Nutritional Treatment as a Synergic Intervention to Pharmacological Therapy in CKD Patients.

Nutritional and pharmacological therapies represent the basis for non-dialysis management of CKD patients. Both kinds of treatments have specific and unchangeable features and, in certain cases, they also have a synergic action. For instance, dietary sodium restriction enhances the anti-proteinuric and anti-hypertensive effects of RAAS inhibitors, low protein intake reduces insulin resistance and enhances responsiveness to epoetin therapy, and phosphate restriction cooperates with phosphate binders to reduce the net phosphate intake and its consequences on mineral metabolism. It can also be speculated that a reduction in either protein or salt intake can potentially amplify the anti-proteinuric and reno-protective effects of SGLT2 inhibitors. Therefore, the synergic use of nutritional therapy and medications optimizes CKD treatment. Quality of care management is improved and becomes more effective when compared to either treatment alone, with lower costs and fewer risks of unwanted side effects. This narrative review summarizes the established evidence of the synergistic action carried out by the combination of nutritional and pharmacological treatments, underlying how they are not alternative but complementary in CKD patient care.

Vitamin D and Calcium Supplementation and Urolithiasis: A Controversial and Multifaceted Relationship.

Patients with urolithiasis, and particularly those with hypercalciuria, frequently have a marked reduction of bone mineral content up to the levels of osteoporosis, with a significant increase in bone fracture risk. For these reasons, the indication to prescribe vitamin D and/or calcium supplementations is very frequent in such patients. On the other hand, both calcium supplementation, and even more vitamin D therapy, can worsen the risk of developing urolithiasis by increasing calcium, phosphate, and oxalate urinary excretion. Despite the clinical and practical relevance of this issue, the evidence on this topic is scarce and contradictory. Therefore, some concerns exist about how and whether to prescribe such supplements to a patient with a history of kidney stones. In this narrative review, we resume some pivotal pathophysiological concepts strictly related to the dealt topic, and we draw some considerations and personal opinions on the pros and cons of such prescriptions. Finally, we share with the reader our pragmatic algorithm for handling the urolithiasis risk in patients who have strong indications to be prescribed vitamin D and calcium supplementations.

Kidney Stone Prevention: Is There a Role for Complementary and Alternative Medicine?

Complementary and alternative medicine (CAM) is often implemented in kidney stone patients. It consists of preparations including different ingredients, such as herbs, probiotics, and vitamins, often together with alkali, that are classified within the dietary supplementation category. The majority of dietary supplements claiming to treat or prevent kidney stones contain ingredients with conflicting or no scientific evidence to support their claims. Clinicians should advise stone formers that the effects of most supplements are unknown or unstudied in humans and that the absence of evidence does not imply absence of potential harm. Unfortunately, the CAM preparation consists of a mix of different molecules, often including alkali, with different potential mechanisms of action and, even when favorable results are reported, the role of the single molecules cannot be assessed. Despite all these concerns, CAM products remain quite popular among kidney stone patients. The scarce knowledge in this field prevents one from recommending CAM products in daily clinical practice; only a weak suggestion for their use in kidney stone patients may be reasonable.

Interactions between Food and Drugs, and Nutritional Status in Renal Patients: A Narrative Review.

Drugs and food interact mutually: drugs may affect the nutritional status of the body, acting on senses, appetite, resting energy expenditure, and food intake; conversely, food or one of its components may affect bioavailability and half-life, circulating plasma concentrations of drugs resulting in an increased risk of toxicity and its adverse effects, or therapeutic failure. Therefore, the knowledge of these possible interactions is fundamental for the implementation of a nutritional treatment in the presence of a pharmacological therapy. This is the case of chronic kidney disease (CKD), for which the medication burden could be a problem, and nutritional therapy plays an important role in the patient's treatment. The aim of this paper was to review the interactions that take place between drugs and foods that can potentially be used in renal patients, and the changes in nutritional status induced by drugs. A proper definition of the amount of food/nutrient intake, an adequate definition of the timing of meal consumption, and a proper adjustment of the drug dosing schedule may avoid these interactions, safeguarding the quality of life of the patients and guaranteeing the effectiveness of drug therapy. Hence, a close collaboration between the nephrologist, the renal dietitian, and the patient is crucial. Dietitians should consider that food may interact with drugs and that drugs may affect nutritional status, in order to provide the patient with proper dietary suggestions, and to allow the maximum effectiveness and safety of drug therapy, while preserving/correcting the nutritional status.

Calcifediol supplementation in adults on hemodialysis: a randomized controlled trial.

BACKGROUND: Vitamin D deficiency is associated with increased risks of mortality in people with chronic kidney disease. The benefits and harm of vitamin D supplementation on cardiovascular outcomes and mortality are unknown. We aimed to assess the effectiveness of calcifediol in reducing mortality in patients with vitamin D insufficiency on hemodialysis compared to no additional therapy. METHODS: A phase III, multicenter, randomized, open-label trial was conducted including 284 adults with vitamin D insufficiency undergoing hemodialysis who were randomly assigned to receive oral calcifediol or standard care for 24 months. RESULTS: Two hundred eighty-four participants were enrolled (143 assigned to the calcifediol group and 141 to the no additional therapy group). The primary outcome (mortality) occurred in 34 and 31 participants in the calcifediol and control group, respectively [hazard ratio (HR) 1.03; 95% confidence interval (CI) 0.63-1.67]. Calcifediol had no detectable effects on cardiovascular death (HR 1.06; 95% CI 0.41-2.74), non-cardiovascular death (HR 1.13; 95% CI 0.62-2.04), nonfatal myocardial infarction (HR 0.20; 95% CI 0.02-1.67) or nonfatal stroke (HR could not be estimated). The incidence of hypercalcemia and hyperphosphatemia was similar between groups. None of the participants underwent parathyroidectomy. CONCLUSIONS: In adults treated with hemodialysis and who had vitamin D insufficiency, calcifediol supplementation for 24 months had inconclusive effects on mortality and cardiovascular outcomes. TRIAL REGISTRATION NUMBER: NCT01457001.

Protection of Residual Renal Function and Nutritional Treatment: First Step Strategy for Reduction of Uremic Toxins in End-Stage Kidney Disease Patients.

The retention of uremic toxins and their pathological effects occurs in the advanced phases of chronic kidney disease (CKD), mainly in stage 5, when the implementation of conventional thrice-weekly hemodialysis is the prevalent and life-saving treatment. However, the start of hemodialysis is associated with both an acceleration of the loss of residual kidney function (RKF) and the shift to an increased intake of proteins, which are precursors of uremic toxins. In this phase, hemodialysis treatment is the only way to remove toxins from the body, but it can be largely inefficient in the case of high molecular weight and/or protein-bound molecules. Instead, even very low levels of RKF are crucial for uremic toxins excretion, which in most cases are protein-derived waste products generated by the intestinal microbiota. Protection of RKF can be obtained even in patients with end-stage kidney disease (ESKD) by a gradual and soft shift to kidney replacement therapy (KRT), for example by combining a once-a-week hemodialysis program with a low or very low-protein diet on the extra-dialysis days. This approach could represent a tailored strategy aimed at limiting the retention of both inorganic and organic toxins. In this paper, we discuss the combination of upstream (i.e., reduced production) and downstream (i.e., increased removal) strategies to reduce the concentration of uremic toxins in patients with ESKD during the transition phase from pure conservative management to full hemodialysis treatment.

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.

Medical Nutritional Therapy for Patients with Chronic Kidney Disease not on Dialysis: The Low Protein Diet as a Medication.

The 2020 Kidney Disease Outcome Quality Initiative (KDOQI) Clinical Practice Guideline for Nutrition in chronic kidney disease (CKD) recommends protein restriction to patients affected by CKD in stages 3 to 5 (not on dialysis), provided that they are metabolically stable, with the goal to delay kidney failure (graded as evidence level 1A) and improve quality of life (graded as evidence level 2C). Despite these strong statements, low protein diets (LPDs) are not prescribed by many nephrologists worldwide. In this review, we challenge the view of protein restriction as an "option" in the management of patients with CKD, and defend it as a core element of care. We argue that LPDs need to be tailored and patient-centered to ensure adherence, efficacy, and safety. Nephrologists, aligned with renal dietitians, may approach the implementation of LPDs similarly to a drug prescription, considering its indications, contra-indications, mechanism of action, dosages, unwanted side effects, and special warnings. Following this framework, we discuss herein the benefits and potential harms of LPDs as a cornerstone in CKD management.

A diagnostic-therapeutic pathway for patients with kidney stone disease: 2020 update / Percorso diagnostico-terapeutico per il paziente con calcolosi renale: update 2020

The natural history of urinary kidney stone disease includes the risk of relapses and can be associated with the risk of chronic kidney disease, bone and cardiovascular disease. For this reason, a wide clinical-metabolic assessment of the kidney stone patient is of great importance since the first presentation of the stone, to set an appropriate preventive treatment. The proposed diagnostic-therapeutic pathway includes a careful medical history, in order to highlight a secondary kidney stone disease and the main risk factors for kidney stones, chronic renal disease, or cardiovascular and bone disease; a metabolic evaluation on multiple levels, according to the severity of the disease, and the presence or absence of risk factors, and appropriate instrumental investigations. Thus, the information collected makes it possible to set a preventive treatment consisting of general rules and, if necessary, specific pharmacological or nutritional interventions. This paper has been prepared by the Italian Multidisciplinary Study Group for Kidney Stone Disease, and it is addressed to the several professional figures involved in the management of patients suffering from nephrolithiasis, from the emergency doctor to the general practitioner, urologist, nephrologist, radiologist, and dietician. A diagnostic-therapeutic pathway for patients with kidney stone disease was first published on this Journal in 2010. The present contribution aims at amending and updating the article published exactly ten years ago, to serve as an easy-to-use reference and to guide good clinical practice in this field.

[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).

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).

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.

Low vitamin K1 intake in haemodialysis patients.

BACKGROUND & AIMS: Vitamin K acts as a coenzyme in the γ-carboxylation of vitamin K-dependent proteins, including coagulation factors, osteocalcin, matrix Gla protein (MGP), and the growth arrest-specific 6 (GAS6) protein. Osteocalcin is a key factor for bone matrix formation. MGP is a local inhibitor of soft tissue calcification. GAS6 activity prevents the apoptosis of vascular smooth muscle cells. Few data on vitamin K intake in chronic kidney disease patients and no data in patients on a Mediterranean diet are available. In the present study, we evaluate the dietary intake of vitamin K1 in a cohort of patients undergoing haemodialysis. METHODS: In this multi-centre controlled observational study, data were collected from 91 patients aged >18 years on dialysis treatment for at least 12 months and from 85 age-matched control subjects with normal renal function. Participants completed a food journal of seven consecutive days for the estimation of dietary intakes of macro- and micro-nutrients (minerals and vitamins). RESULTS: Compared to controls, dialysis patients had a significant lower total energy intake, along with a lower dietary intake of proteins, fats, carbohydrates, fibres, and of all the examined minerals (Ca, P, Fe, Na, K, Zn, Cu, and Mg). With the exception of vitamin B12, vitamins intake followed a similar pattern, with a lower intake in vitamin A, B1, B2, C, D, E, folates, K1 and PP. These finding were confirmed also when normalized for total energy intake or for body weight. In respect to the adequate intakes recommended in the literature, the prevalence of a deficient vitamin K intake was very high (70-90%) and roughly double than in controls. Multivariate logistic model identified vitamin A and iron intake as predictors of vitamin K deficiency. CONCLUSIONS: Haemodialysis patients had a significantly low intake in vitamin K1, which could contribute to increase the risk of bone fractures and vascular calcifications. Since the deficiency of vitamin K intake seems to be remarkable, dietary counselling to HD patients should also address the adequacy of vitamin K dietary intake and bioavailability. Whether diets with higher amounts of vitamin K1 or vitamin K supplementation can improve clinical outcomes in dialysis patients remains to be demonstrated.

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.

Keto-analogues and essential aminoacids and other supplements in the conservative management of chronic kidney disease.

The manipulation of dietary protein intake is the mainstay of nutritional treatment of patients affected by chronic renal insufficiency, with the aim to reduce the burden of uremic toxins in order to decrease uremic toxicity and delay the need for dialysis. Consensus exists regarding the benefit of progressive protein restriction towards delaying the progression of renal failure and the need for dialysis, provided adequate energy supply. Although pivotal, protein restriction is only one aspect of the dietary management of chronic kidney disease (CKD) patients. Additional features, though strictly related to proteins, include modifications in sodium, phosphorus and energy intake, as well as in the source (animal or plant derived) of protein and lipids. In addition, supplements play an important role as a means to obtain both beneficial effects and nutritional safety in the renal patient. Essential amino acid and ketoacid mixtures are the most utilized types of supplementation in CKD patients on restricted protein regimens. The essential amino acids plus ketoacid supplementation is mandatory in conjunction with a very low-protein diet in order to assure an adequate essential amino acid supply. It is needed to safely implement a very low protein (and phosphorus) intake, so as to obtain the beneficial effect of a severe protein restriction while preventing malnutrition. Protein-free products and energy supplements are also crucial for the prevention of protein-energy wasting in CKD patients. Calcium, iron, native vitamin D and omega-3 PUFAs are other types of supplementation of potential benefits in the CKD patients on conservative management.

Low protein diets in patients with chronic kidney disease: a bridge between mainstream and complementary-alternative medicines?

Dietary therapy represents an important tool in the management of chronic kidney disease (CKD), mainly through a balanced reduction of protein intake aimed at giving the remnant nephrons in damaged kidneys a "functional rest". While dialysis, transplantation, and pharmacological therapies are usually seen as "high tech" medicine, non pharmacological interventions, including diets, are frequently considered lifestyle-complementary treatments. Diet is one of the oldest CKD treatments, and it is usually considered a part of "mainstream" management. In this narrative review we discuss how the lessons of complementary alternative medicines (CAMs) can be useful for the implementation and study of low-protein diets in CKD. While high tech medicine is mainly prescriptive, prescribing a "good" life-style change is usually not enough and comprehensive counselling is required; the empathic educational approach, on which CAMs are mainly, though not exclusively based, may support a successful personalized nutritional intervention.There is no gold-standard, low-protein diet for all CKD patients: from among a relatively vast choice, the best compliance is probably obtained by personalization. This approach interferes with the traditional RCT-based analyses which are grounded upon an assumption of equal preference of treatments (ideally blinded). Whole system approaches and narrative medicine, that are widely used in the study of CAMs, may offer ways to integrate EBM and personalised medicine in the search for innovative solutions respecting individualization, but gaining sound data, such as with partially-randomised patient preference trials.

"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.

Vitamin D in patients with chronic kidney disease: a position statement of the Working Group "Trace Elements and Mineral Metabolism" of the Italian Society of Nephrology.

In the late 1970s, calcitriol was introduced into clinical practice for the management of secondary renal hyperparathyroidism in chronic kidney disease (CKD). Since then, the use of calcifediol or other native forms of vitamin D was largely ignored until the publication of the 2009 Kidney Disease Improving Global Outcomes (KDIGO) recommendations. The guidelines suggested that measurement of circulating levels of 25(OH)D (calcifediol) and its supplementation were to be performed on the same basis as for the general population. This indication was based on the fact that the precursors of active vitamin D had provided to CKD patients considerable benefits in survival, mainly due to their pleiotropic effects on the cardiovascular system. However, despite the long-term use of various classes of vitamin D in CKD, a clear definition is still lacking concerning the most appropriate time for initiation of therapy, the best compound to prescribe (active metabolites or analogs), the proper dosage, and the most suitable duration of therapy. The aim of this position statement is to provide and critically appraise the current plentiful evidence on vitamin D in different clinical settings related to CKD, particularly focusing on outcomes, monitoring and treatment-associated risks. However, it should be taken in account that position statements are meant to provide guidance; therefore, they are not to be considered prescriptive for all patients and, importantly, they cannot replace the judgment of clinicians.