Ketoanalogue Supplementation in Patients with Non-Dialysis Diabetic Kidney Disease: A Systematic Review and Meta-Analysis.

The effects of supplemental ketoanalogues (KA) in patients with diabetic kidney disease (DKD) are not well characterized. Several databases for peer-reviewed articles were systematically searched to identify studies reporting outcomes associated with the effects of a low-protein diet (LPD) or very-low protein diet (VLPD) in combination with supplemental KA in adults with DKD. Meta-analyses were conducted when feasible. Of 213 identified articles, 11 could be included in the systematic review. Meta-analyses for renal outcomes (4 studies examining glomerular filtration rate; 5 studies examining 24-h urinary protein excretion), metabolic outcomes (5 studies examining serum urea; 7 studies examining blood glucose), clinical outcomes (6 studies examining blood pressure; 4 studies examining hemoglobin), and nutritional outcomes (3 studies examining serum albumin; 4 studies examining body weight) were all in favor of KA use in DKD patients. Data from individual studies that examined other related parameters also tended to show favorable effects from KA-supplemented LPD/VLPD. The regimens were safe and well tolerated, with no evidence of adverse effects on nutritional status. In conclusion, LPD/VLPD supplemented with KA could be considered effective and safe for patients with non-dialysis dependent DKD. Larger studies are warranted to confirm these observations.

Current Management of Hyperkalemia in Non-Dialysis CKD: Longitudinal Study of Patients Receiving Stable Nephrology Care.

BACKGROUND: No study has explored the limitations of current long-term management of hyperkalemia (HK) in outpatient CKD clinics. METHODS: We evaluated the association between current therapeutic options and control of serum K (sK) during 12-month follow up in ND-CKD patients stratified in four groups by HK (sK ≥ 5.0 mEq/L) at baseline and month 12: Absent (no-no), Resolving (yes-no), New Onset (no-yes), Persistent (yes-yes). RESULTS: We studied 562 patients (age 66.2 ± 14.5 y; 61% males; eGFR 39.8 ± 21.8 mL/min/1.73 m2, RAASI 76.2%). HK was "absent" in 50.7%, "resolving" in 15.6%, "new onset" in 16.6%, and "persistent" in 17.1%. Twenty-four hour urinary measurements testified adherence to nutritional recommendations in the four groups at either visit. We detected increased prescription from baseline to month 12 of bicarbonate supplements (from 5.0 to 14.1%, p < 0.0001), K-binders (from 2.0 to 7.7%, p < 0.0001), and non-K sparing diuretics (from 34.3 to 41.5%, p < 0.001); these changes were consistent across groups. Similar results were obtained when using higher sK level (≥5.5 mEq/L) to stratify patients. Mixed-effects regression analysis showed that higher sK over time was associated with eGFR < 60, diabetes, lower serum bicarbonate, lower use of non-K sparing diuretics, bicarbonate supplementation, and K-binder use. Treatment-by-time interaction showed that sK decreased in HK patients given bicarbonate (p = 0.003) and K-binders (p = 0.005). CONCLUSIONS: This observational study discloses that one-third of ND-CKD patients under nephrology care remain with or develop HK during a 12-month period despite low K intake and increased use of sK-lowering drugs.

[Nutritional diet therapy in the management of the patient with Chronic Kidney Disease in advanced phase to delay the beginning and reduce the frequency of dialysis. An option also in the pre-emptive transplant program].

The Italian nephrology has a long tradition and experience in the field of dietetic-nutritional therapy (DNT), which is an important component in the conservative management of the patient suffering from a chronic kidney disease, which precedes and integrates the pharmacological therapies. The objectives of DNT include the maintenance of an optimal nutritional status, the prevention and / or correction of signs, symptoms and complications of chronic renal failure and, possibly, the delay in starting of dialysis. The DNT includes modulation of protein intake, adequacy of caloric intake, control of sodium and potassium intake, and reduction of phosphorus intake. For all dietary-nutritional therapies, and in particular those aimed at the patient with chronic renal failure, the problem of patient adherence to the dietetic-nutritional scheme is a key element for the success and safety of the DNT and it can be favored by an interdisciplinary and multi-professional approach of information, education, dietary prescription and follow-up. This consensus document, which defines twenty (20) essential points of the nutritional approach to patients with advanced chronic renal failure, has been written, discussed and shared by the Italian nephrologists together with representatives of dietitians (ANDID) and patients (ANED).

[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.

Safety and effectiveness of low-protein diet supplemented with ketoacids in diabetic patients with chronic kidney disease.

BACKGROUND: The impact of the low-protein diet on nutrition in CKD diabetics is uncertain. METHODS: The metabolic and nutritional effects of a low-protein (0.5-0.6 g/kg/d), normal-high energy (30-35 kcal/kg/d) diet supplemented with ketoacids (LPD-KA) were prospectively evaluated in CKD patients with (DM) and without (non-DM) diabetes mellitus. RESULTS: 197 patients on CKD stages 3-5 were enrolled. DM (n = 81) and non-DM (n = 116) were comparable for gender (Male 58 vs 55%), age (66 ± 9 vs 63 ± 18 years), renal function (eGFR 23 ± 13 vs 24 ± 13 mL/min). After 6-month, serum urea (DM: 131 ± 58 to 105 ± 49 mg/dl, p < 0.05; non-DM: 115 ± 52 to 88 ± 36, p < 0.05) and phosphate (DM: 4.5 ± 1.3 to 4.1 ± 1.2 mg/dl, p = 0.06; non-DM: 4.3 ± 1.0 to 3.7 ± 0.8, p < 0.05) declined. Fasting glucose decreased in DM (126 ± 52 to 103 ± 29 mg/dl, p < 0.05) without insulin dose increase. These effects were preserved after 3-year. Serum albumin did not change after 6 months (DM: 3.7 ± 0.6 to 3.8 ± 0.4 mg/dl; non-DM: 4.0 ± 0.6 to 4.0 ± 0.4) and in the long-term. Body weight (BW) declined after the diet start (DM: 68.9 ± 14.3 to 65.1 ± 12.1 kg, p < 0.05; non-DM: 66.6 ± 15.1 to 64.1 ± 15.1, p < 0.05) and was stable at 6 months and 3 years. Muscle strength at baseline was reduced in all patients and remained stable during the diet period. Changes of nutritional markers during the study were similar among groups and diabetes was not associated to any nutritional change at the multivariate analysis. As attain wasting, lower BMI (< 23 kg/m2) and albumin (< 3.8 g/dl) levels were present in 1/3 patients at start and along 3 years, cholesterol never dropped below the lower threshold (< 100 mg/dl) and poorer FM (< 10%) was less than 10% during the study in both groups. CONCLUSIONS: In diabetic CKD patients a low-protein diet supplemented with ketoacids improves uremia and diabetes, causes sudden decline of body weight which remains stable over time and has not a negative effect on wasting and muscle mass and fitness. In diabetic CKD patients the LPD-KA is safe and the nutritional impact is the same as in non-diabetics CKD.

Nutritional treatment of advanced CKD: twenty consensus statements.

The Italian nephrology has a long tradition and experience in the field of dietetic-nutritional therapy (DNT), which is an important component in the conservative management of the patient suffering from a chronic kidney disease, which precedes and integrates the pharmacological therapies. The objectives of DNT include the maintenance of an optimal nutritional status, the prevention and/or correction of signs, symptoms and complications of chronic renal failure and, possibly, the delay in starting of dialysis. The DNT includes modulation of protein intake, adequacy of caloric intake, control of sodium and potassium intake, and reduction of phosphorus intake. For all dietary-nutritional therapies, and in particular those aimed at the patient with chronic renal failure, the problem of patient adherence to the dietetic-nutritional scheme is a key element for the success and safety of the DNT and it can be favored by an interdisciplinary and multi-professional approach of information, education, dietary prescription and follow-up. This consensus document, which defines twenty essential points of the nutritional approach to patients with advanced chronic renal failure, has been written, discussed and shared by the Italian nephrologists together with representatives of dietitians (ANDID) and patients (ANED).

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.

"Dietaly": practical issues for the nutritional management of CKD patients in Italy.

Evidence exists that nutritional therapy induces favorable metabolic changes, prevents signs and symptoms of renal insufficiency, and is able to delay the need of dialysis. Currently, the main concern of the renal diets has turned from the efficacy to the feasibility in the daily clinical practice.Herewith we describe some different dietary approaches, developed in Italy in the last decades and applied in the actual clinical practice for the nutritional management of CKD patients.A step-wise approach or simplified dietary regimens are usually prescribed while taking into account not only the residual renal function and progression rate but also socio-economic, psychological and functional aspects.The application of the principles of the Mediterranean diet that covers the recommended daily allowances for nutrients and protein (0.8 g/Kg/day) exert a favorable effect at least in the early stages of CKD. Low protein (0.6 g/kg/day) regimens that include vegan diet and very low-protein (0.3-0.4 g/Kg/day) diet supplemented with essential amino acids and ketoacids, represent more opportunities that should be tailored on the single patient's needs.Rather than a structured dietary plan, a list of basic recommendations to improve compliance with a low-sodium diet in CKD may allow patients to reach the desired salt target in the daily eating.Another approach consists of low protein diets as part of an integrated menu, in which patients can choose the "diet" that best suits their preferences and clinical needs.Lastly, in order to allow efficacy and safety, the importance of monitoring and follow up of a proper nutritional treatment in CKD patients is emphasized.

A Delphi consensus panel on nutritional therapy in chronic kidney disease.

The conservative management of chronic kidney disease (CKD) includes nutritional therapy (NT) with the aim to reduce the intake of proteins, phosphorus, organic acids, sodium, and potassium, while ensuring adequate caloric intake. While there is evidence that NT may help to prevent and control metabolic alterations in CKD, the criteria for implementing a low-protein regimen in CKD are still debated. There is no final consensus on the composition of the diet, nor indications for specific patient settings or different stages of CKD. Also when and how to start dietary manipulation of different nutrients in CKD is not well defined. A group of Italian nephrologists participated, under the auspices of the Italian Society of Nephrology, in a Delphi exercise to explore the consensus on some open questions regarding the nutritional treatment in CKD in Italy, generating a consensus opinion for 23 statements on: (1) general principles of NT; (2) indications for and initiation of NT; (3) role of protein-free products; (4) NT safety; (5) integrated management of NT. This Delphi exercise shows that there is broad consensus regarding NT in CKD across a wide range of management areas. These clinician-led consensus statements provide a framework for appropriate guidance on NT in patients with CKD, and are intended as a guide in decision-making whenever possible.

Very low-protein diet plus ketoacids in chronic kidney disease and risk of death during end-stage renal disease: a historical cohort controlled study.

BACKGROUND: Very low-protein intake during chronic kidney disease (CKD) improves metabolic disorders and may delay dialysis start without compromising nutritional status, but concerns have been raised on a possible negative effect on survival during dialysis. This study aimed at evaluating whether a very low-protein diet during CKD is associated with a greater risk of death while on dialysis treatment. METHODS: This is an historical, cohort, controlled study, enrolling patients at dialysis start previously treated in a tertiary nephrology clinic with a very low-protein diet supplemented with amino acids and ketoacids (s-VLPD group, n = 184) or without s-VLPD [tertiary nephrology care (TNC) group, n = 334] and unselected patients [control (CON) group, n = 9.092]. The major outcome was survival rate during end-stage renal disease associated to s-VLPD treatment during CKD. The propensity score methods and Cox regression model were used to match groups at the start of dialysis to perform survival analysis and estimate adjusted hazard ratio (HR). RESULTS: In s-VLPD, TNC and CON groups, average age was 67.5, 66.0 and 66.3 years, respectively (P = 0.521) and male prevalence was 55, 55 and 62%, respectively (P = 0.004). Diabetes prevalence differed in the three groups (P < 0.001), being 18, 17 and 31% in s-VLPD, CON and TNC, respectively. A different prevalence of cardiovascular (CV) disease was found (P < 0.001), being similar in TNC and CON (31 and 25%) and higher in s-VLPD (41%). Median follow-up during renal replacement therapy (RRT) was 36, 32 and 36 months in the three groups. Adjusted HR estimated on matched propensity patients was 0.59 (0.45-0.78) for s-VLPD versus CON. Subgroup analysis showed a lower mortality risk in s-VLPD versus matched-CON in younger patients (<70 years) and those without CV disease. No significant difference in HRs was found between s-VLPD and TNC. CONCLUSION: s-VLPD during CKD does not increase mortality in the subsequent RRT period.

Do ketoanalogues still have a role in delaying dialysis initiation in CKD predialysis patients?

Early versus later start of dialysis is still a matter of debate. Low-protein diets have been used for many decades to delay dialysis initiation. Protein-restricted diets (0.3-0.6 g protein/kg/day) supplemented with essential amino acids and ketoanalogues (sVLPD) can be offered, in association with pharmacological treatment, to motivated stage 4-5 chronic kidney disease (CKD) patients not having severe comorbid conditions; they probably represent 30-40% of the concerned population. A satisfactory adherence to such dietary prescription is observed in approximately 50% of the patients. While the results of the studies on the effects of this diet on the rate of progression of renal failure remain inconclusive, they are highly significant when initiation of dialysis is the primary outcome. The correction of uremic symptoms allows for initiation of dialysis treatment at a level of residual renal function lower than that usually recommended. Most of the CKD-associated complications of cardiovascular and metabolic origin, which hamper both lifespan and quality of life, are positively influenced by the diet. Lastly, with regular monitoring jointly assumed by physicians and dietitians, nutritional status is well preserved as confirmed by a very low mortality rate and by the absence of detrimental effect on the long-term outcome of patients once renal replacement therapy is initiated. On account of its feasibility, efficacy and safety, sVLPD deserves a place in the management of selected patients to safely delay the time needed for dialysis.

Low-protein diet or nutritional therapy in chronic kidney disease?

The use of a low-protein diet in treating chronic kidney disease dates back many decades. Initially, the low intake of proteins was used to reduce uremic symptoms. Thereafter, the hope of significantly slowing and even halting the progression of renal failure toward dialysis grew among nephrologists. This proved not to be effective and the low-protein diet was largely abandoned. This review focuses on the reasons why a low-protein diet, and mainly comprehensive nutritional therapy, should still be considered a cornerstone in the treatment of chronic renal failure.

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.

Protein-restricted diets plus keto/amino acids--a valid therapeutic approach for chronic kidney disease patients.

Chronic kidney disease (CKD) is increasingly common, and there is an increasing awareness that every strategy should be used to avoid complications of CKD. Restriction of dietary protein intake has been a relevant part of the management of CKD for more than 100 years, but even today, the principal goal of protein-restricted regimens is to decrease the accumulation of nitrogen waste products, hydrogen ions, phosphates, and inorganic ions while maintaining an adequate nutritional status to avoid secondary problems such as metabolic acidosis, bone disease, and insulin resistance, as well as proteinuria and deterioration of renal function. This supplement focuses on recent experimental and clinical findings related to an optimized dietary management of predialysis, dialysis, and transplanted patients as an important aspect of patient care. Nutritional treatment strategies are linked toward ameliorating metabolic and endocrine disturbances, improving/maintaining nutritional status, as well as delaying the renal replacement initiation and improving outcomes in CKD patients. A final consensus states that dietary manipulations should be considered as one of the main approaches in the management program of CKD patients and that a reasonable number of patients with moderate or severe CKD benefit from dietary protein/phosphorus restriction.

Stability of target hemoglobin levels during the first year of epoetin treatment in patients with chronic kidney disease.

BACKGROUND AND OBJECTIVES: Instability of hemoglobin levels during epoetin therapy is a new problem in hemodialysis. We evaluated extent and correlates of time in target, that is, the time spent with hemoglobin > or = 11 g/dl during the first year of epoetin and its association with renal survival. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data were collected in 917 visits for 12.0 mo in 119 patients with chronic kidney disease; thereafter, patients started renal survival analysis for 10.1 mo. At baseline, hemoglobin was 10.0 +/- 0.8 g/dl and GFR was 22.1 +/- 14.2 ml/min per 1.73 m2. RESULTS: Hemoglobin target, reached in 1.5 mo, was steadily maintained in only 24% of patients. Time in target was not merely due to differences in time to target; after first achievement of target, in fact, a reduction of hemoglobin < 11 g/dl occurred in 51% of patients. At multivariate analysis, male gender, basal GFR and hemoglobin levels, first epoetin dose, and iron supplementation were directly associated with length of time in target. A lower risk for renal death (dialysis n = 53; death n = 8) was detected in the higher tertile of time in target (11.3 mo) versus lower tertile (3.2 mo). This difference persisted at Cox analysis after adjustment for age, gender, GFR, BP, and proteinuria. CONCLUSIONS: In chronic kidney disease, time in target during the first year of epoetin therapy is frequently short depending not only on time to target but also on post-target hemoglobin reductions, correlates with male gender, timing, and intensity of initial therapy and is coupled with better renal survival.

Long-term L-carnitine administration reduces erythropoietin resistance in chronic hemodialysis patients with thalassemia minor.

BACKGROUND AND AIM: Both thalassemia and carnitine deficiency represent independent causes of erythropoietin resistance, and thus anemia, in uremic patients. We evaluated the unknown long-term effects of L-carnitine administration in ß-thalassemic on chronic hemodialysis. METHODS: We studied twelve subjects (M = 8; F = 4) affected by ß-thalassemia minor (ß-thal; HbA2 level = 6.6 ± 0.6%) and forty non-thalassemic subjects (M = 24; F = 16) as controls (C), on chronic hemodialysis treatment. Patients and controls were at target hemoglobin levels (11-12g/dl) prior to the study and underwent to i.v. L-carnitine administration for a one year period-time. RESULTS: Groups were comparable for age, gender, serum levels of hemoglobin (Hb), iron, ferritine, PTH and aluminum, transferrin saturation, and dialysis modalities. During the study both groups showed significant Hb increase and erythropoietin (EPO) decrease; as a difference, such changes emerged at the 3rd month in C but at the 8th month in ß-thal. At start, during the dialysis session the erythrocyte MCV reduced in C but not in ß-thal (65.3 ± 3.2 to 65.5 ± 3.2 fl; NS); along carnitine administration period, however, MCV during dialysis decreased also in ß-thal, starting since the 9th month of treatment. CONCLUSION: This study provides evidence of the lowering of EPO resistance in ß-thalassemia patients on hemodialysis due to long-term carnitine administration. Thus, prolonged carnitine supplementation should be suggested to patients on dialysis affected by ß-thalassemia with poorly responsive anemia, or requiring large doses of erythropoietin.

Postdialytic rebound of serum phosphorus: pathogenetic and clinical insights.

To gain insights into postdialytic rebound of serum phosphate (PDR-P), serum phosphate (P), calcium (Ca), and parathyroid hormone (PTH), levels were compared from the end of treatment (T0) to the subsequent 30 to 120 min and up to 68 hr in uremic patients who underwent with crossover modality a single session of two dialytic treatments characterized by different convective removal: standard hemodialysis (HD) and hemodiafiltration (HDF). In HDF, versus HD, P removal was greater (1171 +/- 90 versus 814 +/- 79 mg; P < 0.05) in the presence of similar predialytic P levels (6.0 +/- 0.2 and 5.9 +/- 0.4 mg/dl) and Kt/V (1.35 +/- 0.06 and 1.34 +/- 0.05); however, the serum P values at T0 did not differ (3.0 +/- 0.2 versus 3.3 +/- 0.2 mg/dl). In HDF, PDR-P was more rapid (30 min versus 90 min) and of a greater extent (at T120: +69 +/- 6% versus +31 +/- 4%; P < 0.0001). The higher P levels were maintained throughout the interdialytic period. Ca x P and PTH changed in parallel. Thereafter, patients were randomized to receive either HD or HDF for 3 mo. During this period, in the presence of similar Kt/V, protein intake, and dose of phospate binder, predialytic serum P levels diminished in HDF (from 5.8 +/- 0.2 to 4.4 +/- 0.3 mg/dl; P < 0.05), but they remained unchanged in HD. A similar pattern of changes was detected in Ca x P. Therefore, PDR-P is likely dependent on the mobilization of phosphate from a deep compartment induced by the intradialytic removal of this solute. Enhancement of convective removal acutely amplifies the entity of the phenomenon but allows a better control of Ca-P homeostasis in the medium term.