Nutritional therapy reduces protein carbamylation through urea lowering in chronic kidney disease.

Background: Protein carbamylation is one of the non-enzymatic reactions involved in protein molecular ageing. We sought to investigate the relationship between urea levels and protein carbamylation, and whether a Mediterranean diet (MD) and a very low protein diet (VLPD) reduce protein carbamylation through reduction in urea levels in patients with chronic kidney disease (CKD). Methods: This is a prospective, randomized, crossover controlled trial that investigated 60 patients with CKD grades 3B-4 (46 males, mean age of 67 years). The enrolled CKD patients were randomly assigned (1:1) to two different nutritional treatment arms: (i) 3 months of free diet (FD), 6 months of VLPD, 3 months of FD and 6 months of MD; and (ii) 3 months of FD, 6 months of MD, 3 months of FD and 6 months of VLPD. Blood levels of lysine (Lys) and homocitrulline (Hcit) and their ratio were used as markers of cyanate levels. Due to a lack of pre-existing data on the potential effects of different dietary regimens and in light of the exploratory nature of the study, no formal sample size estimation was carried out. Results: At study completion, lower diastolic blood pressure and decreased serum levels of urea, sodium, phosphorus and parathyroid hormone, but higher serum levels of bicarbonate and haemoglobin, were noted with MD and VLPD. When compared with FD, both MD and VLPD were also associated with a decrease in serum Hcit levels and Hcit/Lys ratios (P < 0.001). Notably, reductions in urea levels correlated with substantial reductions in Hcit levels (R2 = 0.16 and 0.17 for VLPD and MD, respectively). Conclusion: In conclusion, nutritional treatments that significantly decrease serum levels of urea are associated with reduced protein carbamylation.

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.

Phosphate attenuates the anti-proteinuric effect of very low-protein diet in CKD patients.

BACKGROUND: High phosphate levels attenuate nephroprotection through angiotensin-converting enzyme inhibition in patients with proteinuric chronic kidney disease (CKD). Whether this phenomenon holds true for other nephroprotective interventions like very-low-protein diet (VLPD) is unknown. METHODS: We tested the hypothesis that phosphate interferes with the anti-proteinuric response to VLPD in a non-randomized, sequential study in 99 proteinuric CKD patients who sequentially underwent low-protein diet (LPD; 0.6 g/kg) and VLPD (0.3 g/kg) supplemented with keto-analogues, each for periods longer than 1 year. RESULTS: Serum phosphate significantly reduced during VLPD (3.2 ± 0.6 mg/dL) when compared with LPD (3.7 ± 0.6 mg/dL, P < 0.001), an effect paralleled by a substantial decline in phosphate excretion (LPD, 649 ± 180 mg/day; VLPD, 462 ± 97 mg/day; P < 0.001). The median proteinuria during LPD was 1910 mg/24 h (interquartile range: 1445-2376 mg/24 h) and reduced to 987 mg/24 h (656-1300 mg/24 h) during VLPD (P < 0.001). No significant change in the estimated glomerular filtration rate (eGFR) was observed during the two diet periods. In linear mixed models including the diagnosis of renal disease, eGFR, 24-h urine sodium and urea and other potential confounders, there was a strong interaction between serum phosphate (P = 0.04) and phosphaturia (P < 0.001) with the anti-proteinuric response to VLPD. Accordingly, 24-h proteinuria reduced modestly in patients who maintained relatively higher serum phosphate levels or relatively higher phosphaturia to be maximal in those who achieved the lowest level of serum and urine phosphate. CONCLUSION: Phosphate is an important modifier of the anti-proteinuric response to VLPD. Reducing phosphate burden may decrease proteinuria and slow the progression of renal disease in CKD patients, an issue that remains to be tested in specific clinical trials.

Conversion from epoetin and darbepoetin to C.E.R.A. in non-dialysis CKD patients: a multicenter Italian prospective study in nephrology practice.

BACKGROUND: In non-dialysis patients (ND-CKD), C.E.R.A. has been extensively investigated in ESA-naïve subjects but no data are available on its efficacy after switch from other ESA. METHODS: In this prospective, multicenter, open-label study lasting 24 weeks, ND-CKD patients (n = 157) receiving ESA were converted to C.E.R.A. at doses lower than recommended. Primary outcome was the prevalence of Hb target (11-12.5 g/dl). RESULTS: Age was 73 ± 13 years and GFR was 26.2 ± 9.4 ml/min/1.73 m(2); male gender, diabetes and prior cardiovascular disease were 49, 33 and 19%, respectively. Doses of darbepoetin (25 ± 16 µg/week, n = 124) and epoetin (5,702 ± 3,190 IU/week, n = 33) were switched to low dose C.E.R.A. (87 ± 17 µg/month). During the study, prevalence of Hb target increased from 60% to 68% at week-24, while that of Hb < 11 g/dl declined from 32% to 16% (p < 0.001). Hb increased from 11.3 ± 0.8 at baseline to 11.7 ± 0.9 g/dl at week-24 (p = 0.01) without changes in C.E.R.A. dose. Significant predictors of Hb increase were low BMI, low Hb and longer dosing intervals before switch. These factors also predicted the risk of Hb overshooting (Hb > 12.5 g/dl) occurring in 57 patients. CONCLUSIONS: In ND-CKD, conversion from other ESAs to C.E.R.A. is associated with a better anemia control induced by a greater Hb increase in patients previously treated with ESAs at extended dosing interval. This parameter should be considered when switching to long-acting ESA for its potential impact on the risk of overshooting.

Assessment of nutritional practice in Italian chronic kidney disease clinics: a questionnaire-based survey.

BACKGROUND: The prevention of malnutrition in patients with progressive chronic kidney disease (CKD) presents a challenge to nephrologists. We evaluated nutritional practice and routines, at a national level, related to the nutritional management of nondialyzed CKD patients. METHODS: A questionnaire-based survey (32 open and 9 multiple-choice questions) was used to assess the evaluation of nutritional status in nondialyzed CKD outpatients at baseline and during follow-up. Data were obtained for 230 Italian public nephrology centers (63% of the total number of Italian public nephrology centers). RESULTS: There was a dedicated dietitian at only 19% of the centers. At baseline, body weight, body mass index, and serum albumin were determined in almost all centers, nutrient intakes and bioimpedance analysis in half the centers, and subjective global assessment and skinfold thickness in a small proportion of centers. During follow-up, the rate of assessments decreased by 8% for weight, 14% for nutrient intake, and 29% for subjective global assessment and skinfold thickness. Overall, the K/DOQI minimum criteria for nutritional assessment were fulfilled in only two thirds and half of the clinics at baseline and during follow-up, respectively. Multivariate analysis showed that the number of nutritional variables evaluated was significantly related to the size of the CKD clinic and the presence of a dietitian at baseline, but only with the presence of dietitian during follow-up. Daily urinary output was collected at 90% of the centers, but urea and sodium excretions were determined in only 59% and 57% of cases, respectively. The rate of assessment for urinary solutes during follow-up was higher at centers where a very low protein diet was prescribed. CONCLUSIONS: The indications about nutritional assessment for CKD patients are poorly translated into practice patterns, especially with respect to the evaluation of nutrient intakes and additional but simple variables such as skinfold-thickness measurement and bioimpedance analysis. The presence of a dedicated dietitian appears to improve the quality of nutritional assessment in CKD.

Glifozines and cardiorenal outcomes.

Diabetes mellitus, with its complications, is one of the major health problems in economically developed countries and its prevalence is constantly increasing. Kidneys and heart involvement represent main comorbidities in diabetic patients often leading to organ failure. The treatments available until a few years ago are often associated with hypoglycemia, weight gain, gastro-intestinal disorders and other side effects together with serious adverse effects on renal function. The new frontiers of diabetic cardionephropathy treatment are mainly focused on delay of heart and renal failure both on diabetic and nondiabetic patients ad it was shown by last data reports. In the following review, we will focus on Gliflozins, one of the newest classes of hypoglycemic drugs that have shown to hold peculiar pharmacological properties in managing cardiac and renal complications.

Correction to: Treatment of metabolic acidosis with sodium bicarbonate delays progression of chronic kidney disease: the UBI Study.

It occurred to us that a simple but significant calculation error was made in Table 2 in the dose of bicarbonate administered. Indeed, contrary to what reported in Table 2, the dose of sodium bicarbonate administered during study was.

Very Low Protein Diet for Patients with Chronic Kidney Disease: Recent Insights.

Use of nutritional therapy (NT) in chronic kidney disease (CKD) patients is still debated among nephrologists, but it represents a fundamental point in the conservative treatment of CKD. It has been used for years and it has new goals today, such as (1) the reduction of edema, diuretics, and blood pressure values with a low sodium-content diet; (2) the dose reduction of phosphate levels and phosphate binders; (3) the administration of bicarbonate with vegetables in order to correct metabolic acidosis and delay CKD progression; (4) the reduction of the number and the doses of drugs and chemical substances; and (5) the lowering of urea levels, the cure of intestinal microbioma, and the reduction of cyanates levels (such as indoxyl-sulphate and p-cresol sulphate), which are the most recent known advantages achievable with NT. In conclusion, NT and especially very low protein diet (VLPD) have several beneficial effects in CKD patients and slows the progression of CKD.

Treatment of metabolic acidosis with sodium bicarbonate delays progression of chronic kidney disease: the UBI Study.

BACKGROUND: Metabolic acidosis is associated with accelerated progression of chronic kidney disease (CKD). Whether treatment of metabolic acidosis with sodium bicarbonate improves kidney and patient survival in CKD is unclear. METHODS: We conducted a randomized (ratio 1:1). open-label, controlled trial (NCT number: NCT01640119. www.clinicaltrials.gov ) to determine the effect in patients with CKD stage 3-5 of treatment of metabolic acidosis with sodium bicarbonate (SB) on creatinine doubling (primary endpoint), all-cause mortality and time to renal replacement therapy compared to standard care (SC) over 36-months. Parametric, non-parametric tests and survival analyses were used to assess the effect of SB on these outcomes. RESULTS: A total of 376 and 364 individuals with mean (SD) age 67.8 (14.9) years, creatinine clearance 30 (12) ml/min, and serum bicarbonate 21.5 (2.4) mmol/l were enrolled in SB and SC, respectively. Mean (SD) follow-up was 29.6 (9.8) vs 30.3 (10.7) months in SC and SB. respectively. The mean (SD) daily doses of SB was 1.13 (0.10). 1.12 (0.11). and 1.09 (0.12) mmol/kg*bw/day in the first, second and third year of follow-up, respectively. A total of 87 participants reached the primary endpoint [62 (17.0%) in SC vs 25 (6.6%) in SB, p < 0.001). Similarly, 71 participants [45 (12.3%) in SC and 26 (6.9%) in SB, p = 0.016] started dialysis while 37 participants [25 (6.8%) in SC and 12 (3.1%) in SB, p = 0.004] died. There were no significant effect of SB on blood pressure, total body weight or hospitalizations. CONCLUSION: In persons with CKD 3-5 without advanced stages of chronic heart failure, treatment of metabolic acidosis with sodium bicarbonate is safe and improves kidney and patient survival.

[Inapparent charges for the assistance to nephropathic patient on dialysis].

The increasing technological effectiveness has undoubtedly produced an improvement in clinical parameters of dialysis patients, but this satisfactory therapeutic result did not follow an adequate improvement in mortality or in the perception of quality of life as per patients. Furthermore, dialysis treatment is often associated with "inapparent charges" that reduce the perception of well-being, independently of clinical changes. Thirty years ago, we carried out a national survey on inapparent charges, which represent frustrating aspects that negatively affect patients' perception of their quality of life. Thirty years later, it seemed important for us to repeat the survey to understand if Italian legislative remodeling have introduced changes in procedures and social aspects of dialysis, as preservation of quality of life is an important aspect of the replacement treatment.

Nutritional therapy in autosomal dominant polycystic kidney disease.

CKD-related nutritional therapy (NT) is a crucial cornerstone of CKD patients' treatment, but the role of NT has not been clearly investigated in autosomal dominant polycystic kidney disease (ADPKD). Several clinical studies have focused on new pharmacological approaches to delay cystic disease progression, but there are no data on dietary interventions in ADPKD patients. The aim of this paper is to analyze the evidence from the literature on the impact of five nutritional aspects (water, sodium, phosphorus, protein intake, and net acid load) in CKD-related ADPKD extrapolating-where information is unavailable-from what occurs in CKD non-ADPKD patients Sodium intake restriction could be useful in decreasing the growth rate of cysts. Although further evidence is needed, restriction of phosphorus and protein intake restriction represent cornerstones of the dietary support of renal non-ADPKD patients and common sense can guide their use. It could be also helpful to limit animal protein, increasing fruit and vegetables intake together with a full correction of metabolic acidosis. Finally, fluid intake may be recommended in the early stages of the disease, although it is not to be prescribed in the presence of moderate to severe reduction of renal function.

A strategy to reduce inflammation and anemia treatment's related costs in dialysis patients.

This is a post-hoc analysis evaluating erythropoiesis stimulating agents' (ESA) related costs while using an additional ultrafilter (Estorclean PLUS) to produce ultrapure dialysis water located within the fluid pathway after the treatment with reverse osmosis and before the dialysis machine. Twenty-nine patients (19 treated with epoetin alfa and 10 with darboepoetin alfa) were included in the analysis. We showed to gain savings of 210 € per patient (35 € per patient each month) with epoetin alfa during the experimental period of 6 months, compared to the control period and of 545 € per patient (90 € per patient each month) with darboepoetin alfa. Estorclean PLUS had a cost of 600 € (25 € per month per each patient) and was used for 6 months. Intravenous iron therapy with sodium ferrigluconate had a cost of 0,545 €/62,5 mg. In conclusion, during the experimental period with the use of Estorclean, we obtained global savings of 11 € per patient per month with epoetin alfa and 30 € per patient per month with darboepoetin alfa to treat anemia in dialysis patients.

Controversial issues in CKD clinical practice: position statement of the CKD-treatment working group of the Italian Society of Nephrology.

This position paper of the study group "Conservative treatment of Chronic Kidney Disease-CKD" of the Italian Society of Nephrology addresses major practical, unresolved, issues related to the conservative treatment of chronic renal disease. Specifically, controversial topics from everyday clinical nephrology practice which cannot find a clear, definitive answer in the current literature or in nephrology guidelines are discussed. The paper reports the point of view of the study group. Concise and practical advice is given on several common issues: renal biopsy in diabetes; dual blockade of the renin-angiotensin-aldosterone system (RAAS); management of iron deficiency; low protein diet; dietary salt intake; bicarbonate supplementation; treatment of obesity; the choice of conservative therapy vs. dialysis. For each topic synthetic statements, guideline-style, are reported.

Effects of efficiency and length of acetate-free biofiltration session on postdialysis solute rebound.

BACKGROUND: Postdialytic rebound (PDR) of plasma solutes is a relevant drawback of intermittent hemodialysis, but its pathophysiological process remains undefined. We assessed the independent effects of efficiency and length of dialytic session on PDR of urea, phosphate, and potassium. METHODS: Uremic patients were evaluated at the beginning and end of dialysis and after 180 minutes in 2 randomized crossover studies. In study 1, we compared the effect of standard versus higher efficiency acetate-free biofiltration (AFB) while maintaining the same duration of 4 hours. In study 2, we compared the effect of 3- versus 5-hour AFB sessions while maintaining similar efficiency. RESULTS: In study 1, greater Kt/V (1.49 +/- 0.20 versus 1.22 +/- 0.15; P < 0.0001) was coupled with significant increases in both absolute removal and PDR of urea and phosphate (PDR of urea, +45% versus +29%; PDR of phosphate, +79% versus +52%), but not of potassium. Similarly, in study 2, shortening the AFB session while maintaining similar absolute removal and Kt/V (1.28 +/- 0.09 versus 1.31 +/- 0.09) significantly increased PDR of urea and phosphate (PDR of urea, +32% versus +19%; PDR of phosphate, +63% versus +36%), but not of potassium. In both studies, greater PDRs of urea and phosphate were associated with estimated greater removal of these solutes per hour. CONCLUSION: The rate of removal of phosphate and urea is a critical determinant of their PDR; conversely, potassium is not influenced by removal rate, likely because of its marked cell compartmentalization.

Sleeping disorders in early chronic kidney disease.

Studies in patients on maintenance hemodialysis have disclosed a high prevalence of sleeping disorders, which have been linked to various factors including blood urea levels, creatinine levels, parathyroid hormone levels, anemia, systolic and diastolic blood pressure, quality of life, disease intrusiveness, and comorbidities. In contrast, few studies have been performed in patients with chronic kidney disease (CKD), who represent the target of the present study. A group of 52 CKD patients were enrolled after characterization of their renal function. Comorbidities were evaluated by means of the Charlson Comorbidity Index. Sleep disorders were evaluated by means of the Sleep Disorder Questionnaire (SDQ), a 26-item questionnaire providing a hierarchic classification for relevant insomnia, relevant hypersomnia, subclinical disorders, or absence of sleep complaints. Results indicate that, in the early stages of CKD, at a time the comorbidity index is low, sleep disorders are present in 80.7% of patients. This finding, which needs to be confirmed in a larger cohort of patients, indicates that sleep disorders affect the lives of CKD patients as soon a diagnosis of disease potentially progressing to end-stage renal disease was made.

Influence of the cyclic variation of hydration status on hemoglobin levels in hemodialysis patients.

BACKGROUND: Maintenance hemodialysis (HD) patients were studied to assess the effect on hemoglobin (Hb) concentration induced by the cyclic variation in hydration status. METHODS: Forty-nine HD patients were examined in three consecutive HD sessions in a 1-week treatment period. In a subgroup of 23 patients, Hb levels also were investigated during the long interdialytic interval. RESULTS: Hb levels at the end of the long interdialytic interval were significantly lower by 0.5 to 0.6 g/dL (5 to 6 g/L) than those at the end of short intervals. Among all pre-HD and post-HD Hb values, levels measured at the end of short intervals were closest to the mean Hb value of the week, derived from calculation of the area under the curve (12.0 +/- 0.2 g/dL [120 +/- 2 g/L]). Intradialytic Hb increments were different in the three sessions (+1.6 +/- 0.1 g/dL [+16 +/- 1 g/L] after the long interval, +1.1 +/- 0.1 g/dL [+11 +/- 1 g/L] and +1.1 +/- 0.1 g/dL [+11 +/- 1 g/L] after short intervals [P < 0.001] and proportionate to weight loss [-3.4 +/- 0.1, -2.7 +/- 0.1, and -2.6 +/- 0.1 kg, respectively; P < 0.001]). Hb level increment and weight loss correlated directly (r = 0.527; P < 0.0001); each 1 L of ultrafiltration (UF) led to an increase in Hb level of approximately 0.4 g/dL (4 g/L). Plasma refilling accounted for an approximately 45% decrement in the intradialytic increase in Hb level 2 hours post-HD. CONCLUSION: This study suggests that: (1) the end of the short interdialytic period is the most appropriate timing for anemia assessment, and (2) the remarkable hemodiluting effect of post-HD plasma refilling protects against excessive increments in Hb levels induced by UF.

Vascular access for hemodialysis: the impact on morbidity and mortality.

BACKGROUND: In chronic hemodialysis (HD), central venous catheter (CVC) use seems associated with an increased risk of death. This study, using registry data, evaluated the morbidity and mortality risk associated with the use of different permanent vascular access (VA) in a HD patient cohort. METHOD: We evaluated hospitalization and death rate in prevalent and incident HD patients recorded in the uremic registry of Campania (southern Italy) for 2001. Patients were divided into three groups: CVC, artero-venous graft (AVG) and artero-venous fistula (AVF). RESULTS: One hundred and eleven dialysis units in the Campania region (69%) provided data. A total of 2201 out of 3387 prevalent HD patients were included: 92 patients (4.2%) were on CVC, 24 patients (1.1%) were on AVG and 2085 patients (94.7%) were on AVF. In comparison with AVF, the CVC group had a greater prevalence of female gender, old age, diabetes, comorbidities, hypoalbuminemia, anemia, erythropoietin (EPO) resistance, and less frequent synthetic membrane use, but had a similar dialysis duration (hr/week). Similar data were collected in the 635 incident patients registered in 2001. During the study, in both prevalent and incident CVC patients, either hospitalization or death rates were enhanced; however, the difference in the relative risk (RR) of death disappeared after correction for age, gender, malnutrition, diabetes, hemoglobin, albumin and comorbidity. Among incident patients, survival analysis was performed in patients remaining on the same VA type throughout the follow-up period; while a similar survival between groups was demonstrated in the 1st year of follow-up, survival was worse in the CVC group during the 2nd year of follow-up; however, this difference also disappeared in the adjusted analysis. CONCLUSION: This cohort study demonstrates that in chronic dialysis patients CVC choice, with respect to AVF, is mainly associated with female gender, advanced age and worse clinical conditions at baseline, and a worst outcome in both prevalent and incident CVC patients compared to AVF patients. Hospitalization, mortality rate and RR of death increased significantly; however, differences disappeared after correction for comorbidity. Therefore, these data suggest that CVC use per se is not associated with increased mortality risks with respect to AVF.