Fabry disease due to D313Y and novel GLA mutations.

OBJECTIVES: Our aim is to report four novel α-gal A gene (GLA) mutations resulting in Fabry disease (FD) and provide evidence of pathogenicity of the D313Y mutation regarding which contradictory data have been presented in the literature. SETTING AND PARTICIPANTS: Twenty-five family members of nine unrelated patients with definite FD diagnosis, 10 clinically suspected cases and 18 members of their families were included in this polycentric cohort study. PRIMARY AND SECONDARY OUTCOME MEASURES: Genotyping and measurement of lyso-Gb3 was performed in all individuals. The α-Gal A activity was measured in all men as well as plasma and urine Gb3 concentration in selected cases. Optical and electron microscopy was performed in kidney biopsies of selected patients. All the above were evaluated in parallel with the clinical data of the patients. RESULTS: Fourteen new cases of FD were recognised, four of which were carrying already described GLA mutations. Four novel GLA mutations, namely c.835C>T, c.280T>A, c.924A>C and c.511G>A, resulting in a classic FD phenotype were identified. Moreover, FD was definitely diagnosed in five patients carrying the D313Y mutation. Eight D313Y carriers were presenting signs of FD despite not fulfilling the criteria of the disease, two had no FD signs and two others were apparently healthy. CONCLUSIONS: Four novel GLA pathogenic mutations are reported and evidence of pathogenicity of the D313Y mutation is provided. It seems that the D313Y mutation is related to a later-onset milder phenotype than the typical phenotype with normal lysoGb3 concentration. Our study underlines the significance of family member genotyping and newborn screening to avoid misdiagnoses and crucial delays in diagnosis and treatment of the disease.

Associations of adiponectin and leptin levels with protein-energy wasting, in end stage renal disease patients / Asociaciones de las concentraciones de adiponectina y leptina con el desgaste proteico-energético en pacientes con nefropatía terminal

Objective: The aim of the study was to examine the prevalence of protein-energy wasting (PEW) in hemodialysis (HD) and peritoneal dialysis (PD) patients in our center and determine whether adiponectin and leptin are involved in the development of PEW. Design: Prospective (18 months). Setting: University Hospital of Heraklion, Crete, Greece. Subjects: Seventy-four end-stage-renal-disease patients, 47 on HD and 27 on PD. Main outcome measures: At three sequential time points (baseline, 6 and 18 months) anthropometric, nutritional and inflammatory status data were collected. Serum adiponectin and leptin were also assessed at each time point. Patients were allocated to 3 strata according to PEW severity (0, 1-2 and ≥3 criteria for PEW). Results: Adiponectin and leptin levels were greater among PD compared to HD patients (p≤0.035). Adiponectin levels were incrementally greater across increasing strata of PEW (p≤0.002). Leptin showed the opposite trend, with lower levels in malnourished patients and higher levels in patients with zero PEW criteria (p≤0.042). Alterations of adiponectin levels during the observation period were dependent on PEW stratum (p≤0.021) and mode of dialysis (p≤0.002), after adjustment for age, dialysis vintage, gender and fat mass index. Particularly, adiponectin levels increased over time in HD patients with ≥3 criteria for PEW, whereas adiponectin levels decreased in PD patients with ≥3 criteria for PEW throughout the study. Leptin alterations over time were not affected by dialysis mode or PEW stratification. Conclusions: Our study provides evidence that increased adiponectin and decreased leptin levels are independently associated with PEW and thus, poor prognosis (AU)

Objetivo: El objetivo del estudio era analizar la prevalencia del desgaste proteico-energético (DPE) en los pacientes en hemodiálisis (HD) y diálisis peritoneal (DP) de nuestro centro, y determinar si la adiponectina y la leptina intervienen en el desarrollo del DPE (AU). Diseño: Prospectivo (18 meses). Ámbito: Hospital Universitario de Heraklion, Creta, Grecia. Sujetos: Setenta y cuatro pacientes con nefropatía terminal, 47 en HD y 27 en DP. Variables principales: Se recogieron datos antropométricos, nutricionales y sobre el estado inflamatorio. También los valores séricos de adiponectina y leptina en cada punto temporal. Se dividió a los pacientes en 3 estratos en función de la intensidad del DPE (0, 1-2 y ≥3 criterios de DPE. Resultados: Las concentraciones de adiponectina y leptina eran mayores en los pacientes en DP que en los sometidos a HD (p≤0,035). Los valores de adiponectina eran incrementalmente mayores al aumentar el estrato de DPE (p≤0,002). La leptina mostraba la tendencia opuesta, con niveles más bajos en los pacientes desnutridos y más altos en los pacientes con ningún criterio de DPE (p≤0,042). Las alteraciones de las concentraciones de adiponectina durante el período de observación dependían del estrato de DPE (p≤0,021) y del modo de diálisis (p≤0,002), previo ajuste por edad, antigüedad de la diálisis, sexo e índice de grasa corporal. En particular, los valores de adiponectina aumentaban con el tiempo en los pacientes en HD con ≥3 criterios de DPE, mientras que descendían en los pacientes en DP con ≥3 criterios de DPE durante todo el estudio. Ni el modo de diálisis ni la estratificación en función del DPE influyeron en las alteraciones de la leptina. Conclusiones: Nuestro estudio aporta pruebas de que el aumento de las concentraciones de adiponectina y el descenso de los valores de leptina se asocian independientemente con el DPE y, en consecuencia, con un mal pronóstico (AU)

Associations of adiponectin and leptin levels with protein-energy wasting, in end stage renal disease patients.

OBJECTIVE: The aim of the study was to examine the prevalence of protein-energy wasting (PEW) in hemodialysis (HD) and peritoneal dialysis (PD) patients in our center and determine whether adiponectin and leptin are involved in the development of PEW. DESIGN: Prospective (18 months). SETTING: University Hospital of Heraklion, Crete, Greece. SUBJECTS: Seventy-four end-stage-renal-disease patients, 47 on HD and 27 on PD. MAIN OUTCOME MEASURES: At three sequential time points (baseline, 6 and 18 months) anthropometric, nutritional and inflammatory status data were collected. Serum adiponectin and leptin were also assessed at each time point. Patients were allocated to 3 strata according to PEW severity (0, 1-2 and ≥3 criteria for PEW). RESULTS: Adiponectin and leptin levels were greater among PD compared to HD patients (p≤0.035). Adiponectin levels were incrementally greater across increasing strata of PEW (p≤0.002). Leptin showed the opposite trend, with lower levels in malnourished patients and higher levels in patients with zero PEW criteria (p≤0.042). Alterations of adiponectin levels during the observation period were dependent on PEW stratum (p≤0.021) and mode of dialysis (p≤0.002), after adjustment for age, dialysis vintage, gender and fat mass index. Particularly, adiponectin levels increased over time in HD patients with ≥3 criteria for PEW, whereas adiponectin levels decreased in PD patients with ≥3 criteria for PEW throughout the study. Leptin alterations over time were not affected by dialysis mode or PEW stratification. CONCLUSIONS: Our study provides evidence that increased adiponectin and decreased leptin levels are independently associated with PEW and thus, poor prognosis.

The use of pulse wave velocity in predicting pre-eclampsia in high-risk women.

In this study, we evaluated the diagnostic utility of pulse wave velocity (PWV) alone or in combination with other diagnostic markers in predicting pre-eclampsia (PE) in high-risk women. Pregnant women at high risk for PE were recruited between 22 and 26 weeks of gestation and were assessed for (a) PWV, (b) serum levels of the placental soluble fms-like tyrosine kinase 1 (sFlt-1) protein and uric acid and (c) 24-h urinary protein and calcium excretion. Sensitivities and specificities were derived from receiver operating characteristic curves. Of 118 women recruited, 11 and 10 women developed early-onset PE (<34 weeks) and late-onset PE (≥34 weeks), respectively. Of the five diagnostic markers tested, PWV showed the highest detection rate for all cases (21) of PE (81%) and for early-onset PE (82%) at a fixed 10% false-positive rate (FPR), and when combined with sFlt-1, these figures increased to 90% and 92%, respectively. Despite the reduced ability of PWV to predict late-onset PE (detection rate 20%), the combination of PWV with sFlt-1 achieved a detection rate of 50% at a fixed 10% FPR. A suggested cutoff value of 9 m/s for PWV resulted in optimal sensitivity (91%) and specificity (86%) for predicting early-onset PE. This study is the first to show that PWV may be a potentially promising predictor of early-onset PE in women at high risk for PE. The combination of PWV with sFlt-1 may further improve the screening efficacy for predicting PE.

Rapamycin induced ultrastructural and molecular alterations in glomerular podocytes in healthy mice.

BACKGROUND: In the normal kidney, rapamycin is considered to be non-nephrotoxic. In the present study, we investigated whether rapamycin is indeed non-nephrotoxic by examining the ultrastructural and molecular alterations of podocytes in healthy mice. METHODS: Balb/c mice were given three different intraperitoneal doses of rapamycin for 1 week (dose model)-low-dose group: 1 mg/kg/day, intermediate-dose (ID) group: 1.5 mg/kg/day and high-dose (HD) group: 3 mg/kg/day; four mice in each group. An ID of rapamycin was also given for three different periods (time model): 1, 4 and 8 weeks; four mice were in each group. Mice treated with dimethyl sulphoxide served as controls. Body weight was measured weekly. Renal function was assessed by serum creatinine at the time of sacrifice. For estimation of albuminuria, 24-h urine collections were performed before treatment and weekly thereafter. Glomerular content of nephrin, podocin, Akt and Ser473-phospho-Akt was estimated by western blot and immunofluorescence. Nephrin and podocin messenger RNA (mRNA) were measured by real-time polymerase chain reaction. Mean podocyte foot process width (FPW) was measured by electron microscopy. RESULTS: Urine albumin levels increased in the HD and 4-week groups. Renal function was modestly deteriorated in the HD group. The mean FPW increased in a dose-dependant manner at Week 1, further deteriorated at Week 4 and finally improved at Week 8. Nephrin and podocin mRNA levels showed a significant decrease at Week 1 and were restored at Week 4 and 8. Nephrin and podocin protein levels were reduced at Week 4 and recovered at Week 8. Ser473-phospho-Akt significantly increased in all rapamycin-treated groups. CONCLUSIONS: Rapamycin induced significant ultrastructural and molecular alterations in podocytes in association with albuminuria. These alterations happened early during treatment and they tended to improve over an 8-week treatment period.

The role of serum magnesium and calcium on the association between adiponectin levels and all-cause mortality in end-stage renal disease patients.

BACKGROUND: Adiponectin (ADPN) is the most abundant adipocyte-specific cytokine that plays an important role in energy homeostasis by regulating lipid and glucose metabolism. Studies of the impact of ADPN on clinical outcomes have yielded contradictory results so far. Here, we examined the association of ADPN with serum magnesium (s-Mg) and calcium (s-Ca) levels and explored the possibility whether these two factors could modify the relationship between ADPN and all-cause mortality in patients with end-stage renal disease. METHODOLOGY/PRINCIPAL FINDINGS: After baseline assessment, 47 hemodialysis and 27 peritoneal dialysis patients were followed- up for a median period of 50 months. S-Mg and s-Ca levels emerged as positive and negative predictors of ADPN levels, respectively. During the follow-up period 18 deaths occurred. There was a significant 4% increased risk for all-cause mortality for each 1-µg/ml increment of ADPN (crude HR, 1.04; 95% CI, 1.01-1.07), even after adjustment for s-Mg and s-Ca levels, dialysis mode, age, albumin and C-reactive protein. Cox analysis stratified by s-Mg levels (below and above the median value of 2.45 mg/dl) and s-Ca levels (below and above the median value of 9.3 mg/dl), revealed ADPN as an independent predictor of total mortality only in the low s-Mg and high s-Ca groups. Furthermore, low s-Mg and high s-Ca levels were independently associated with malnutrition, inflammation, arterial stiffening and risk of death. CONCLUSIONS/SIGNIFICANCE: The predictive value of ADPN in all-cause mortality in end-stage renal disease patients appears to be critically dependent on s-Mg and s-Ca levels. Conversely, s-Mg and s-Ca may impact on clinical outcomes by directly modifying the ADPN's bioactivity.

Prolactin levels, endothelial dysfunction, and the risk of cardiovascular events and mortality in patients with CKD.

BACKGROUND AND OBJECTIVES: Both prolactin clearance and production are altered in CKD. In nonrenal populations, emerging evidence suggests that prolactin participates in the atherosclerotic process. Given the elevated cardiovascular risk of CKD, this study examined links between prolactinemia, vascular derangements, and outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This observational study was conducted in two cohorts: one with 457 nondialyzed CKD patients (mean age 52±12 years; 229 men) with measurements of flow-mediated dilation (FMD) and carotid intima-media thickness and one with 173 hemodialysis patients (65±12 years; 111 men) with measurements of pulse wave velocity (PWV). Patients were followed for cardiovascular events (n=146, nondialyzed cohort) or death (n=79, hemodialysis cohort). RESULTS: Prolactin levels increased along with reduced kidney function. Prolactin significantly and independently contributed to explain the variance of both FMD (in nondialyzed patients) and PWV (in hemodialysis patients), but not intima-media thickness. In Cox analyses, the risk of cardiovascular events in nondialyzed patients increased by 27% (hazard ratio [HR], 1.27; 95% confidence interval [95% CI], 1.17-1.38) for each 10 ng/ml increment of prolactin. Similarly, the risk for all-cause and cardiovascular mortality in hemodialysis patients increased by 12% (HR, 1.12; 95% CI, 1.06-1.17) and 15% (HR, 1.15; 95% CI, 1.08-1.21), respectively. This was true after multivariate adjustment for confounders and after adjustment within the purported causal pathway (FMD or PWV). CONCLUSIONS: Prolactin levels directly associated with endothelial dysfunction/stiffness and with increased risk of cardiovascular events and mortality in two independent cohorts of CKD patients.

Low serum testosterone, arterial stiffness and mortality in male haemodialysis patients.

BACKGROUND: In the general population, accumulating data support a link between low testosterone levels and mortality by all causes, but especially by cardiovascular disease (CVD). Also, accelerated arterial stiffness has been recognized as an important cardiovascular risk factor. Here, we explored the association between testosterone levels and risk of death in male haemodialysis (HD) patients, whose arterial system is characterized by generalized stiffening. METHODS: In this three-centre prospective observational study, 111 male HD patients after completion of baseline assessment, including measurement of male sex hormones and pulse wave velocity (PWV), were followed up for CVD and all-cause mortality. RESULTS: Of the 111 patients studied, 54 were found with and 57 without testosterone deficiency, defined as testosterone levels <8 nmol/L. During a median follow-up period of 37 months, 49 deaths occurred, 28 (57%) of which were caused by CVD. Testosterone deficiency patients had increased CVD and all-cause mortality {crude hazard ratio: 3.14 [95% confidence interval (CI), 1.21-8.16] and 3.09 (95% CI, 1.53-6.25), respectively}, even after adjustment for age, body mass index, serum albumin and C-reactive protein, prevalent CVD and HD vintage. The association of testosterone with CVD mortality, but not with all-cause mortality, was lost after adjusting for PWV, an index of arterial stiffness. Testosterone levels were inversely related to PWV (r = -0.441; P < 0.001). CONCLUSION: We showed that testosterone deficiency in male HD patients is associated with increased CVD and all-cause mortality and that increased arterial stiffness may be a possible mechanism explaining this association.

Long-term complication rates and survival of peritoneal dialysis catheters: the role of percutaneous versus surgical placement.

Considerable controversy currently exists in the literature concerning the mode of catheter placement and its impact on the technical success of peritoneal dialysis (PD). We decided to compare the impact of the surgical versus the percutaneous insertion technique on peritoneal dialysis catheter (PDCs) complications and survival. Our study population comprised 152 patients in whom 170 PDCs were inserted between January 1990 and December 2007 at the main PD unit on the island of Crete. Eighty four catheters were surgically placed (S group) and 86 were placed percutaneously by nephrologists (N group). The total experience accumulated was 4997 patient-months. The overall complications did not differ between the two groups. Only early leakage was more frequent in N group than S group (10.3 versus 1.9 episodes per 1000 patient-months; p < 0.001). However, it was easily treated and did not constitute a cause of early catheter removal. Catheter survival was 91.1%, 80.7%, and 73.2%, in the S group versus 89.5%, 83.7%, and 83.7% for the N group at 1, 2, and 3 years, respectively (p = 0.2). Catheter survival has significantly increased over the last decade. Factors positively affecting PDC survival appeared to be the use of mupirocin for exit site care and the utilization of the coiled type of catheter, practices implemented mainly after 1999. Peritonitis-free survival and patient survival were not associated with the mode of placement, while in Cox regression analysis, were longer in patients treated with automated PD. The placement mode did not affect PD outcomes. Percutaneous implantation proved a safe, simple, low cost, immediately available method for PDC placement and helped to expand our PD program.

Cinacalcet-induced leukocytoclastic vasculitis.

An 80-year-old woman on maintenance hemodialysis therapy developed severe hypercalcemia under vitamin D treatment for secondary hyperparathyroidism. To avoid the toxic calcemic effects, cinacalcet was introduced and the dose of vitamin D was substantially decreased. Cinacalcet targets the calcium-sensing receptor and decreases parathyroid hormone levels without increasing calcium and phosphorus levels. Three days after starting cinacalcet therapy, the patient developed palpable purpura on both upper and lower extremities that resolved after discontinuation of cinacalcet and administration of steroids. Skin biopsy of the initial eruption showed leukocytoclastic vasculitis. According to the Naranjo adverse drug reaction probability scale, leukocytoclastic vasculitis probably was caused by cinacalcet introduction. Drug-induced vasculitis is a poorly defined disorder, and, in most cases, no pathogenetic mechanism can be described. An idiosyncratic reaction to the agent often is proposed. Cinacalcet should be considered a causative agent of cutaneous leukocytoclastic vasculitis, and although this is the result of only a clinical observation, further attention is required in the future because cinacalcet recently has been introduced in the treatment of secondary hyperparathyroidism in patients on long-term hemodialysis therapy.

Percutaneous ethanol injection therapy: a surgery-sparing treatment for primary hyperparathyroidism.

OBJECTIVE: To describe our 3-year experience in the long-term efficacy and safety of percutaneous ethanol injection therapy (PEIT), as an alternative to surgery for the management of patients with primary hyperparathyroidism (p-HPT). DESIGN: Prospective study with a mean follow-up of 19.6 +/- 10.6 months. PATIENTS: Our study population included 19 consecutive high risk patients with p-HPT, who met the criteria for surgery. MEASUREMENTS: Under ultrasonic guidance, ethanol (95%) was injected into parathyroid glands with a volume of >or= 0.15 cm(3). With the aim of normalizing intact parathormone (iPTH) values, repeated ethanol injections were carried out, in an interval of 2 weeks, until normalization of iPTH was reached or until no residual blood supply was detected by ultrasound in the gland. Biochemical parameters were monitored throughout the study. RESULTS: At 6-month follow-up, normalization of iPTH levels (10-65 ng/l) was achieved in 11 (58%) patients (responders). Of the eight remaining patients (nonresponders), six patients had reduced (but not normalized) iPTH levels and two patients required parathyroid surgery. Seventeen (11 responders and 6 nonresponders) of the 19 patients (89.5%) became normocalcaemic (serum Ca 200 ng/l. The only complication was a transient dysphonia noticed in three patients. CONCLUSIONS: PEIT is a safe and effective nonsurgical treatment for patients with p-HPT, who are unsuitable for surgical intervention.

Acute renal failure, translocational hyponatremia and hyperkalemia following intravenous immunoglobulin therapy.

BACKGROUND/AIMS: Intravenous immunoglobulin (IVIG) therapy has been associated with renal adverse effects and electrolyte disturbances. METHODS: We retrospectively evaluated a cohort of 66 unselected patients with idiopathic thrombocytopenic purpura, who received 140 courses of IVIG therapy. Acute renal failure (ARF), hyponatremia and hyperkalemia, as potential complications of IVIG therapy, were assessed from 100 IVIG courses with sufficient data for analysis. RESULTS: Thirteen out of 100 (13%) IVIG courses in 10 (15%) patients were complicated with ARF. Risk factors included advanced age, pre-existing renal impairment, use of diuretics and the presence of diabetes mellitus. All patients recovered renal function 1-2 weeks after IVIG infusion. Serum sodium (sNa) fell by 5.7 and 2.7 mmol/l (p < 0.01) in patients with and without ARF, respectively. Correspondingly, serum potassium increased by 0.7 and 0.23 mmol/l (p < 0.01). There was a strong inverse correlation (r = -0.308; p < 0.01) between changes in sNa and creatinine. Changes in serum potassium could be independently predicted by changes in both sNa and creatinine (R(2) = 0.11; p < 0.01). These data suggested that both hyponatremia and hyperkalemia were (a) due to the translocational effect of the osmotic load of sucrose, and (b) largely depended on the extent of IVIG nephropathy. CONCLUSION: In our series, ARF attributable to IVIG therapy, although not rare, was usually mild and fully reversible. High-risk patients were more susceptible to IVIG-related renal complications. Translocational hyponatremia and hyperkalemia following IVIG therapy, although unimportant in patients with normal renal function, may be of clinical significance in patients with severely compromised renal function, resulting in impaired sucrose excretion.

Altered proximal aortic stiffness and endothelin plasma levels in diabetic patients with end-stage renal disease.

Peripheral artery stiffness is altered in diabetic patients with end-stage renal disease (ESRD), whereas few data exist to confirm this trend for proximal aortic stiffness. The pulse wave velocity of the proximal aorta (PWVr) and of the carotid-to-femoral aortic segment (PWVcf) were determined by ultrasound imaging in 160 patients with ESRD (70 diabetic) and in 160 matched control subjects. Also, plasma levels of endothelin, homocysteine, and high-sensitivity C-reactive protein were determined in both groups. Patients with ESRD had increased pulse pressure, left ventricular (LV) end-diastolic diameter, LV mass index, PWVr, and PWVcf compared with control subjects (p < 0.05). Diabetic patients had increased LV mass index, PWVr, and PWVcf compared with nondiabetic patients with ESRD (p < 0.05). Endothelin levels exhibited a strong relation with PWVr (r = 0.32, p < 0.001) and PWVcf (r = 0.33, p < 0.001) measurements in ESRD patients. Multivariate linear regression analysis revealed that age, diabetes, and plasma levels of endothelin were major determinants of increased PWVr measurements in the total ESRD population. After adjustment for age, body surface area, time on dialysis, systolic blood pressure, history of hypertension, and plasma endothelin levels, diabetes was an independent factor associated with PWVr in ESRD subjects. Diabetic patients with ESRD had significantly increased proximal aortic stiffness and significantly altered plasma levels of endothelin as compared with the nondiabetic.

Arterial stiffness alterations during hemodialysis: the role of dialysate calcium.

BACKGROUND/AIMS: We investigated the way dialysate calcium (dCa) level can influence arterial stiffness (AS), measured by stiffness index (SI), a surrogate of pulse wave velocity, and reflection index (RI), a measure of the amount of pulse wave reflection, derived by digital volume pulse (DVP). METHODS: Fourteen hemodialysis (HD) patients underwent two consecutive midweek 4-hour HD treatments in randomized order with a low dCa concentration of 1.25 mmol/l (LdCa) and a high dCa concentration of 1.75 mmol/l (HdCa), respectively. Before HD and at 1-hour intervals during the subsequent 4-hour HD sessions, SI and RI measurements were obtained from DVP contour analysis. Blood pressure (BP) and heart rate (HR) were measured after each measurement of AS. Ionized serum calcium (iCa) was measured before HD and at 120 and 240 min into the HD session. RESULTS: iCa increased and decreased by 15.3 and 5.4% in the HdCa and LdCa groups, respectively, at the end of HD. SI and RI increased by 5.7 and 6% in the HdCa group, respectively, whereas they remained unchanged in the LdCa group. The treatment effect and the time x treatment effect were significant for both indices (ANOVA). BP and HR changes did not differ between treatments. CONCLUSION: Contrary to LdCa, HdCa treatment induced a BP-independent, significant increase in measured AS parameters. In the long run, HD with LdCa, by reducing the incidence of HD-induced hypercalcemia, may have a beneficial role in minimizing the cardiovascular risk related to the intermittent, intradialytic increase in AS, inherent in the chronic use of HdCa.

Androgen deficiency and endothelial dysfunction in men with end-stage kidney disease receiving maintenance hemodialysis.

OBJECTIVES AND METHODS: Two thirds of men with end-stage kidney disease (ESKD) have serum testosterone levels in the hypogonadal range. We examined if low serum testosterone levels were correlated with measures of endothelial dysfunction in ESKD. Bilateral common carotid artery (CCA) intima-media thickness (IMT) and atherosclerotic plaque occurrence, left ventricular mass index, flow- (FMD) and nitrate-mediated vasodilatation (NMD) of the brachial artery were determined by ultrasound imaging in 100 nondiabetic men with ESKD (50 men exhibited androgen deficiency; serum testosterone concentrations <300 ng/dl). RESULTS: Left-ventricular mass index, CCA diameter, CCA-IMT and atherosclerotic plaque occurrence were all significantly increased in ESKD patients with androgen deficiency compared with patients without androgen deficiency (p < 0.05). Also, FMD and NMD measurements were significantly reduced in the former compared with the latter (p < 0.05). Testosterone levels were inversely correlated with age and duration of hemodialysis therapy (r = -0.44 and r = -0.55; p < 0.001). Testosterone levels were negatively correlated to CCA-IMT and atherosclerotic plaque occurrence in patients with androgen deficiency (r = -0.32, p < 0.003, and r = -0.23, p < 0.04, respectively). FMD and NMD measurements were positively correlated to total (r = 0.65 and r = 0.61; both p < 0.0001) and free (r = 0.52 and r = 0.48; both p < 0.001) testosterone levels in patients with low androgenicity. CONCLUSION: The present results indicated that ESKD patients with androgen deficiency had increased CCA-IMT, atherosclerotic plaque occurrence and reduced FMD and NMD compared with patients without androgen deficiency. Testosterone serum levels were negatively correlated to CCA-IMT and positively correlated to endothelium-dependent vasodilatation in ESKD patients with androgen deficiency.

Parathyromatosis and the challenge of treatment.

Parathyromatosis, consisting of hyperfunctioning parathyroid tissues scattered throughout the neck, is a rare cause of recurrent hyperparathyroidism after parathyroidectomy. Medical management of patients with parathyromatosis usually is ineffective. Repeated surgery often is necessary, but generally is unsuccessful. We describe a case of parathyromatosis as a cause for recurrent hyperparathyroidism. A 32-year-old woman with a history of end-stage renal disease on hemodialysis therapy for 13 years developed secondary hyperparathyroidism requiring subtotal parathyroidectomy. Three years later, hyperparathyroidism relapsed. A technetium Tc 99m-sestamibi scan showed remnant parathyroid tissue on the left inferior thyroid lobe. Percutaneous ethanol infusion therapy failed to suppress parathormone excess, and neck exploration was performed. Histological examination of pathological lesions confirmed the diagnosis of parathyromatosis. Despite extended resection of multiple parathyroid nodules, symptoms worsened, leading progressively to severe morbidity. Imaging studies at this point showed widespread hyperfunctioning parathyroid tissue within the neck. The patient refused a third operation; thus, we resorted to coadministration of paricalcitol, a less hypercalcemic vitamin D analogue, and ibandronate, a new-generation bisphosphonate. Parathormone secretion was suppressed partially with this regimen, even at the expense of hypercalcemia and hyperphosphatemia. Sustained normalization of hormone levels and normocalcemia were accomplished only after substitution of ibandronate for the calcimimetic agent cinacalcet. The question of whether calcimimetics may maximize the chance of complete cure of parathyromatosis, especially when surgical treatment fails or is not feasible, remains to be answered by future studies.

Adiponectin and cardiovascular remodeling in end-stage renal disease and co-morbid diabetes mellitus.

OBJECTIVES AND METHODS: Altered plasma high-sensitivity C-reactive protein (hs-CRP) and adiponectin (ADP) may contribute to increased vascular inflammation and accelerated atherosclerosis in patients with end-stage renal disease (ESRD) and co-morbid diabetes. Common carotid artery intima-media thickness (CCA-IMT) and atherosclerotic plaque occurrence, left-ventricular mass index (LVMI), and pulse wave velocity of the proximal aorta (PWVr) were determined by ultrasound imaging in 120 ESRD (55 diabetic) patients, and 83 age-, sex-, and blood pressure-matched controls. Also, plasma levels of ADP and hs-CRP were determined and their relationships with the above cardiovascular alterations were analyzed. RESULTS: LVMI, PWVr, CCA-IMT and atherosclerotic plaque occurrence were all increased in ESRD patients compared to controls (all p < 0.001). LVMI (p < 0.05), PWVr (p < 0.001), CCA-IMT (p < 0.001) and atherosclerotic plaque occurrence (p < 0.001) were increased in diabetic compared to nondiabetic ESRD patients. Hs-CRP levels were increased and ADP levels were decreased in diabetic compared to nondiabetic ESRD patients (both p < 0.001). ADP levels correlated inversely with hs-CRP (r = -0.473, p < 0.0001) in ESRD patients. Hs-CRP was positively correlated with LVMI (r = 0.365, p < 0.0001), PWVr (r = 0.42, p < 0.0001) and CCA-IMT (r = 0.18, p = 0.047) while ADP inversely correlated with PWVr (r = -0.263, p = 0.0035) and CCA-IMT (r = -0.207, p = 0.022) in ESRD patients. CONCLUSION: The present results indicate diabetic disease-specific alterations in the biochemical parameters of hs-CRP and ADP in ESRD patients. The above biochemical parameters were intimately linked to the cardiovascular measurements of LVMI, PWVr and CCA-IMT in patients with ESRD and co-morbid diabetes mellitus.

Dialysate magnesium level and blood pressure.

BACKGROUND: We investigated the way dialysate magnesium (dMg) concentrations could affect blood pressure (BP) during hemodialysis (HD). METHODS: Eight HD patients underwent four midweek HD treatments consecutively, using, during each four-hour HD session, one of the following four dialysate formulations, in randomized order, which differed only with regard to dMg and dialysate calcium (dCa) concentrations (in mmol/L): 0.75 dMg, 1.75 dCa (group I); 0.25 dMg, 1.75 dCa (group II); 0.75 dMg, 1.25 dCa (group III); 0.25 dMg, 1.25 dCa (group IV). Before HD and at four 60-minute intervals during the HD sessions, BP and noninvasive measurements of cardiac index (CI) were obtained. Additionally, 14 HD patients were treated for four weeks with 0.5 mmol/L dMg, followed by four weeks with 0.25 mmol/L dMg, and another four weeks with 0.75 mmol/L dMg, in random order. In all treatments dCa was 1.25 mmol/L. BP and symptoms were recorded during each HD session. RESULTS: Mean arterial pressure (MAP) decreased to a significantly (P < 0.05) greater extent in group IV compared to the other groups. This substantial drop in MAP by 15.2% in group IV, paralleled by a 12.1% and 17% drop in CI and stroke index, respectively, was not seen in group II, despite comparable reductions in intradialytic serum Mg (sMg) of about 35% in both groups. In groups I and III, the increase in sMg by 2% did not compromise BP via vasodilatation. In the second study, treatment with 0.75 mmol/L dMg was superior to the other two treatments regarding intradialytic morbidity (P < 0.001) and BP stability (P < 0.05). CONCLUSION: We (1) identified a dialysis solution containing 0.25 mmol/L Mg and 1.25 mmol/L Ca as a major cause of intradialytic hypotension (IDH) due to an impairment of myocardial contractility, and (2) showed that increasing dMg level to 0.75 mmol/L could prevent IDH frequently seen with the use of 1.25 mmol/L dCa. Thus, manipulating dMg levels independently or in concert with dCa levels might have important implications with regard to dialysis tolerance.

Dialysate calcium profiling during hemodialysis: use and clinical implications.

BACKGROUND: Low dialysate calcium (LdCa) concentration is used to prevent or treat hemodialysis (HD)-induced hypercalcemia, but its use has been complicated by intradialytic hypotension in some patients. Our goal was to explore the possibility that dialysis calcium profiling (dCaP) can ameliorate intradialytic hypotension in HD patients who need to have dialysis performed with LdCa. METHODS: In a randomized crossover design, eighteen HD patients underwent one four-hour HD session with LdCa of 1.25 mmol/L (LdCa group) and one four-hour HD session with LdCa of 1.25 mmol/L during the first two hours and high dCa of 1.75 mmol/L during the remaining two hours (dCaP group). After that, they underwent another four-hour HD session with medium dCa of 1.5 mmol/L (MdCa group). Before HD and at four 60-minute intervals during the HD sessions, blood pressure (BP), heart rate (HR) and noninvasive measurements of cardiac index (CI), using bioelectrical impedance, were obtained. Ionized serum calcium (iCa) also was measured before HD and at 120 and 240 minutes into the HD session. In a separate study, eight HD patients were treated for three weeks with 1.25 mmol/L dCa and three weeks with the dCaP technique described above, in random order. A three-week treatment with MdCa followed. BP and symptoms were recorded during each HD session. RESULTS: During the LdCa treatment the iCa values remained unchanged, whereas mean arterial pressure (MAP) and CI decreased by 16.5 +/- 8.3% and 14.2 +/- 14.6%, respectively, at the end of HD. During the first half of the dCaP treatment, iCa, MAP and CI decreased by 2.2 +/- 4.1%, 12.6 +/- 12.3%, and 9.6 +/- 13.4%, respectively, whereas during the second half of the same treatment, iCa, MAP and CI values increased by 10.2 +/- 3.3%, 7.8 +/- 7.2% and 10.8 +/- 9.1%, respectively, from the middle HD values. ANOVA showed that the time x treatment effect was significant for iCa, MAP and CI. Total peripheral resistance and HR changes were insignificant and similar among treatments. Hemodynamic effects were comparable between LdCa and MdCa treatments. Intradialytic events were reduced (P < 0.05) only with the dCaP treatment. CONCLUSIONS: The drop in BP observed during the last two hours of HD in both the LdCa and MdCa groups was abolished in the dCaP group. The latter was accomplished via an increase in cardiac output, due to an iCa-induced increase in myocardial contractility. Therefore, dCaP, by individualizing the dCa concentrations used and timing the switching between them, may improve intradialytic BP instability and simultaneously minimize the risk for HD patients to develop hypercalcemia.