Maurizio Gallieni

Vascular access in oncology patients

Adequate vascular access is of paramount importance in oncology patients. It is important in the initial phase of surgical treatment or chemotherapy, as well as in the chronic management of advanced cancer and in the palliative care setting. We present an overview of the available vascular access devices and of the most relevant issues regarding insertion and management of vascular access. Particular emphasis is given to the use of ultrasound guidance as the preferred technique of insertion, which has dramatically decreased insertion‐related complications. Vascular access management has considerably improved after the publication of effective guidelines for the appropriate nursing of the vascular device, which has reduced the risk of late complications, such as catheter‐related bloodstream infection. However, many areas of clinical practice are still lacking an evidence‐based background, such as the choice of the most appropriate vascular access device in each clinical situation, as well as prevention and treatment of thrombosis. We suggest an approach to the choice of the most appropriate vascular access device for the oncology patient, based on the literature available to date.

Matrix GLA Protein Gene Polymorphisms: Clinical Correlates and Cardiovascular Mortality in Chronic Kidney Disease Patients

Background: Increased vascular calcification plays an important role in the pathogenesis of cardiovascular events in chronic kidney disease (CKD) patients. It is the result of an active ossification process counteracted by ‘protective’ proteins, such as matrix GLA protein (MGP). Polymorphisms of MGP have been identified. Methods: The aim of this study was to define the distribution of two MGP polymorphisms (–7, –138) in 99 hemodialysis (HD) patients, in 26 patients with CKD stage 3 and in 135 age- and sex-matched healthy controls. Patients were followed up for 12 months to record any cardiovascular deaths. The cause of death was determined by medical doctors, considering the medical history of each patient. The primers were designed with Primer Express software. Results: MGP –138TT homozygotes were more frequent in the HD group versus controls (p = 0.0004). Additionally, the frequency of the T allele was significantly higher in the HD group (p = 0.0006). The frequency of the A allele of MGP-7 was significantly higher both in the HD group (p = 0.033) and in the CKD group (p = 0.0017) versus controls. MGP-7 GG homozygotes were significantly less common in the CKD group than in controls (p = 0.037). Combination –138TT –7AA was significantly more frequent in both CKD patients (p = 0.001) and in HD patients (p = 0.029) than in controls. Seventeen out of 99 HD patients experienced fatal cardiovascular events. Sixteen (94.1%) were –138TT homozygotes and either –7AA homozygotes or –7GA heterozygotes. Conclusion: This study suggests that CKD and HD patients have a different distribution of MGP gene polymorphism as compared with the normal population. Altered MGP gene polymorphism may be a negative prognostic factor for the progression to end-stage renal disease and for cardiovascular events in CKD patients.

Hyperparathyroidism and Anemia in Uremic Subjects: A Combined Therapeutic Approach

Several factors are involved in conditioning renal anemia, and a critical role is attributed to parathyroid hormone (PTH) oversecretion, which has some direct effects on endogenous erythropoietin (EPO) synthesis, bone marrow erythroid progenitors, and red cell survival. Indirect effects are mainly based on the induction of bone marrow fibrosis. Indirect evidence of the role of PTH is based on the observation that parathyroidectomy, when performed in uremic patients, is often followed by restoration of the hematocrit. The interpretations of such positive results are based on the observation of the restored bone marrow space after operation and also in a rise of immunoreactive EPO serum concentrations observed in the first weeks after gland removal. Another field of clinical interest is the possible beneficial effects of vitamin D therapy in controlling PTH secretion, which in turn determines an improvement of anemia of uremic subjects. Several uncontrolled studies confirmed this possibility, indicating that patients who respond to calcitriol or its analogs also show an increase of their hemoglobin levels. Thus, a combined therapeutic approach to PTH oversecretion and anemia is possible by intravenous calcitriol or parathyroidectomy pointing to the possible reversibility of bone marrow fibrosis, which is a common feature of secondary hyperparathyroidism. The increased sensitivity to EPO therapy can also induce a successful reduction of its dosage, thus allowing an interesting reduction of costs.

Warfarin use, mortality, bleeding and stroke in haemodialysis patients with atrial fibrillation

BACKGROUND Oral anticoagulation therapy (OAT) is the choice treatment for thromboembolism prevention in atrial fibrillation (AF), although data about OAT use in haemodialysis (HD) patients with AF are contradictory. METHODS The effect of OAT on the risk of mortality, stroke and bleeding was prospectively evaluated in a population of HD patients with AF. All the patients of 10 HD Italian centres alive on 31 October 2010 with documented AF episode(s) were recruited and followed-up for 2 years. OAT and antiplatelet intake, age, dialytic age, comorbidities and percentage time in the target international normalized ratio (INR) range (target therapeutic range; TTR) were considered as predictors of hazard of death, thromboembolic and bleeding events. RESULTS At recruitment, 134 patients out of 290 were taking OAT. During the follow-up, 115 patients died (4 strokes, 3 haemorrhagic and 1 thromboembolic). Antiplatelet therapy, but not OAT, was associated with increased mortality (HR 1.71, CI 1.10-2.64, P = 0.02). The estimated survival of patients always taking OAT tended to be higher than that of patients who stopped taking (68.6 versus 49.6%, P = 0.07). OAT was not correlated to a significant decreased risk of thromboembolic events (HR 0.12, CI 0.00-3.59, P = 0.20), while it was associated with an increased risk of bleeding (HR 3.96, CI 1.15-13.68, P = 0.03). Higher TTR was associated with a reduced bleeding risk (HR 0.09, CI 0.01-0.76, P = 0.03), while previous haemorrhagic events were associated with higher haemorrhagic risk (HR 2.17, CI 1.09-4.35, P = 0.03). CONCLUSIONS In our population of HD patients with AF, the mortality is very high. OAT is not associated with increased mortality, while antiplatelet drugs are. OAT seems, on the contrary, associated with a better survival; however, it does not decrease the incidence of ischaemic stroke, whereas it increases the incidence of bleeding. Bleeding risk is lower in subjects in whom the INR is kept within the therapeutic range.

Vitamin K, vertebral fractures, vascular calcifications, and mortality: VItamin K Italian (VIKI) dialysis study.

Vitamin K (vitamin K1 or phylloquinone and vitamin K2, a series of menaquinones [MKs]) is involved in the production of bone and matrix amino acid γ‐carboxy‐glutamic acid (Gla) proteins, regulating bone and vascular calcification. Low vitamin K concentrations are associated with increased risks of fractures and vascular calcification, and frequent complications in hemodialysis patients. We carried out an observational study to establish the prevalence of vitamin K deficiency and to assess the relationship between vitamin K status, vertebral fractures, vascular calcification, and survival in 387 patients on hemodialysis for ≥1 year. We determined plasma levels of vitamin K compound, bone‐Gla‐protein, matrix‐Gla‐protein, and routine biochemistry. Vertebral fractures (reduction in vertebral body height by ≥20%) and aortic and iliac calcifications were also investigated in a spine (D5–L4) radiograph. Three‐year patient survival was analyzed. Important proportions of patients had deficiency of MK7 (35.4%), vitamin K1 (23.5%), and MK4 (14.5%). A total of 55.3% of patients had vertebral fractures, 80.6% had abdominal aorta calcification, and 56.1% had iliac calcification. Vitamin K1 deficiency was the strongest predictor of vertebral fractures (odds ratio [OR], 2.94; 95% confidence interval [CI], 1.38–6.26). MK4 deficiency was a predictor of aortic calcification (OR, 2.82; 95% CI, 1.14–7.01), whereas MK5 deficiency actually protected against it (OR, 0.38; 95% CI, 0.15–0.95). MK7 deficiency was a predictor of iliac calcification (OR, 1.64; 95% CI, 1.03–2.60). The presence of vertebral fractures was also a predictor of vascular calcifications (OR, 1.76; 95% CI, 1.00–3.08). Increased alkaline phosphatase and C reactive protein (CRP), age, and cerebrovascular events were predictors of mortality. Our study suggests that the vitamin K system may be important for preserving bone mass and avoiding vascular calcification in hemodialysis patients, pointing out a possible role of vitamin K in bone and vascular health. Based on our results, we suggest that the general population should also be studied for vitamin K deficiency as a possible cause of both vertebral fractures and vascular calcification.

Calcium and phosphate plasma levels in dialysis patients after dietary Ca-P overload: Role of gastric acid secretion

In normal subjects, the gastric ionisation of calcium and phosphate seems to be a prerequisite for their intestinal absorption. We investigated the behavior of the plasma calcium and phosphate profile in 30 patients on regular dialysis treatment in the 6 h following a meal containing 1 g of calcium and 2 g of phosphate. Moreover, to assess the role of gastric acidity, the study was repeated after 3 days on omeprazole administration, to nearly abolish gastric acid secretion. Both total plasma calcium and ionized calcium peaked after the meal (at 30 and 120 min, respectively) only in basal study, while no peak was observed after the administration of omeprazole. Surprisingly, both in basal and in the omeprazole study the levels of plasma phosphate did not increase after the test meal. In conclusion, as in normal subjects, the gastric ionization of dietary calcium promotes the intestinal absorption of calcium in uremic patients on dialysis treatment, while the acute gastric acid inhibition by omeprazole reduced the intestinal calcium transport. In contrast, with the ‘trade off’ hypothesis we did not observe any postprandial phosphate peak after the dietary load, and, in contrast with normal subjects, omeprazole administration did not influence the phosphate profile.

Chronic kidney disease and cardiovascular risk in six regions of the world (ISN-KDDC): a cross-sectional study

BACKGROUND Chronic kidney disease is an important cause of global mortality and morbidity. Data for epidemiological features of chronic kidney disease and its risk factors are limited for low-income and middle-income countries. The International Society of Nephrologys Kidney Disease Data Center (ISN-KDDC) aimed to assess the prevalence and awareness of chronic kidney disease and its risk factors, and to investigate the risk of cardiovascular disease, in countries of low and middle income. METHODS We did a cross-sectional study in 12 countries from six world regions: Bangladesh, Bolivia, Bosnia and Herzegovina, China, Egypt, Georgia, India, Iran, Moldova, Mongolia, Nepal, and Nigeria. We analysed data from screening programmes in these countries, matching eight general and four high-risk population cohorts collected in the ISN-KDDC database. High-risk cohorts were individuals at risk of or with a diagnosis of either chronic kidney disease, hypertension, diabetes, or cardiovascular disease. Participants completed a self-report questionnaire, had their blood pressure measured, and blood and urine samples taken. We defined chronic kidney disease according to modified KDIGO (Kidney Disease: Improving Global Outcomes) criteria; risk of cardiovascular disease development was estimated with the Framingham risk score. FINDINGS 75,058 individuals were included in the study. The prevalence of chronic kidney disease was 14·3% (95% CI 14·0-14·5) in general populations and 36·1% (34·7-37·6) in high-risk populations. Overall awareness of chronic kidney disease was low, with 409 (6%) of 6631 individuals in general populations and 150 (10%) of 1524 participants from high-risk populations aware they had chronic kidney disease. Moreover, in the general population, 5600 (44%) of 12,751 individuals with hypertension did not know they had the disorder, and 973 (31%) of 3130 people with diabetes were unaware they had that disease. The number of participants at high risk of cardiovascular disease, according to the Framingham risk score, was underestimated compared with KDIGO guidelines. For example, all individuals with chronic kidney disease should be considered at high risk of cardiovascular disease, but the Framingham risk score detects only 23% in the general population, and only 38% in high-risk cohorts. INTERPRETATION Prevalence of chronic kidney disease was high in general and high-risk populations from countries of low and middle income. Moreover, awareness of chronic kidney disease and other non-communicable diseases was low, and a substantial number of individuals who knew they were ill did not receive treatment. Prospective programmes with repeat testing are needed to confirm the diagnosis of chronic kidney disease and its risk factors. Furthermore, in general, health-care workforces in countries of low and middle income need strengthening. FUNDING International Society of Nephrology.

Serum fetuin-A levels link inflammation and cardiovascular calcification in hemodialysis patients

Background: Cardiovascular disease (CVD) is the leading cause of mortality in hemodialysis (HD). An elevated incidence of cardiovascular calcifications (CVC) is observed in HD. Fetuin-A is an important inhibitor of CVC. Reduced fetuin-A levels associate with inflammation and increased cardiovascular (CV) mortality in HD. In this study we investigated the association of fetuin-A levels and CVC. Method: We evaluated a cohort of 115 patients (67 males), aged 63 ± 16 years with a HD vintage ≧9 months. Presence of CVC was assessed by ultrasound imaging of the abdominal aorta, common carotid arteries, bilateral ilio-femoral axis, aortic and mitral cardiac valves. The presence of CVC was analyzed as a CVC score (CVCS) (0–7) according to the number of CVC sites. Patients were arbitrary stratified in three groups: group I (CVCS = 0), group II (0 < CVCS < 6) and group III (CVCS ≧ 6). Patients without CVC were younger, non-diabetic and with a negative history for CV events. Results: Patients with evidence of CVC in more than 5 sites had lower serum fetuin-A levels (0.41 ± 0.22 g/l) compared to patients with CVCS = 0 (0.51 ± 0.17 g/l, p = 0.048). In addition a worse CVCS was associated with higher serum levels of C-reactive protein (p = 0.002) and fibrinogen (p < 0.001). Serum fetuin-A levels lower than 0.290 g/l were associated with higher risk of a worse CVCS, independently from traditional risk factors. Conclusion: Chronic inflammation in HD patients leads to lower serum fetuin-A levels. The present study confirms the independent and significant association between reduced serum fetuin-A levels and multi-site CVC in HD.

Trace Elements in Dialysis Fluids and Assessment of the Exposure of Patients on Regular Hemodialysis, Hemofiltration and Continuous Ambulatory Peritoneal Dialysis

Forty-four elements (Al, Sb, As, Ba, Be, B, Br, Cd, Ce, Co, Cr, Cs, Cu, Eu, Ga, Au, Hf, In, Ir, Fe, La, Lu, Mn, Hg, Mo, Nd, Ni, Pb, Rb, Sm, Sc, Se, Ag, Sr, Ta, Tb, Tl, Th, Sn, W, U, V, Zn, Zr) have been determined in the dialysate for hemodialysis (HD) and fluids for hemofiltration (HF) and continuous ambulatory peritoneal dialysis (CAPD). Multiple determinations have been performed for each dialysis fluid. Several trace elements (TE) showed remarkably elevated average levels; moreover, different bathes of the same commercial product may present a wide variability in TE concentration. The data point out the pivotal role of dialysis fluids in contributing to TE imbalance in dialysis patients and allow the assessment of the potential element exposure of patients on regular dialytic treatment. Patients on HD treatment would be exposed on a weekly basis to milligrams of Al, B, Ba, Br, Cu, Fe, Ni, Pb, Rb, Sr and Zn; on HF, the highest exposures are due to Al, B, Br, Fe, Pb and Zn; on CAPD to B, Br, Fe and Zn. The weekly exposure for several TE appears to be 50- to 12,000-fold higher than the corresponding values on the amount absorbed via the diet (HD: Au, Ba, Be, Ce, Ga, La, Sc, Ta, Th, V, Zr; HF: Be, Ce, Ta, Th, V, Zr; CAPD: Au, Be, Ce, Ga, V, Zr).(ABSTRACT TRUNCATED AT 250 WORDS)

Hyperparathyroidism and Anemia in Renal Failure

Patients with severe secondary hyperparathyroidism, usually associated with osteitis fibrosa on bone histology, show considerable resistance to Epoetin, partly because of replacement of the cellular components of the bone marrow by fibrous tissue. In case of unexplained resistance to Epoetin, investigation of secondary hyperparathyroidism is strongly recommended, with measurement of serum parathyroid hormone, calcium, phosphate, and alkaline phosphatase levels and, where needed, skeletal radiology and bone biopsy. Treatment of severe secondary hyperparathyroidism consists of active vitamin D metabolites or parathyroidectomy, although the marrow fibrosis, if present, may be irreversible. The finding of a progressive inability of the bone marrow to respond to Epoetin treatment with higher levels of parathyroid hormone suggests the importance to prevent metabolic bone disease and in particular secondary hyperparathyroidism. Moreover, there are several reports of a beneficial action on hemoglobin levels of an effective treatment of hyperparathyroidism. Larger, controlled studies are necessary to confirm these preliminary and exciting findings, and to elucidate the mechanisms underlying the improvement in anemia after medical or surgical treatment of hyperparathyroidism.