Alvimar G. Delgado

Guidelines to diagnosis and monitoring of Fabry disease and review of treatment experiences.

Ana Maria Martins, MD, PhD, Vânia D’Almeida, MD, Sandra Obikawa Kyosen, MD, Edna Tiemi Takata, MD, Alvimar Goncalves Delgado, MD, PhD, Ângela Maria Barbosa Ferreira Goncalves, MD, Caio Cesar Benetti Filho, MD, Dino Martini Filho, MD, Gilson Biagini, MD, Helena Pimentel, MD, Hugo Abensur, MD, PhD, Humberto Cenci Guimaraes, MD, Jaelson Guilhem Gomes, MD, Jose Sobral Neto, MD, PhD, Luiz Octavio Dias D’Almeida, PhD, Luiz Roberto Carvalho, MD, Maria Beatriz Harouche, MD, Maria Cristina Jacometti Maldonado, MD, Osvaldo J. M. Nascimento, PhD, Paulo Sergio dos Santos Montoril, MD, and Ricardo Villela Bastos, MD

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)(-) <or=22 mM, n = 15) and nonacidotic (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 cause of maintained hypercalciuria after the surgical cure of primary hyperparathyroidism is a defect in renal calcium reabsorption.

The hypercalciuria that eventually remains after the successful removal of a solitary parathyroid adenoma may originate from excessive intestinal calcium absorption, bone resorption or deficient renal reabsorption. In order to clarify this question, ten patients surgically cured from primary hyperparathyroidism (PHPx), ten age-matched normal subjects and five nephrolithiasic patients with renal hypercalciuria (RH) were studied after five days on a low calcium diet, either during fasting or after oral calcium load. Fasting serum calcium, amino-terminal and intact PTH levels and also urinary cAMP excretion were normal in every individual patient. Serum ionized calcium and inulin clearance (GFR) were used for calculations of the filtered load (FL Ca) and the fractional excretion of calcium (FE Ca). Six PHPx patients displayed fasting calciuria above the upper limit calculated for control subjects, despite having the lowest GFR and FL Ca (p<0.05 vs control). These patients (h-PHPx) had a small calciuric response to oral calcium load. Serum 1,25-(OH)2D3 and 250HD3 did not correlate with calciuria. Our findings exclude intestinal hyperabsorption and excessive bone resorption in h-PHPx patients, and strongly suggest a renal tubular defect in calcium reabsorption as the cause of their hypercalciuria. This defect could be primary, as in RH, but only three hPHPx patients had recurrent kidney stones before surgery. On the other hand, as a negative correlation between GFR and FE Ca was only found in PHPx patients, it seems probable that the disturbances in glomerular and tubular functions were secondary to the long standing hypercalcemic hyperparathyroidism.

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-β, 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-β 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.

Changes in Renal Hemodynamics and Tubular Function of Surgically Cured Primary Hyperparathyroid Patients Are Probably Due to Chronic Hypercalcemic Nephropathy

To understand the mechanisms responsible for the persistent hypercalciuria and reduced glomerular filtration rate (GFR) previously found in 6 of 10 patients surgically cured of primary hyperparathyroidism (PHPx), the tubular handling of lithium, sodium, calcium, and phosphate as well as the renal hemodynamics were evaluated in these 10 PHPx patients, in 10 control subjects, and in 5 patients with renal hypercalciuria (RH), during fasting and after an oral calcium load. A positive correlation between the fractional excretions of calcium and sodium was found in all groups, but the PHPx patients excreted more calcium for the same amount of sodium than control subjects. The fractional proximal sodium reabsorption (FPRNa), distal delivery, and fractional phosphate reabsorption were similar in all groups; a significant positive correlation was found between the fractional calcium reabsorption and the FPRNa, indicating that proximal tubular function was preserved and that the urinary calcium losses in RH and in the hypercalciuric PHPx patients (h‐PHPx) occurred in the distal nephron. However, only h‐PHPx patients had reduced renal plasma flow, renal blood flow, and GFR, as well as a high renal vascular resistance, which was even more evident after the calcium challenge. These findings lead us to conclude that RH and h‐PHPx patients are very different, as far as kidney dysfunction is concerned, and that a hypercalcemic nephropathy is the most probable cause of the alterations in distal calcium reabsorption and renal hemodynamics found in the h‐PHPx patients.

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

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‐β (TGF‐β) canonical signalling pathway following early withdrawal of CNI from sirolimus‐based immunosuppressive therapy.

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 β2-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.

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.