Influence of age, risk factors, and cardiovascular and renal disease on arterial stiffness: clinical applications.

Age is the main clinical determinant of large artery stiffness. Central arteries stiffen progressively with age, whereas peripheral muscular arteries change little with age. A number of clinical studies have analyzed the effects of age on aortic stiffness. Increase of central artery stiffness with age is responsible for earlier wave reflections and changes in pressure wave contours. The stiffening of aorta and other central arteries is a potential risk factor for increased cardiovascular morbidity and mortality. Arterial stiffening with aging is accompanied by an elevation in systolic blood pressure (BP) and pulse pressure (PP). Although arterial stiffening with age is a common situation, it has now been confirmed that older subjects with increased arterial stiffness and elevated PP have higher cardiovascular morbidity and mortality. Increase in aortic stiffness with age occurs gradually and continuously, similarly for men and women. Cross-sectional studies have shown that aortic and carotid stiffness (evaluated by the pulse wave velocity) increase with age by approximately 10% to 15% during a period of 10 years. Women always have 5% to 10% lower stiffness than men of the same age. Although large artery stiffness increases with age independently of the presence of cardiovascular risk factors or other associated conditions, the extent of this increase may depend on several environmental or genetic factors. Hypertension may increase arterial stiffness, especially in older subjects. Among other cardiovascular risk factors, diabetes type 1 and 2 accelerates arterial stiffness, whereas the role of dyslipidemia and tobacco smoking is unclear. Arterial stiffness is also present in several cardiovascular and renal diseases. Patients with heart failure, end stage renal disease, and those with atherosclerotic lesions often develop central artery stiffness. Decreased carotid distensibility, increased arterial thickness, and presence of calcifications and plaques often coexist in the same subject. However, relationships between these three alterations of the arterial wall remain to be explored.

Transplantation rénale pédiatrique: expérience lausannoise de 1971 à 1998 [Pediatric renal transplantation: Experience in Lausanne 1971 to 1998].

AIMS OF THE STUDY: Analysis of indications and results of paediatric renal transplantation in a single centre, before and after the introduction of cyclosporine A (CSA). METHODS: Historical retrospective study. RESULTS: 19 transplantations were performed in 14 patients (5 second grafts) between 1971 and 1987 (group I). 13 patients were transplanted between 1988 and 1998 (no second transplant) (group II). In group II, all the patients had immunosuppression with CSA, but none in group I. Group II, with CSA, showed better renal survival than patients without CSA. In group I, obstructive uropathies (posterior urethral valves, pyelo-ureteral junction stenosis, vesico-ureteral reflux) represent a common cause (35%) of terminal chronic renal failure (TCRF), whereas in group II they represent only 15% of the causes and chronic glomerulonephritis is the most common cause (69%) of TCRF. Acute and chronic graft rejections were the cause of 9 and 1 graft losses in group I and II respectively. Living related donors account for 14% of all renal transplantations in group I and 46% in group II. CONCLUSIONS: The incidence of paediatric patients referred to Lausanne for TCRF is stable. We have observed a constant and steady decrease in obstructive uropathies leading to TCRF and renal transplantations, whereas glomerulonephritis are increasingly frequent. Graft survival has much improved since the introduction of cyclosporine A, without an increase in morbidity. In carefully selected cases, intrafamilial renal transplantation provides good results and helps to shorten the time spent on dialysis.

Circulating soluble CR1 (CD35). Serum levels in diseases and evidence for its release by human leukocytes.

C receptor type 1 (CR1, CD35) is present in a soluble form in plasma (sCR1). Soluble CR1 was measured with a specific ELISA assay in normal individuals and in patients with different diseases. The mean serum concentration of sCR1 in 31 normal donors was 31.4 +/- 7.8 ng/ml, and was identical in plasma. An increase in sCR1 was observed in 36 patients with end-stage renal failure on dialysis (54.8 +/- 11.7 ng/ml, p < 0.0001), and in 22 patients with liver cirrhosis (158.3 +/- 49.9 ng/ml, p < 0.0001). The mean sCR1 levels dropped from 181 +/- 62.7 to 52.1 +/- 24.0 ng/ml (p < 0.001) in nine patients who underwent liver transplantation, and was 33.5 +/- 7.3 in 10 patients with functioning renal grafts, indicating that the increase in sCR1 was reversible. Soluble CR1 was elevated in some hematologic malignancies (> 47 ng/ml), which included B cell lymphoma (12/19 patients), Hodgkin's lymphoma (4/4), and chronic myeloproliferative syndromes (4/5). By contrast, no increase was observed in acute myeloid or lymphoblastic leukemia (10) or myeloma (5). In two patients with chronic myeloproliferative syndromes, sCR1 decreased rapidly after chemotherapy. The mean concentration of sCR1 was not significantly modified in 181 HIV-infected patients at various stages of the disease (34.8 +/- 14.4 ng/ml), and in 13 patients with active SLE (38.3 +/- 19.6 ng/ml), although in both groups the number of CR1 was diminished on E. There was a weak but significant correlation between sCR1 and CR1 per E in HIV infection and SLE (r = 0.39, p < 0.0001, and r = 0.60, p < 0.03 respectively). In vitro, monocytes, lymphocytes, and neutrophils were found to release sCR1 into culture supernatants. In vivo, sCR1 was detected in the serum of SCID mice populated with human peripheral blood leukocytes. The sCR1 levels correlated with those of human IgG (r = 0.97, p < 0.0001), suggesting synthesis of sCR1 by the transferred lymphocytes. The mechanisms underlining the increased levels of sCR1 and its biologic consequences remain to be defined.

La fonction rénale sous inhibition de l'enzyme de conversion de l'angiotensine [Renal function after administration of angiotensin-converting enzyme inhibitors]

Angiotensin converting enzyme (ACE) inhibitors are widely used today for the management of hypertension and congestive heart failure. These agents inhibit angiotensin II synthesis. In some particular circumstances they may be responsible for deterioration of renal function, e.g. in hypertensive patients with bilateral renal artery stenosis or with stenosis of the artery supplying a single kidney, or in patients with severe congestive heart failure or marked nephroangiosclerosis. In these patients renal perfusion pressure may become too low to maintain adequate glomerular filtration as there remains no angiotensin II to increase the tone of the efferent arteriole. In high risk patients it is therefore recommended that serum creatinine be checked after initiating therapy with an ACE inhibitor.

Heritability of renal function in hypertensive families of African descent in the Seychelles (Indian Ocean).

BACKGROUND: We estimated the heritability of three measures of glomerular filtration rate (GFR) in hypertensive families of African descent in the Seychelles (Indian Ocean). METHODS: Families with at least two hypertensive siblings and an average of two normotensive siblings were identified through a national hypertension register. Using the ASSOC program in SAGE (Statistical Analysis in Genetic Epidemiology), the age- and gender-adjusted narrow sense heritability of GFR was estimated by maximum likelihood assuming multivariate normality after power transformation. ASSOC can calculate the additive polygenic component of the variance of a trait from pedigree data in the presence of other familial correlations. The effects of body mass index (BMI), blood pressure, natriuresis, along with sodium to potassium ratio in urine and diabetes, were also tested as covariates. RESULTS: Inulin clearance, 24-hour creatinine clearance, and GFR based on the Cockcroft-Gault formula were available for 348 persons from 66 pedigrees. The age- and gender-adjusted correlations (+/- SE) were 0.51 (+/- 0.04) between inulin clearance and creatinine clearance, 0.53 (+/- 0.04) between inulin clearance and Cockcroft-Gault formula and 0.66 (+/- 0.03) between creatinine clearance and Cockcroft-Gault formula. The age- and gender-adjusted heritabilities (+/- SE) of GFR were 0.41 (+/- 0.10) for inulin clearance, 0.52 (+/- 0.13) for creatinine clearance, and 0.82 (+/- 0.09) for Cockcroft-Gault formula. Adjustment for BMI slightly lowered the correlations and heritabilities for all measurements whereas adjustment for blood pressure had virtually no effect. CONCLUSION: The significant heritability estimates of GFR in our sample of families of African descent confirm the familial aggregation of this trait and justify further analyses aimed at discovering genetic determinants of GFR.

Dual transplant of marginal kidneys. Case report and review of the literature.

INTRODUCTION: Double transplantation is one possible answer to the shortage of donor organs. While each donor kidney would be unsuitable when considered as a single allograft, use of both kidneys should provide sufficient nephron mass for effective glomerular filtration. CASE REPORT: This is the first Swiss report of a dual adult transplant of marginal kidneys in a 46-year-old man, who was transplanted for the fourth time. Follow-up at 6 months is excellent without acute rejection. CONCLUSION: Recent analysis of dual marginal versus single ideal transplant outcomes, found a comparable 1-yr graft survival in both of the procedures. Long term results are still lacking and guidelines to decide between single, double or no transplantation are emerging.

Osteoprotegerin and bone mineral density in hemodiafiltration patients.

A newly identified cytokine, osteoprotegerin (OPG) appears to be involved in the regulation of bone remodeling. In vitro studies suggest that OPG, a soluble member of the TNF receptor family of proteins, inhibits osteoclastogenesis by interrupting the intercellular signaling between osteoblastic stromal cells and osteoclast progenitors. As patients with chronic renal failure (CRF) often have renal osteodystrophy (ROD), we investigated the role of osteoprotegerin (OPG) in ROD, and investigated whether there was any relationship between serum OPG, intact parathyroid (PTH) (iPTH), vitamin D, and trabecular bone. Serum OPG combined with iPTH might be a useful tool in the noninvasive diagnosis of ROD, at least in cases in which the range of PTH values compromises reliable diagnosis. Thirty-six patients on maintenance hemodiafiltration (HDF) and a control group of 36 age and sex matched healthy subjects with no known metabolic bone disease were studied. The following assays were made on serum: iPTH, osteocalcin (BGP), bone alkaline phosphatase, 25(OH)-cholecalciferol, calcium, phosphate, OPG, IGF-1, estradiol, and free testosterone. Serum Ca++, P, B-ALP, BGP, IGF-1, iPTH, and OPG levels were significantly higher in HDF patients than in controls, while DXA measurements and quantitative ultrasound (QUS) parameters were significantly lower. On grouping patients according to their mean OPG levels, we observed significantly lower serum IGF-1, vitamin D3 concentrations, and lumbar spine and hip bone mineral density in the high OPG groups. No correlation was found between OPG and bone turnover markers, whereas a negative correlation was found between serum OPG and IGF-1 levels (r=-0.64, p=0.032). Serum iPTH concentrations were positively correlated with bone alkaline phosphatase (B-ALP) (r=0.69, p=0.038) and BGP (r=0.92, p<0.001). The findings made suggest that an increase in OPG levels may be a compensatory response to elevated bone loss. The low bone mineral density (BMD) levels found in the high OPG group might have been due to the significant decrease in serum IGF-1 and vitamin D3 observed. In conclusion, the findings made in the present study demonstrate that increased OPG in hemodiafiltration patients is only partly due to decreased renal clearance. As it may partly reflect a compensatory response to increased bone loss, this parameter might be helpful in the identification of patients with a marked reduction in trabecular BMD.

Insuffisance rénale terminale d'origine lithiasique : fréquence, causes et prévention [Nephrolithiasis-induced ESRD: frequency, causes and prevention].

Nephrolithiasis still remains a too frequent - and under-appreciated - cause of end-stage renal disease (ESRD), and this is all the most unfortunate since such an untoward course is now preventable in most cases. Among 1391 patients who started maintenance dialysis at Necker hospital between 1989 and 2000, nephrolithiasis was identified as the cause of ESRD in 45 of them, an overall prevalence of 3.2%. Infection stones accounted for 42.2% of cases, calcium stones for 26.7%, uric acid stones for 17.8% and hereditary diseases for 13.3%. The proportion of nephrolithiasis-associated ESRD declined from 4.7% to 2.2% from the 1989-1991 to the 1998-2000 period, as a result of the decreased incidence of ESRD in patients with infection and calcium nephrolithiasis. Based on our observations and on published reports, it emerges that most cases of nephrolithiasis-associated ESRD were due to sub-optimal management (especially in the case of infection or cystine stones) or to late (or erroneous) etiologic diagnosis, precluding early institution of appropriate therapeutic measures. In particular, several patients with primary hyperoxaluria or 2,8-dihydroxyadeninuria were diagnosed while already on dialysis or after unsuccessful kidney transplantation, due to wrong initial diagnosis. In conclusion, thanks to recent advances in diagnosis and management of stone formers, ESRD should now be prevented in the great majority of patients, at the condition of early etiologic diagnosis based on accurate morphoconstitutional analysis of calculi and metabolic evaluation, and early implementation of appropriate preventive medical treatment.

Measurement of glomerular filtration rate in obese patients: pitfalls and potential consequences on drug therapy.

Epidemiological studies have shown that obesity is associated with chronic kidney disease and end stage renal disease. These studies have used creatinine derived equations to estimate glomerular filtration rate (GFR) and have indexed GFR to body surface area (BSA). However, the use of equations using creatinine as a surrogate marker of glomerular filtration and the indexation of GFR for BSA can be questioned in the obese population. First, these equations lack precision when they are compared to gold standard GFR measurements such as inulin clearances; secondly, the indexation of GFR for 1.73 m(2) of BSA leads to a systematic underestimation of GFR compared to absolute GFR in obese patients who have BSA that usually exceed 1.73 m(2). Obesity is also associated with pathophysiological changes that can affect the pharmacokinetics of drugs. The effect of obesity on both renal function and drug pharmacokinetics raises the issue of correct drug dosage in obese individuals. This may be particularly relevant for drugs known to have a narrow therapeutic range or excreted by the kidney.

Secretory IgA in human serum.

Secretory component (SC) was detected by the radioactive single radial diffusion technique in nearly all sera examined. The SC was shown to be associated with polymeric serum IgA. The mean level of secretory IgA (SIgA) in normal sera from India, Africa and Europe was about 0.03 to 0.04 mg/ml. The mean level was elevated in patients with a variety of disorders involving secretory surfaces (e.g., acute bacterial enterocolitis or respiratory tract carcinoma), but also in disorders with no known involvement of secretory surfaces. The highest levels were seen in lactating women, with a mean level five times higher than that in the general population. SIgA was also found at lower levels in cord serum, serum from breast-fed newborns and serum from children 3 to 10 years old.

Parameters for successful monthly extended dosing of darbepoetin-alpha in patients undergoing hemodialysis.

AIM: To document the feasibility and report the results of dosing darbepoetin-alpha at extended intervals up to once monthly (QM) in a large dialysis patient population. MATERIAL: 175 adult patients treated, at 23 Swiss hemodialysis centres, with stable doses of any erythropoiesis-stimulating agent who were switched by their physicians to darbepoetin-alpha treatment at prolonged dosing intervals (every 2 weeks [Q2W] or QM). METHOD: Multicentre, prospective, observational study. Patients' hemoglobin (Hb) levels and other data were recorded 1 month before conversion (baseline) to an extended darbepoetin-alpha dosing interval, at the time of conversion, and once monthly thereafter up to the evaluation point (maximum of 12 months or until loss to follow-up). RESULTS: Data for 161 evaluable patients from 23 sites were included in the final analysis. At 1 month prior to conversion, 73% of these patients were receiving darbepoetin-alpha weekly (QW) and 27% of the patients biweekly (Q2W). After a mean follow-up of 9.5 months, 34% received a monthly (QM) dosing regimen, 52% of the patients were receiving darbepoetin-alpha Q2W, and 14% QW. The mean (SD) Hb concentration at baseline was 12.3 +/- 1.2 g/dl, compared to 11.9 +/- 1.2 g/dl at the evaluation point. The corresponding mean weekly darbepoetin-alpha dose was 44.3 +/- 33.4 microg at baseline and 37.7 +/- 30.8 microg at the evaluation point. CONCLUSIONS: Conversion to extended darbepoetin-alpha dosing intervals of up to QM, with maintenance of initial Hb concentrations, was successful for the majority of stable dialysis patients.

Oxidized LDL modulates apoptosis of regulatory T cells in patients with ESRD.

Increased levels of oxidized low-density lipoproteins (oxLDL) contribute to the increased risk for atherosclerosis, which persists even after adjusting for traditional risk factors, among patients with ESRD. Regulatory T cells (CD4+/CD25+ Tregs), which down-regulate T cell responses to foreign and self-antigens, are protective in murine atherogenesis, but whether similar immunoregulation occurs in humans with ESRD is unknown. Because cellular defense systems against oxLDL involve proteolytic degradation, the authors investigated the role of oxLDL on proteasome activity of CD4+/CD25+ Tregs in patients with ESRD. CD4+/CD25+ Tregs isolated from uremic patients' peripheral blood, especially that of chronically hemodialyzed patients, failed to suppress cell proliferation, exhibited cell-cycle arrest, and entered apoptosis by altering proteasome activity. Treating CD4+/CD25+ Tregs with oxLDL or uremic serum ex vivo decreased the number and suppressive capacity of CD4+/CD25+ Tregs. In vitro, oxLDL promoted the accumulation of p27Kip1, the cyclin-dependent kinase inhibitor responsible for G1 cell cycle arrest, and increased apoptosis in a time- and concentration-dependent manner. In summary, proteasome inhibition by oxLDL leads to cell cycle arrest and apoptosis, dramatically affecting the number and suppressive capacity of CD4+/CD25+ Tregs in chronically hemodialyzed patients. This response may contribute to the immune dysfunction, microinflammation, and atherogenesis observed in patients with ESRD.

Salt subtraction in patients on maintenance hemodialysis. Efficacy and limitations.

In 6 hypertensive patients with terminal renal failure maintained on hemodialysis, the effects of 'salt subtraction' and of sequential ultrafiltrating were evaluated. Following each of 3 weekly hemodialysis sessions, salt subtraction was carried out by ultrafiltrating 1 liter and simultaneously infusing an equal volume of 5% dextrose. This resulted in a net sodium loss without hypovolemia. After a 2-week period of this procedure, the blood pressure prior to dialysis was lower (156/76 +/- 12/5 mm Hg) than after a comparable number of sequential ultrafiltration sessions (181/88 +/- 10/6 mm Hg; mean +/- SEM). This difference was not statistically significant. At the same time, body weight was comparable at 64.4 +/- 3 and 64.7 +/- 4 kg, respectively. Neither plasma renin activity nor plasma catecholamines responded with a clear increase to either procedure. The limited effect on blood pressure and the renin system of a marked sodium removal during salt subtraction suggests that sodium must still be present in excess in these patients. The procedure of salt subtraction appears safe and subjectively well tolerated, but it can probably not be used as the sole means of decreasing total body sodium without associating dietary measures to reduce sodium intake.

Low-pressure environment and remodelling of the forearm vein in Brescia-Cimino haemodialysis access.

BACKGROUND: The aim of the study was to determine which, and to what extent, haemodynamic parameters contribute to the remodelling of the venous limb of the Brescia-Cimino haemodialysis access. METHODS: The dimensions of the radial artery and the venous limb of the haemodialysis access were measured by an echo-tracking technique. In six ESRD patients undergoing primary arteriovenous fistula (AVF) formation, vessel diameter, wall thickness, blood pressure and blood flow were measured after the operation, and at 1 and 3 months follow-up. The contralateral forearm vessels in their native position served as baseline values for comparison. RESULTS: The diameter of the proximal antecubital vein progressively increased over the study period without reaching significant differences (4430, 5041 and 6620 microm at weeks 1, 4 and 12 respectively), whereas the intima-media thickness remained unchanged. The venous dilatation was associated with a reduction of the mean shear stress that culminated after the operation and progressively returned to normal venous values at 3 months (24.5 vs 10.4 dyne/cm(2), P<0.043). Thus the venous limb of the AVF undergoes eccentric hypertrophy as demonstrated by the increase in wall cross-sectional area (4.42 vs 6.32 mm(2) at week 1 vs week 12, P<0.028). At the time of the operation, the blood pressure in the AVF was 151+/-14/92.4+/-11 mmHg vs 49+/-19/24.5+/-6 mmHg (means+/-SEM) for the radial artery and the venous limb of the vascular access, respectively. One year after the operation the blood pressure in the venous limb had not changed: 42+/-14/25.3+/-7 mmHg (means+/-SEM). Under these conditions, the systolo-diastolic diameter changes observed in the radial artery and the antecubital vein were within a similar range at all time points: 56+/-17 vs 90+/-26 microm (means+/-SEM) at week 12. CONCLUSIONS: The increased circumferential stress resulting from the flow-mediated dilatation rather than the elevation of blood pressure appears to represent the main contributing factor to the eccentric hypertrophy of the venous limb of Brescia-Cimino haemodialysis access.

Diabète et insuffisance rénate terminate. Evolution en huit ans dans le canton de Vaud [Diabetes and end stage renal disease. Eight year progression in the Canton de Vaud, Switzerland].

Diabetic nephropathy is the first cause of endstage renal disease. The demographic expansion, the increase in the incidence of diabetes and the prolonged survival rates explain the steep increase observed these last 30 years. In the United States, improved treatment has brought to a decline in the incidence of end-stage renal disease in the diabetic population since the mid nineties. We examined the change in prevalence of diabetics on dialysis from 2001 and 2009 in the Canton de Vaud, Switzerland. The prevalence of diabetics on dialysis increased from 18% to 31% in dialysis centers and increased from 1.1/1000 to 1.9/1000 in the diabetic population. These are strong indicators that efforts are needed to improve the renal outcome of patients with diabetic nephropathy.