Nutrition Prescription to Achieve Positive Outcomes in Chronic Kidney Disease: A Systematic Review

In Chronic Kidney Disease (CKD), management of diet is important in prevention of disease progression and symptom management, however evidence on nutrition prescription is limited. Recent international CKD guidelines and literature was reviewed to address the following question “What is the appropriate nutrition prescription to achieve positive outcomes in adult patients with chronic kidney disease?” Databases included in the search were Medline and CINAHL using EBSCOhost search engine, Embase and the Cochrane Database of Systematic Reviews published from 2000 to 2009. International guidelines pertaining to nutrition prescription in CKD were also reviewed from 2000 to 2013. Three hundred and eleven papers and eight guidelines were reviewed by three reviewers. Evidence was graded as per the National Health and Medical Research Council of Australia criteria. The evidence from thirty six papers was tabulated under the following headings: protein, weight loss, enteral support, vitamin D, sodium, fat, fibre, oral nutrition supplements, nutrition counselling, including protein and phosphate, nutrients in peritoneal dialysis solution and intradialytic parenteral nutrition, and was compared to international guidelines. While more evidence based studies are warranted, the customary nutrition prescription remains satisfactory with the exception of Vitamin D and phosphate. In these two areas, additional research is urgently needed given the potential of adverse outcomes for the CKD patient.


Introduction
Chronic kidney disease (CKD) is a prevalent chronic condition and the incidence of End-Stage Renal Disease (ESRD) is expected to continue to climb in the coming decade [1]. CKD has significant health and lifestyle implications for those affected, including increased risk of cardiovascular disease [2], malnutrition [3] and is a public health burden particularly in those patients who progress to end stage renal failure (or ESRD) and require kidney replacement therapy (dialysis) or transplantation [4]. The health cost burden is disproportionate to the prevalence with 5% of the health budget in the United States being consumed by 1% of the population requiring renal replacement [5]. CKD poses a significant public health issue and optimal treatment and management of this disease is indicated [6].
In CKD, nutrition and diet play an important role both in prevention of disease progression and in symptom management. The Dietitians Association Australia's (DAA) Evidence based guidelines for the nutritional management of Chronic Kidney Disease (CKD) stages 1-5 [7] provide statements of evidence against clinical questions in line with the Nutrition Care Process (NCP) [8]. The guidelines are designed to be employed by dietitians in clinical practice as the basis of nutritional management of patients with CKD and are based on the nutrition component of several recognized international guidelines. The evidence used, dates from published guidelines to 2005, and some of these guidelines varied in the method of rating evidence. Since 2006, a number of new international guidelines have been published or revised using an agreed grading system [9] and together with new literature these need to be reflected in dietetic practice, specifically the nutrition intervention or prescription employed by clinical dietitians. This article reviews the evidence presented in recent international guidelines and literature that address the clinical question "What is the appropriate nutrition prescription to achieve positive outcomes in adult patients with chronic kidney disease?"

Methods
A systematic literature review of studies was designed to answer the clinical question. Databases included in the search were Medline and CINAHL using EBSCOhost search engine, Embase and the Cochrane Database of Systematic Reviews. MeSH terms for Medline and CINAHL were "kidney failure, chronic" AND "diet therapy" OR "nutrition intervention" and for Cochrane "kidney failure, chronic". M-tree headings in EMBASE were "chronic kidney disease" AND "diet therapy" and further derivatives of diet therapy such as protein, phosphate. Results were limited to those published from 2000 to 2009, papers reported in the English language and studies involving adult humans. Articles were excluded if they were not reported in full or if they were presented as tutorials, editorials, news, letters or comments. Articles were also excluded if they were included within any systematic reviews or meta-analyses retrieved. The research aims and outcome measures reported on were used to assess applicability of the studies. Reference lists of retrieved papers were also reviewed and studies included where relevant. Nutritional management of acute renal disease, transplantation and nephrotic syndrome were not included in this review.
In addition to this systematic literature search, hand searches of recognised international guidelines published since 2006 and pertaining to nutrition were conducted. These included: • European Renal Association/European Dietitian and Transplant Nurses Association ERA/EDTNA European Best Practice Guideline on Nutrition, 2007 [10], • Guidelines for the management of chronic kidney disease by the Canadian Medical Association, 2008 [11], • Diagnosis and management of chronic kidney disease: A national clinical guideline by the Scottish Intercollegiate Guidelines Network, 2008 [12], • National Institute for Health and Clinical Excellence in the United Kingdom Chronic kidney disease: national clinical guideline for early identification and management in adults in primary and secondary care, 2008 [13], • Caring for Australians with Renal Impairment (also known as CARI guidelines), 2013 [14][15][16], • Kidney Disease: Improving Global Outcomes (KDIGO): Clinical practice guideline for the evaluation and management of Chronic Kidney Disease, 2012 [5,17], • American Dietetic Association Chronic Kidney Disease Evidence-Based Nutrition Practice Guideline, 2010 [18], • British Dietetic Association Evidence-based guidelines for the protein requirements of adults undergoing maintenance haemodialysis or peritoneal dialysis, 2013 [19].
Papers obtained through the literature search were categorized according to the aspect of nutrition prescription addressed in the research question, for example protein, phosphate, fat, vitamin D, oral nutrition support. The strength of evidence of these papers was then assessed by three independent reviewers and categorized according to recommendations from the National Health and Medical Research Council (NHMRC) evidence hierarchy [20]. The NHMRC grades the level of evidence from I, a systematic review of all relevant randomized controlled trials to IV evidence obtained from case series. An overall grading of evidence is provided by NHMRC whereby level of evidence, consistency across studies, clinical impact and generalisability is also assessed from A, where the body of evidence can be trusted to guide practice to D were the body of evidence is weak and recommendations should be applied with caution. This system has been recognized as equivalent to the Kidney Disease Improving Global Outcomes (KDIGO) criteria [21].
In a similar fashion, evidence statements from international guidelines were then grouped according to aspects of the nutrition prescription addressed with their corresponding levels of evidence. The grading systems and definitions for levels of evidence and strength of practice recommendations used by the various institutions guidelines are compared in Appendix 1. Statements from the recent guidelines were then listed against each of the nutrition parameters defined above.

Results
Database searches using the search terms described above yielded 325 individual papers. Following grading of the evidence quality and exclusion of papers of lower level evidence, 34 papers remained for inclusion in this review. Of these, five papers were systematic reviews, fourteen were randomized controlled trials, nine were prospective cohort or comparative studies with controls and six were interrupted time series or case series. Table 1 compares the systematic reviews of protein intake both in those with and without diabetes, weight management and enteral support on renal outcomes. Table 2 compares the evidence for the remaining studies according to nutrient parameters, such as protein, vitamin D, fats, sodium, fibre; or intervention, such as oral nutrition support, dietetic counseling, including phosphate, nutrients in peritoneal solution, intradialytic parenteral nutrition or percutaneous endoscopic gastrostomy feeding. Table 3 outlines statements from international guidelines against each of these parameters.
In Table 1, the systematic reviews of protein intake [22][23][24] indicate that in pre-dialysis, protein should be reduced to 0.6 g/kg body weight/day or equivalent if using keto-analogues and diet combined. Reduction to this level resulted in a 32% reduction in renal deaths (RR 0.68, 95% CI 0.55 to 0.8, p = 0.0002). For those with diabetes, both Types 1 and 2, reducing protein is associated with moderate non-significant slowing in progression of diabetic nephropathy resulting in renal failure [24]. Protein intakes <0.8 g/kg body weight/day showed no compromise in anthropometry or biochemical indicators [23]. One systematic review was retrieved that examined weight loss interventions in CKD [25]. This review analysed 13 studies, two RCTs and 11 observational studies and found that only modest evidence exists to support the role of intentional weight loss on slowing CKD progression in mild-moderate CKD. A systematic review of enteral feeding in maintenance HD included 5 RCT and 13 non-RCT and concluded that enteral feeding, including oral nutrition support vs. routine care increased protein and energy intake and improved serum albumin by 0.23 g/dL but there was insufficient data to examine the effect on clinical outcomes [26]. Table 2 outlines individual papers. There is evidence that for those patients with ESRD either Stage 4 or 5, a very low protein diet (0.3 g/kg/day) with added keto-analogues and adequate energy (35 kcal/day) can delay dialysis with no adverse effect on mortality [27]. Elderly patients with glomerular filtration rate (GFR) between 5 and 7 mL/min on a similar diet, when compared to those on dialysis, had better outcomes with an improved survival of 3.6% (95% CI, −17 to +10; p = 0.002) [28]. In dialysis, protein intakes of >1.2 g/kg/day resulted in significant increases in body mass index (BMI, kg/m 2 ) of 0.97 (p < 0.001) [29]. The association between protein intake and all-cause mortality and cardiovascular mortality amongst a large retrospective cohort, found that survival was best at protein intakes between 1.0 and 1.4 g/kg/day and that intakes <0.8 g/kg/day and >1.4 g/kg/day were associated with increased mortality. However, this effect was diminished significantly when adjusted for malnutrition inflammation complex syndrome [30].

Fats-experimental studies
Beavers [37] RCT (double blind, permuted- Over the counter omega-3 fatty acids at 6 g per day have no effect on total homocysteine compared to a placebo. II     Energy-dialysis

KDOQI (2000) [60], BDA (2013) [19]
The recommended daily energy intake for maintenance haemodialysis or chronic peritoneal dialysis patients is 35 kcal/kg ideal body weight/day (146 kJ/kg IBW/day) for those who are less than 60 years of age and 30 to 35 kcal/kg body weight/day (126-146 kJ/kg IBW/day) for individuals 60 years or older. C Protein-pre-dialysis

CARI (2013) [15]
We recommend for patients with early CKD consume a normal protein diet of 0.75-1.0 g/kg IBW/day with adequate energy. This is the Recommended Dietary Intake for the general population. 1C A low protein diet (≤0.6 g/kg IBW/day) to slow down CKD progression is not recommended because of the risk of malnutrition. 1C We suggest that patients with excess protein intakes reduce their intakes to the RDI levels as a high protein diet may accelerate renal function decline in mild renal insufficiency 2C Protein-pre-dialysis with keto acids

ADA (2010) [18]
For adults with CKD without diabetes, not on dialysis, with an eGFR < 20 mL/min, a very low protein controlled diet providing 0.3 g-0.5 g dietary protein per kg of body weight per day with addition of keto acid analogs to meet protein requirements may be recommended. International studies report that additional keto acid analogs and vitamin or mineral supplementation are needed to maintain adequate nutrition status for patients with CKD who consume a very low protein controlled diet (0.3-0.5 g/kg/day) Strong, conditional evidence Table 3. Cont.

KDOQI (2000) [59] BDA (2013) [19]
The recommended dietary protein intake for clinically and weight stable maintenance HD patients is 1.1 g/kg ideal body weight/day. At least 50% of the dietary protein should be of high biological value. For clinically and weight stable PD patients, the recommended protein intake is 1.0-1.2 g/kg ideal body weight/day. Those who are not stable may need higher levels of protein.
C Sodium-pre-dialysis

CARI (2013) [15]
We recommend that early CKD patients restrict their dietary sodium intake to below 100 mmoL per day or less, as it reduces blood pressure and albuminuria in patients with CKD. 1C

KDOQI (2000)[59]
Dietary sodium intake of less than 2.4 g/day (less than 100 mmol/day) should be recommended in most adults with CKD and hypertension. A Fluid-pre-dialysis

CARI (2013) [15]
We suggest that patients drink fluids in moderation. For most patients with early CKD, a daily fluid intake of 2-2.5 L (including fluid content of foods) is sufficient, although this may need to be varied for individual circumstances. 2C Phosphate-pre-dialysis

CARI (2013) [15]
We suggest that early CKD patients (stages 1-3) should not restrict dietary phosphate intake as restrictions of dietary phosphate does not influence renal or cardiovascular outcomes in these patients. 2C

KDIGO (2009) [17]
In patients with CKD stages 3-5, we suggest maintaining serum phosphorus in the normal range. 2C In patients with CKD stages 3-5 we suggest using phosphate-binding agents in the treatment of hyperphosphatemia.
2D It is reasonable that the choice of phosphate binder takes into account CKD stage, presence of other components of CKD-MBD, concomitant therapies, and side-effect profile.

KDIGO (2009) [17]
In patients with CKD stage 5D, we suggest lowering elevated phosphorus levels toward the normal range. 2C In patients with CKD stages 5D we suggest using phosphate-binding agents in the treatment of hyperphosphatemia. 2B It is reasonable that the choice of phosphate binder takes into account CKD stage, presence of other components of CKD-MBD, concomitant therapies, and side-effect profile. Not graded In patients with CKD stages 3-5D and hyperphosphatemia, we recommend restricting the dose of calcium-based phosphate binders and/or the dose of calcitriol or vitamin D analog in the presence of persistent or recurrent hypercalcemia.

1B
In patients with CKD stages 3-5D and hyperphosphatemia, we suggest restricting the dose of calcium based phosphate binders in the presence of arterial calcification and/or adynamic bone disease and/or if serum PTH levels are persistently low.

2C
In patients with CKD stages 3-5D, we recommend avoiding the long-term use of aluminum-containing phosphate binders and, in patients with CKD stage 5D, avoiding dialysate aluminum contamination to prevent aluminum intoxication.

1C
In patients with CKD stages 3-5D, we suggest limiting dietary phosphate intake in the treatment of hyperphosphatemia alone or in combination with other treatments. 2D Fibre

CARI (2103) [15]
We suggest patients with early CKD consume a diet rich in dietary fibre that is associated with reduced inflammation and mortality in CKD patients. 2D Potassium-pre-dialysis

CARI (2013) [15]
We suggest that early CKD patients with persistent hyperkalaemia restrict their dietary potassium intake with the assistance of a qualified dietitian. 2D A few minutes in Australian summer for fair skinned people and 2-3 h of sunlight/week in winter in southern regions. 2D We recommend a prescription of vitamin D therapy for early CKD patients with secondary hyperparathyroidism, as it has been shown to be effective in suppressing elevated levels of parathryroid (PTH) hormone. There is insufficient evidence to determine whether this improves patient-level outcomes and the potential benefits of vitamin D therapy must be weighed against its potential deleterious effects, including hypercalcaemia, hyperphosphataemia, vascular calcification, adynamic bone disease and accelerated progression of CKD.

1A
We recommend that early CKD patients on vitamin D therapy have their calcium, phosphate, PTH, alkaline phosphate and 25(OH) vitamin D level monitored regularly. 1C Vitamin D-dialysis

KDIGO (2009) [17]
In patients with CKD stage 5D and elevated or rising PTH, we suggest calcitriol, or vitamin D analogs, or calcimimetics, or a combination of calcimimetics and calcitriol or vitamin D analogs be used to lower PTH. 2B

CARI (2013) [15]
We recommend that overweight/obese patients with CKD should be prescribed caloric restriction under the management of an appropriately qualified dietitian. A reduction in weight can mean an improvement of CKD. 1C We suggest, in the absence of specific recommendations for CKD, overweight and obese patients are encouraged to aim for a body mass index (BMI) of between 18.5 and 24.9 kg/m 2 and waist circumference of ≤102 cm for men and ≤88 cm for women.

CMA (2008) [11]
Obese (BMI > 30.0 kg/m 2 ) and overweight (BMI 25.0-29.9 kg/m 2 ) people should be encouraged to reduce their BMI to lower their risk of chronic kidney diseaseand end-stage renal disease. D Maintenance of a health body weight (BMI 18.5-24.9 kg/m 2 ; waistcircumference < 102 cm for men, <88 cm for women) is recommended to prevent hypertension. C Or to reduce blood pressure in those with hypertension. B All overweight people with hypertension should be advised to lose weight. B Table 3. Cont.

CARI (2013) [15]
Fruit and vegetables-we suggest adults with early CKD consume a balanced diet rich in fruit and vegetables, as these appear to reduce blood pressure and have renoprotective effects comparable to sodium bicarbonate. 2C Mediterranean diet-we suggest adults with CKD consume a Mediterranean style diet to reduce dyslipidemia and to protect against lipid peroxidation and inflammation. 2C Counselling

CARI (2013) [15]
We suggest that patients with progressive CKD have individualised dietary interventions involving an appropriately qualified dietitian.

NICE (2008) [13]
Where the clinician in discussion with the patient has decided that dietary intervention to influence progression of CKD is indicated, an appropriately trained professional should discuss the risks and benefits of dietary protein restriction, with particular reference to slowing down the progression of disease vs. protein-calorie malnutrition.

2C
Where dietary intervention is agreed this should occur within the context of education, detailed dietary assessment and supervision to ensure malnutrition is prevented.
Not graded Offer dietary advice to people with progressive CKD concerning potassium, phosphate, protein, calorie and salt intake when indicated.

CMA (2008) [11]
Renal programs and care providers for patients with progressive chronic kidney disease who choose not to pursue renal replacement therapies should ensure patients have access to an interdisciplinary team to provide comprehensive conservative management. • All chronic kidney disease programs and care providers should have a mechanism by which to develop documents and processes for advanced-care planning.
• Comprehensive conservative management protocols should include symptom management, psychological care and spiritual care.
• Coordinated end-of-life care should be available to patients and families.

Not graded
The Australian CARI guidelines, shown in Table 3, state that a protein-controlled diet consisting of 0.75-1.0 g/kg/day, is recommended for adults pre-dialysis (Stages 3-4) [15]. The administration of a low protein diet (<0.6 g/kg/day) to slow renal failure progression is not justified when the reported clinically modest benefit on glomerular filtration rate decline is weighed against the concomitant significant declines in clinical and biochemical parameters of nutrition [15]. It is the most recent of the international guidelines assessing this question and is at odds with the systematic reviews [22,23].
The British Dietetic Association's guidelines on protein intake in both haemodialysis (HD) and peritoneal dialysis (PD) recommend a lower level of protein intake than previous guidelines at 1.1 g/kg ideal body weight/day for those undergoing maintenance haemodialysis and 1.0-1.2 g/kg ideal body weight/day for those on maintenance peritoneal dialysis [19]. These recommendations are graded C using the Scottish Intercollegiate Guideline Network criteria, that is based on well-conducted cohort or case control studies with a low risk of confounding and a moderate probability that the relationship is causal [12]. The authors emphasise the importance of adequate energy (126-167 kJ/day in HD and 146 kJ/day for PD in adults under 60 years and 126-146 kJ/day for those over 60 years). This recommendation is slightly lower than previously recommended and is based on medically well patients with stable body weights and the authors caution when applying these recommendations to less well patients [19].
The guidelines on vitamin D (Table 3) focus on the general population decline in serum 25 hydroxy vitamin D and methods to address this in early CKD (Stages 1-4) [15]. In later stages of disease, recent guidelines focus on the combined effects of calcium, phosphate, parathyroid hormone (PTH) and vitamin D on outcome [14,17]. The cohort study by Wang et al. aimed to explore the relationship between serum 25(OH)-hydroxy vitamin D (25(OH)D) in PD patients and long term clinical outcomes [36]. They found that 87% of the cohort were deficient or insufficient in 25(OH)D (i.e., <75 nmol/L) and that lower serum 25(OH)D levels were associated with an increased risk of cardiovascular events but not long term mortality [36]. The effects of oral paricalcitol supplementation on biochemical markers (including proteinuria) have been studied in both pre-dialysis and early CKD patients (Stages 1-4). A small, six month randomized controlled trial (RCT) found a modest effect size of oral paricalcitol supplementation of 1 μg/day vs. placebo, with the intervention group demonstrating a 17.6% decrease in spot urinary protein-creatinine ratio vs. a 2.9% increase for controls (p = 0.04) [34]. It was also noted in this study that serum iPTH fell significantly amongst those who received paricalcitol supplementation (p = 0.01) [34]. Agarwal et al. similarly found that oral paricalcitol supplementation (mean dose 9.5 μg/week) was significantly associated with 51% vs. 25% (p = 0.004) reduction in proteinuria in the intervention group compared to controls and 3.2 greater odds for a reduction in proteinuria independent of treatment for Renal Angiotensin Aldosterone blockade [35]. The KDIGO guidelines (see Table 3) recommend calcitriol or other vitamin therapy in those with elevated parathryroid hormone [17]. The CARI guidelines while recommending vitamin D therapy in early kidney disease for those with elevated PTH warn against the risk of vitamin D therapy in the face of elevated serum calcium and phosphate levels, which should be monitored regularly [15].
The evidence for the modification of fat in CKD to moderate cardiovascular outcomes is limited. Beavers et al. found that supplementation of 6 g omega-3 fatty acids had no effect on total homocysteine levels in HD patients over 6 months [37]. Saltissi et al. found that dietary compliance was a major issue [38]. A dialysis dietary prescription modified to meet the National Heart Foundation guidelines of reduced intake of saturated fat and cholesterol, led to a significant reduction in total cholesterol and low density lipoprotein (LDL) cholesterol in HD patients with little effect in PD patients [38]. All guidelines published since 2006, recommend controlling salt intake below 100 mmol sodium/day (2.3 g sodium) as an important feature of managing hypertension [11,12,15,18], although not addressed at any particular stage of CKD. One randomized controlled double blind crossover study of 34 patients with proteinuria and without diabetes was located reporting the effect of a low sodium diet (50 mmol/day) being as efficacious as treatment with hydrocholorothiazide (an angiotensin receptor II antagonist) at reducing proteinuria and blood pressure when combined with a diuretic [39]. Sodium restriction itself exerted a modest, yet significant, antiproteinuric effect [37]. Actively restricting sodium to less than 100 mmol/day (5 g salt) in those undergoing haemodialysis resulted in less hypertensive medications used (7% vs. 42%), better ventricular function and less intradialytic hypotension compared to those whose blood pressure was controlled by medication [40]. Using sodium excretion as a surrogate for sodium intake, Boudville showed that excretions in the lowest tertile (114 mmol/day) resulted in significantly fewer hypertensive medications (2 vs. 2.7, p = 0.01) used in those with GFR < 30 mL/min, than those in the highest tertile (166.7 mmol/day). This effect was even more marked in those with GFR ≤ 15 mL/min [41].
The effect of dietary fibre supplements and a high fibre diet, on patient reported symptoms of constipation amongst a PD population, suggested that 6-12 g/day of partially hydrolysed guar gum added to usual intake was as effective as usual laxative treatment for preventing constipation in the majority of included PD patients and was associated with less unfavorable side effects [42]. Both Saltissi and Sutton studies were case series without control groups [38,42].
Compliance with diet prescription remains an issue. Twenty-eight per cent (28%) of participants under-reported protein intake in both a very low protein diet (VLPD) of 0.3 g/kg/day plus keto-acids (KA) diet to a level of 0.66 g/kg/day and a low protein diet (LPD) of 0.6 g/kg/day in pre-dialysis patients. While compliance was poor in both groups, the prescription of the VLPD + KA delivered improved biochemical markers, with significant improvements noted in serum urea nitrogen, serum bicarbonate and urinary phosphorous [31]. In 423 pre-dialysis patients (Stages 4 and 5) randomized to receive two different protein levels, LPD (0.55 g/kg/day) or a Moderate Protein Diet (MPD) of 0.8 g/kg/day, for 3 months with follow up to 48 months there were no differences between groups at 6 and 18 months, however there was greater compliance with the MPD [32]. In a case control study of Stage 3-5 CKD patients, Kanazawa demonstrated the compliant group, with dietary protein intakes maintained at 0.69 g/kg body weight/day, had smaller decline in GFR, however no measures of change in body composition were recorded and there was no difference in health-related quality of life [33].
Teixido-Planas et al. conducted a 12 month open RCT of 65 PD participants, comparing daily consumption of 200 mL 1.0 kcal/mL liquid oral nutrition support (ONS), in addition to usual dietary intake, against those who consumed only their usual dietary intake [43]. Based on an "intention to treat" analysis, only an improvement in total lymphocyte count (p = 0.0066) between intervention and controls reached significance. The supplement was not found to be suitable for long term use due to non-compliance with 31% of the intervention group dropping out. A similar study by Caglar et al. with ONS showed improvements in albumin, pre-albumin and SGA [44], however the compliance rate (32%) was similar, with a 46% dropout rate.
Five studies investigating the effect of structured dietetic counseling on compliance with dietary prescriptions have shown differing results. Campbell et al. randomized 56 pre-dialysis patients (Stages 4 and 5) to fortnightly, individualized counseling on a prescription of 0.75 g/kg/day protein and 145 kJ/kg/day energy vs. written education material for 3 months [46]. The intervention group had a significantly lower reduction in body cell mass and improvement of 17.7 kJ/kg/day energy intake and subjective global assessment (SGA). Improvements in nutritional status in the intervention group translated to significant improvements in the symptoms, cognitive functioning and vitality subscales in the Kidney Disease Quality of Life tool, KDQoL [47]. Sullivan also showed in 279 HD patients in a cluster RCT for 3 months that counseling on reducing phosphates in foods compared to usual care significantly reduced serum phosphate levels by 0.6 mg/dL, largely through improvements in food label reading [48]. Conversely, Morey in 67 HD patients randomized to monthly vs. 6 monthly counseling was unable to maintain a reduction in serum phosphate of 0.25 mg/dL at 3 months, at the 6 month follow-up [49]. A retrospective cohort study over 2 years of 65 HD patients receiving a 6 monthly dietetic review with intensive follow-up for nutrition parameters falling below recommended levels, showed a significant reduction in malnutrition (SGA-B reducing from 14% to 3%), maintained serum albumin, potassium an dry weight and significant reduction in serum phosphate [50].
The evidence for the effect of nutrients in peritoneal dialysis solution is limited to two small studies [51,52]. Improvements in overall protein balance improved in a randomized cross over study of 8 patients over 14 days [51] and also in another study which was open labeled and not controlled in 16 patients over 3 months [52]. The use of intradialytic parenteral nutrition (IDPN) solution in HD patients has also only been conducted in small studies, showing improvements in hepatic albumin synthesis and whole body fat free mass [53][54][55][56][57]. In the cross over study of 8 patients using both IDPN and oral supplements, the oral administration resulted in persistent anabolic benefits in the post dialysis phase, which was not seen with IDPN [55]. In a case series over 12 months of 24 malnourished PD patients, in which there was significant attrition >50%, the IDPN was associated with increased body weight and improved serum albumin levels [57]. A small case series in haemodialysis patients, using Percutaneous Endoscopic Gastrostomy feeding showed improvements in anthropometric measures over a 3 month period [58].

Discussion
The focus of guidelines on nutrition and CKD published since 2006 has been on early prevention and lifestyle modification required to prevent progression to ESRD [11,12,15] or the management of renal bone disease [17]. The KDOQI guidelines on nutrition have not been updated since 2000 [59]. Addressing general population's sub-optimal serum vitamin D levels, as well as in early CKD is a priority. Other chronic diseases, such as obesity, diabetes and hypertension, which affect the population at large, require management to prevent progression to CKD [15]. The treatment of these diseases has a large nutrition component which needs to be recognized [6].
The approach for managing elevated serum phosphate, through the use of phosphate binders as an adjunct to the restriction of dietary intake, has also been recognized. The KDIGO guidelines continue to recommend restricting dietary phosphate in combination with other treatments, however the evidence is poor [5]. The CARI guidelines state clearly that restriction of diet runs the risk of precipitating malnutrition and thus has promoted moderate restrictions in protein, phosphate and sodium in the pre-dialysis period to levels commensurate with the general population [15]. The studies, specifically looking at dietitian led control of phosphate intake, showed promise but further studies need to be conducted on the frequency of dietetic counseling to ensure long term impact on dietary control [49,50].
Issues of compliance with restricted diets remains a weakness in many of the studies reported here and those promoting regular contact with a dietitian mostly report improved outcomes. The previous DAA guidelines [7] have had wide currency with dietitians in Australia and New Zealand and are largely still relevant in the present day. These guidelines used the Nutrition Care Process (NCP) to guide the development of clinical questions. The NCP consists of nutrition assessment, diagnosis, intervention and monitoring and evaluation [8] and is outcome driven in that nutritional parameters collected as part of the nutrition assessment and addressed through the nutrition prescription, are then re-assessed or evaluated to establish the impact of the nutrition intervention. These outcomes commonly include intermediate outcomes, such as nutrient intake, anthropometric measures and biochemical markers. Studies on the effect of nutrition prescription on clinical outcomes, such as mortality, hospitalization or cost are limited. While the NCP is useful for practical purposes, grading of evidence in line with international recommendations on harmonizing guidelines is still required [21]. One advantage of these nutrition guidelines is the rigorous independent review process undertaken using the Appraisal of Guidelines for Research and Evaluation (AGREE) tool, which has been recommended for future evaluation of guidelines [60]. Areas requiring most revision for the future include recommendations on vitamin D and phosphate. Further studies on the effect of intradialytic parenteral nutrition and enteral support on dialysis are also warranted.

Conclusions
Overall, the body of evidence supporting nutritional interventions for improving patient outcomes in CKD is primarily based on low level evidence or isolated randomized clinical trials. Much of the evidence around dietary prescription relies on retrospective and uncontrolled cohort studies and the quality of the body of evidence is poor. Most outcomes assessed are generally biochemical endpoints, such as change in serum levels, rather than clinical ones, such as mortality, hospitalization, cost and patient quality of life. There is general agreement across guideline recommendations for the levels of protein in early CKD and on dialysis; however, guidance on the use of very low protein diets with keto-analogues in conservative treatment of those with GFR < 15 mL/min is warranted. While the evidence from a few observational trials suggests that these diets pose no greater risk on mortality than dialysis as treatment, better controlled trials are required to confirm this. Further research on the optimal intakes of sodium, phosphate, fats and fibre in well controlled studies are required, as are studies into micronutrients and other components such as antioxidants. Studies on sun exposure combined with diet are required to determine optimal vitamin D status. The collaborative effort to use a global approach to international guidance in management of chronic kidney disease is welcome. While more evidence based studies are warranted, the customary nutrition prescription remains satisfactory with the exception of Vitamin D and phosphate. In these two areas, additional research is urgently needed, given the potential of adverse outcomes for the CKD patient. The role of nutrition in the management of CKD is important and needs to be included in further promotion of research outcomes and future guidelines.

Conflicts of Interest
The authors declare no conflict of interest.