Fibroblast growth factor 23 in chronic kidney disease: bridging the gap between bone mineral metabolism and left ventricular hypertrophy.

BACKGROUND: Left ventricular hypertrophy (LVH) is a major cardiovascular complication in chronic kidney disease (CKD) patients. For a successful management of LVH, the comprehensive understanding of the classical and the new emerging factors associated with LVH is of paramount importance. The aim of the present study was to evaluate the clinical correlates of bone mineral metabolism with the occurrence of LVH in nondialyzed CKD patients. METHODS: This cross-sectional study included 96 patients with stages 2-4 CKD. Demographic characteristics, clinical profiles, laboratory tests and transthoracic echocardiogram were performed. RESULTS: LVH was observed in 36% of the patients. Patients with LVH were older, had a higher prevalence of hypertension, and higher levels of intact parathormone, fibroblast growth factor 23 and C-reactive protein. Serum phosphorus, alkaline phosphatase and vitamin D were not associated with the presence of LVH. In the multiple logistic regression analyses only FGF23 remained as a variable independently associated with LVH. CONCLUSION: We confirmed the high prevalence of LVH in nondialyzed CKD patients and showed that FGF23, an early marker of phosphorus load, was an important factor associated with LVH in these patients. Monitoring of FGF23 could be important for the management of LVH in this population.

Osteoporosis in hemodialysis patients revisited by bone histomorphometry: a new insight into an old problem.

Osteoporosis in hemodialysis patients is associated with high morbidity and mortality and, although extensively studied by noninvasive methods, has never been assessed through bone biopsy. The aim of this study was to use histomorphometry to evaluate osteoporosis and identify factors related to its development in hemodialysis patients. We conducted a cross-sectional study involving 98 patients (35 women and 63 men; mean age: 48.4 +/- 13 years) on hemodialysis for 36.9 +/- 24.7 months. Patients were submitted to transiliac bone biopsy with double tetracycline labeling. The bone metabolism factors ionized calcium, phosphorus, bone alkaline phosphatase, deoxypyridinoline, intact parathyroid hormone, and 25(OH) vitamin D were evaluated, as were the bone remodeling cytokines osteoprotegerin (OPG), soluble receptor-activator of NF-kappabeta ligand (sRANKL) and tumor necrosis factor-alpha (TNF)alpha. Osteoporosis was defined as trabecular bone volume (BV/TV) greater than 1 s.d. below normal (men <17.4%; women <14.7%). Forty-five patients (46%) presented osteoporosis, which was correlated with white race. We found BV/TV to correlate with age, OPG/sRANKL ratio, TNFalpha levels, and length of amenorrhea. In multiple regression analysis adjusted for sex and age, length of amenorrhea, white race, and OPG/sRANKL ratio were independent determinants of BV/TV. Histomorphometric analysis demonstrated that osteoporotic patients presented normal eroded surface and low bone formation rate (BFR/BS). Osteoporosis is prevalent in hemodialysis patients. Low BFR/BS could be involved in its development, even when bone resorption is normal. Cytokines may also play a role as may traditional risk factors such as advanced age, hypogonadism, and white race.

Short-term effects of a very-low-protein diet supplemented with ketoacids in nondialyzed chronic kidney disease patients.

OBJECTIVE: To evaluate the effects on the nutritional and metabolic parameters of a very-low-protein diet supplemented with ketoacids (VLPD+KA) in comparison with a conventional low-protein diet (LPD) in chronic kidney disease (CKD) patients. DESIGN: Prospective, randomized, controlled clinical study. SETTING: Outpatient Clinic of the Nephrology Division of Federal University of Sao Paulo, Brazil. SUBJECTS: The study involved 24 patients with advanced CKD (creatinine clearance <25 ml/min) that were randomly assigned to either a VLPD+KA (VLPD+KA group, 12 patients) or to a conventional LPD with 0.6 g/kg/day (LPD group, 12 patients). The patients were followed for 4 months. RESULTS: Nutritional status was adequately maintained with both diets for the studied period. Protein intake and serum urea nitrogen decreased significantly only in the VLPD+KA group (from 0.68+/-0.17 to 0.43+/-0.12 g/kg/day, P<0.05; from 61.4+/-12.8 to 43.6+/-14.9 mg/dl, P<0.001; respectively). Ionized calcium did not change in the VLPD+KA group but tended to decrease in the LPD group. Serum phosphorus tended to decrease in the VLPD+KA group probably as a result of a significant reduction in dietary phosphorus (529+/-109 to 373+/-125 mg/day, P<0.05) associated to the phosphorus-binding effect of the ketoacids. No change in these parameters was found in the LPD group. Serum parathormone increased significantly only in the LPD group (from 241+/-138 to 494+/-390 pg/ml, P<0.01). The change in PTH concentration was negatively correlated with changes in ionized calcium concentration (r=-0.75, P=0.02) and positively correlated with changes in serum phosphorus (r=0.71, P=0.03) only in the LPD group. CONCLUSION: This study indicates that a VLPD+KA can maintain the nutritional status of the patients similarly to a conventional LPD. Besides, an improvement in calcium and phosphorus metabolism and a reduction in serum urea nitrogen were attained only with the VLPD+KA. Thus, VLPD+KA can constitute another efficient therapeutic alternative in the treatment of CKD patients.

Parathyroid hormone changes during phosphorus load in patients with chronic renal insufficiency with low serum parathyroid hormone or adynamic bone disease.

UNLABELLED: Adynamic bone disease (ABD) is frequently associated with low serum parathyroid hormone (PTH) concentrations. Many clinical and therapeutic conditions have been associated with ABD, and recently, a low phosphorus intake accompanied by low serum concentration of phosphorus and PTH has been described. AIM: To evaluate the parathyroid gland response of chronic renal insufficiency patients (CRI) with low serum PTH or ABD to a phosphorus load. METHODS: We examined the effects of 0.5 and 1.0 g/d of phosphorus load over a period of 60 days in 18 patients with mild CRI with a bone biopsy showing ABD (n = 7) or with low serum PTH (serum intact PTH < or = 40 ng/l) and serum phosphorus < 4.5 mg/dl (n = 11). RESULTS: Serum intact PTH increased significantly only after 1 g of phosphorus (58.5 to 83 ng/l) with a median percent increase of 72%. PTH secretion increased more in patients with lower basal PTH levels (81%). Serum phosphorus did not change significantly and urinary phosphorus increased from 487 to 1,062 mg/dl (p < 0.05). Significant decreases in serum ionized calcium (from 1.26 to 1.19 mmol/l) and calcitriol (from 34.5 to 24.9 pg/ml) were observed. Changes in PTH were inversely correlated with changes in serum ionized calcium (r = -0.54, p < 0.05) and the final PTH concentrations were positively correlated with changes in serum phosphorus (r= 0.52, p < 0.05). CONCLUSIONS: The parathyroid glands of chronic renal insufficiency patients with "relative hypoparathyroidism" or ABD responded to a phosphorus load with an increase in serum PTH levels. The decrease in serum ionized calcium and calcitriol as well as minimal changes in serum phosphorus appeared to be involved in this response.

Effect of etidronate treatment on bone mass of male nephrolithiasis patients with idiopathic hypercalciuria and osteopenia.

Osteopenia is frequently found among calcium stone forming (CSF) patients with hypercalciuria. We investigated the effect of a 2-year therapeutic course of etidronate, a bone-sparing agent, in 7 young male CSF patients. The treatment consisted of a cyclic intermittent administration of phosphate followed by sodium etidronate and calcium supplementation every 74 days. Bone mineral density (BMD) measured at 12-month intervals and bone biopsies performed at baseline and after 2 years were the primary efficacy parameters. Mean lumbar spine BMD increased significantly after the 1st year by 2.6 +/- 1.0% (mean +/- SE, p < 0.05) and nonsignificantly after the 2nd year by 5.6 +/- 2.6%. Nonsignificant changes were observed for femoral neck mean BMD after either the 1st or the 2nd year (decrease of 2.0 +/- 1.0% and 2.0 +/- 3.0%, respectively). Mean histomorphometric parameters showed that bone volume, osteoid volume, and eroded surfaces did not differ from baseline (13.9 +/- 2.2 vs. 12.2 +/- 1.1%, 1.2 +/- 0.7 vs. 2.6 +/- 0.7%, and 20.7 +/- 6.2 vs. 13. 7 +/- 1.3%, respectively). Osteoid surface was significantly lower than baseline values (9.5 +/- 5.2 vs. 18.8 +/- 5.3%, p < 0.05). These data suggest that etidronate given to young male CSF patients presenting with hypercalciuria and osteopenia led to a significant amelioration of BMD, evident only in the lumbar spine after 1 year of treatment. There was no histological evidence of long-term improvement in bone remodeling.

Left ventricular hypertrophy as a risk factor for arrhythmias in hemodialysis patients.

The contribution of left ventricular hypertrophy in determining ventricular arrhythmias (VAS) was studied in 81 chronic renal failure patients in chronic hemodialysis using two-dimensional echocardiographic and electrocardiogram Holter monitoring. The prevalence of LVH was 93% (96% in hypertensive and 87% in normotensive patients). The prevalence of VA was 48%. These arrhythmias were associated with increased cardiac mass, lack of potassium supplementation to the hemodialysis bath, and low K+ and PaO2 during dialysis. Severe forms of VA occurred in 19 of 78 patients, and the risk factors for this occurrence were (a) largely increased cardiac mass indices (exceeding in more than 40% the upper limit of normal for each sex) and (b) prolonged periods of time in hemodialysis treatment (34 +/- 5.5 vs. 17 +/- 2.7 months, p less than 0.05). Changes in potassium or oxygen content of the blood were not significantly associated with the occurrence of severe forms of VA.

Radioimmunoassay of carboxyl and amino terminal fragments of parathyroid hormone for the evaluation of secondary hyperparathyroidism in chronic renal failure.

1. Some parameters of calcium and phosphorus metabolism and the radioimmunoassay of plasma concentrations of both the carboxyl (COOH) (residues 53-84) and amino (NH2) terminal (residues 1-34) fragments of parathyroid hormone (PTH) were measured to evaluate secondary hyperparathyroidism in 68 patients with chronic renal failure (CRF), 34 of whom were on hemodialysis therapy. 2. The upper limits of the normal values for serum PTH-NH2 and PTH-COOH concentrations were 28 and 146 pmol/l, respectively. Patients with mild CRF (plasma creatinine (CRp) 1.2-2 mg/dl) had normal mean serum total calcium, low mean serum phosphorus, undetectable plasma levels of PTH-NH2 (less than 10 pmol/l), slightly elevated mean plasma PTH-COOH concentration and normal fractional excretion of phosphorus (FEP). Patients with moderate CRF (CRp 2.1-4 mg/dl) had normal mean serum concentrations of both total calcium and phosphorus, and elevated mean levels of both plasma PTH-COOH and PTH-NH2 associated with increased FEP. Patients with end-stage CRF (CRp greater than 4 mg/dl) and those on hemodialysis had elevated mean serum phosphorus levels and decreased mean serum total calcium concentrations compared with those with mild and moderate CRF, and more pronounced increases in both mean plasma PTH-COOH and PTH-NH2. 3. The logarithm of plasma PTH-NH2, but not PTH-COOH, concentration correlated positively with FEP and serum phosphorus concentration and negatively with total serum calcium concentration, while the logarithms of both PTH-NH2 and PTH-COOH levels correlated positively with CRp.(ABSTRACT TRUNCATED AT 250 WORDS)

Radioimmunoassay of carboxyl and amino terminal fragments of parathyroid hormone for the evaluation of secondary hyperparathyroidism in chronic renal failure

1. Some parameters of calcium and phosphorus metabolism and the radioimmunoassay of plasma concentrations of both the carboxyl (COOH) (residues 53-84) and amino (NH2) terminal (residues 1-34) fragments of parathyroid hormone (PTH) were measured to evaluate secondary hyperparathyroidism in 68 patients with chronic renal falure (CRF), 34 of whon were on hemodialysis therapy. 2. The upper limits of the normal values for serum PTH-NH2 and PTH-COOH concentrations were 28 and 146 pmol/l, respectively. Patients with mild CRF (plasma creatinine (CRp) 1.2-2 mg/dl) hadh normal mean serum total calcium, low mean phosphorus, undetectable plasma levels of PTH-COOH concentration and normal fractional excretion of phosphorus (FEP). Patients with moderate CRF (CRp2.1-4 mg/dl) had normal mean serum concentrations of both total calcium and phosphorus, and elevated mean levels of both plasma PTH-COOH and PTH-NH2 associated with increased FEP. Patients with end-stage CRF (CRp > 4mg/dl) and those on hemodialysis had elevated mean serum phosphorus levels and decreased mean serum total calcium concentrations compared with those with mild and modetate CRF, and more pronounced, increases in both mean plasma PTH-COOH and PTH-NH2. 3. The logarithm of plasma PTH-NH2, but not PTH-COOH, concentration correlated positively with FEP and serum phosphorus concentration and negatively with total serum calcium concentration, while the logarithms of both PTH-NH2 and PTH-COOH levels correlated positively with CRp. 4. Calcium infusion (2 mg Kg-1 h-1 for 90 min) in eight patients with high plasma levels of PTH-NH2, and PTH-COOH resulted in a significant decrease of plasma PTH-NHL but not of plasma PTH-COOH concentration. 5. These data demonstrate increased plasma PTH levels in moderate renal failure and suggest that the assay of plasma PTH-NH2 rather than PTH-COLL is more appropriate for the evaluation of secondary hyperparathyroidism in chronic renal failure