HR-pQCT detects alterations in bone microstructure in men with CKD stages 3 and 4, which are influenced by hormonal changes and body composition
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INTRODUCTION: Factors associated with osteodystrophy in predialysis patients are poorly understood. In the present study, we attempted to evaluate the impact of body composition and hormonal regulatory factors on the bone microstructure in a group of men with chronic kidney disease (CKD) stages 3 and 4. MATERIALS AND METHODS: 46 men, aged 50 - 75 years, with previously unrecognized CKD were evaluated by high-resolution peripheral quantitative computed tomography (HR-pQCT), and dual-energy X-ray absorptiometry (DXA). HR-pQCT parameters were correlated with estimated glomerular filtration rate (eGFR), age, body mass index (BMI), muscle mass index (MMI), and biochemistry. RESULTS: As compared to patients in stage 3 CKD, those with stage 4 CKD showed lower serum 25-hydroxyvitamin D (25(OH)D) and bicarbonate levels, and higher serum fibroblast growth factor 23 (FGF-23) and parathyroid hormone (PTH) levels. They also exhibited lower total, trabecular, and cortical volumetric bone mineral density, lower trabecular bone volume/tissue volume, trabecular number, trabecular and cortical thickness, and increased heterogeneity of the trabecular network. In the whole cohort, cortical bone density and thickness were negatively associated with age, PTH, and FGF-23, and positively with BMI. Trabecular bone parameters were positively associated with MMI and 25(OH)D. After simultaneously adjusting for age and eGFR, BMI, and MMI remained significantly associated with bone microstructural variables. CONCLUSION: HR-pQCT showed significant differences in bone microstructure in stage 4 vs. stage 3 CKD patients. Increased BMI, probably due to increased muscle mass, may favorably affect bone architecture in predialysis CKD patients.
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Bone Density Is Directly Associated With Glomerular Filtration and Metabolic Acidosis but Do Not Predict Fragility Fractures in Men With Moderate Chronic Kidney Disease.

Hyperparathyroidism, vitamin D deficiency, increased fibroblast growth factor-23 (FGF-23), and metabolic acidosis promote bone fragility in chronic kidney disease (CKD). Although useful in predicting fracture risk in the general population, the role of dual-energy X-ray absorptiometry (DXA) in CKD remains uncertain. This cross-sectional study included 51 men aged 50-75 yr with moderate CKD. The stage 4 CKD patients had higher levels of parathyroid hormone (p<0.001), FGF-23 (p=0.029), and lowest 25-hydroxyvitamin D (p=0.016), bicarbonate (p<0.001), total femur (p=0.003), and femoral neck (p=0.011) T-scores compared with stage 3 CKD patients. Total femur and femoral neck T-scores were directly correlated with serum bicarbonate (p=0.003, r=0.447 and p=0.005, r=0.427, respectively) and estimated glomerular filtration rate (p=0.024, r=0.325 and p=0.003, r=0.313, respectively) but were not significantly associated with parathyroid hormone, 25-hydroxyvitamin D, or FGF-23. Only 3.9% of the participants had osteoporosis on DXA scan, whereas 31.4% reported a low-impact fracture. Our data point to a pivotal role of metabolic acidosis for bone impairment and to the inadequacy of DXA to evaluate bone fragility in CKD patients.

Tubular dysfunction in renal transplant patients using sirolimus or tacrolimus.

BACKGROUND: Tubular dysfunction is prevalent among kidney transplant patients using calcineurin inhibitors, but our knowledge of the tubular effects of mTOR inhibitors is more limited. METHODS: 60 kidney transplant outpatients using either the calcineurin inhibitor tacrolimus or the mTOR inhibitor sirolimus were investigated for renal tubular dysfunction. Proximal tubule function was assessed by quantification of albumin and ß2-microglobulin, tubular reabsorption of phosphate and fractional excretion of bicarbonate. Distal tubular function was evaluated by water deprivation test and by urinary acidification test using furosemide and fludrocortisone for pH, ammonium and titratable acidity measurements. RESULTS: The prevalence of distal renal tubular acidosis (dRTA) was 17% for both treatment groups. 70% of patients treated with sirolimus and 94% using tacrolimus presented with urine concentrating defect (p=0.04). CONCLUSION: Distal RTA and urine concentrating defect were highly prevalent after kidney transplantation both in the sirolimus and tacrolimus treated patients. Acidification test was essential for the appropriate diagnosis of dRTA while dipstick urine specific gravity test was able to detect urine concentrating defect in this population.

Early withdrawal of calcineurin inhibitor from a sirolimus-based immunosuppression stabilizes fibrosis and the transforming growth factor-ß signalling pathway in kidney transplant.

AIM: The focus in renal transplantation is to increase long-term allograft survival. One of the limiting factors is calcineurin inhibitor (CNI)-induced fibrosis. This study attempted to examine the histological aspect of interstitial fibrosis and the modulation of the transforming growth factor-ß (TGF-ß) canonical signalling pathway following early withdrawal of CNI from sirolimus-based immunosuppressive therapy. METHODS: Forty-five kidney transplant recipients with low-medium immunologic risk were randomized and underwent protocol biopsies obtained at the time of transplantation and at 3 and 12 months thereafter. The recipients were taking tacrolimus, sirolimus and prednisone. After the 3rd month, patients were randomized into two groups: sirolimus (SRL) (removed CNI and increased sirolimus) and tacrolimus (TAC) (maintained CNI). Renal biopsies were analyzed according to Banff's 2007 criteria. The sum of Banff's ct and ci constituted the chronicity index. Fibrosis was evaluated by the histomorphometrical analysis of the total collagen and myofibroblast deposition. Immunohistochemical characterization and quantification of TGF-ß, TGF-ß receptor 1 (TGF-ß-R1), receptor 2 (TGF-ß-R2) and phospho-Smad2/3 (p-Smad2/3) were performed. RESULTS: Maintenance of CNI was associated with the increase of the surface density of collagen and α-smooth muscle actin (α-SMA), (P = 0.001). Furthermore, increased TGF-ß (P = 0.02), TGF-ß-R1 (P = 0.02), p-Smad2/3 (P = 0.03) and stabilized TGF-ß-R2. On the other hand, the removal of CNI with increase in the dose of sirolimus limited the enhancement of the chronicity index at 12 m (SRL, 2.18 vs TAC, 3.12, P = 0.0007), diminished the deposition of fibrosis and promoted the stabilization of TGF-ß, TGF-ß-R2, p-Smad2/3 and myofibroblasts as well as the reduction of TGF-ß-R1 (P = 0.01). CONCLUSION: The early withdrawal of CNI limited the fibrosis progression through the stabilization of chronicity index and of the canonical TGF-ß signalling pathway.

Renal tubular dysfunction in patients with primary Sjögren syndrome.

Primary Sjögren's syndrome (pSS) is an important cause of renal tubular dysfunction in adults, mainly due to acquired type 1 distal renal tubular acidosis (RTA 1) and concentration defects (CD). This cross-sectional study evaluated renal tubular function of patients with pSS, by detecting proximal tubular injury (through measurements of urinary ß2 microglobulin and albumin), RTA 1 (through an acidification protocol using furosemide and fludrocortisone), and CD (through water deprivation test, WDT). A total of 25 patients with pSS were evaluated and despite a preserved renal function (eGFR 92.5 ± 26.3 mL/min/1.73 m(2)), 24% were diagnosed as RTA 1. On the other hand, CD was diagnosed in 28% of the patients who presented worse renal function (eGFR 68.6 ± 27.7 mL/min/1.73 m(2)). Increased ß2 microglobulin was found in 16% of the patients, and all of them had impaired renal function (eGFR 39.5 ± 11.9 mL/min/1.73 m(2)). These data showed a high prevalence of tubular dysfunction, mainly RTA 1 and CD, in patients with pSS, and suggest that patients with this disorder should be evaluated by the acidification protocol used in this study and WDT for proper diagnosis. Proximal tubular injury was less common, and probably associated with worsening of renal function.

Effects of propolis on inflammation markers in patients undergoing hemodialysis: A randomized, double-blind controlled clinical trial.

BACKGROUND AND AIMS: Several studies have been performed in vitro and in animals showing that propolis (a resin made by bees) has excellent anti-inflammatory properties, but no study has been performed in patients with chronic kidney disease (CKD) on hemodialysis (HD). The present study aimed to evaluate the effects of propolis supplementation on inflammatory markers in patients with CKD on HD. METHODS: This is a longitudinal, double-blind, placebo-controlled trial with patients randomized into two groups: propolis (4 capsules of 100 mg/day containing concentrated and standardized dry EPP-AF® green propolis extract) or placebo (4 capsules of 100 mg/day containing microcrystalline cellulose, magnesium stearate and colloidal silicon dioxide) for two months. Routine parameters were analyzed using commercial kits. The plasma levels of inflammatory cytokines were evaluated by flow luminometry. RESULTS: Forty-one patients completed the follow-up, 21 patients in the propolis group (45 ± 12 years, 13 women, BMI, 22.8 ± 3.7 kg/m2) and 20 in the placebo group (45.5 ± 14 years, 13 women, BMI, 24.8 ± 6.8 kg/m2). The obtained data revealed that the intervention with propolis significantly reduced the serum levels of tumour necrosis factor α (TNFα) (p = 0.009) as well as had the tendency to reduce the levels of macrophage inflammatory protein-1ß (MIP-1ß) (p = 0.07). There were no significant differences in the placebo group. CONCLUSION: Short-term EPP-AF® propolis dry extract 400 mg/day supplementation seems to mitigate inflammation, reducing the plasma levels of TNFα and MIP-1ß in patients with CKD on HD. This study was registered at clinicaltrials.gov (NCT04411758).

Influence of renal function and diet on acid-base status in chronic kidney disease patients.

OBJECTIVE: We investigated the influence of potential renal acid load (PRAL) and renal function on the degree of metabolic acidosis in patients with chronic kidney disease (CKD). DESIGN: This was a cross-sectional study. SETTING: This study was conducted at the Nephrology Outpatient Division of the Hospital Universitário Clementino Fraga Filho (Rio de Janeiro, Brazil). PATIENTS: Thirty CKD patients undergoing conservative treatment were divided according to plasma HCO(3)(-) values into acidotic (HCO(3)(-) 22 mM, n = 15). MAIN OUTCOME MEASURE: Biochemical, nutritional, and anthropometric parameters and PRAL were measured. RESULTS: The mean of plasma HCO(3)(-) values was 17.7 +/- 2.8 mM in the acidotic group, and 25.1 +/- 2.2 mM in the nonacidotic group. There was no significant difference in mean PRAL values between the acidotic (9.8 +/- 6.4 mEq/day) and nonacidotic (12.7 +/- 10.0 mEq/day) groups, but there was a significant correlation between plasma HCO(3)(-) and creatinine clearance (r = 0.78, P < .0001). Based on the receiver operating characteristic curve, the level of creatinine clearance to begin detection of acidosis was 31.8 mL/min, with a sensitivity and specificity of 86.7%. CONCLUSION: The acid-base status of this group of CKD patients undergoing conservative treatment was mainly determined by degree of renal insufficiency rather than diet.

The protective role of fucosylated chondroitin sulfate, a distinct glycosaminoglycan, in a murine model of streptozotocin-induced diabetic nephropathy.

BACKGROUND: Heparanase-1 activation, albuminuria, and a decrease in glomerular heparan sulfate (HS) have been described in diabetic nephropathy (DN). Glycosaminoglycan (GAG)-based drugs have been shown to have renoprotective effects in this setting, although recent trials have questioned their clinical effectiveness. Here, we describe the effects of fucosylated chondroitin sulfate (FCS), a novel GAG extracted from a marine echinoderm, in experimentally induced DN compared to a widely used GAG, enoxaparin (ENX). METHODS: Diabetes mellitus (DM) was induced by streptozotocin in male Wistar rats divided into three groups: DM (without treatment), FCS (8 mg/kg), and ENX (4 mg/kg), administered subcutaneously. After 12 weeks, we measured blood glucose, blood pressure, albuminuria, and renal function. The kidneys were evaluated for mesangial expansion and collagen content. Immunohistochemical quantifications of macrophages, TGF-ß, nestin and immunofluorescence analysis of heparanase-1 and glomerular basement membrane (GBM) HS content was also performed. Gene expression of proteoglycan core proteins and enzymes involved in GAG assembly/degradation were analyzed by TaqMan real-time PCR. RESULTS: Treatment with GAGs prevented albuminuria and did not affect the glucose level or other functional aspects. The DM group exhibited increased mesangial matrix deposition and tubulointerstitial expansion, and prevention was observed in both GAG groups. TGF-ß expression and macrophage infiltration were prevented by the GAG treatments, and podocyte damage was halted. The diabetic milieu resulted in the down-regulation of agrin, perlecan and collagen XVIII mRNAs, along with the expression of enzymes involved in GAG biosynthesis. Treatment with FCS and ENX positively modulated such changes. Heparanase-1 expression was significantly reduced after GAG treatment without affecting the GBM HS content, which was uniformly reduced in all of the diabetic animals. CONCLUSIONS: Our results demonstrate that the administration of FCS prevented several pathological features of ND in rats. This finding should stimulate further research on GAG treatment for this complication of diabetes.

Sublethal exposure from microcystins to renal insufficiency patients in Rio de Janeiro, Brazil.

In November 2001, a cyanobacterial bloom dominated by Microcystis and Anabaena occurred in the Funil Reservoir and the Guandu River, both of which supply drinking water to Rio de Janeiro, Brazil. Using ELISA, microcystins were detected at a concentration of 0.4 microg/L in the drinking water, whereas a concentration of 0.32 microg/L was detected in activated carbon column-treated water for use at the renal dialysis center of Clementino Fraga Filho Hospital (HUCFF) at the Federal University of Rio de Janeiro. A total of 44 hemodialysis patients who received care at this center were believed to be exposed. Initial ELISA analyses confirmed the presence of serum microcystin concentrations > or = 0.16 ng/mL in 90% of serum samples collected from these patients. Twelve patients were selected for continued monitoring over the following 2-month period. Serum microcystin concentrations ranged from < 0.16 to 0.96 ng/mL during the 57 days after documented exposure. ELISA-positive samples were found throughout the monitoring period, with the highest values detected 1 month after initial exposure. ESI LC/MS analyses indicated microcystins in the serum; however, MS/MS fragmentation patterns typical of microcystins were not identified. LC/MS analyses of MMPB for control serum spiked with MCYST-LR. and patient sera revealed a peak at retention time of 8.4 min and a mass of 207 m/z. These peaks are equivalent to the peak observed in the MMPB standard analysis. Taken together ELISA, LC/MS, and MMPB results indicate that these renal dialysis patients were exposed to microcystins. This documents another incident of human microcystin exposure during hemodialysis treatment.

Manifestações bucais e doença renal crônica: revisão de literatura / Oral findings and chronic renal failure: literature review

Este artigo é uma revisão da literatura sobre as manifestações bucais com Doença Renal Crônica (DRC) enfatizando uma possível associação entre DRC e Doença Periodontal. Esta associação tem sido apresentada em estudos mais recentes e com metodologias mais adequadas. Algumas sugestões de mecanismos biológicos para tal associação também são exploradas.