Gilles Dumoulin

No trend toward a spontaneous improvement of hyperparathyroidism and high bone turnover in normocalcemic long-term renal transplant recipients

Although hyperparathyroidism is a common feature in renal transplant recipients, the long-term course of parathyroid hormone (PTH) secretion in these patients is not well established, and the actual contribution of PTH to posttransplant bone disease remains incompletely understood. Therefore, we studied calcium-regulating hormones and serum osteocalcin, as a marker of bone remodeling, in 82 normocalcemic renal transplant recipients with good renal function who had received a graft 6 to 73 months previously and in 82 healthy subjects matched for age and sex. In all subjects, fasting serum and 24-hour urinary samples were collected. The transplant recipients had excessive PTH secretion (serum PTH, 6.9 +/- 0.5 pmol/L in recipients v 3.0 +/- 0.1 pmol/L in healthy subjects; P < 0.001) and high bone turnover (osteocalcin, 16.6 +/- 0.8 microg/L v 8.0 +/- 0.3 microg/L; P < 0.001). (Values are mean +/- SEM.) In addition, transplant recipients had a slightly higher ionized calcium than the healthy subjects, providing definite evidence of an inappropriate PTH secretion in renal transplant recipients. Furthermore, in subgroups of 25 recipients and 25 healthy controls matched for creatinine clearance, the results superimposed those obtained in the whole groups, suggesting that excessive PTH secretion and high bone turnover in renal transplant recipients did not merely reflect the moderately reduced renal function of some recipients. In the whole group of transplant recipients, PTH correlated positively with osteocalcin (r = 0.40; P < 0.001), suggesting that PTH contributes at least partly to posttransplant bone disease. Conversely, there was no correlation between serum PTH or osteocalcin and the delay from grafting. Therefore, our results provide no evidence for a spontaneous improvement of either persistent hyperparathyroidism or high bone turnover in normocalcemic long-term renal transplant recipients.

Pretransplant Serum Vitamin D Levels and Risk of Cancer After Renal Transplantation

Background. Serum levels of 25-OH-D3 inversely correlate with the incidence of various types of cancers in the general population. Because risk factors and incidence of cancer in renal transplant recipients (RTRs) are different from the general population, this study was designed to determine whether pretransplant 25-OH-D3 levels could be predictive of cancer risk in RTRs. Methods. Pretransplant 25-OH-D3 levels were reviewed in 363 consecutive RTRs. The impact of 25-OH-D3 levels on the development of cancer was then analyzed with respect to other known risk factors. Results. One hundred twenty-four patients (34.2%) showed vitamin D deficiency, 185 (51%) vitamin D insufficiency, and 54 (14.8%) with normal vitamin D levels. Thirty-two cancers (8.8%) occurred in 32 patients. A higher incidence of cancer was observed in patients with vitamin D deficiency (13.7% vs. 7% for patients with vitamin D insufficiency [P=0.068] and 3.7% for those with normal vitamin D levels [P=0.007]). 25-OH-D3 levels were lower in patients who developed cancer after transplantation (13.7±6 vs. 18.3±17.8 ng/mL, P=0.022). Age (hazard ratio, 1.06; 95% confidence interval, 1.02–1.11, for each 1 year increase; P=0.009) and low 25-OH-D3 levels (hazard ratio, 1.12; 95% confidence interval, 1.04–1.23, for every 1 ng/mL decrease; P=0.021) were independent risk factors for development of cancer. Conclusion. Pretransplant level of 25-OH-D3 is an important determinant for subsequent development of cancer after transplantation. Future studies should examine whether 25-OH-D3 supplementation can effectively decrease the incidence of cancer in RTRs.

Cardiovascular autonomic control during short-term thermoneutral and cool head-out immersion.

BACKGROUND Moderately cold head-out water immersion stimulates both baro- and cold-receptors, and triggers complex and contradictory effects on the cardiovascular system and its autonomic nervous control. OBJECTIVES To assess the effects of water immersion and cold on cardiovascular status and related autonomic nervous activity. METHODS Hemodynamic variables and indexes of autonomic nervous activity (analysis of heart rate and blood pressure variability) were evaluated in 12 healthy subjects during 3 exposures of 20 min each in the upright position, i.e., in air (AIR, 24-25 degrees C), and during head-out water immersion at 35-36 degrees C (WIn) and 26-27 degrees C (WIc). RESULTS Plasma noradrenaline, systolic and diastolic blood pressure, and total peripheral resistances were reduced during WIn compared to AIR (263.9 +/- 39.4 vs. 492.5 +/- 35.7 pg x ml(-1), 116.5 +/- 3.7 and 65.4 +/- 1.7 mmHg vs. 140.8 +/- 4.7 and 89.8 +/- 2.8 mmHg, 14.1 +/- 1.0 vs. 16.3 +/- 0.9 mmHg x L(-1) x min, respectively) while they were increased during WIc (530.8 +/- 84.7 pg ml(-1), 148.0 +/- 7.0 mmHg, 80.8 +/- 3.0 mmHg, and 25.8 +/- 1.9 mmHg x L(-1) x min, respectively). The blood pressure variability was reduced to the same extent during WIc and Win compared to AIR. Heart rate decreased during WIn (67.8 +/- 2.7 vs. 81.2 +/- 2.7 bpm during AIR), in parallel with an increased cardiac parasympathetic activity. This pattern was strengthened during WIc (55.3 +/- 2.2 bpm). CONCLUSIONS Thermoneutral WI lowered sympathetic activity and arterial tone, while moderate whole-body skin cooling triggered vascular sympathetic activation. Conversely, both WI and cold triggered cardiac parasympathetic activation, highlighting a complex autonomic control of the cardiovascular system.

Relationships between Adipose Tissue and Psoriasis, with or without Arthritis.

Psoriasis (Pso) is a common chronic cutaneous inflammatory disease involving the skin that is associated with serious comorbidities. Comorbidities in Pso include psoriatic arthritis (PsA), reduced quality of life, malignancy, depression, but also a constellation of associated conditions that enhance the cardiovascular (CV) risk. Indeed, obesity is common in patients with Pso or PsA and is considered to be a risk factor for the onset of these diseases. Patients with Pso and PsA share common obesity-related complications such as metabolic syndrome (MetS), dyslipidemia, diabetes or insulin resistance, and CV diseases. Chronic inflammation in Pso and PsA partially explains the development of atherosclerosis and CV diseases. In parallel, body composition is disturbed in patients with Pso or PsA, as suggested by anthropometric measurements, while an excess of abdominal adiposity is observed in PsA, enhancing the risk of MetS and CV diseases. Adipokines may link the adipose tissue to the obesity-related complications of Pso and PsA. Indeed, altered circulating levels of the adipokines leptin, adiponectin, visfatine, and resistin have been found in patients with Pso or PsA. In addition, an excess of adipose tissue may compromise the therapeutic response to traditional drugs or biological agents in Pso and PsA. This paper reviews the comorbidities that contribute to enhanced CV risk, the body composition results, and the potential role of adipokines in systemic inflammation and energetic balance in Pso and PsA.

Serum adipokines and adipose tissue distribution in rheumatoid arthritis and ankylosing spondylitis. A comparative study.

Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are inflammatory rheumatic diseases that may modify body composition. Adipose tissue has the ability to release a wide range of products involved in physiologic functions, but also in various pathological processes, including the inflammatory/immune response. RA and AS are both associated with the development of cardiovascular complications. It is has been established that central/abdominal, and particularly intra-abdominal or visceral adiposity is closely linked to cardiovascular events. Thus, in this study, we aimed to evaluate the body composition of patients with RA or AS compared to healthy controls (HC), with a special emphasis on the visceral region. In parallel, we measured adipose products or adipokines, namely leptin, adiponectin and its high molecular weight (HMW) isoform, resistin, and ghrelin, a gastric peptide that plays a role in energetic balance. The homeostasis model assessment for insulin resistance (HOMA-IR) and atherogenic index were used to evaluate cardiovascular risk. One hundred and twelve subjects were enrolled (30 patients with RA, 31 with AS, and 51 HC). Body composition was measured using dual-energy X-ray absorptiometry to determine total fat mass and lean mass, adiposity, fat in the android and gynoid regions, and visceral fat. Patients and HC did not differ in terms of body mass index. On the contrary, adiposity was increased in RA (p = 0.01) while visceral fat was also increased, but only in women (p = 0.01). Patients with AS tended to have lower total fat mass (p = 0.07) and higher lean mass compared to HC (p = 0.07). Leptin and leptin/fat mass were decreased in male patients with AS (p < 0.01), while total adiponectin and the ratio of HMW to total adiponectin were both increased in RA (p < 0.01). There were no changes in serum resistin and ghrelin in any group of patients. HOMA-IR and the atherogenic index were not modified in RA and AS. These results confirm that body composition was altered in RA and AS, affecting distinct soft tissue compartments. The effect of the increased visceral adipose tissue on cardiovascular risk is presumably attenuated by the favorable cardiometabolic profile in women with RA, as suggested by the normal HOMA-IR and atherogenic index.

Lack of evidence that cyclosporine treatment impairs calcium-phosphorus homeostasis and bone remodeling in normocalcemic long-term renal transplant recipients.

Since the effects of cyclosporine on mineral and bone metabolism are controversial, we studied calcium regulating hormones, calcium-phosphorus (Ca-P) metabolism, and bone remodeling, assessed by serum osteocalcin, in long-term renal transplant recipients (RT). Forty-seven normocalcemic patients with good renal function receiving cyclosporine (CT, n = 27) or not (NC, n = 20) were studied at baseline and after an oral Ca load. CT and NC had similar age, daily dose of steroids, GFR level, and duration of transplantation. Baseline evaluation included 24-hr urinary Ca, P, TRP, TmP/GFR, fasting serum intact PTH, 1,25-(OH)2D, 25OHD, osteocalcin, Ca, and P. Subjects of the two groups had excessive secretion of PTH, tubular P wasting, and high serum osteocalcin level, as is usual in RT. However, there was no difference between CT and NC regarding any baseline variable. Ten CT and ten NC, matched for duration of transplantation and serum PTH level, ingested 1g Ca to achieve an acute dynamic study of PTH secretion and Ca-P metabolism. In both CT and NC, this Ca load caused the same decreases in serum PTH (P < 0.001), NcAMP (P < 0.05), and urinary P (P < 0.001) and the same increases in serum and urinary Ca (P < 0.001), and in both TmP/GFR and TRP (P < 0.001). These results strongly suggest that cyclosporine treatment had no significant effect on calcium-regulating hormone secretion, P-Ca metabolism, and bone remodeling level. We therefore consider that cyclosporine is unlikely to have any prominent role in the abnormalities of bone endocrine and mineral metabolism that are common in long-term kidney recipients.

Elevated Adiponectin Serum Levels in Women with Systemic Autoimmune Diseases

Adipose tissue produces a wide range of proteins that may influence the immune system. In this study, we assessed the serum levels of leptin, adiponectin, and ghrelin, in association with the measurements of body composition, in 15 female patients with various autoimmune diseases (systemic lupus erythematosus, primary Sjögrens syndrome, sarcoidosis, mixed connective tissue disease, vasculitis, CREST syndrome, and polymyositis) and in 15 healthy female controls. There were no statistically significant differences between the patients and controls with regard to serum leptin, serum ghrelin, global fat mass, adiposity, and fat mass in the android or gynoid regions, whereas serum adiponectin levels were higher in patients than controls (16.3 ± 1.6 μg/mL versus 9.7 ± 0.6 μg/mL; P = .01). As adiponectin is known to exhibit potent anti-inflammatory properties, a high adiponectinemia in patients with systemic autoimmune disease may mitigate the inflammatory response. However, the precise consequences of these elevated serum adiponectin levels on the metabolic syndrome development and atherosclerotic cardiovascular risk in this patient population still needs to be determined.

Graded vascular autonomic control versus discontinuous cardiac control during gradual upright tilt.

Indexes of heart rate variability (HRV) and the slope of cardiac baroreflex are extensively used for non invasive assessment of circulatory autonomic control in pathophysiology. We performed this study (1) to assess the sensitivity of these indexes towards small graded postural stimulations and (2) to delineate the informations provided about the settings of both vascular tone and cardiac activity. Twenty healthy subjects were randomly tilted for eight minutes at each of the six angles: -10 degrees, 0 degrees (supine), 10 degrees, 30 degrees, 45 degrees, and 60 degrees. Instant RR-interval and finger blood pressure (BP) were continuously recorded, and venous blood was collected at the end of each 8 min position for catecholamines determination. Group average heart rate, noradrenaline and diastolic BP (DBP) increased linearly with head-up tilt angle from 10 degrees. Systolic BP (SBB) ranked only two distinct series -10 degrees, 0 degrees, 10 degrees versus 30 degrees, 45 degrees, 60 degrees, as did the number of spontaneous baroreflex (SBR) sequences. The spectral power of the low-frequency (LF) and high-frequency (HF) of RR variability and the ratio LF/HF changed rather abruptly from either 30 degrees or 45 degrees, depending on each individual. Both HF/tot i.e. the ratio of HF to total spectral RR variability and the slope of SBR decreased markedly from 10 degrees to 30 degrees and less but more gradually from 30 degrees to 60 degrees. Thus, our observations argue for gradual adjustments of vascular tone as reflected by highly consistent changes in plasma noradrenaline and diastolic arterial pressure, contrasting with a main discontinuous autonomic setting of cardiac activity as reflected by changes in the harmonic components of spectral RR variability and in the slope of cardiac baroreflex. The pattern of changes in systolic arterial pressure attested the discontinuous cardiac autonomic control rather than the gradual setting of arterial tone. We submit that these different patterns of autonomic adjustments should be considered when assessing pathophysiological states.

Two-Dimensional Strain and Twist by Vector Velocity Imaging in Adolescents With Severe Obesity

The prevalence of severe obesity is increasing worldwide in adolescents. Whether it is associated with functional myocardial abnormalities remains largely unknown, potentially because of its frequent association with other cardiovascular risk factors and also use of insensitive techniques to detect subclinical changes in myocardial function. We used 2D vector velocity imaging (VVI) to investigate early changes in left ventricular (LV) myocardial function in youths with isolated severe obesity. Thirty‐seven asymptomatic severely obese adolescents free of diabetes and hypertension, and 24 lean controls were enrolled. LV longitudinal, basal, and apical circumferential strain, strain rate (SR), rotations, and LV twist were measured. Obese adolescents had greater LV mass and reduced systolic and early diastolic tissue Doppler imaging (TDI) velocities than lean counterparts. L strain (−24%) and systolic and early diastolic SR were also diminished in the obese, whereas no intergroup differences existed for the circumferential deformation indexes. LV twist was more pronounced in the obese (+1.7°, P < 0.01) on account of greater apical rotation only (4.1 ± 0.9 vs. 5.2 ± 1.2°, P < 0.01), potentially compensating for the loss in longitudinal function. Systolic—diastolic coupling, an important component of early filling and diastolic function, was maintained with severe obesity. No intergroup differences were reported regarding time to peak values for all VVI indexes highlighting that dynamics of strain and twist/untwist along the cardiac cycle was preserved with severe obesity. Isolated severe obesity in adolescents, at a preclinical stage, is associated with changes in myocardial deformation and torsional mechanics that could be in part related to alterations in relaxation and contractility properties of subendocardial fibers.

The role of leptin in the pathophysiology of rheumatoid arthritis.

The past 20 years of research on leptin has provided important insights into its role in rheumatoid arthritis (RA). Leptin is one of the different adipokines produced by the adipose tissue that influences the endocrine system, energy homeostasis and the immune response in several ways. Leptin is known to have predominantly pro-inflammatory effects, especially in the setting of chronic inflammation. Animal models of arthritis have illustrated well the participation of leptin in the inflammatory response within the joints. In patients with RA, numerous studies have evaluated the concentrations of leptin in the bloodstream and/or the joint cavity, showing higher levels compared to control populations. Leptin has also been found to correlate with clinical or biological measurements of disease activity of RA. Conversely, the relationship between serum leptin and joint structural damage is less evident. Leptin may also promote the development of atherosclerosis in RA and may contribute to the cardiovascular consequences of the metabolic syndrome that coexists with RA. Indeed, leptin could be a link between inflammation, metabolic risk factors and cardiovascular diseases in RA. Finally, due to abnormal body composition phenotypes with an increased prevalence of obesity in RA, the therapeutic response to traditional DMARDs and/or biological agents may be attenuated. This review discusses the multiple interplays that have been described between leptin and the clinical, radiographic and therapeutic aspects of RA.