Giuliano Barsotti

Plasma Parameters of the Prothrombotic State in Chronic Uremia

We measured plasma parameters of the prothrombotic state, namely thrombin-antithrombin III complex (TAT), fibrinopeptide A (FPA). D-dimer (DD), von Willebrand factor (vWF), tissue-type plasminogen activator (tPA), beta-thromboglobulin (beta TG), platelet factor 4 (PF4) and serotonin (5HT) in a series of 51 adult patients with chronic uremia: 22 were on maintenance hemodialysis (MHD) and 29 on conservative dietary treatment. Serum tumor necrosis factor alpha (TNF) was determined as well. Uremics presented significantly higher levels of TAT, FPA, DD, vWF, TNF, beta TG and 5HT than normal controls. Patients on conservative treatment showed lower levels of TAT, DD, TNF and beta TG than patients on MHD. Our results provide evidence that a prothrombotic state exists in chronic uremia and that MHD patients have a higher degree of hypercoagulation. Both hemodialysis procedure and uremia-related factors are likely to contribute to the hemostatic derangement.

Anaemia and resistance to erythropoiesis-stimulating agents as prognostic factors in haemodialysis patients: results from the RISCAVID study

BACKGROUND Resistance to erythropoiesis-stimulating agents (ESAs) is often associated with chronic inflammation. Here, we investigated how anaemia, ESA resistance and the plasma levels of biological markers of inflammation could influence all-cause and cardiovascular disease morbidity and mortality. METHODS Seven hundred and fifty-three haemodialysis (HD) patients (mean age 66 ± 14.2 years, mean dialytic age 70 ± 77 months and diabetes 18.8%) were enrolled and followed-up for 36 months. Demographic, clinical and laboratory data, co-morbidity conditions, administered drugs, all-cause mortality and fatal/non-fatal cardiovascular (CV) events were recorded. We measured ESA resistance index, C-reactive protein (CRP) and interleukin-6 (IL-6). RESULTS Six hundred and fifty-one patients (86.4%) received ESAs. Patients with haemoglobin level <11 g/dL (n = 225) showed increased risk of CV [relative risk (RR) 1.415, 95% confidence interval (CI) 1.046-1.914] and overall mortality (RR 1.897, 95% CI 1.423-2.530) versus patients with haemoglobin levels >11 g/dL. ESA resistance values categorized into quartiles (Quartile I <5.6, Quartile II 5.7-9.6, Quartile III 9.7-15.4 and Quartile IV >15.4) correlated with all-cause mortality and fatal/non-fatal CV events (RR 1.97, 95% CI 1.392-2.786; RR 1.619, 95% CI 1.123-2.332, respectively). Furthermore, albumin was significantly reduced versus reference patients and correlated with all-cause mortality and CV events; CRP levels were higher in hyporesponders (Quartile IV) (P < 0.001) and predicted all-cause mortality and CV events. IL-6 but not CRP was a strong predictor of ESA resistance. CONCLUSIONS ESA responsiveness can be considered a strong prognostic factor in HD patients and seems to be tightly related to protein-energy wasting and inflammation.

Long-term treatment with cinacalcet and conventional therapy reduces parathyroid hyperplasia in severe secondary hyperparathyroidism

Background. The effect of cinacalcet on the structural pattern of hyperplastic parathyroid glands was evaluated, using high-resolution colour Doppler (CD) sonography, in haemodialysis patients with severe, inadequately controlled, secondary hyperparathyroidism (sHPT). Methods. Nine patients (6 males, 3 females; mean age ± SD, 55.5 ± 12.6 years) received cinacalcet, with adaptation of existing concomitant therapies. Biochemical parameters and the morphology and vascular pattern of hyperplastic parathyroid glands were measured at baseline and every 6 months thereafter, for a follow-up period of 24–30 months. Results. At baseline, 28 hyperplastic glands were identified. Cinacalcet led to a reduction in glandular volume during the course of the study: 68% in glands with a baseline volume <500 mm3 and 54% in glands with a baseline volume ≥500 mm3. The mean volume ± SD of glands <500 mm3 changed significantly from the baseline (233 ± 115 mm3) to the end of follow-up (102 ± 132 mm3, P = 0.007). Levels of mean serum phosphorus, calcium and calcium–phosphorus product decreased, but not significantly, whereas there were significant decreases in mean parathyroid hormone ± SD levels (1196 ± 381 pg/ml versus 256 ± 160 pg/ml; P < 0.0001) and alkaline phosphatase ± SD levels (428 ± 294 versus 223 ± 88 IU/l; P = 0.04), accompanied by an improvement in a subjective clinical score. Conclusions. Cinacalcet, in combination with conventional treatments, led to an improvement in biochemical and clinical parameters of sHPT and reduced glandular volume in patients with severe sHPT. Volume reduction was more evident in smaller glands. Longer term, larger, randomized clinical trials are needed to confirm these preliminary findings and to further define a more systematic approach in the treatment of sHPT.

Effects on Renal Function of a Low-Nitrogen Diet Supplemented with Essential Amino Acids and Ketoanalogues and of Hemodialysis and Free Protein Supply in Patients with Chronic Renal Failure

Creatinine clearance has been repeatedly measured in three groups of chronic uremics. In the first control group (31 cases), following a conventional low-protein diet, creatinine clearance declined linearly with time. In the second group (12 cases), following very low nitrogen diet supplemented with essential amino acids and ketoanalogues, creatinine clearance remained practically constant with only one exception in which it continued to decline. In the third group of uremics (13 cases) on repeated dialysis therapy, the deterioration of creatinine clearance was markedly accelerated. The possible explanations and the practical implications of these findings are discussed.

Potassium Removal Increases the QTc Interval Dispersion during Hemodialysis

This study was planned to clarify the mechanism(s) by which hemodialysis increases the QTc dispersion, a marker of risk of ventricular arrhythmias. To this aim, 10 uremic patients, without any relevant heart diseases, underwent two different types of hemodialysis schedules. In the first, 1 h of isolated high rate ultrafiltration preceded the standard diffusive procedure. In the second, during the first hour of standard bicarbonate hemodialysis, the decrease of plasma potassium concentration was prevented by increasing K+ concentration in the dialysate, according to its pre dialysis plasma levels. During the high rate ultrafiltration period, together with ECG signs of increased sympathetic nervous system activity and catecholamines secretion, the QTc dispersion did not change significantly. Instead, an evident increment was observed 1 h after the start of the diffusive hemodialysis, then slowly progressing until the end of the dialysis and finally returning to the pre dialysis values within 2 h after the end of the session. To the contrary, the increase of the QTc dispersion was totally blunted during a standard hemodialysis procedure in absence of plasma K+ decrease, but appeared again when the K+ dialysate fluid concentration was restored to 2 mmol/l. This study provides evidence that the increase of QTc dispersion occurring on hemodialysis is mainly related to the diffusive process, more precisely to the K+ removal. This is one more reason to focus attention on K+ removal rate especially when hemodialysis treatment is given in uremics affected by cardiac diseases with high risk of arrhythmias.

A Low-Nitrogen Low-Phosphorus Vegan Diet for Patients with Chronic Renal Failure

The nutritional treatment of chronic renal failure with a low-protein low-phosphorus diet (conventional low-protein diet, CLPD) is effective in reducing uremic intoxication, slowing the progression of renal failure and preventing secondary hyperparathyroidism. Unfortunately, in some patients, the poor palatability and the high cost of the protein-free substitutes, together with difficulties in following the diet away from home, can make good compliance difficult, possibly causing low energy intake and malnutrition. Here the results are reported of an attempt we made to overcome these drawbacks, using a diet supplying only natural foods of plant origin in definite proportions to give an essential amino acid supply satisfying the recommended dietary allowance. This is possible thanks to an appropriate cereal-legume mixture, supplying proteins complementary for essential amino acids. Additional positive features of this special vegan diet (SVD) are the high ratio of unsaturated to saturated fatty acids, the absence of cholesterol, and the lower net acid production in comparison with a mixed diet. This study indicates that the results obtained with the SVD are similar to those obtained with the CLPD. Therefore the SVD can be a substitute for the CLPD in the management of patients with mild chronic renal failure. The SVD is the diet of choice when products made of starch are not available or poorly tolerated.

Effect of Hemodialysis on the Dispersion of the QTc Interval

The QTc dispersion reflects the underlying regional heterogeneity of the recovery of the ventricular excitability, thereby it is considered as a novel marker of risk of ventricular arrhythmias. Because a higher incidence of ventricular arrhythmias is described during and after hemodialysis, the aim of this study has been to evaluate the QTc dispersion before and after uncomplicated hemodialysis session. Twenty chronic uremics without heart failure, ischemic heart disease or dialysis hypotension were selected. The QTc dispersion was determined as the difference between the longer and the shorter QTc interval measured on a 12-lead electrocardiogram. Following the hemodialysis session, the QTc dispersion increased from 30 ± 9 to 54 ± 17 ms (p < 0.001) associated with the expected reduction of potassium and magnesium and with the increase of extracellular calcium concentration. However, no correlation has been observed between the QTc dispersion increase and the degree of the intradialytic changes of plasma electrolytes, blood pressure or body weight. In summary, the hemodialysis treatment per se does induce an increase of the QTc dispersion, likely due to the rapid changes of electrolyte plasma concentrations. This can potentially contribute to the arrhythmogenic effect of the hemodialysis procedure, reflecting an enhanced regional heterogeneity of ventricular repolarization. The clinical importance of the increase of QTc dispersion as risk factor of ventricular arrhythmias, particularly in hemodialyzed patients suffering from ischemic or hypertrophic heart diseases, should be the matter of further investigations.

Comprehensive Study of Haemostasis in Nephrotic Syndrome

A comprehensive study of haemostasis has been performed in a homogeneous group of 20 patients with nephrotic syndrome without renal failure. We have found unchanged number of platelets and a significant increase of platelet adhesiveness and aggregation; increased levels of activity and related antigen of fibrinogen, of factor VIII, of activity of factors II, VII and X and of antigens of factors XIII. Antithrombin III was unchanged in plasma and was detected in the urine. Euglobulin lysis times were decreased, and levels of plasminogen and its activators were increased after a venous occlusion test. At the same time urokinase inhibitors and antiplasmins were increased not only after, but also before a venous occlusion test. Fibrinogen degradation products have been found in the urine of all our patients but not in their sera.

In Defense of Creatinine Clearance

The ratios creatinine clearance (Crcl)/inulin clearance (INcl) obtained in 523 measurements and reported in 14 papers have been analyzed and the values of CRcl corresponding to those of INcl have been evaluated. The day-to-day coefficient of variation of CRcl has also been measured in 123 persons, including patients with stable chronic renal failure and patients with normal renal function. The data obtained indicate that CRcl is not less sensitive than INcl, and that its changes are not blunted, if compared with similar changes of INcl. The day-to-day coefficient of variation has been found not to be greater than that of INcl. In conclusion, CRcl is not a misleading method to obtain approximate information on renal function, if it is correctly executed and interpreted.

Left ventricular function and calcium phosphate plasma levels in uraemic patients.

Background.  Recent investigations have focused on the pathogenetic role of disturbances of calcium phosphate metabolism in causing cardiovascular morbidity and mortality in haemodialysis patients. The aim of the present study was to assess left ventricular function and its relationship to phosphate and calcium plasma levels in stable uraemic patients on haemodialysis treatment.