Chronic kidney disease: diet Search date September 2014 Catherine M. Clase, Andrew Smyth ABSTRACT INTRODUCTION: Continued progression of kidney disease will lead to renal function too low to sustain healthy life. In developed countries, such people will be offered renal replacement therapy in the form of dialysis or renal transplantation. Requirement for dialysis or transplantation is termed end-stage renal disease (ESRD). METHODS AND OUTCOMES: We conducted a systematic review, aiming to answer the following clinical questions: What are the effects of a low-sodium diet to reduce progression rate of chronic kidney disease? What are the effects of a low-protein diet to reduce progression rate of chronic kidney disease? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2014 (BMJ Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview). RESULTS: We found seven studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic overview we present information relating to the effectiveness and safety of the following interventions: low-protein diet versus control, different low-protein diets versus each other (lowprotein diet versus very low-protein diet), low-sodium diet versus control, different low-sodium diets versus each other.

QUESTIONS What are the effects of a low-sodium diet to reduce progression rate of chronic kidney disease?. . . . . . . . . . . 5 What are the effects of a low-protein diet to reduce progression rate of chronic kidney disease?. . . . . . . . . . . . 7 INTERVENTIONS LOW-SODIUM DIET TO REDUCE PROGRESSION RATE OF CKD Unknown effectiveness

LOW-PROTEIN DIET TO REDUCE PROGRESSION RATE OF CKD Unknown effectiveness

Low-sodium diet versus usual diet New . . . . . . . . . 5

Low-protein diet (low-protein diet or very low-protein diet) versus usual diet New . . . . . . . . . . . . . . . . . . . . . . . 7 Covered elsewhere in Clinical Evidence End-stage renal disease

Key points • Chronic kidney disease (CKD) is usually first recognised by an elevated serum creatinine or low estimated GFR. Continued progression of kidney disease will lead to renal function too low to sustain healthy life. In developed countries, such people will be offered renal replacement therapy in the form of dialysis or renal transplantation. Requirement for dialysis or transplantation is termed end-stage renal disease (ESRD). Diabetes, glomerulonephritis, hypertension, pyelonephritis, renovascular disease, polycystic kidney disease, and certain drugs may cause chronic kidney disease. • We searched for RCTs of 6 months' or longer duration on the effects of low-sodium diets or low-protein diets in people with CKD. • Because sodium intake affects blood pressure in some people, and because blood pressure control is considered to be important in preventing progression of kidney disease, it has been hypothesised that reduction in dietary sodium intake would reduce the progression of kidney disease in people with CKD. However, we found no RCTs on the effects of low-sodium diets. • We found RCTs and systematic reviews on the effects of low-protein diets in adults without diabetes, in children, and in adults with diabetic nephropathy. The low-protein diets and control diets examined in RCTs varied widely, and most individual studies and reviews did not report on harms. Individual large RCTs and long-term follow-up of participants in RCTs found no benefit for low-protein diet in terms of prevention of death or ESRD in adults without diabetes or in children. One meta-analysis suggested a large difference in the composite outcome death or ESRD in adults without diabetes; however, the findings were only significant for very low-protein diets but not for low-protein diets as usually implemented in clinical practice. • One meta-analysis found an improvement in glomerular filtration rate (GFR) or creatinine clearance with low-protein diet in adults with diabetic nephropathy, but the evidence was difficult to interpret, and we found no evidence on mortality or disease progression (dialysis or transplantation) in this group. • We found no good evidence on cardiovascular effects or quality of life measures. © BMJ Publishing Group Ltd 2015. All rights reserved.

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• The greatest clinical concern is malnutrition, because people with CKD, especially those who are older, are at risk for malnutrition from CKD and comorbidity, and spontaneous caloric and protein intake is lower in people with lower GFR. • In children in carefully supervised settings we found no evidence of increased risk of malnutrition or poor growth with low-protein diet, but the evidence mainly derives from one RCT of around 200 children. • Adult participants in RCTs have mean ages in the 50s to 60s, whereas many people in clinical practice with CKD are in their 70s and 80s. Older people and those with higher levels of comorbidity may be more likely to have cognitive impairment, face financial or practical challenges in implementing dietary advice, and be at greater risk from malnutrition from poorly-understood or poorly-implemented alterations to their diet. Clinical context

GENERAL BACKGROUND Chronic kidney disease (CKD) is prevalent, especially in older people and those with hypertension or diabetes. CKD is mostly managed in primary care. People with CKD and physicians often ask if there are dietary interventions that can help reduce the rate of progression of kidney disease and reduce the risk of adverse outcomes such as cardiovascular events and end-stage renal disease (ESRD). On the other hand, people with CKD spontaneously reduce their protein intake as their glomerular filtration rate (GFR) falls, and in people with severe CKD, malnutrition sometimes occurs. When malnutrition does occur, it greatly increases morbidity and mortality. Diet is part of culture and lifestyle, and has implications for budget, relationships, and social activities. Healthcare providers should not lightly suggest changes and they should be aware that adherence to advice in this area is problematic and that suggested changes may lead to unintended consequences.

FOCUS OF THE REVIEW Sodium in diet is implicated in the pathogenesis of hypertension, and through hypertension, of cardiovascular disease. Since hypertension is also a mediator in the pathogenesis of progressive kidney disease, sodium intake is an appropriate candidate to examine as a possible therapeutic diet for people with CKD, to reduce the risk of progression of low GFR to ESRD, and of cardiovascular events. Protein intake leads to circulating amino acids, which are vasodilatory in the kidney and lead to increased intraglomerular pressure. Intraglomerular pressure is thought to contribute to the pathogenesis of progressive kidney disease in people with reduced nephron number, whatever the primary cause of loss of nephrons may be. An alternative intervention that is thought to work by reducing intraglomerular pressure is the use of drugs that interrupt the renin-angiotensin-aldosterone system. These interventions have been shown in RCTs to reduce renal progression. For this reason, it is postulated that low-protein diets may be beneficial to people with CKD.

COMMENTS ON EVIDENCE We found no RCTs on low-sodium diets. On low-protein diets, we found one systematic review containing 10 RCTs in adults without diabetes, and longer-term reports of two of these RCTs; one systematic review in children containing two RCTs; and one systematic review in adults with diabetic nephropathy containing 11 RCTs. We found little evidence on cardiovascular effects or quality of life or harms data. Some of the RCTs were unblinded, but reported on objective outcomes. The low-protein diets and control diets varied widely between different RCTs. Also of note is that the RCTs in children were in carefully supervised settings and that adult participants in RCTs have mean ages in the 50s to 60s, whereas many people in clinical practice with CKD are in their 70s and 80s. These may both affect the generalisability of the results.

SEARCH AND APPRAISAL SUMMARY The update literature search for this overview was carried out from the date of the last search, October 2010, to September 2014. A search back-dated to 1966 was performed for the new options added to the scope at this update. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the overview, please see the Methods section. Searching of electronic databases retrieved 344 studies. After deduplication and removal of conference abstracts, 265 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 156 studies and the further review of 109 full publications. Of the articles evaluated, three systematic reviews and four RCTs were included at this update. DEFINITION

Chronic kidney disease (CKD) is usually first recognised by an elevated serum creatinine or low estimated glomerular filtration rate (GFR). Since 2002, the Kidney Disease Improving Global Outcomes (KDIGO) statement and subsequent re-iterations define low GFR as a GFR of less than 2 60 mL/minute/1.73 m on two occasions at least 3 months apart, and CKD as low GFR, or urinary [1] abnormalities, or clinically important structural abnormalities present for more than 3 months. [2] Low GFR corresponds approximately to serum creatinine concentration greater than 137 micro[3] mol/L in men and more than 104 micromol/L in women. Current KDIGO guidelines, published

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in 2012, further classify people with low GFR as follows: G3a (GFR 45–59 mL/minute); G3b (GFR 30–44 mL/minute); G4 (GFR 15–29 mL/minute); and G5 CKD (GFR 180 micromol/L in men or >135 micromol/L in women [corresponding to a GFR of about 2 [23] 30 mL/minute/1.73 m ]) was 0.244% a year. Studies suggest prevalence rises dramatically [24] [25] with age. In the UK, the 2010 Health Survey of England found a prevalence of CKD of 6%

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[26]

in men and 5% in women. New Opportunities for Early Renal Intervention by Computerised Assessment (NEOERICA), also in the UK, identified a prevalence of 6% in men and 11% in women [24] (based on clinically-ordered laboratory testing). In the US, by national survey, the prevalence of CKD was: 1.8% for G1 A2–3 (see Definition); 3.2% for G2 A2–3; 7.6% for G3 A1–3; and 0.4% [25] for G4 A1–3. Repeated national surveys in the US suggest that prevalence is increasing over time, beyond the expected increase associated with the changing age structure of the population. [25]

AETIOLOGY/ Little is known about the epidemiology of the underlying cause of CKD in people without diabetes RISK FACTORS in the community or in primary care. In people managed at referral centres, and in people who progress to ESRD, glomerulonephritis, hypertension or renovascular disease, and polycystic kidney disease are the most common diagnoses, with a smaller proportion of people having tubulointerstitial [27] [28] [29] disease or vasculitis. In people with CKD who progress to ESRD in Canada, diabetes is the most common cause (24%), followed by glomerulonephritis (20%), unknown (14%), hypertension (10%), pyelonephritis (7%), renovascular disease (7%), polycystic kidney disease (6%), [30] and drug-induced disease (commonly by lithium, analgesics, and NSAIDs, 2%). PROGNOSIS

A 10-year, community-based cohort study in Japan found that higher serum creatinine levels may [31] lead to an increase in the risk of developing ESRD. In a community-based cohort in Tromsø, Norway, the 10-year cumulative incidence of renal failure (identified through clinical laboratory 2 screening as having a GFR of 30–60 mL/minute/1.73 m ) was 4% (95% CI 3% to 6%) and mortal[32] ity was 51% (95% CI 48% to 55%). In a 5-year follow-up of a cohort identified through the laboratories of a large managed care organisation in the US, the rate of ESRD was 1% and mortality 2 24% for people with a GFR of 30–60 mL/minute/1.73 m , and ESRD was 20% and mortality 46% 2 [33] for those with a GFR of 15–30 mL/minute/1.73 m . In a cohort study of men with serum creatinine greater than 300 micromol/L and women with serum creatinine more than 250 micromol/L, identified [34] through clinical laboratories, 80% reached ESRD at follow-up of 55 to 79 months. In a UK community-based study of clinical laboratory serum creatinine values, chronic renal failure was defined as a single creatinine value of more than 180 micromol/L in men or greater than 135 micro2 [23] mol/L in women (corresponding to a GFR of about 30 mL/minute/1.73 m ). In those people meeting this definition, but who had not been referred to a nephrologist, and in whom repeat serum creatinine levels were obtained, the annual rate of decline in GFR was less than 2 mL/minute/year in 79% of people and 5 mL/minute/year or greater in 8% of people. In NHANES III (conducted be2 tween 1986–1994), 4.3% of the group had a low GFR (30–60 mL/minute/1.73 m ) and 0.2% had 2 [1] a very low GFR (15–30 mL/minute/1.73 m ). In addition, in the United States Renal Data Survey [35] (USRDS) for 1990, 0.06% of the group required renal replacement therapy. The data from these two studies strongly suggest that many unreferred people with a low GFR do not have progressive disease, or are either of an age or carrying a burden of comorbidity such that the competing risk of death outweighs the risk of ESRD. Proteinuria is a consistent multivariable risk factor for [28] [36] [37] progression of renal failure and for ESRD and can be classified in many ways. In addition to the classification by urine albumin:creatinine ratio (A1 [normal to mildly increased], 30 mg/mmol) [5] recommended for initial assessment of CKD, proteinuria may be quantified by dipstick (0, 1+, 2+, and 3+), by 24-hour collection (non-proteinuric, 3000 mg/day), and by protein:creatinine ratio. Hypertension and cigarette smoking have also been shown to be risk factors for progression to [38] ESRD. People referred to nephrologists differ from those in primary care in both prognostic markers and rates of progression. For example, in the Modification of Diet in Renal Disease (MDRD) 2 study A (GFR 25–55 mL/minute/1.73 m ), 27% of participating people had higher than 1000 mg [38] daily proteinuria, whereas in NHANES III only 3% of participants with a GFR of 2 [39] 30–60 mL/minute/1.73 m showed more than 288 mg daily of albuminuria. Rate of progression also seems to differ between referred and unreferred people. In a review summarising studies of [40] mostly referred people, the weighted mean loss of GFR was 7.56 mL/minute/year. By contrast with this, in a community-based study of unreferred people conducted in the UK, only 21% of 2 people showed evidence of progression of renal disease (defined as at least 2.0 mL/minute/1.73 m [23] a year), and the remaining 79% showed no evidence of progression (see table 1, p 20 ).

AIMS OF To prevent ESRD or prolong time before renal replacement therapy is required; to prevent death; INTERVENTION to prevent progression of renal disease to levels of kidney function at which clinically important increases in cardiovascular morbidity and mortality occur and at which metabolic complications (malnutrition, bone disease, and anaemia) occur, with minimal adverse effects of treatment. OUTCOMES

Mortality (all causes; mortality caused by MI, congestive heart failure, or stroke); cardiovascular effects morbidity (caused by MI, congestive heart failure, or stroke); renal disease progression; time to requirement of renal replacement therapy/initiation of dialysis; progression of renal disease

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(usually defined by the outcome cluster initiation of dialysis or increase in creatinine by some fixed amount or percentage change from baseline). Where rate of decline of GFR was the primary outcome of the study, these data were extracted in addition to data on time to requirement of renal replacement therapy or progression of renal disease (because such studies were likely to be underpowered to show a difference in these clinically important outcomes). Nutritional status (weight, anthropomometry, albumin); quality of life, including satisfaction with diet, intrusiveness of diet; adverse effects. METHODS

Search strategy BMJ Clinical Evidence search and appraisal September 2014. Databases used to identify studies for this systematic overview included: Medline 1966 to September 2014, Embase 1980 to September 2014, The Cochrane Database of Systematic Reviews, 2014, issue 9 (1966 to date of issue), the Database of Abstracts of Reviews of Effects (DARE), and the Health Technology Assessment (HTA) database. Inclusion criteria Study design criteria for inclusion in this systematic overview were systematic reviews and RCTs published in English; open studies were acceptable, and included studies needed to contain 20 or more individuals (with a minimum of 10 participants in each arm). Although studies would ideally have a minimum level of follow-up of 80%, studies with any level of follow-up were considered. Included studies had to have a minimum followup period of 6 months. This overview is limited to people with chronic kidney disease. We excluded studies undertaken in people with acute kidney injury (acute renal failure) or end-stage renal disease (ESRD). BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributors. In consultation with the expert contributors, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the review. In addition, information that did not meet our predefined criteria for inclusion in the benefits and harms section, may have been reported in the 'Further information on studies' or 'Comment' section. Adverse effects All serious adverse effects, or those adverse effects reported as statistically significant, were included in the harms section of the overview. Pre-specified adverse effects identified as being clinically important were also reported, even if the results were not statistically significant. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributors may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robustness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Data and quality To aid readability of the numerical data in our overviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue which may affect the weight a reader may put on an individual study, or the generalisability of the result. These issues may be reflected in the overall GRADE analysis. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table, p 21 ). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

QUESTION

What are the effects of a low-sodium diet to reduce progression rate of chronic kidney disease?

OPTION

LOW-SODIUM DIET. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . New



For GRADE evaluation of interventions for Chronic kidney disease: diet, see table, p 21 .



We found no RCTs of 6 months' duration or longer.

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Because sodium intake affects blood pressure in some people, and because blood pressure control is considered to be important in preventing progression of kidney disease, it has been hypothesised that reduction in dietary sodium intake would reduce the progression of kidney disease in people with chronic kidney disease (CKD).



There is a subgroup of people with CKD who have uncontrolled hypertension despite several medications, severe oedema, or other manifestations of congestive heart failure, who are likely to benefit directly from sodium restriction in terms of blood pressure control (which predicts cardiovascular outcomes) and symptoms. Benefits and harms

Low-sodium diet versus normal/standard/control sodium diet: We found no RCTs (see Comment, p 5 ). Different levels of low target sodium intake versus each other: We found no RCTs. Comment:

In this option, we have only reported RCTs of 6 months' duration or longer. Because sodium intake affects blood pressure in some people, and because blood pressure control is considered to be important in preventing progression of kidney disease, it has been hypothesised that reduction in dietary sodium intake would reduce the progression of kidney disease in people with CKD. There is a complex relationship between dietary sodium intake (salt intake, 1 g sodium = 2.5 g salt) and health. Current guideline recommendations suggest that optimal sodium intake is less than [41] [42] [43] [44] [45] [46] [47] 2.3 g/day (1.3 [5] [6] g/day), who should probably be advised to reduce to less than 1.3 g/day. Otherwise, the uncertainty and risks suggest that a low-protein diet is best employed in selected people managed by nephrologists practising in a well-resourced multidisciplinary care environment. In people with low GFR, phosphate retention occurs. In people with GFR below 2 30 mL/minute/1.73m , this may progress to hyperphosphataemia. Phosphate is implicated in the pathogenesis of metabolic bone disease and its consequences of bone pain and fracture, and in the pathogenesis of vascular and valvular calcification with its consequences of stroke and myocardial infarction. Because of this, it is common practice to restrict phosphate intake to a greater or lesser extent in people with CKD and hyperphosphataemia. Phosphate and protein are correlated in foods, so that a person prescribed a phosphate-restricted diet is inevitably protein restricted. For our overview, we were interested in protein restriction as a method of reducing rate of progression of kidney disease. Reduced rate of progression should prolong time to reaching a threshold GFR, and therefore prolong the time to ESRD. However, protein restriction also reduces protein metabolites that contribute to the symptoms and signs of the uraemic syndrome. Because the decision to start dialysis treatment or proceed to transplantation is a subjective one based on symptoms and signs in the context of GFR, it is possible that protein restriction, if effective, might operate through the mechanism of delaying the onset or reducing the severity of uraemic syndrome rather than reducing rate of progression. Finally, because of this mechanism, it is possible that protein restriction might reduce symptoms or even prolong life in people who choose palliative care or maximal conservative therapy rather than renal replacement therapy at the point where renal replacement therapy is offered, and for those people in communities that are unable to offer renal replacement therapy.

GLOSSARY Chronic renal insufficiency Chronic renal failure. Proteinuria The excretion of protein in the urine, usually described as pathological when in excess of 0.3 g/day. Renal replacement therapy Dialysis or renal transplantation. Chronic kidney disease Defined by the 2012 Kidney Disease Improving Global Outcomes (KDIGO) statement as abnormalities of kidney structure or function, present for 3 months, with implications for health. Chronic kidney disease includes chronic renal failure, but it also includes predictors of chronic renal failure in people with normal kidney function (e.g., proteinuria) and end-stage renal disease (ESRD). Chronic renal failure Chronically (at least 3 months' duration) reduced kidney function (clearance, glomerular filtration rate [GFR]). Renal function declines normally with age, and the exact level of decline at a given age that should be considered pathological is not known. The Kidney Disease Improving Global Outcomes (KDIGO) statement considers 2 a GFR of

Chronic kidney disease.

Continued progression of kidney disease will lead to renal function too low to sustain healthy life. In developed countries, such people will be offer...
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