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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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.

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.