Plasma bone Gla protein concentrations in healthy adults. Dependence on sex, age, and glomerular filtration

Plasma bone Gla protein (BGP) was determined by radio-immunoassay in 266 healthy adults, men (n = 132) and women (n = 134), aged 20-79 years. In the women aged 30-69 years, plasma BGP increased significantly with age (r = 0.44, p less than 0.001), and a particularly steep increase was seen from 1.1 +/- 0.5 (mean +/- 1 SD) in the fifth decade to 2.0 +/- 1.4 nmol/l in the seventh decade. In men, aged 30-69 years, no correlation was found between plasma BGP and age (r = -0.07, NS). Plasma bone Gla protein is removed from the circulation mainly by the kidneys and the increased plasma BGP in the women could be caused by decreased renal clearance. The interrelationship was analysed by means of partial correlation. When creatinine clearance was held constant in women, BGP still correlated positively with age (r = 0.40, p less than 0.001), but not with creatinine clearance (r = 0.003, NS) when age was fixed. Plasma BGP was significantly increased above normal in 35 patients with chronic renal failure (10.2 +/- 14.6 nmol/l). Non-linear regression analysis showed that plasma BGP was within the normal range when 24-h creatinine clearance was greater than 30 ml/min, and large increases in plasma BGP did not occur until the 24-h creatinine clearance was below 20 ml/min. We conclude that, in normal subjects and patients with mild to moderate renal failure, plasma elevations of BGP reflect increased bone turnover rather than decreased renal clearance.     

Increase in serum bone gamma-carboxyglutamic acid protein with aging in women. Implications for the mechanism of age-related bone loss.

Because it is unclear whether age-related bone loss results from increased bone resorption, decreased bone formation or both, we measured the serum level of bone Gla-protein (BGP), a specific marker for bone turnover, in 174 women, ages 30 to 94 yr. Serum BGP increased linearly with aging (r = 0.44, P less than 0.001) from 4.4 +/- 0.4 (mean +/- SE) in the 4th decade to 8.9 +/- 0.9 ng/ml in the 10th decade. This increase correlated inversely (P less than 0.001) with concomitant decreases in bone mineral density at the lumbar spine, midradius, and distal radius. Using partial correlation coefficients, serum BGP still correlated positively with age (r = 0.31, P less than 0.001) after creatinine clearance was fixed but not with creatinine clearance (r = -0.04, NS) when age was fixed. Urinary hydroxyproline (r = 0.29, P less than 0.001), an index of bone resorption, and serum alkaline phosphatase (r = 0.31, P less than 0.001), an index of bone formation, also increased with age and these increases correlated with increases in serum BGP (r = 0.39, P less than 0.001 and r = 0.43, P less than 0.001, respectively). Serum immunoreactive parathyroid hormone concentrations (r = 0.39, P less than 0.001) and urinary cyclic AMP excretion (r = 0.38, P less than 0.001) increased, suggesting that PTH secretion increased with age; these increases correlated significantly with increases in serum BGP. A subgroup of 32 women who were found to have vertebral fractures, hip fractures, or both had significantly higher values for serum BGP than the remainder. These data suggest that overall bone turnover increases in women with aging and, especially considering the concomitant decrease in skeletal mass, do not support the view that age-related bone loss results primarily from decreased bone formation.     

Estimation of bone turnover evaluated by 47Ca-kinetics. Efficiency of serum bone gamma-carboxyglutamic acid-containing protein, serum alkaline phosphatase, and urinary hydroxyproline excretion.

Bone gamma-carboxyglutamic acid-containing (Gla) protein (BGP, osteocalcin) is a noncollagenous protein of bone present in plasma and removed by the kidney. Plasma BGP has been shown to be elevated in patients with certain bone diseases. The present study evaluates serum BGP (S-BGP), serum alkaline phosphatase (S-AP), and urinary hydroxyproline excretion (U-OHP) in diseases with differing bone turnover rates, and compares the accuracy of these measurements for estimating bone mineralization (m) and resorption (r) rates. S-BGP, S-AP, U-OHP, and creatinine clearance (Clcr) were measured in patients with primary hyperparathyroidism (n = 13), hyperthyroidism (n = 6), and hypothyroidism (n = 6). Bone mineralization and resorption rates were calculated from a 7-d combined calcium balance and 47Ca turnover study. A highly significant correlation (r = 0.69, P less than 0.001) was found between S-BGP and m. Multiple regression analysis disclosed a partial correlation between S-BGP and m when Clcr was taken into account (r = 0.82, P less than 0.001), and between S-BGP and Clcr when m was taken into account (r = -0.62, P less than 0.005). In accordance with this, a stronger correlation (r = 0.89, P less than 0.0001) was found between S-BGP X Clcr and m than between S-BGP and m. A less significant correlation was found between S-AP and m (r = 0.45, P less than 0.05). Furthermore, U-OHP showed a highly significant positive correlation to r (r = 0.78, P less than 0.001). Thus, in the studied disorders of calcium metabolism, individual serum levels of BGP depend on both mineralization rate and renal function. Serum levels of BGP corrected for alterations in renal function are superior to uncorrected S-BGP and to S-AP levels in the estimation of bone mineralization rates.     

Seasonal variation of serum bone GLA protein

The seasonal variation of serum Bone Gla Protein (BGP) was investigated in 15 normal young individuals (seven women and eight men, aged 27-39 years). Serum BGP exhibited a significant seasonal variation of 23% around the yearly mean (p less than 0.001) with zenith in February and nadir in July. Significant seasonal variations were noted also for serum alkaline phosphatase (p less than 0.01) and serum phosphate (p less than 0.01). Serum calcium, bone mineral content (BMC) and creatinine clearance revealed no significant seasonal variation. The seasonal variation of BGP did not follow the variation in serum total alkaline phosphatase. The seasonal variation of BGP has to be taken into account when using the protein as a marker of bone remodelling activity. The variation was probably caused by changes in the production rate of the protein, since the renal excretion of the protein, as reflected in creatinine clearance, remained unchanged throughout the year.     

Determination of bone Gla protein (osteocalcin) by enzyme-linked immunosorbent assay

Bone Gla protein (BGP, osteocalcin) is a marker of bone formation. We present a novel enzyme-linked immunosorbent assay for measuring BGP in plasma and serum. The antibody used was raised in rabbits following immunisation with highly purified bovine BGP conjugated with keyhole limpet hemocyanin. The binding of the antibody to BGP was calcium-dependent. The sensitivity, inaccuracy, and imprecision of the assay equal or exceed existing radioimmunoassays, and the present assay is less tedious. Plasma BGP in 249 healthy adults, aged from 20 to 93 yr, was 8.3 +/- 6.6 micrograms/l (mean +/- 2 SD). A significant decrease was seen in both sexes from the third to the forth decade of life. A subsequent significant increase was seen with age in women. but not in men. Plasma BGP was significantly higher in young men than in young women, and significantly higher in elderly women than in elderly men. Values were in the same range as those found with existing radioimmunoassays.     

Changes in cortical thickness of the clavicle and serum bone gamma-carboxyglutamic acid-containing protein in the elderly in an island community in western Japan

The cortical thickness of the clavicle (CTC), concentrations of bone gamma-carboxyglutamic acid-containing (Gla) protein (s-BGP, osteocalcin), alkaline phosphatase (s-ALP), calcium (s-Ca) and inorganic phosphorus (s-P) in serum, and calcium/creatinine (u-Ca/Cr) and inorganic phosphorus/creatinine (u-P/Cr) ratios in urine were examined in 211 subjects aged over 40 years in Oshima Island in Nagasaki prefecture. CTC decreased and s-BGP increased with age in both sexes, especially in women. Serum BGP was significantly higher in women than in men at the ages of 50's and over. Serum ALP in women increased until the ages of 60's. Serum Ca at the ages of 50's and s-P at the ages of 60's and over were higher in women than in men. As the increase in s-BGP is reported to be coincident with active bone formation, our findings do not support the view that age-related bone loss, especially in women, primarily results from decrease in bone formation.     

Plasma cystatin C as a marker of renal function in patients with liver cirrhosis

Cystatin C is a low molecular weight protein and the plasma level of cystatin C is mainly determined by glomerular filtration, making cystatin C an endogenous marker of glomerular filtration rate. The aim of the study was to elucidate the applicability of plasma cystatin C as a marker of renal function in patients with liver cirrhosis. Serum cystatin C and creatinine concentrations were compared with creatinine clearance. Thirty-six patients (14 females and 22 males aged between 33 and 81 years) with liver cirrhosis with normal to severely impaired kidney function were included. Plasma cystatin C was measured by an automated particle-enhanced nephelometric immunoassay (Dade Behring Diagnostics) and plasma creatinine by an enzymatic method. Plasma levels of cystatin C and creatinine were found to increase with decreasing values of creatinine clearance. The reciprocal values of cystatin C and creatinine were compared with those for creatinine clearance revealing an r 2 of 0.37 and 0.18, respectively. Comparison of the areas under the curves (AUC ) of the non-parametric receiver-operating characteristic plots for plasma cystatin C (AUC = 0.7364; SE = 0.0929) and plasma creatinine (AUC = 0.6309; SE = 0.1028) revealed a significant difference between plasma cystatin C and plasma levels of creatinine (p-value = 0.03). The results demonstrate that the diagnostic accuracy of plasma cystatin C was better than plasma creatinine in identifying liver cirrhotic patients with reduced glomerular filtration rate.     

Plasma cystatin C as a marker of renal function in patients with liver cirrhosis

Cystatin C is a low molecular weight protein and the plasma level of cystatin C is mainly determined by glomerular filtration, making cystatin C an endogenous marker of glomerular filtration rate. The aim of the study was to elucidate the applicability of plasma cystatin C as a marker of renal function in patients with liver cirrhosis. Serum cystatin C and creatinine concentrations were compared with creatinine clearance. Thirty-six patients (14 females and 22 males aged between 33 and 81 years) with liver cirrhosis with normal to severely impaired kidney function were included. Plasma cystatin C was measured by an automated particle-enhanced nephelometric immunoassay (Dade Behring Diagnostics) and plasma creatinine by an enzymatic method. Plasma levels of cystatin C and creatinine were found to increase with decreasing values of creatinine clearance. The reciprocal values of cystatin C and creatinine were compared with those for creatinine clearance revealing an r2 of 0.37 and 0.18, respectively. Comparison of the areas under the curves (AUC) of the non-parametric receiver-operating characteristic plots for plasma cystatin C (AUC=0.7364; SE=0.0929) and plasma creatinine (AUC=0.6309: SF=0.1028) revealed a significant difference between plasma cystatin C and plasma levels of creatinine (p-value=0.03). The results demonstrate that the diagnostic accuracy of plasma cystatin C was better than plasma creatinine in identifying liver cirrhotic patients with reduced glomerular filtration rate.     

Evaluation of renal function in intensive care: plasma cystatin C vs. creatinine and derived glomerular filtration rate estimates.

Plasma cystatin C, a new marker of glomerular filtration rate (GFR), was prospectively evaluated in surgical intensive care. Cystatin C was measured (immunonephelometry, Dade-Behring) in 10 patients selected to cover a full range of GFR (phase I) and in 28 unselected consecutive patients followed for 5 days post-admission (phase II). Results were compared with (51)Cr-EDTA clearance (phase I only), plasma creatinine (kinetic Jaffe, Roche), 24-h or estimated by Cockcroft and Gault (CG) creatinine clearance (CrCl), and modified diet in renal disease (MDRD)-estimated GFR. In phase I, the highest correlation with(51)Cr-EDTA clearance (22-198 mL/min) was noted for CG CrCl (r(2): 0.883, p<0.001). During phase II follow-up, 24-h CrCl could not be calculated in 25% of daily evaluations. Cystatin C correlated with creatinine (0.856, p<0.0001) and CG CrCl with MDRD GFR (0.926, p<0.0001) in renal failure (10-78 mL/min, n=60). There was a +40% (p<0.001) median difference between cystatin C and creatinine (as a % of upper normal cut-off). Sensitivity/specificity to detect a <80 mL/min CG CrCl was 88/97% for cystatin C vs. 48/100% for creatinine (laboratory cut-off). In patients with normal and stable renal function (n=14), day-to-day intra-individual variation was 7.4% for cystatin C (vs. 10.6% for creatinine). In intensive care unit surgical adult patients, CG CrCl provides an easy and cost-effective estimate of GFR. Superior to creatinine, plasma cystatin C can be measured in selected patients where CG CrCl is known to be inaccurate.     

Plasma clearance of iodine contrast media as a measure of glomerular filtration rate in critically ill patients

OBJECTIVE: The selection of the optimal method for assessing renal function relies on the accuracy of the technique. Plasma clearance of nonradioactive iodine contrast media (i.e., iohexol or iopromide) has been suggested as a reliable alternative to the renal clearance of inulin for estimating glomerular filtration rate (GFR). The accuracy of this method when used with critically ill patients displaying different levels of renal function in an intensive care unit (ICU) has not, until now, been examined. DESIGN: The accuracy of double- and multiple-point iohexol or iopromide plasma clearances was compared with that of already established techniques for measuring GFR (creatinine clearance, formula clearance by Cockcroft and Gault) and with that of inulin clearance, which is regarded as the gold standard for the measurement of GFR. PATIENTS: Values were obtained from 31 ICU patients who exhibited a wide range of renal function (serum creatinine: 0.6-6.7 mg/dL). MEASUREMENTS: Inulin clearance was performed using the constant-infusion technique. Creatinine clearance was determined from 24-hr urine samples. The clearance formula was calculated according to Cockcroft and Gault's formula. Iohexol or iopromide were applied as a single intravenous dose, and blood samples were taken up to 6 hrs after the injection. Iodine concentrations were determined by radiographic fluorescence. RESULTS: Plasma clearance of iohexol/iopromide measured after the single injection of contrast media and that of the conventional inulin clearance was almost identical (y = 0.971x + 7.65, r2 =.96; n = 31). Two-point clearance of iohexol/iopromide (double sampling technique) was as reliable as the three-point clearance (three-slope-intercept method, y = 0.995x + 0.62, r2 =.999; n = 18). With respect to inulin clearance, GFR measurements determined by creatinine clearance or according to the formula given by Cockcroft and Gault revealed errors that increased proportionally (y = 1.03x, r2 =.88; n = 27; and y = 0.93x, r2 =.62; n = 31, respectively). It could also be shown that the accuracy of GFR measurements involving plasma clearance of iohexol was not greatly affected by the degree of renal insufficiency or the route by which contrast media were applied. CONCLUSION: These findings indicate that the determination of plasma clearance of iohexol/iopromide is a simple, rapid, and accurate method that can indeed be used for estimating GFR in ICU patients with normal renal function or even different degrees of renal insufficiency.     

New biochemical marker for bone metabolism. Measurement by radioimmunoassay of bone GLA protein in the plasma of normal subjects and patients with bone disease.

gamma-Carboxyglutamic acid-containing protein of bone (BGP) is an abundant noncollagenous protein of mammalian bone. BGP has a molecular weight of 5,800 and contains three residues of the vitamin K-dependent amino acid, gamma-carboxyglutamic acid. We have applied a radioimmunoassay based on calf BGP for the measurement of the protein in the plasma of 109 normal humans and 112 patients with various bone diseases. BGP in human plasma was demonstrated to be indistinguishable from calf BGP by assay dilution studies and gel permeation chromatography. The mean (+/- SE) concentration of BGP in normal subjects was 6.78 (+/- 0.20) ng/ml, 7.89 (+/- 0.32) for males and 4.85 (+/- 0.35) for females. Plasma BGP was increased in patients with Paget's disease of bone, bone metastases, primary hyperparathyroidism, renal osteodystrophy, and osteopenia. Plasma BGP did correlate with plasma alkaline phosphatase (AP) in some instances, but there were dissociations between the two. It was additionally observed that patients with liver disease had normal plasma BGP despite increased plasma AP, a reflection of the lack of specificity of AP measurements for bone disease. Our studies indicate that the radioimmunoassay of plasma BGP can be a useful and specific procedure for evaluating the patient with bone disease.     

Changes in plasma cystatin C after renal transplantation and acute rejection in adults

BACKGROUND: Cystatin C has recently been proposed as an alternative marker of glomerular filtration rate. The diagnostic value of plasma cystatin C for the longitudinal assessment of kidney function after renal transplantation, however, has not been addressed. METHODS: Renal function was evaluated in 30 adults receiving renal transplants (46 +/- 9 years, mean +/- SD) and in 56 healthy controls (38 +/- 10 years) using cystatin C. Plasma cystatin C was determined daily starting the day of surgery and for 3 weeks after surgery by an immunonephelometric assay. RESULTS: Plasma concentration significantly decreased during the first week (-44% vs -29% for creatinine). Plasma cystatin C correlated with plasma creatinine (r = 0.741; P <0.0001) and the reciprocal of the creatinine clearance estimated by the Cockcroft-Gault formula (r = 0.882; P <0.001). In all three cases of acute renal impairment, the increase in plasma cystatin C values was more prominent than that of creatinine. CONCLUSIONS: Plasma cystatin C is an alternative and accurate marker of allograft function in adult transplant patients. Increased sensitivity compared with creatinine for the detection of acute reduction in glomerular filtration rate allows in some cases a more rapid diagnosis of acute rejection or treatment nephrotoxicity.     

Renal tubular sodium handling and plasma atrial natriuretic peptide, renin activity and aldosterone in untreated men under normal living conditions

The associations between renal tubular sodium handling and plasma levels of atrial natriuretic peptide, renin activity and aldosterone were studied in 295 untreated men under normal living conditions. The renal clearance of ingested lithium was used as a marker of proximal tubular sodium handling. Plasma atrial natriuretic peptide was inversely related to creatinine clearance (r = -0.148, P less than 0.01) and directly and significantly related to the overall fractional excretion of sodium (r = 0.213, P less than 0.001) and to distal (r = 0.151, P less than 0.01) fractional sodium excretion. Plasma renin activity was inversely related to sodium excretion at both proximal (r = -0.145, P less than 0.05) and distal (r = -0.236, P less than 0.001) tubular site, whereas plasma aldosterone was significantly and inversely related to distal sodium excretion only (r = -0.305, P less than 0.001). The association between plasma atrial natriuretic peptide and distal sodium excretion in a large sample of men under normal living conditions supports the view of a possible tubular effect of the hormone of the overall control of sodium excretion in man.     

Ontogeny of fetal renal organic cation excretion: a study with cimetidine and ranitidine during the latter half of gestation in the pregnant ewe

The organic cation cimetidine undergoes renal tubular secretion in the near-term ovine fetus. We investigated the ontogeny of renal tubular secretion of organic cations in the fetus from 80 days of gestation (term = 145). Sixteen sheep were administered both cimetidine and ranitidine in random order by a combination of bolus and i.v. infusion to achieve steady-state plasma concentrations of 1000 to 2000 ng/ml. A further two sheep received cimetidine only. Steady-state plasma concentrations were reached within 2 to 3 hr. Creatinine was used as a marker of glomerular filtration rate. Maternal renal clearance of cimetidine (0.51 +/- 0.18 l/min) and ranitidine (0.54 +/- 0.14 l/min) were not correlated with the period of gestation. Cimetidine/creatinine and ranitidine/creatinine renal clearance ratios were higher than unity being 5.48 +/- 1.91 and 5.65 +/- 1.18, respectively. Fetal creatinine renal clearance increased exponentially with gestational age (r2 = 0.577, P less than .001). Fetal renal clearance of both cimetidine and ranitidine also increased exponentially with gestational age, this trend being more clear-cut for cimetidine (r2 = 0.582, P less than .001) than for ranitidine (r2 = 0.254, P = .046). The rates of increase for cimetidine and ranitidine were similar to that for creatinine (P greater than .05). At 80 days, cimetidine/creatinine and ranitidine/creatinine renal clearance ratios (3.0 and 4.4, respectively) were higher than unity and did not increase further during the remainder of gestation. Therefore, the ovine fetus possesses an efficient tubular secretory pathway for organic cations by 80 days of gestation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Validity of creatinine clearance estimates in the assessment of renal function

In clinical practice, estimations of renal function are commonly used to calculate the appropriate dose for drugs that are renally cleared. Continuous-infusion inulin clearance (CLIN), 4-hour creatinine clearance (CLCR,m), and 24-hour creatinine clearance (CLCR,a) were measured in 109 subjects (86 men and 23 women) with varying degrees of stable renal function (CLIN, 6 to 209 ml/min) and compared with CLCR values as predicted by five equations on the basis of plasma creatinine concentrations, age, weight, and/or height. The CLCR,m was positively correlated with CLIN (r = 0.92; p less than 0.0001) but exceeded CLIN by 15% between the range of 30 and 209 ml/min (CLIN). Similarly, CLCR,a correlated well with both CLCR,m (r = 0.84; p less than 0.0005) and CLIN (r = 0.84; p less than 0.0001). The relative role of tubular secretion in the overall clearance of creatinine increased with declining CLIN and exceeded 40% when CLIN was below 30 ml/min. CLCR estimated by the Cockcroft-Gault and Mawer methods did not significantly differ from either CLCR,m or CLCR,m, whereas the other equations generally underestimated CLCR. Among the numerous mathematical equations, CLCR as estimated by the method proposed either by Mawer or Cockcroft and Gault was the best predictor of CLIN (CLIN = 1.05CLRCR - 18.38 or CLIN = 1.12CLCR - 20.60, respectively; r = 0.81; p less than 0.0001). The present data support the use of estimator equations proposed by Cockcroft and Gault or Mawer for rapid estimation of renal function in the clinical setting.     

Comparison of creatinine and inulin clearances in multiple trauma

Creatinine clearance (Ccr) is a good predictor of renal dysfunction. However, numerous analytical interferences have been observed with the classical measurement of creatinine by Jaffé's procedure. This prospective study was conducted to compare 4 methods for determining creatinine; and also endogenous creatinine clearance with inulin clearance (Cin) to estimate the glomerular filtration rate. The 4 different techniques for measuring creatinine were: 1) 2 techniques using Jaffé's colorimetric reaction: one with rapid and the other with slow kinetics: 2) 2 more selective methods: enzymatic procedure and high performance liquid chromatography (HPLC). Measurements were performed in 13 multiple trauma patients after stabilization and in 5 comatose patients (control group) over a 3-day period, with strict 24-h urine collection. On the second day, inulin clearance and para-aminohippuric acid clearance (Cpah) were measured. Measurement of creatinine by Jaffé's procedure yields significantly higher levels than those obtained by the other methods. Higher levels of both plasma and urinary creatinine were observed in the multiple trauma patients with all the methods used. There were no significant differences in Ccr, Cin, Cpah between the multiple trauma patients and the control patients. The best correlations between inulin clearance and creatinine clearance were observed for Jaffé's rapid kinetics (r = 0.90) in the control group and for the enzymatic procedure in the multiple trauma group (r = 0.55). Plasma creatinine is not a useful indicator in multiple trauma. The correlation between creatinine clearance and inulin clearance is not very strong in multiple trauma, indicating that the relative evolution (not the absolute values) of creatinine clearance is of interest.     

Plasma polyunsaturated fatty acids and the decline of renal function

BACKGROUND: Recent studies suggest an association between polyunsaturated fatty acids (PUFAs) and the development of chronic kidney disease. The aim of this study was to examine the relationship between PUFAs and renal function in older adults. METHODS: We performed a cross-sectional and prospective analysis of 931 adults, > or = 65 years old, enrolled in the InCHIANTI study, a population-based cohort in Tuscany, Italy. Plasma PUFAs were measured at enrollment, and creatinine clearance was estimated by the Cockcroft-Gault equation at baseline and after 3-year follow-up. RESULTS: At enrollment, participants with higher creatinine clearance had higher concentrations of HDL cholesterol, total plasma PUFAs, plasma n-3 fatty acid (FA), and plasma n-6 FA and lower triglycerides. From enrollment to the 3-year follow-up visit, creatinine clearance declined by 7.8 (12.2) mL/min (P <0.0001). Baseline total plasma PUFAs, n-3 FA, n-6 FA, and linoleic, linolenic, and arachidonic acids were strong independent predictors of less steep decline in creatinine clearance from baseline to follow-up (P <0.0001, after adjusting for baseline creatinine clearance). After adjusting for baseline creatinine, baseline total plasma PUFAs, n-3 FA, and linoleic, linolenic, and arachidonic acids were negatively associated with creatinine at 3-year follow-up. Participants with higher plasma PUFAs at enrollment had a lower risk of developing renal insufficiency, defined by a creatinine clearance <60 mL/min, during 3-year follow-up. CONCLUSION: High PUFA concentrations, both n-3 FA and n-6 FA, may attenuate the age-associated decline in renal function among older community-dwelling women and men.     

Plasma acylation stimulating protein, adipsin and lipids in non-obese and obese populations

BACKGROUND: Acylation stimulating protein (ASP) is a potent stimulator of TG synthesis in human adipocytes. DESIGN: In the present study, we have analysed plasma ASP and adipsin levels and their relationships to plasma lipids in non-obese and obese groups. RESULTS: The results show that the frequency distribution of ASP is skewed but that of adipsin is normal in both groups. In the non-obese population, the mean levels of plasma ASP and adipsin were 20.2 nmol L-1 (median) and 66.6 +/- 19 nmol L-1 (mean) respectively. No difference was observed between men and women for each of the parameters. In the obese population, the median plasma ASP was increased by 246% (69.9 nmol L-1) and adipsin by 31% (87.0 +/- 22.7 nmol L-1) above that of the control group. Although the levels for men and women were not statistically different for adipsin, the median ASP plasma concentration was 1.9-fold higher in obese women than in obese men (71.8 nmol L-1 vs. 37.6 nmol L-1, P < 0.05). Best subset regression analysis provided a model with variables that best predict plasma ASP [r2 = 0.160, P < 0.008 for body mass index (BMI), P < 0.05 for triacylglycerol (TG), P < 0.03 for free fatty acid (FFA)] and plasma adipsin (r2 = 0.057, P < 0.017 for BMI) in a non-obese population. In obese subjects, the model was different for plasma ASP (P = NS for any of the variables) and plasma adipsin (r2 = 0.356, P < 0.008 for FFA, P < 0.0002 for BMI, P < 0.02 for age). There was no correlation between ASP and adipsin in either the non-obese or the obese group. CONCLUSION: The present data suggest involvement of the ASP/adipsin pathway in the pathogenesis of obesity.     

Plasma BGP: an indicator of spontaneous bone loss and of the effect of oestrogen treatment in postmenopausal women

One hundred and ninety-one healthy early postmenopausal women, aged 45-54 years, were randomized to 2 years of treatment with (a) percutaneous 17 beta-oestradiol combined with progesterone (n = 29) or placebo (n = 28); (b) oral oestradiol valerate combined with cyproterone acetate (n = 37) or placebo (n = 39); (c) 24R, 25 (OH)2D3 (n = 29) or placebo (n = 29). We measured the plasma bone Gla-protein (BGP), bone mineral content of the proximal forearms (BMC), bone mineral density in the spine (BMDspine) and total body bone mineral (TBBM) in all the women before, and during, the study. In the groups of women receiving the oestrogen preparations, the plasma BGP decreased highly significantly (P less than 0.001) to a premenopausal level. The initial plasma BGP concentration was significantly related to the loss of BMC (P less than 0.001) in the placebo groups. The changes in plasma BGP were an indicator of the oestrogen response on BMC. We conclude that serial determinations of plasma BGP are useful for determination of the effect of oestrogen therapy in groups of patients, and that plasma BGP measured at the time of the menopause indicates what the rate of bone loss will be.     

Clinical usefulness of cystatin C for the estimation of glomerular filtration rate in type 1 diabetes: reproducibility and accuracy compared with standard measures and iohexol clearance

OBJECTIVE-Assessment and follow-up of early renal dysfunction is important in diabetic nephropathy. Plasma creatinine is insensitive for a glomerular filtration rate (GFR) >50 ml/min and creatinine clearance is unwieldy and subject to collection inaccuracies. We aimed to assess the reproducibility, reliability, and accuracy of plasma cystatin C as a measure of GFR ranging from normal to moderate impairment due to type 1 diabetes in the presence of a normal plasma creatinine concentration. RESEARCH DESIGN AND METHODS-A sensitive immunoturbidimetric cystatin C assay was examined in 29 subjects with type 1 diabetes and 11 nondiabetic subjects. Duplicate measurements of the following were collected from each subject, 2 weeks apart: cystatin C, enzymatic plasma creatinine, 24-h creatinine clearance, GFR estimated from plasma creatinine by the Cockcroft-Gault equation, and iohexol clearance as a gold standard. RESULTS-Iohexol clearance ranged from 35 to 132 ml. min(-1). 1.73 m(-2). Plasma cystatin C compared well with the other clinically used tests. The reliability of cystatin C, as assessed by the discriminant ratio, was superior to creatinine clearance (3.4 vs. 1.5, P < 0.001) and the correlation of cystatin C with iohexol clearance (Rs -0.80) was similar to that of creatinine clearance (Rs -0.74) and superior to that of plasma creatinine and the Cockcroft-Gault estimate (Rs -0.54 and 0.66, respectively). Duplicate estimations were used to provide an unbiased equation to convert plasma cystatin C to GFR. CONCLUSIONS-Based on this study, cystatin C is a more reliable measure of GFR than creatinine clearance, is more highly correlated with iohexol clearance than plasma creatinine, and is worthy of further investigation as a clinical measure of GFR in type 1 diabetes.