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Very low protein diet supplemented with keto analogues compared to low protein diet in pre-dialysis chronic kidney disease patients

Uso de dieta muy baja en proteínas con keto análogos comparado con dieta baja en proteínas en pacientes con enfermedad renal crónica pre diálisis

Abstract

Introduction It has been proposed that a very low protein diet supplemented with keto analogues in pre-dialysis chronic kidney disease patients can slow the progression to a terminal disease and delay the start of renal replacement therapy, without a malnutrition risk. However, its common use has not yet been implemented due to the uncertainty of its efficacy and safety.

Methods We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach.

Results and conclusions We identified eight systematic reviews including 14 studies overall, of which 12 were randomized trials. We concluded that a very low protein diet supplemented with keto analogues delays the progression to end-stage kidney disease, probably reduces the fall or deterioration of renal function, could reduce mortality by any cause y result in little or no difference in malnutrition risk, but the certainty of the evidence is low for these last two results.

Problem

Chronic kidney disease is defined as the presence of renal injury or glomerular filtration rate <60 mL/min/1,73m2 for at least three months independent of the cause [1]. Chronic kidney disease is a worldwide public health problem, due to its high and increasing prevalence, elevated costs and poor prognosis. The most important complications are acute renal failure, end-stage kidney disease, cardiovascular disease and increased mortality.

Due to the high impact chronic kidney disease has, strategies have been looked for to slow down the progression and ameliorate the symptoms. Because protein related by-products accumulate in chronic kidney disease (nitrogen products, acids, phosphorus, among others), and moreover, an excess of proteins generates renal parenchymal damage; a protein restricted diet has been proposed as a therapeutic measure [2]. 

In fact, a low protein diet of 0.6-0.8 g/kg/day could be beneficial in avoiding progression to end-stage kidney disease [3]. It has been stated that an even higher protein restriction (0.3 g/kg/day) can increase the benefit as long as the correct calorie intake is kept [4]. This may be achieved by a keto analogue supplementation, which are nutrients similar to amino acids, but free of the nitrogen branch. It has been proposed that a very low protein diet supplemented with keto analogues may reduce nitrogen ingestion, increase calorie intake and avoid excess protein deleterious effects in chronic kidney disease.

Methods

We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others, to identify systematic reviews and their included primary studies. We extracted data from the identified reviews and reanalyzed data from primary studies included in those reviews. With this information, we generated a structured summary denominated FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos) using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analysis of the total of studies when it is possible, a summary of findings table following the GRADE approach and a table of other considerations for decision-making.

Key messages

  • Very low protein diet supplemented with keto analogues in pre-dialysis slightly delays the progression to end-stage kidney disease.
  • Very low protein diet supplemented with keto analogues may reduce mortality by any cause (low certainty evidence).
  • Very low protein diet supplemented with keto analogues probably reduces the fall or deterioration of renal function.
  • Very low protein diet supplemented with keto analogues could result in little or no difference in the risk of malnutrition (low certainty evidence).

About the body of evidence for this question

What is the evidence.
See the evidence matrix in Epistemonikos below
.

We identified eight systematic reviews [5], [6], [7], [8], [9], [10], [11], [12], including 14 primary studies reported in 29 references [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41] of which 12 are randomized trials reported in 26 references [14], [15], [17], [18], [19], [20], [21], [22], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41].

Three of the identified randomized trials [17], [20], [28] also reported the results of trials that did not assess the use of keto analogs. Although these are reflected in the evidence matrix, they were not included in this summary.

The table and summary in general are based on the 12 randomized trials [14], [15], [17], [19], [20], [28], [30], [31], [33], [35], [36], [37], as the observational studies did not increase the level of certainty of the evidence, nor added any additional relevant information.

What type of patients did the studies include? * 

All trials were made in adult patients with chronic kidney disease in pre-dialysis stage.

Eleven trials describe the chronic kidney disease stage of the patients [14], [15], [17], [19], [20], [28], [30], [31], [33], [35], [37]. Ten included patients with glomerular filtration rate of 30 ml/min/1,73m2 or less [14], [15], [17], [19], [20], [28], [30], [31], [33], [37] and one trial included patients with creatinine clearance between 20 and 50 ml/min/1,73m2 [35]. One trial does not describe the chronic kidney disease stage of the patients [36].

Ten trials excluded patients with comorbidities such as cancer, systemic diseases, poorly controlled hypertension or insulin-requiring diabetes mellitus [14], [15], [19], [20], [28], [31], [33], [35], [36], [37].

What type of interventions did the studies include? * 

All trials evaluated a very low protein diet (0.3 gr/kg/day) supplemented with keto analogues with or without essential amino acids.

All trials compared against a low protein diet (0.6 g/kg/day). Only one trial added a placebo in the control group [35] and only one trial added a calcium supplement to the control group [30].

What type of outcomes did they measure 

The trials evaluated multiple outcomes, which were grouped by the systematic reviews as follows:

  • Mortality: all cause death, renal death
  • End stage kidney disease progression
  • End or change in glomerular filtration rate
  • Protein energy wasted
  • Blood levels of: blood urea nitrogen, albumin, creatinine, calcium, phosphorus, parathormone, cholesterol, triglycerides, haemoglobin
  • Nutritional parameters such as: body mass index, final weight, lean mass, arm muscle circumference
  • Others: proteinuria, systolic blood pressure, diastolic blood pressure.

The average follow up of the trials was 17 months, with a range between 2 to 50 months.

*Information on primary studies is extracted from the identified systematic reviews, not directly from the studies unless otherwise specified.

Summary of results

The information about the effects of a very low protein diet supplemented keto analogues is based on 12 randomized trials which included 1064 patients. Five trials measured the outcome death by any cause (584 patients) [14], [20], [28], [31], [33]; eight trials measured the outcome end stage kidney disease progression (849 patients) [14], [15], [17], [20], [28], [31], [33], [37]; four trials measured the outcome fall or deterioration of renal function (535 patients) [15], [20], [28], [33]; seven trials measured the outcome malnutrition (477 patients) [15], [19], [20], [28], [31], [33], [35]. No systematic review analysed the outcomes hospitalizations and cardiovascular death.

The summary of the results is as follows:

  • The use of very low protein diet supplemented keto analogues compared to low protein diet in pre dialysis patients may reduce mortality by any cause (low certainty evidence).
  • The use of very low protein diet supplemented keto analogues compared to low protein diet in pre dialysis patients reduces the progression to end-stage kidney disease.
  • The use of very low protein diet supplemented keto analogues compared to low protein diet in pre dialysis patients probably reduces the fall or deterioration of renal function.
  • The use of very low protein diet supplemented keto analogues compared to low protein diet in pre dialysis patients may make little or no difference in malnutrition (low certainty evidence).
  • No evidence was found that looked at cardiovascular death.
  • No evidence was found that looked at hospitalizations.



Follow the link to access the interactive version of this table (Interactive Summary of Findings - iSoF)

Other considerations for decision-making

To whom this evidence applies and to whom it does not apply.
  • These results apply to adult patients capable of following a strict diet, with chronic kidney disease in pre dialysis stage, with a glomerular filtration rate ≤30 mL/min/1,73m2.
  • These results may be applied to chronic kidney disease patients and estimated glomerular filtration rate >30 mL/min/1,73m2, but there are no studies that confirm its utility in these patients.
  • These results do not apply in patients with important comorbidities, such as systemic diseases, badly controlled hypertension and insulin-requiring diabetes.

About the outcomes included in this summary

  • The outcomes included in the summary of findings table are, according to the authors, those clinically relevant for decision making. This generally matches with what was reported by the systemic reviews, except for hospitalizations and cardiovascular death, which were not reported by any review.
  • As the outcome malnutrition was not measured directly, serum albumin level was used as an indirect parameter to estimate nutritional state because there is a correlation between serum albumin levels and mortality in chronic kidney disease [42].

Balance between benefits and risks, and certainty of the evidence

  • The benefits of a very low protein diet with ketoanalogues include the reduction in progression to end-stage chronic kidney disease (high certainty of evidence) and its use could reduce death by any cause, even though this result has a low certainty of evidence.
  • On the other hand, very low protein diet with ketoanalogues compared to low protein diet in chronic kidney disease in pre dialysis stage could result in little or no difference in malnutrition and probably reduces the fall or deterioration of glomerular filtration rate.
  • Considering the observed effects, the risk/benefit balance probably favours the use of a very low protein diet with ketoanalogues over a low protein diet alone.

Resource considerations

  • No systematic review identified made an analysis on the differences in costs between the interventions. Nonetheless, a very low protein diet with ketoanalogues represents an additional cost for the patient as it includes a new drug and extra nutritional and medical evaluations.

What would patients and their doctors think about this intervention 

  • Patients which manage to pay for this intervencion are, in general, happy with it, as it is relatively simple and it gives them a chance to delay renal replacement therapy and its repercussions.
  • The experience for their doctors has been positive, managing a good therapy adherence from their patients to the treatment. The main problem they see is the price of this therapy, as it must be paid by the patients.

Differences between this summary and other sources 

  • The conclusions of this summary are consistent with all included systematic reviews [2], [7], [17] which consider that there is a benefit of stepwise removal on the outcomes of pulp exposure, restoration failure and signs of pulp pathology. However, there is uncertainty given that the level of confidence of the evidence is low.
  • From clinical practice guidelines consulted [14], [15], [16], only the Ministry of Health of Chile guideline [16] mentions the two-step technique (stepwise) for the management of caries lesions in permanent teeth, and temporary vital and asymptomatic caries lesions that require operative treatment. It is recommended to perform partial caries removal therapies in one or two stages. 

Could this information change in the future? 

  • The outcomes death by any cause and malnutrition may change as new trials appear, as their certainty of evidence was low.
  • The outcome fall or deterioration of filtration rate may not change as new trials appear, as its certainty of evidence is moderate.
  • It is unlikely that the outcome progression to end-stage kidney disease changes as its results have a high level of certainty and consistency.
  • We found one systematic review in progress in PROSPERO [46] and three ongoing randomized controlled trials in International Clinical Trials Registry Platform [47], [48], [49], results which have not yet been published, which can contribute with new findings to the outcomes measured.

 

How we conducted this summary 

We collected all the relevant evidence for this question and presented it in an evidence matrix using automated and collaborative methods.

Follow the link to access the interactive versionKeto Analogues and Very Low Protein Diet in Pre Dialysis Chronic Kidney Disease

Notes

If new systematic reviews on this topic are published after the publication of this abstract, a "new evidence" notification will be displayed at the top of the matrix. While the project provides regular updates of these abstracts, users are invited to comment on the Medwave website or contact the authors by e-mail if they believe evidence warrants an earlier update.

After creating an Epistemonikos account, by saving the matrices, you will receive automatic notifications whenever there is new evidence that potentially answers this question.

This article is part of the Epistemonikos evidence synthesis project. It is elaborated with a pre-established methodology, following rigorous methodological standards and an internal peer review process. Each of these articles corresponds to a summary, called FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos), whose main objective is to synthesize the body of evidence of a specific question, in a friendly manner for physicians. The main resources are based on the Epistemonikos evidence matrix and the analysis of the result is based on the GRADE methodology. Further details of this FRISBEE elaboration method are described here.

The Epistemonikos Foundation is an organization that seeks to bring information closer to health decision-makers through the use of technologies. Its main source is the Epistemonikos database (www.epistemonikos.org).