[The Power of Phosphaturia in the Infrequent Hemodialysis]. / L'importanza della Fosfaturia nei pazienti in Emodialisi Infrequente.

INTRODUCTION: Residual renal function (RRF) and phosphaturia had not stimulated particular interest in studies regarding patients on hemodialysis. In the current year the Authors have selected a series of patients with RRF undergoing infrequent hemodialysis treatments. PURPOSE: The Authors have carried out a study of the phosphate balance in patients on infrequent hemodialysis with the hypothesis that the phosphaturia was always neglected in hemodialysis patients, but it could represent a positive impact element on the cardiovascular events and mortality in hemodialysis. METHODS: During 6 months, the Authors have conducted forty urine collections in 10 patients on twice a week hemodialysis (TWH) (age: 69,3 years, dialysis vintage: 42,7 months and 40.9 months on TWH) and eighty urine collections in 8 patients on once a week hemodialysis and low-protein diet (CDDP) (age: 69.6 years, dialysis vintage: 24.7 months and 24 months in CDDP) to determine RRF and phosphaturia. We compared the balance of phosphate compared with a thrice-weekly hemodialysis considering on phosphate removal: dialysis efficiency, phosphate-binders power on the protein- phosphates intake and the extent of phosphaturia. RESULTS: The patients on infrequent hemodialysis have demonstrated a significant share of urinary phosphate output leading to a weekly phosphoric balance equal to zero or even negative. CONCLUSIONS: The phosphoric balance in infrequent hemodialysis patients is a decisive way to remove the phosphates, confirming that this factor could be decisive on the improved survival and reduced cardiovascular mortality compared to patients receiving thrice-weekly hemodialysis. The Authors stress again the need to keep as long as possible the FRR.

Low-protein diets for chronic kidney disease patients: the Italian experience.

BACKGROUND: Nutritional treatment has always represented a major feature of CKD management. Over the decades, the use of nutritional treatment in CKD patients has been marked by several goals. The first of these include the attainment of metabolic and fluid control together with the prevention and correction of signs, symptoms and complications of advanced CKD. The aim of this first stage is the prevention of malnutrition and a delay in the commencement of dialysis. Subsequently, nutritional manipulations have also been applied in association with other therapeutic interventions in an attempt to control several cardiovascular risk factors associated with CKD and to improve the patient's overall outcome. Over time and in reference to multiple aims, the modalities of nutritional treatment have been focused not only on protein intake but also on other nutrients. DISCUSSION: This paper describes the pathophysiological basis and rationale of nutritional treatment in CKD and also provides a report on extensive experience in the field of renal diets in Italy, with special attention given to approaches in clinical practice and management. Italian nephrologists have a longstanding tradition in implementing low protein diets in the treatment of CKD patients, with the principle objective of alleviating uremic symptoms, improving nutritional status and also a possibility of slowing down the progression of CKD or delaying the start of dialysis. A renewed interest in this field is based on the aim of implementing a wider nutritional therapy other than only reducing the protein intake, paying careful attention to factors such as energy intake, the quality of proteins and phosphate and sodium intakes, making today's low-protein diet program much more ambitious than previous. The motivation was the reduction in progression of renal insufficiency through reduction of proteinuria, a better control of blood pressure values and also through correction of metabolic acidosis. One major goal of the flexible and innovative Italian approach to the low-protein diet in CKD patients is the improvement of patient adherence, a crucial factor in the successful implementation of a low-protein diet program.

Dietary Management of Incremental Transition to Dialysis Therapy: Once-Weekly Hemodialysis Combined With Low-Protein Diet.

Initiation of thrice-weekly hemodialysis often results in a rapid loss of residual kidney function (RKF) including reduction in urine output. Preserving RKF longer is associated with better outcomes including greater survival in dialysis patients. An alternative approach aimed at preserving RKF is an incremental transition with less frequent hemodialysis sessions at the beginning with gradual increase in hemodialysis frequency over months. In addition to favorable clinical and economic implications, an incremental transition would also enhance a less stressful adaptation of the patient to dialysis therapy. The current guidelines provide only limited recommendations for incremental hemodialysis approach, whereas the potential role of nutritional management of newly transitioned hemodialysis patients is largely overlooked. We have reviewed previous reports and case studies of once-weekly hemodialysis treatment combined with low-protein, low-phosphorus, and normal-to-high-energy diet especially for nondialysis days, whereas on dialysis days, high protein can be provided. Such an adaptive dietary regimen may elicit more favorable outcomes including better preserved RKF, lower ß2-microglobulin levels, improved phosphorus control, and lower doses of erythropoiesis-stimulating agents. Clinical and nutritional status and RKF should be closely monitored throughout the transition to once and then twice-weekly regimen and eventually thrice-weekly hemodialysis. Further studies are needed to verify the long-term safety and implications of this approach to dialysis transition.

[Incremental approach to hemodialysis: twice a week, or once weekly hemodialysis combined with low-protein low-phosphorus diet?]. / Approccio incrementale di inizio dialisi: emodialisi bisettimanale, o monosettimanale associata a dieta ipoproteica-ipofosforica?

The start of dialysis treatment is a critical step in the care management of chronic renal failure patients. When hemodialysis is performed three times a week, rapid loss of kidney function and of urine volume output generally occur and this represents an unfavorable prognostic factor. Instead, reducing frequency of hemodialysis sessions, as well as peritoneal dialysis, can contribute to a lesser decrease of residual renal function. Unfortunately, the existing protocols for an incremental hemodialysis approach are not particularly common and they are generally limited to a twice a week hemodialysis schedule. In addition to clinical and economic reasons, an incremental approach to ESRD also contributes to better social and psychological adaptation by the patients to the dramatic change in living conditions linked to the maintenance dialysis treatment. In patients who have attitude for low-protein nutritional therapy, a once weekly dialysis schedule combined with low-protein, low-phosphorus, normal to high energy diet in the remaining six days of the week can be implemented in selected patients. In our experience, this kind of program produced important clinical results and reduction in costs and hospitalization. When compared with a three times a week dialysis schedule, a greater protection of residual renal function and of urine volume output, lower increase in 2 microglobulin, better control of phosphorus and less consumption of phosphate binders and erythropoietin were observed. Careful clinical monitoring and nutrition is essential for the safety and optimization of infrequent hemodialysis. Long-term follow-up analysis shows favorable effects on the overall survival. Furthermore, twice a week hemodialysis is not the only option for an incremental approach of dialysis commencing. In patients who have a good attitude for low-protein nutritional therapy, its arrangement with a program of once weekly dialysis represents a real and effective alternative.

The incremental treatment of ESRD: a low-protein diet combined with weekly hemodialysis may be beneficial for selected patients.

BACKGROUND: Infrequent dialysis, namely once-a-week session combined with very low-protein, low-phosphorus diet supplemented with ketoacids was reported as a useful treatment schedule for ESRD patients with markedly reduced residual renal function but preserved urine output. This study reports our findings from the application of a weekly dialysis schedule plus less severe protein restriction (standard low-protein low-phosphorus diet) in stage 5 CKD patients with consistent dietary discipline. METHODS: This is a multicenter, prospective controlled study, including 68 incident CKD patients followed in a pre-dialysis clinic with Glomerular Filtration Rate 5 to 10 ml/min/1.73/ m2 who became unstable on the only medical treatment. They were offered to begin a Combined Diet Dialysis Program (CDDP) or a standard thrice-a-week hemodialysis (THD): 38 patients joined the CDDP, whereas 30 patients chose THD. Patients were studied at baseline, 6 and 12 months; hospitalization and survival rate were followed-up for 24 months. RESULTS: Volume output and residual renal function were maintained in the CDDP Group while those features dropped quickly in THD Group. Throughout the study, CDDP patients had a lower erythropoietin resistance index, lower ß2 microglobulin levels and lower need for cinacalcet of phosphate binders than THD, and stable parameters of nutritional status. At 24 month follow-up, 39.4% of patients were still on CDDP; survival rates were 94.7% and 86.8% for CDDP and THD patients, respectively, but hospitalization rate was much higher in THD than in CDDP patients. The cost per patient per year resulted significantly lower in CDDP than in THD Group. CONCLUSIONS: This study shows that a CDDP served to protect the residual renal function, to maintain urine volume output and to preserve a good nutritional status. CDDP also blunted the rapid ß2 microglobulin increase and resulted in better control of anemia and calcium-phosphate abnormalities. CDDP was also associated with a lower hospitalization rate and reduced need of erythropoietin, as well as of drugs used for treatment of calcium-phosphate abnormalities, thus leading to a significant cost-saving. We concluded that in selected ESRD patients with preserved urine output attitude to protein restriction, CDDP may be a beneficial choice for an incremental hemodialysis program.

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.

A novel amino acids oral supplementation in hemodialysis patients: a pilot study.

BACKGROUND: Protein malnutrition and lowering serum albumin is frequent in hemodialysis patients. A special amino acid formulation has recently been used with favorable effects in elderly people but no data exist in renal patients. AIM: To assess the effects of this novel amino acid formulation in stable hemodialysis patients with reduced albumin levels. METHODS: Thirty stable hemodialysis patients with serum albumin levels <3.5 g/dL, normalized protein nitrogen appearance (nPNA) <1.1 g/kg/d, and body mass index (BMI) >20 kg/m(2) were selected: 15 patients were randomized to oral amino acid supplementation (4 g thrice a day) for 3 months and 15 patients comparable for age, gender, and dialysis durations formed the control group. Biochemistry and bioimpedentiometry parameters were measured at baseline and at the end of treatment. RESULTS: No difference was observed between study group and control group at baseline. At the end of the study period, no change occurred in the studied parameters in the control group, whereas increase in serum albumin (3.1 ± 0.3 vs. 3.6 ± 0.2 g/dL, p < 0.001) and in total proteins (5.7 ± 0.4 vs. 6.4 ± 0.7 g/dL, p < 0.001) occurred in the study group. Hemoglobin rose from 10.7 ± 0.9 to 11.7 ± 0.8 g/dL (p < 0.05) at the same erythropoiesis-stimulating agent (ESA) dosage. C-Reactive protein (CRP) levels decreased in the study group (8.7 ± 7.3 vs. 3.8 ± 3.1 mg/L, p < 0.01). Increase of body weight and of equilibrated protein catabolic rate (ePCR) was observed in the study group. CONCLUSIONS: Oral amino acids supplementation was able to improve albumin and total protein in hypoalbuminemia hemodialysis patients. This effect was associated with reduction of CRP levels that is with lowering of pro-inflammatory status and anemia improvement.

Vagus nerve stimulation increases norepinephrine concentration and the gene expression of BDNF and bFGF in the rat brain.

Vagus nerve stimulation therapy, effective for treatment-resistant epilepsy, has recently been approved also for treatment-resistant depression; nevertheless, the molecular mechanism(s) underlying its therapeutic action remains unclear. Given that neurotrophic factors and monoamines could play a crucial role in the pathophysiology of depression, we tested whether vagus nerve stimulation increases the expression of brain-derived neurotrophic factor, fibroblast growth factor, and nerve growth factor as well as the concentration of norepinephrine in the rat brain. Rats were implanted with a vagus nerve stimulator device and the effects of acute stimulation were evaluated on the growth factors mRNA levels and norepinephrine concentration by ribonuclease protection assay and microdialysis, respectively. We found that acute vagus nerve stimulation increased the expression of brain-derived neurotrophic factor and fibroblast growth factor in the hippocampus and cerebral cortex, decreased the abundance of nerve growth factor mRNA in the hippocampus, and, similar to the antidepressant drug venlafaxine, increased the norepinephrine concentration in the prefrontal cortex. This study demonstrates that acute vagus nerve stimulation triggers neurochemical and molecular changes in the rat brain involving neurotransmitters and growth factors known to play a crucial role in neuronal trophism. These new findings contribute to the elucidation of the molecular mechanisms underlying the therapeutic actions of vagus nerve stimulation in both treatment-resistant depression and epilepsy.

Flumazenil selectively prevents the increase in alpha(4)-subunit gene expression and an associated change in GABA(A) receptor function induced by ethanol withdrawal.

The actions of ethanol on gamma-aminobutyric acid type A (GABA(A)) receptors are still highly controversial issues but it appears that some of its pharmacological effects may depend on receptor subunit composition. Prolonged ethanol exposure produces tolerance and dependence and its withdrawal alters GABA(A) receptor subunit gene expression and function. Whereas benzodiazepines are clinically effective in ameliorating ethanol withdrawal symptoms, work in our laboratory showed that benzodiazepines also prevent, in vitro, some of the ethanol withdrawal-induced molecular and functional changes of the GABA(A) receptors. In the present work, we investigated the effects, on such changes, of the benzodiazepine receptor antagonist flumazenil that can positively modulate alpha(4)-containing receptors. We here report that flumazenil prevented both the ethanol withdrawal-induced up-regulation of the alpha(4)-subunit and the increase in its own modulatory action. In contrast, flumazenil did not inhibit ethanol withdrawal-induced decrease in alpha(1)- and delta-subunit expression as well as the corresponding decrease in the modulatory action on GABA(A) receptor function of both the alpha(1)-selective ligand zaleplon and the delta-containing receptor preferentially acting steroid allopregnanolone. These observations are the first molecular and functional evidence that show a selective inhibition by flumazenil of the up-regulation of alpha(4)-subunit expression elicited by ethanol withdrawal.

Plastic neuronal changes in GABA(A) receptor gene expression induced by progesterone metabolites: in vitro molecular and functional studies.

Expression of specific gamma-aminobutyric acid type A (GABA(A)) receptor subunit genes in neurons is affected by endogenous modulators of receptor function such as neuroactive steroids. Neuroactive steroids such as the progesterone metabolite allopregnanolone might thus exert differential effects on GABA(A) receptor plasticity in neurons, likely accounting for some of the physiological actions of these compounds. Here we summarise experimental data obtained in vitro that show how fluctuations in the concentration of progesterone regulate both the expression and function of GABA(A) receptors. The data described in this manuscript are in agreement with the notion that fluctuations in the concentrations of progesterone and its metabolite allopregnanolone play a major role in the temporal pattern of expression of various subunits of the GABA(A) receptor. Thus, rapid and long-lasting increases or decreases in the concentrations of these steroid derivatives observed in physiological and patho-physiological conditions, or induced by pharmacological treatments, might elicit selective changes in GABA(A) receptor gene expression and function in specific neuronal populations. Given both the importance of GABA(A) receptors in the regulation of neuronal excitability and the large fluctuations in the plasma and brain concentrations of neuroactive steroids associated with physiological conditions and the response to environmental stimuli, these compounds are likely among the most relevant endogenous modulators that could affect emotional and affective behaviors.

Distinct patterns of expression and regulation of GABA receptors containing the delta subunit in cerebellar granule and hippocampal neurons.

Neuronal plasticity is achieved by regulation of the expression of genes for neurotransmitter receptors such as the type A receptor (GABA(A)R) for gamma-aminobutyric acid. We now show that two different rat neuronal populations in culture manifest distinct patterns of GABA(A)R plasticity in response to identical stimuli. Whereas prolonged exposure to ethanol had no effect on expression of the delta subunit of GABA(A)Rs at the mRNA or protein level in cerebellar granule neurons, it increased the abundance of delta subunit mRNA and protein in hippocampal neurons. Subsequent ethanol withdrawal transiently down-regulated delta subunit expression in cerebellar granule neurons and gradually normalized that in hippocampal neurons. These effects of ethanol exposure and withdrawal were accompanied by corresponding functional changes in GABA(A)Rs. GABA(A)Rs containing the delta subunit were also distributed differentially in the cerebellar and hippocampal neurons. These findings reveal complex and distinct mechanisms of regulation of the expression of GABA(A)Rs that contain the delta subunit in different neuronal types.

Modulation of GABA(A) receptor gene expression by allopregnanolone and ethanol.

Expression of specific gamma-aminobutyric acid type A (GABA(A)) receptor subunit genes in neurons is affected by endogenous modulators of receptor function such as neuroactive steroids. This effect of steroids appears to be mediated through modulation of GABA(A) receptor signalling mechanisms that control the expression of specific receptor subunit genes. Furthermore, the specific outcomes of such signalling appear to differ among neurons in different regions of the brain. Neuroactive steroids such as the progesterone metabolite allopregnanolone might thus exert differential effects on GABA(A) receptor plasticity in distinct neuronal cell populations, likely accounting for some of the physiological actions of these compounds. Here we summarise experimental data obtained both in vivo and in vitro that show how fluctuations in the concentration of allopregnanolone regulate both the expression and function of GABA(A) receptors and consequently affect behaviour. Such regulation is operative both during physiological conditions such as pregnancy and lactation as well as in pharmacologically induced states such as pseudopregnancy and long-term treatment with steroid derivatives or anxiolytic-hypnotic drugs. Accordingly, long-lasting exposure of GABA(A) receptors to ethanol, as well as its withdrawal, induces marked effects on receptor structure and function. These results suggest the possible synergic action between endogenous steroids and ethanol in modulating the functional activity of specific neuronal populations.

Ethanol withdrawal-induced up-regulation of the alpha2 subunit of the GABAA receptor and its prevention by diazepam or gamma-hydroxybutyric acid.

The gamma-aminobutyric acid type A (GABA(A)) receptor is an important pharmacological target of ethanol. The effect of ethanol withdrawal on the expression of the alpha(2) subunit of this receptor was examined with rat cerebellar granule cells in primary culture. Long-term exposure of these cells to ethanol (100 mM, 5 days) did not affect the abundance of the mRNA for the alpha(2) subunit, as revealed by an RNase protection assay. In contrast, subsequent ethanol withdrawal for 3 h induced a marked increase in the amount of this mRNA (2.6-fold) as well as in that of the encoded polypeptide (2.2-fold), the latter revealed by immunoblot analysis. Exposure of the cells to gamma-hydroxybutyric acid (100 mM) during ethanol withdrawal prevented the increase in the amounts of both the alpha(2) mRNA and polypeptide, whereas similar treatment with diazepam (10 microM) blocked the increase in the abundance of the alpha(2) polypeptide but not that in the amount of the alpha(2) mRNA. The effect of gamma-hydroxybutyric acid was not blocked by the competitive GABA(B) receptor antagonist SCH 50911(10 microM). Given that the alpha(2) subunit of the GABA(A) receptor mediates the anxiolytic action of benzodiazepines, its up-regulation during discontinuation of long-term ethanol exposure might be relevant to the therapeutic efficacy of these drugs in the treatment of anxiety associated with ethanol withdrawal.