Mario Meola

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.

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.

Low Urine Citrate Excretion as Main Risk Factor for Recurrent Calcium Oxalate Nephrolithiasis in Males

To better define the relative role of metabolic factors in the recurrence of stone formation, we studied the 24-hour urinary excretion of calcium (uCa), citrate (uCit), oxalic acid (uOx) and uric acid (uUa) in 73 male patients with primary calcium oxalate urolithiasis. According to the episodes of stone formation per year, we identified 51 recurrent stone formers (RSF) and 22 single stone formers (SSF). 20 normal adult males constituted the control group (C). uCa and uOx were higher in RSF than in C, but quite similar in SSF and RSF. The only difference between RSF and SSF was uCit, significantly lower (2.06 +/- 1.04 mmol/24 h) in RSF than in SSF (3.22 +/- 1.18 mmol/24 h, p less than 0.001) and in C (3.42 +/- 1.33 mmol/24 h, p less than 0.001). Hypocitraturia (uCit less than 1.5 mmol/24 h) was found in 16 of 51 RSF (31.4%) and in 1 of 22 SSF (4.5%). These data confirm that high levels of uCa and uOx represent a risk factor for lithogenesis, but also strongly indicate the low uCit excretion as the most important urinary abnormality accounting for the recurrence of calcium oxalate stones.

Responses of the skin microcirculation to acetylcholine in patients with essential hypertension and in normotensive patients with chronic renal failure.

Aims: To assess the endothelial function of the skin microcirculation in chronic renal failure (CRF) independent of hypertension, we investigated the changes of the cutaneous blood flow induced by iontophoretic delivery of acetylcholine (ACh) and of sodium nitroprusside (SNP) in CRF patients free from arterial hypertension and in patients with essential hypertension. Methods: The study included 20 patients affected by CRF (mean creatinine clearance 12 ± 2 ml/min) without arterial hypertension (mean blood pressure 96 ± 1 mm Hg), 15 patients affected by essential hypertension (mean blood pressure 124 ± 1 mm Hg), and 20 normal controls. The changes of skin blood flow following iontophoretic delivery of ACh and of SNP were measured by laser Doppler flowmetry. Results: Following maximal ACh or SNP delivery, the change of blood flow from the baseline was similar both in normals (683 ± 92 vs. 684 ± 87%) and in CRF patients (778 ± 108 vs. 803 ± 124%), whereas in the hypertensives the response to ACh was lower than to SNP (434 ± 48 vs. 702 ± 98%, p < 0.01). Since the third ACh delivery dose, the skin blood flow increments were significantly lower in the hypertensive than in the CRF or in the normal control groups, whereas no difference was observed between uremics and controls. Conclusions: The endothelium-dependent hyperemia following ACh iontophoretic delivery is impaired in the skin microcirculation of essential hypertensive patients, but this is not the case in CRF patients with no history of arterial hypertension. This suggests that CRF per se, independent of arterial hypertension, is not associated with endothelial dysfunction of skin microcirculation.

Secondary Hyperparathyroidism in Severe Chronic Renal Failure Is Corrected by Very-Low Dietary Phosphate Intake and Calcium Carbonate Supplementation

The main purpose of our study was to verify the effect of a very-low-protein, low-phosphorus diet, supplemented with essential amino acids and keto analogues and with calcium carbonate, on circulating levels of intact parathyroid hormone (i-PTH) in severe chronic renal failure patients with secondary hyperparathyroidism, not treated with any vitamin D preparation. To this aim, we shifted 21 chronic uremics (12 males, 9 females; age 56 ± 13 years) with serum creatinine >6.5 mg/dl and i-PTH >150 pg/ml, from a standard low-protein diet (0.6 g/kg/day approximately) to a very-low-protein (0.3 g/kg/day), very-low-phosphorus (5 mg/kg/day) diet supplemented with a mixture of essential amino acids and calcium keto analogues (Ketodiet), calcium carbonate (2–4 g/day), iron, and vitamin B12 preparations. The energy supply of both diets was 30–35 kcal/kg/day. Exclusion criteria were a poor compliance with dietary or supplement prescriptions or signs of autonomic hyperparathyroidism. After 4 ± 2 months of Ketodiet, the i-PTH serum levels decreased by 49% as a mean (from 441 ± 233 to 225 ± 161 pg/ml, p < 0.001); serum phosphorus and alkaline phosphatase decreased, whereas serum calcium increased. The great reduction of serum and urinary urea demonstrated a good compliance with Ketodiet, and no sign of protein malnutrition was observed. These findings confirm that even in severe chronic uremic patients dietary phosphorus restriction and calcium carbonate supplementation lower i-PTH serum levels. This is one of the goals of the dietary treatment that can be safely achieved, provided good compliance both with the dietary prescriptions and with adequate energy and supplement intakes.

Free-hand ultrasound-guided renal biopsy: report of 650 consecutive cases.

In the past 4 years we have carried out 650 percutaneous renal biopsies (PRB), 54 on transplanted and 596 on native kidneys. PRB was performed with a 14-gauge one-piece disposable needle that was introduced free-handedly into the lumbar wall without any form of fixed guidance or support. Ultrasound was used to locate the kidney pole and to follow the progression of the needle tip in the renal parenchyma. The time needed for the whole procedure was about 5 min. The tissue specimen was adequate for histological evaluation in 98.8% of the cases. The prevalence of post-biopsy complications (haematuria, pain, anaemia) was 2.5%. Haematuria was not a common complication (1.6%) in our series, whereas clinically silent perirenal haematoma was common. Mild perirenal bleeding (volume < 5 ml) was found in 40 of a series of 150 patients (26.6%) who underwent ultrasound scan 24 h after the PRB. Haematoma exceeding 100 ml was revealed with US in only 0.6% of the patients. We conclude that free-hand ultrasound-guided PRB makes this technique easier, highly successful, time-saving and almost free of severe side effects.

Phosphate control in dialysis

Prevention and correction of hyperphosphatemia is a major goal of chronic kidney disease–mineral and bone disorder (CKD–MBD) management, achievable through avoidance of a positive phosphate balance. To this aim, optimal dialysis removal, careful use of phosphate binders, and dietary phosphate control are needed to optimize the control of phosphate balance in well-nourished patients on a standard three-times-a-week hemodialysis schedule. Using a mixed diffusive–convective hemodialysis tecniques, and increasing the number and/or the duration of dialysis tecniques are all measures able to enhance phosphorus (P) mass removal through dialysis. However, dialytic removal does not equal the high P intake linked to the high dietary protein requirement of dialysis patients; hence, the use of intestinal P binders is mandatory to reduce P net intestinal absorption. Unfortunately, even a large dose of P binders is able to bind approximately 200–300 mg of P on a daily basis, so it is evident that their efficacy is limited in the case of an uncontrolled dietary P load. Hence, limitation of dietary P intake is needed to reach the goal of neutral phosphate balance in dialysis, coupled to an adequate protein intake. To this aim, patients should be informed and educated to avoid foods that are naturally rich in phosphate and also processed food with P-containing preservatives. In addition, patients should preferentially choose food with a low P-to-protein ratio. For example, patients could choose egg white or protein from a vegetable source. Finally, boiling should be the preferred cooking procedure, because it induces food demineralization, including phosphate loss. The integrated approach outlined in this article should be actively adapted as a therapeutic alliance by clinicians, dieticians, and patients for an effective control of phosphate balance in dialysis patients.

The Key Role of Color Doppler Ultrasound in the Work-up of Hemodialysis Vascular Access

Vascular access (VA) is the lifeline for the hemodialysis patient and the native arterio‐venous fistula (AVF) is the first‐choice access. Among the different tests used in the VA domain, color Doppler ultrasound (CD‐US) plays a key role in the clinical work‐up. At the present time, three are the main fields of CD‐US application: (i) evaluation of forearm arteries and veins in surgical planning; (ii) testing of AVF maturation; (iii) VA complications. Specifically, during the AVF maturation, CD‐US allows to measure the diameter and flow volume in the brachial artery and calculate the peak systolic velocity (PSV) of the arterial axis, anastomosis and efferent vein, to detect critical stenosis. The borderline stenosis, revealed by the discrepancies between access flow rate and PSV, should be followed up with subsequent tests to detect progression of stenosis; the cases with significant changes in brachial flow should be referred to angiography. In conclusion, clinical monitoring remains the backbone of any VA program. CD‐US is of utmost importance in a patient‐centered VA evaluation, because it allows the appropriate management of all aspects of VA care. These are the main reasons why we strongly advocate the adoption of a VA surveillance program based on CD‐US.