New agents to reduce cholesterol levels: implications for nephrologists.

Statins and ezetimibe effectively reduce the burden of cardiovascular (CV) disease in patients with chronic kidney disease (CKD). Unfortunately, many subjects still die or have CV events despite cholesterol-lowering therapy. This is particularly true in patients with more advanced CKD. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that induces the degradation of the low-density lipoprotein receptor by targeting it for lysosomal destruction. Its inhibition causes a dramatic fall in cholesterol levels on top of maximized statin therapy. This goal is obtained with different therapeutic approaches, spanning from monoclonal antibodies to non sense oligonucleotides and silencing RNA (siRNA). Two human, monoclonal antibodies are approved for clinical use; they are still very expensive. Both agents significantly lower cholesterol levels. Evolocumab and alirocumab reduce significantly the risk for CV disease without relevant safety issues. Inclisiran is an siRNA molecule that produces PCSK9-specific RNA silencing. Data from a Phase II study showed significant cholesterol-lowering efficacy. The experience accumulated so far is limited in the CKD population. PCSK9 inhibition also has the potential to reduce the burden of CV in this subset by obtaining a much greater decrease in serum cholesterol compared with statin therapy or ezetimibe. Doubts exist that this approach will improve the outcome of dialysis patients, in whom vascular calcifications predominate.

Targeting Immunity in End-Stage Renal Disease.

BACKGROUND: Despite the stable incidence of end-stage renal disease (ESRD), it continues to be associated with an unacceptably high cardiovascular risk. SUMMARY: ESRD is characterized by enhanced oxidative stress and severe inflammation, which boost cardiovascular risk, thus increasing cardiovascular-associated mortality rate. While substantial effort has been made in the technological innovation of dialytic techniques, few significant advances have been made to reduce inflammation in patients with ESRD. Indeed, this contrasts with the extensive scientific breakthroughs made in the basic field of science in targeting inflammation. There is thus a pressing need for clinical trials to test the effect of reducing inflammation in patients with ESRD. Here, we will revisit the negative effect of ESRD on inflammation and explore the impact of enhanced inflammation on cardiovascular outcomes and survival in patients with ESRD. Finally, we will discuss the need for clinical trials that target inflammation in ESRD, as well as weigh potential disadvantages and offer novel innovative approaches. Key Message: We will try to understand why the issue of inflammation has not been successfully addressed thus far in patients with ESRD, while at the same time weighing the potential disadvantages and offering novel innovative approaches for targeting inflammation in patients with ESRD.

Insights into the real-world practice of vascular access care pathways in Italy: data from a national survey.

BACKGROUND: International guidelines issued recommendations for vascular access (VA) care for hemodialysis, but there are no registry data regarding this topic in Italy. METHODS: A survey consisting of 17 items was sent to all Italian dialysis wards, via the Italian Society of Nephrology (SIN) website, from April to June 2021. The items were defined, discussed and approved by experts in vascular access management within the Italian Society of Nephrology. A total of 124 dialysis units answered, accounting for 14% of all dialysis units. The survey thus encompasses all regions within the country, with some regional variations in terms of adherence. RESULTS: One hundred twenty-four facilities provided data, regarding 12,276 patients: 61% had an arteriovenous fistula (AVF), 34% had a central venous catheter (CVC), and 5% had an arteriovenous graft (AVG). Among them, two-thirds of the facilities reported having a vascular access care pathway, formally standardized in 79% of cases. Forty-six % of centers had a fully equipped vascular access care pathway, encompassing preoperative mapping (80%), vascular access setup (71%), arteriovenous fistula maturation monitoring (76%), first-level (80%) and second-level (78%) monitoring, and surgical and/or endovascular treatment of complications (66%). Vascular access monitoring was computerized in 39% of facilities. First-level monitoring (physical examination) was primarily done by nurses in two-thirds of facilities. Of note, 45% of centers had nurses who were skilled in ultrasound-guided cannulation. Quite surprisingly, facilities with less than 100 patients had a greater prevalence of arteriovenous fistulas than those with more than 100 patients (p = 0.0023). A protocolled vascular access care pathway was associated with a higher likelihood of having an arteriovenous fistula (70% AVF vs 42,1% CVC; p = 0.04). The presence in the facility of interventional nephrologists or nurses with ultrasound-guided cannulation skills significantly reduced the prevalence of central venous catheters. CONCLUSION: These survey data further strengthen the need for formal and shared vascular access monitoring protocols.

The safety of corticosteroid therapy in IGA nephropathy: analysis of a real-life Italian cohort.

BACKGROUND: Systemic steroids are recommended for patients with IgA nephropathy (IgAN) and proteinuria. However, there are concerns about their safety due to an excess of serious adverse events (SAEs) in previous randomised trials. This study evaluates the incidence of SAEs in IgAN patients receiving different treatment regimens in clinical practice. METHODS: Multicentre, retrospective, observational cohort study of 1209 patients (M/F: 864/345, mean age: 41.73 ± 14.92 years) with biopsy-proven IgAN treated with renin angiotensin system (RAS) inhibitors (RASI) (n = 285), intravenous + oral steroids (n = 633), oral steroids (n = 99), steroids + immunosuppressants (n = 192). RESULTS: A total of 119 (9.8%) adverse events were reported, of which 67 (5.5%) were considered treatment-emergent, and 36 (2.9%) were SAEs (n = 23, 63.8% were infections). One patient died due to sepsis. A significant association was observed between AEs and immunosuppression [8 (2.8%) in RASI, 60 (9.4%) in steroids + immunosuppressants, 14 in oral steroids (14.1%) and 37 pts (19.2%) in steroids + immunosuppressants (p < 0.01)], age and estimated glomerular filtration rate (eGFR), but not with proteinuria and sex. On multivariate analysis, only older age was associated with the occurrence of SAEs. CONCLUSIONS: According to our findings, the incidence of SAEs during therapy with steroids alone or associated with immunosuppressors is lower in everyday clinical practice than in randomised clinical trials.

[The ambiguous concept of predialysis: proposal for a model]. / L'ambiguita' del concetto di predialisi: proposta di un modello.

In 2009, 90% of nephrology centers in Lombardy declared to have a ''predialysis'' outpatient department, without, however, specifying its meaning. Research carried out in 2008 among nephrology centers in Piemonte showed how ambiguous this term was. According to the 2007 EDTA-ERA Registry, about 68% of European nephrology centers stated that they had an outpatient department for stage 4-5 CKD patients, but no information was available about the role of patients in the choice of dialysis. It is known that when the predialysis phase is poorly managed, the patient's rehabilitation will be more difficult. Dissatisfaction with dialysis often leads to withdrawal from dialysis, as several registries have shown. For this reason, we created a predialysis course at our center, involving a nephrologist, a nurse, and a dietician. The nephrologist helps the patient choose the most suitable therapeutic strategy, which means that doctor and patient share the responsibility for the treatment choice. The offered options are hemodialysis, peritoneal dialysis, preemptive kidney transplant, and a conservative dietary-pharmacological program. The nurse plans at least 4 meetings: 1) to talk with the patient in order to get to know him or her and his/her family; 2) to provide information about the dialysis procedure and establish the patient's preferences; 3) to clear any doubts about the treatment and deliver a booklet with information about the chosen dialysis procedure; 4) to explain the chosen dialysis procedure; 5) to meet the patient after their preparation for dialysis (vascular access or peritoneal catheter). The dietician manages the dietary programs both for patients who are close to starting dialysis and those on a longlasting conservative program. The predialysis course includes a meeting among all those involved with the patient (nephrologists, nurses, dieticians) to exchange information with the purpose of shared evaluation and decision-making.

Renal involvement in sarcoidosis: histological patterns and prognosis, an Italian survey.

BACKGROUND: Granulomatous interstitial nephritis in sarcoidosis (sGIN) is generally clinically silent, but in <1% causes acute kidney injury (AKI). METHODS: This Italian multicentric retrospective study included 39 sarcoidosis-patients with renal involvement at renal biopsy: 31 sGIN-AKI, 5 with other patterns (No-sGIN-AKI), 3 with nephrotic proteinuria. We investigate the predictive value of clinical features, laboratory, radiological parameters and histological patterns regarding steroid response. Primary endpoint: incident chronic kidney disease (CKD) beyond the 1°follow-up (FU) year; secondary endpoint: response at 1°line steroid therapy; combined endpoint: the association of initial steroid response and outcome at the end of FU. RESULTS: Complete recovery in all 5 No-sGIN-AKI-patients, only in 45% (13/29) sGIN-AKI-patients (p=0.046) (one lost in follow-up, for another not available renal function after steroids). Nobody had not response. Primary endpoint of 22 sGIN-AKI subjects: 65% (13/20) starting with normal renal function developed CKD (2/22 had basal CKD; median FU 77 months, 15-300). Combined endpoint: 29% (6/21) had complete recovery and final normal renal function (one with renal relapse), 48% (10/21) had partial recovery and final CKD (3 with renal relapse, of whom one with basal CKD) (p=0.024). Acute onset and hypercalcaemia were associated to milder AKI and better recovery than subacute onset and patients without hypercalcaemia, women had better endpoints than men. Giant cells, severe interstitial infiltrate and interstitial fibrosis seemed negative predictors in terms of endpoints. CONCLUSIONS: sGIN-AKI-patients with no complete recovery at 1°line steroid should be treated with other immunosuppressive to avoid CKD, in particular if males with subacute onset and III stage-not hypercalcaemic AKI.

[Utility of computerized vascular access monitoring: a pilot study].

The surveillance of a vascular access (VA) is of primary importance for its outcome and for the patients' survival. However, there is still confusion about its usefulness, who should make it (physician or nurse) and when, and what is the best functional test to use. This retrospective analysis reports our experience of VA monitoring; it is based on the collaboration between concept doctors and nurses and on parameters integration, realized with the help of a software for vascular access monitoring (SMAV) designed by us. The analysis confronts the data gathered on a group of 100 patients, 13 months before the adoption of the SMAV, and another 100 patients, 19 months after. Of these patients, 13 belonged to both groups and were "controls of themselves". The number of thrombosis and angioplasties (PTA) plummeted in the 19 months in which the SMAV was used, from 10 (10%; 0.008 thrombosis/patient month) to 1 (1%; 0.0005 thrombosis/patient month) (p <0.01) and from 49 (49%; 0.037 PTA/patient month) to 27 (27%; 0.014PTA/patient month) (p <0.05) respectively. In the 13 control patients, a reduction of 70% in the number of PTA (from 26 to 8) was observed. SMAV allowed us to integrate the many functional parameters, making it easy to share information, encouraging teamwork, strengthening professional skills, and favouring the best management of AVs. The result was a reduction in thrombotic events and, surprisingly, a reduction of the need for PTA, most likely thanks to the higher level of attention in the evaluation and puncture of AV.

Low Plasma Lecithin: Cholesterol Acyltransferase (LCAT) Concentration Predicts Chronic Kidney Disease.

Low high-density lipoprotein-cholesterol (HDL-c) is the most remarkable lipid trait both in mild-to-moderate chronic kidney disease (CKD) patients as well as in advanced renal disease stages, and we have previously shown that reduced lecithin:cholesterol acyltransferase (LCAT) concentration is a major determinant of the low HDL phenotype. In the present study, we test the hypothesis that reduced LCAT concentration in CKD contributes to the progression of renal damage. The study includes two cohorts of subjects selected from the PLIC study: a cohort of 164 patients with CKD (NefroPLIC cohort) and a cohort of 164 subjects selected from the PLIC participants with a basal estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2 (PLIC cohort). When the NefroPLIC patients were categorized according to the LCAT concentration, patients in the 1st tertile showed the highest event rate at follow-up with an event hazard ratio significantly higher compared to the 3rd LCAT tertile. Moreover, in the PLIC cohort, subjects in the 1st LCAT tertile showed a significantly faster impairment of kidney function compared to subjects in the 3rd LCAT tertile. Serum from subjects in the 1st LCAT tertile promoted a higher reactive oxygen species (ROS) production in renal cells compared to serum from subjects in the third LCAT tertile, and this effect was contrasted by pre-incubation with recombinant human LCAT (rhLCAT). The present study shows that reduced plasma LCAT concentration predicts CKD progression over time in patients with renal dysfunction, and, even more striking, it predicts the impairment of kidney function in the general population.

The low-protein diet for chronic kidney disease: 8 years of clinical experience in a nephrology ward.

BACKGROUND: Guidelines indicate that a low-protein diet (LPD) delays dialysis in severe chronic kidney disease (CKD). We assessed the value of these guidelines by performing a retrospective analysis in our renal clinical practice. METHODS: The analysis was performed from 1 January 2010 to 31 March 2018 in 299 CKD Stage 4 patients followed for 70 months in collaboration with a skilled nutritionist. The patients included 43 patients on a controlled protein diet (CPD) of 0.8 g/kg/day [estimated glomerular filtration rate (eGFR) 20-30 mL/min/1.73 m2 body surface (b.s.)], 171 patients on an LPD of 0.6 g/kg/day and 85 patients on an unrestricted protein diet (UPD) who were not followed by our nutritionist (LPD and UPD, eGFR <20 mL/min/1.73 m2 b.s.). RESULTS: eGFR was higher in CPD patients than in UPD and LPD patients (21.9 ± 7.4 mL/min/1.73 m2 versus 17.6 ± 8.00 mL/min/1.73 m2 and 17.1 ± 7.5 mL/min/1.73 m2; P = 0.008). The real daily protein intake was higher in UPD patients than in LPD and CDP patients (0.80 ± 0.1 g/kg/day versus 0.6 ± 0.2 and 0.63 ± 0.2 g/kg/day; P = 0.01). Body mass index (BMI) was stable in the LPD and CPD groups but decreased from 28.5 ± 4.52 to 25.4 ± 3.94 kg/m2 in the UPD group (P < 0.001). The renal survival of UPD, LPD and CPD patients was 47.1, 84.3 and 90.7%, respectively, at 30 months (P < 0.001), 42.4, 72.0 and 79.1%, respectively, at 50 months (P < 0.001) and 42.4, 64.1 and 74.4%, respectively, at 70 months (P < 0.001). The LPD patients started dialysis nearly 24 months later than the UPD patients. Diet was an independent predictor of dialysis [-67% of RR reduction (hazard ratio = 0.33; confidence interval 0.22-0.48)] together with a reduction in BMI. CONCLUSIONS: An LPD recommended by nephrologists in conjunction with skilled dietitians delays dialysis and preserves nutritional status in severe CKD.

Sodium removal and plasma tonicity balance are not different in hemodialysis and hemodiafiltration using high-flux membranes.

BACKGROUND: The clinical benefits of on-line hemodiafiltration (HDF) versus high-flux membranes hemodialysis (hf-HD) are still debated. In fact, although a superiority of one treatment over the other, especially in terms of mortality, did not emerge from the analysis of clinical trials, improved intradialytic vascular stability and cardiovascular mortality have been observed in patients undergoing HDF rather than hf-HD; the lower removal of sodium (Na+) during HDF seems to play a major role. The plasma concentration of Na+ is the major determinant of plasma tonicity, which, by determining the flow of water between the intracellular and the extracellular compartment, contributes to the vascular refilling process and the maintenance of blood pressure during the hemodialysis treatment. Plasma tonicity also depends on plasma glucose concentration, especially in patients with diabetes mellitus with hyperglycaemia at the start of hemodialysis treatment. MATERIALS AND METHODS: We evaluated the removal of Na+ and plasma tonicity balance during a 2-week period by performing 2-3 consecutive sessions of hf-HD followed by 2-3 consecutive sessions of HDF, or vice versa, in 47 patients (40% diabetics) on chronic hemodialysis. Identical parameters were used in all dialytic sessions. RESULTS: Na+ removal per session was - 224 ± 144 mmol and - 219 ± 152 mmol, respectively, in hf-HD and in HDF (p = 0.79). The plasma tonicity balance per session was - 575 ± 310 mOsm and - 563 ± 328 mOsm, respectively, in hf-HD and in HDF (p = 0.75). CONCLUSIONS: The removal of Na+ and plasma tonicity balance did not differ between hf-HD and HDF. This observation suggests that factors other than those assessed in our study might explain the improved cardiovascular stability reported in HDF.

Changes in Proteinuria and Side Effects of Corticosteroids Alone or in Combination with Azathioprine at Different Stages of IgA Nephropathy.

BACKGROUND AND OBJECTIVE: Time-average proteinuria (TAp) is the strongest predictor of renal survival in IgA nephropathy (IgAN). Little is known about the utility and safety of corticosteroids (CS) to obtain TAp<1 g/d in patients with advanced IgAN. This study sought to evaluate TAp at different degree of baseline renal function and histologic severity during CS use and to investigate treatment safety. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed one-stage individual-patient data meta-analysis among 325 patients with IgAN enrolled in three prospective, randomized clinical trials. Patients were divided into three groups according to treatment: no treatment (NT; supportive therapy), CS, and CS plus azathioprine (CS+A). Associations of TAp with histologic grading, treatment, and eGFR at baseline were performed with linear regression models for repeated measures. The median follow-up duration was 66.6 months (range, 12-144 months). RESULTS: In the first 6 months, proteinuria did not change in the NT group and decreased substantially in the other groups(CS: from a mean±SD of 2.20±1.0 to 0.8 [interquartile range, 0.4-1.2] g/d; CS+A: from 2.876±2.1 to 1.0 [interquartile range, 0.5-1.7] g/d), independent of the degree of histologic damage and baseline eGFR. The percentage of patients who maintained TAp<1 g/d was 30.2% in the NT, 67.3% in the CS, and 66.6% in the CS+A group. Thirty-four patients experienced adverse events: none in the NT, 11 (6.4%) in the CS, and 23 (20.7%) in the CS+A group. The risk of developing adverse events increased with decreasing levels of eGFR (from 2.3% to 15.4%). The addition of azathioprine to CS further increased the percentage of patients with adverse events (16.8% versus 5.7% in study 2 and 30.0% versus 15.4% in study 3; overall P<0.001). CONCLUSIONS: In patients with IgAN, CS can reduce proteinuria and increase the possibility of maintaining TAp<1 g/d, regardless of the stage of CKD and the histologic damage. The risk of major adverse events is low in patients with normal renal function but increases in those with impaired renal function and with the addition of azathioprine.

Plasma homocysteine levels and cardiovascular mortality in patients with end-stage renal disease.

Hyperhomocysteinemia is considered an independent risk factor for atherosclerosis in patients with normal renal function. Plasma homocysteine (Hcy) is increased in patients with chronic renal failure (CRF) and could be linked to their high cardiovascular (CV) morbidity and mortality. We prospectively studied 77 patients (47 males and 30 females aged 62.85 +/- 1.53 yrs) who had been on maintenance hemodialysis (HD) (4 hr/x3/week) for 65.5 +/- 7.23 months. Patients were followed-up for 44 months. At baseline, blood samples were taken for hemoglobin (Hb), total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, serum calcium, serum phosphates, parathyroid hormone (PTH), Hcy, vitamin B12, serum and erythrocyte folate and methylentetrahydrofolate-reductase (t-MTH-FR) genotype determination. Plasma Hcy levels of patients were divided into four quartiles. The univariate analysis demonstrated a significant relationship between Hcy and diastolic blood pressure (BP) (r=0.45; p=0.003), and both plasma (r=-0.30; p=0.03) and erythrocyte (r=-0.48; p=0.01) folate levels and CV score (r=0.39; p=0.007). Kaplan-Meier analysis showed that the mortality rate due to CV events was statistically significantly higher in the 4th Hcy quartile (68%; 12 patients) vs. the 3rd quartile (12%; two patients), the 2nd quartile (28%; four patients) and the 1st quartile (14%; two patients) (log-rank test p=0.02). Cox's regression analysis for CV survival showed that Hcy was a positive CV mortality predictor (beta=0.02; hazard ratio=1.031; 95% confidence interval (95% CI): 1.013-1.050; p=0.001), while LDL cholesterol and albumin related negatively to CV mortality (LDL cholesterol: beta=-0.02; hazard ratio=0.095; 95% CI: 0.0957-0.0997; p=0.035; albumin: beta=-2.35; hazard ratio=0.097; 95% CI: 0.011-0.847; p=0.026). Our results show that Hcy is a strong independent mortality predictor in HD patients with a 3% increase in mortality for each 1 micromol/L increase in plasma Hcy concentration. This agrees with previous findings confirming the role of Hcy in predicting CV risk factors in uremic patients.

[Assisted peritoneal dialysis]. / La Dialisi Peritoneale Assistita con l'impiego degli OSS come caregiver.

Peritoneal dialysis (PD) has a prevalence in Italy that does not exceed 10% of patients in substitution treatment. Among the barriers, which hinder access to DP, the lack of patient autonomy or family support has great importance. In 2012 in Lombardy, the lack of support has prevented 155 new patients to use DP and has forced 17 to stop it. According to the Italian Census of 2012, made by the Peritoneal Dialysis Study Group, Assisted DP involved the 24.5% of patients in 2010. In these cases, the caregiver was a family member in 80.8% of cases, a carer in 12.4%, a homecare nurse in 2.5% and the retirement home staff in 3.9%. In Italy, several regional Governments have sought to encourage home dialysis with economic contributions to the patient or the family. However, so far, none of these interventions has managed to increase the use of DP. In January 2004, we started a program of Assisted PD, using health worker as caregiver, in agreement with ASL Milano and ICP Milano Hospital. In the first 6 months of activity we treated 4 patients, 3 of them had been treated with hemodialysis. We had no critical cases and patients have welcomed this solution. In addition, the costs related to the Assisted PD are lower in comparison with the costs of the hospital hemodialysis. Considering the reliability of the first results, ASL has decided to raise the economic contribution for this activity, allowing us to increase the number of patients to include in Assisted PD.

-374 T/A RAGE polymorphism is associated with chronic kidney disease progression in subjects affected by nephrocardiovascular disease.

BACKGROUND: Chronic kidney disease (CKD) patients present elevated advanced glycation end products (AGEs) blood levels. AGEs promote inflammation through binding to their receptor (RAGE), located on the membrane of mesangial cells, endothelial cells and macrophages. Several genetic polymorphisms influence RAGE transcription, expression and activity, including the substitution of a thymine with an adenine (T/A) in the position -374 of the gene promoter of RAGE. Our study investigates the role of -374 T/A RAGE polymorphism in CKD progression in subjects affected by nephrocardiovascular disease. METHODS: 174 patients (119 males (68.4%) mean age 67.2±0.88 years; 55 females (31.6%): mean age 65.4±1.50 years) affected by mild to moderate nephrocardiovascular CKD were studied. Each subject was prospectively followed for 84 months, every 6-9 months. The primary endpoint of the study was a rise of serum creatinine concentrations above 50% of basal values or end stage renal disease. RESULTS: Carriers of the A/A and T/A genotype presented higher plasma levels of interleukin 6 (A/A 29.5±15.83; T/A 30.0±7.89, vs T/T 12.3±5.04 p = 0.01 for both) and Macrophages chemoattractant protein 1 (A/A 347.1±39.87; T/A 411.8±48.41, vs T/T 293.5±36.20, p = 0.04 for both) than T/T subjects. Carriers of the A allele presented a faster CKD progression than wild type patients (Log-Rank test: Chi square = 6.84, p = 0,03). Cox regression showed that -374 T/A RAGE polymorphism (p = 0.037), albuminuria (p = 0.01) and LDL cholesterol (p = 0.038) were directly associated with CKD progression. HDL cholesterol (p = 0.022) and BMI (p = 0.04) were inversely related to it. No relationship was found between circulating RAGE and renal function decline. CONCLUSIONS: -374 T/A RAGE polymorphism could be associated with CKD progression and inflammation. Further studies should confirm this finding and address whether inhibiting RAGE downstream signalling would be beneficial for CKD progression.

Improvement of endothelial function in uraemic patients on peritoneal dialysis: a possible role for 5-MTHF administration.

BACKGROUND: Hyperhomocysteinaemia is an independent risk factor for the development of atherosclerosis. Furthermore, homocysteine induces endothelial dysfunction by an increased inactivation of nitric oxide. In patients with chronic renal failure, the administration of folic acid or its metabolites reduces but does not normalize plasma homocysteine concentrations. METHODS: We examined the effect of oral treatment with 15 mg/daily of 5-methyltetrahydrofolate (5-MTHF) for 12 weeks, on homocysteinaemia and endothelial function in 19 patients undergoing peritoneal dialysis and compared them, for the same period of time, to a control group of patients on peritoneal dialysis. Endothelial function was evaluated by B-mode ultrasonography on the brachial artery. Flow-mediated dilation (FMD) was recorded during reactive hyperaemia produced by the inflation of a pneumatic tourniquet. Nitroglycerine-mediated dilation (NMD) was recorded after sublingual administration of glyceryl trinitrate. Finally, oxidative stress was assessed by evaluating the conjugated dienes plasma levels. RESULTS: Plasma homocysteine concentrations fell by 30% after oral treatment with 5-MTHF. Endothelial function improved significantly after oral 5-MTHF treatment (13.8 +/- 1.2% vs 11.4 +/- 1.4%; P < 0.02) while in the control group we observed a worsening of basal values from 12.1 +/- 2.66% to 8.7 +/- 2.90% (P < 0.02). The conjugated dienes plasma levels did not change either. CONCLUSIONS: Our study demonstrated that 5-MTHF administration improves endothelial dysfunction in patients undergoing peritoneal dialysis. This effect appears to be independent of the reduction in homocysteine plasma levels.

Intraperitoneal hydrostatic pressure and flow characteristics of peritoneal catheters in automated peritoneal dialysis.

BACKGROUND: In automated peritoneal dialysis (APD) one of the most important factors that influence the efficiency of the treatment is the total volume of dialysate infused per session and the dwell time. This study is aimed at examining the relationships between i.p. pressure (IPP), dialysate flow characteristics, and different dialysate fill volumes in order to optimize APD. METHODS: We studied 20 patients who received APD, with the standard fill volume (2 l, A), or individualized fill volumes based on the patient's body surface area (2.5 l/BSA/1.73 m, B) or on body weight (40 ml/kg body weight, C). The patient's tolerance to a given fill volume was evaluated by measuring IPP, and catheter flow characteristics were evaluated by an automated machine. RESULTS: IPP increased with the increase of the infused volume of dialysate (P < 0.05) and tended towards a positive relationship with the patient's body mass index (BMI: A vs IPP: R = 0.39, P = 0.0019; B vs IPP: R = 0.66, P = 0.0012; C vs IPP R = 0.55, P = 0.009). We also found a relationship between fill volume, BMI and IPP: IPP = 1.0839 + 0.53 (beta) x BMI + 0.211 (beta) x fill volume (R = 0.65; r(2) = 0.40 P < 0.01). The mean IPP with different dialysate fill volumes tended to be related to the volume of dialysate drained at the transition point (R = 0.37; P < 0.05). The pre-transition flow rate/mean IPP ratio tended towards a positive relationship with the volume of dialysate drained at the transition point (R = 0.35, P < 0.05), the transition time (R = 0.34; P < 0.05) and a negative one with the transition volume (R = -0.35, P = 0.05). CONCLUSION: It is possible to customize APD, where the tidal percentage coincides with the transition point for a given catheter and a specific initial dialysate fill volume, the tolerance of which can be measured by assessing IPP.

5-methyltetrahydrofolate restores endothelial function in uraemic patients on convective haemodialysis.

BACKGROUND: Hyperhomocysteinaemia is an independent risk factor for the development of atherosclerosis. In patients with chronic renal failure, the administration of folic acid or its metabolites reduces but does not normalize plasma homocysteine concentrations. Furthermore, homocysteine induces endothelial dysfunction by an increased inactivation of nitric oxide. METHODS: We examined the effect of the active metabolite of folic acid, 5-methyltetrahydrofolate (5-MTHF), 45 mg/week i.v. for 10 weeks, combined during the last 2 weeks with vitamin B12, 500 microg s.c. twice weekly, on homocysteinaemia and endothelial function in 15 patients undergoing convective haemodialysis. Endothelial function was evaluated by B-mode ultrasonography on the brachial artery. Flow-mediated dilation (FMD) was recorded during reactive hyperaemia produced by inflation of a pneumatic tourniquet. Nitroglycerine-mediated dilation (NMD) was recorded after administration of isosorbide dinitrate. Finally, the presence of the thermolabile variant of methyltetrahydrofolate reductase (t-MTHFR) was assessed by genotype analysis. RESULTS: Plasma homocysteine concentrations fell by 47% after treatment with 5-MTHF alone and by a further 13.6% after the addition of vitamin B12. The reduction was more marked in homo- and heterozygous patients than in normal genotypes for t-MTHFR. Flow-mediated endothelial vasodilation, measured by ultrasonography of the brachial artery, improved after administration of 5-MTHF (12.52+/- 2.47% vs. 7.03+/-1.65%; P<0.05), but there were no further changes following the addition of vitamin B12. CONCLUSIONS: Our study demonstrated that 5-MTHF administration not only reduced plasma homocysteine but also improved endothelial function in uraemic patients undergoing convective haemodialysis.