluated at baseline and after a 48-month period. Results: At the end of the study, patients who had taken CaMg showed a significant reduction in PP (p < 0.001), LVMI (p = 0.003), aortic (p = 0.004) and mitral valve calcifications (p = 0.03) compared with NPB patients. Patients under CaMg showed a significant reduction of PP (p < 0.001), LVMI (p = 0.01) and aortic valve calcifications (p = 0.02) compared to sevelamer patients. In a multivariable analysis, CaMg therapy was negatively associated with progression of LVMI (p = 0.02) and aortic valve calcifications (p = 0.01). Patients under CaMg showed higher serum Mg levels (0.93 ± 0.14 mmol/l) compared to patients under sevelamer (0.87 ± 0.13) or NPB patients (0.82 ± 0.12; p < 0.001). Conclusions: In prevalent HD patients, the use of CaMg over 48 months was associated with a reduction of PP and LVMI and with a stabilization of aortic valve calcifications. These protective and promising results of this new phosphate binder need to be confirmed in randomized controlled studies.

Hypouricaemia and hyperuricosuria in familial renal glucosuria

Familial renal glucosuria is a rare co-dominantly inherited benign phenotype characterized by the presence of glucose in the urine. It is caused by mutations in the SLC5A2 gene that encodes SGLT2, the Na+-glucose cotransporter responsible for the reabsorption of the bulk of glucose in the proximal tubule. We report a case of FRG displaying both severe glucosuria and renal hypouricaemia. We hypothesize that glucosuria can disrupt urate reabsorption in the proximal tubule, directly causing hyperuricosuria.

Morphologic patterns and treatment of transplant glomerulopathy: A retrospective analysis

Transplant glomerulopathy is mainly due to chronic antibody‐mediated rejection and actually represents a major cause of long‐term allograft failure. The lack of effective treatment remains a serious problem in transplantation. A retrospective and uni‐center study was performed in 48 kidney allograft recipients with transplant glomerulopathy between January 2010 and December 2015. Median time for diagnosis was 7.1 (3.6‐11.8) years post‐transplant. Light microscopy showed severity of transplant glomerulopathy in the majority of patients (cg1=10.4%; cg2=20.8%; cg3=68.8%). Moderate microvascular inflammation was present in 56.3% (g+ptc≥2), and almost half of recipients (51.1%) were C4d positive in immunofluorescence. Female gender (P=.001), age (P=.043), renal dysfunction (P=.002), acute rejection episodes (P=.026), and anti‐HLA class II antibodies (P=.004) were associated with kidney allograft failure. Treatment of transplant glomerulopathy was performed in 67.6% of patients. The histologic and laboratory features that led to a therapeutic intervention were score ptc (P=.021), C4d (P=.03), and the presence of anti‐HLA antibodies (P=.029), whereas score ah (P=.005) was associated with conservative measure. The overall cumulative kidney allograft survival at 10 years was 75%. Treatment of transplant glomerulopathy was ineffective to improve long‐term kidney allograft survival.

The Na+‐coupled glucose transporter SGLT2 interacts with its accessory unit MAP17 in vitro and their expressions overlap in the renal proximal tubule

Na+‐glucose cotransporter 2 is the renal Na+‐coupled glucose transporter responsible for the tubular glucose reabsorption, while MAP17 was recently identified as its accessory unit. Mutations in either of the proteins’ coding genes, SLC5A2 and PDZK1IP1, lead to urinary glucose excretion. To investigate whether MAP17 interacts with SGLT2 in vitro, we engineered a V5‐tagged SGLT2 construct and evaluated HEK293T cells coexpressing it together with a HA tagged MAP17 construct. MAP17 is shown to colocalize and coimmunoprecipitate with SGLT2. Also, in human kidney sections, the expression of both proteins overlaps at the apical surface of tubular epithelia. This interaction provides the rationale behind SGLT2 activation by MAP17 as well the similarity of the SLC5A2 and PDZK1IP1 glucosuric phenotypes.