#NephMadness 2017: Nutrition Region

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Selection Committee Member for the Nutrition Region:

Kamyar Kalantar-Zadeh

Dr. Kalantar-Zadeh, MPH, PhD, is Professor and Chief of Nephrology & Hypertension at UC Irvine. He studied medicine in Germany and received advanced degrees in Epidemiology from the School of Public Health at UC Berkeley. He trained in SUNY Brooklyn and UCSF and is board certified in Internal Medicine, Nephrology, and Pediatrics. Dr. Kalantar-Zadeh is immediate past President of the International Society of Renal Nutrition & Metabolism and a member of the steering committee of the World Kidney DayFollow him @kamkalantar. 

Competitors for the Nutrition Region

Protein Restriction in CKD vs Feeding During Dialysis

Microbiome and the Kidney vs Omega 3 Fatty Acids

Didn’t NephMadness 2015 have nutrition in dialysis? Yes, but this is such an important area that there are plenty of concepts in the field that we feel there will always be room to mine nutrition for new ideas.

Protein Restriction in CKD

First up is protein restriction for CKD. This is certainly an old idea. Nephrologists have been arguing for the ideal protein intake in pre-dialysis CKD forever.

Decreased protein in the diet decreases the nitrogen load than needs to be excreted and so should be good for the kidney. In fact a low-protein diet reduces proteinuria. Gansevoort showed that a low-protein diet could reduce nephrotic-range proteinuria by 17% and was additive on top of ACEi in an uncontrolled trial. Unfortunately, most of the positive trials of protein restriction are, small, uncontrolled, and short. The largest controlled trial that looked at dietary protein and proteinuria found no relationship.

Table 4 from Walser et al, AJKD, © National Kidney Foundation.

This becomes especially stark when looking at the MDRD trial of 1994 which randomized 840 people to usual-protein or low-protein diets. The study actually was two different studies fused into one.

  1. The first study was called Study A. Patients with a measured GFR (mGFR) of 25-55 ml/min were randomized to a diet of either 1.3 g protein/kg/d or 0.58 g protein/kg/d.
  2. In Study B, 255 patients with a mGFR of 13-24 ml/min were randomized to 0.58 g protein/kg/d or 0.28 g protein/kg/d with a keto acid-amino acid supplement.

After a mean follow-up of 2.2 years there no difference in the loss of GFR in Study A patients and there was no difference in the onset of ESRD or death in Study B patients.

The Northern Italian Cooperative Trial also randomized CKD patients to 0.6 g/kg/d or 1.0 g/kg/d and followed them for 2 years. The end point was doubling of creatinine or dialysis. Changes in creatinine is not an ideal end-point since there is an interaction between protein intake and renal creatinine handling. This is why MDRD used iothalamate clearance to measure GFR. The results were inconclusive, with a trend toward better renal survival (P=0.06) that was driven primarily by people with higher pre-randomization GFR. The authors concluded:

The results of this trial offer little, if any, support for the view that protein restriction helps to retard progression of chronic renal failure. These findings could lead to an improvement in patients’ quality of life, since the use of low-protein foods causes a lot of psychological, social, and economic problems.

The 1-2 punch of MDRD and The Northern Italian Cooperative Trial largely put to bed enthusiasm for low-protein diets, though the MDRD authors walked away from many of their own conclusions in a series of subsequent papers that looked at per-protocol and post-hoc analysis. (See a summary of these papers in Dietary Protein Restriction and the Progression of Chronic Renal Disease. What Have All of the Results of the MDRD Study Shown?) In this article the authors present per-protocol results (as opposed to the intention-to-treat analysis in the original manuscript). Here they found that the GFR deterioration was slower by 1.15 ml/min/y for every 0.2 g/kg/d decrease in protein intake. Looking at ESRD, the same reduction in protein intake of 0.2 g/kg/d was associated with a 0.51 relative risk of ESRD or death.

Another interesting post-hoc analysis of MDRD looked at the mGFR and creatinine before patients started dialysis:

Adapted from Levey et al, AJKD, © National Kidney Foundation.

There was clearly an association with lower protein intake and higher creatinine (lower GFR) at the time patients start dialysis. The lower GFR (and higher creatinine) was not associated with increased uremic symptoms, in fact the patients at the lowest protein intake had the fewest symptoms at the start of dialysis. It seems that the physicians just looked at the terrible clearance and decided to start dialysis despite a relative lack of symptoms.

That last conclusion becomes especially compelling with the recent shift in dialysis decision making. Since the Ideal Trial showed no advantage of early start dialysis (GFR 10-14 ml/min compared to a later start (5-7 ml/min, but 75% started at GFR > 7 ml/min primarily, 73%, due to uremia) the importance of the decreased symptoms of a low-protein diet become more important. 

Now that there is RCT data showing that starting dialysis with symptoms rather than a GFR provides the same outcome, the logical extrapolation is that interventions that minimize uremic symptoms should be adopted to delay dialysis, and low-protein diets seem to fit that bill.

One concern is what happens after the patient starts dialysis. Does the low-protein diet have a hangover that influences outcomes after ESKD? There is some conflicting information here. The MDRD team went back and did long term follow-up of the B study (low GFR cohort randomized to low-protein or very-low-protein diet) and found a 2-fold increased risk of death at 6 years!

On the other side are a pair of observational trials. Aparicio published the results of 239 patients who used a low-protein diet and found low mortality on dialysis. Coresh had similar results in an earlier cohort of 67 patients who did not have increased dialysis mortality compared to historical controls.

In the end it is difficult to promote a therapy that has repeatedly failed in intention-to-treat RCTs but looks like a star in post-hoc and per-protocol analysis, but the world of CKD has progressed in the last 30 years and maybe it is time for another look at low-protein diets in CKD. Is that MDRD 2 Fast 2 Furious I hear?

Feeding During Dialysis

Though protein intake in CKD is contentious, once patients go on dialysis there is consensus that patients need a high-protein diet and that perhaps the most powerful predictors of bad outcomes is a low albumin. But how we address this has resulted in a multitude of solutions from oral supplements to intradialytic parenteral nutrition. One of the oldest, and simplest solutions is to stop fasting our patients for 4 hours, three times, every week. Why don’t we feed patients during dialysis? Eating during dialysis can cause dialytic hypotension, and people are appropriately concerned about other feeding risks, such as aspiration and choking, but the risks are irrelevant if there are no advantages. So how does eating during dialysis help patients?

Advanced CKD changes protein metabolism. Normally patients live in nitrogen balance: the amount of nitrogen they consume, as part of protein, equals the amount of nitrogen they excrete. CKD patients have low-protein synthesis and breakdown so that net nitrogen balance remains neutral despite decreased intake. CKD itself is not a catabolic state (see Lim and Koppel for a review of the science showing this). Patients with advanced CKD can remain in protein balance but that low turnover state is fragile and physiologic stress can rapidly put patients into negative protein balance. This happens with hospitalization: Ikizler found that two thirds of dialysis patients go into negative protein balance within a day or two of hospitalization.

Dialysis is another physiologic stress that drives dialysis patients into negative nitrogen balance. Boraj et al performed careful nitrogen balance studies every day of the week for dialysis patients on a low- or high-protein diet. On the low-protein diet, patients were consistently in negative balance, but even on the high-protein diet, on days patients received dialysis they dipped into negative nitrogen balance.

The key question here, though, is not whether patients go into negative nitrogen balance with dialysis but can we reverse it by feeding them and does reversing it provide tangible benefits to patients. Using carbon-13-labelled valine to measure catabolism, Veeneman, et al found that:

…consumption of a protein- and energy-enriched meal abolished the negative effect of dialysis on whole body protein balance. This offers a possibility for nutritional intervention in preventing protein energy malnutrition. It also shows that, even though a meal during dialysis may increase the occurrence of hypotension, it is metabolically useful and should therefore be standard practice.

This has been replicated by Pupim et al using a similar technique.

Longer term studies have shown sustained improvement in nutritional markers with oral intake during dialysis. Cagler et al counseled malnourished dialysis patients on improving protein intake for 3 months and found no improvement in albumin, pre-abumin, or SNA. Then patients were given a can of Nepro (237 mL) with each dialysis. In the subsequent 3 months, albumin, pre-albumin, and subjective global assessment all improved. Of note, patients that were unable to consume 75% of the intradialytic calories were dropped from the study. This ultimately negated 27 of the initial 85 patients enrolled.

Using a double-blind RCT, Eustace, et al was unable to get a statistically significant improvement in albumin by giving oral amino acid supplements 3 times a day. However, HD patients did experience a 0.22 g/dL improvement in albumin. This was similar to the results of a meta-analysis of 18 studies that found enteral nutrition during dialysis was associated with a 0.23 g/dL improvement in albumin.

In 2007 the largest trial of feeding during dialysis was published. The FINE Study pitted parenteral plus oral intradialytic nutrition against oral supplemental nutrition alone. Patients were randomized to each group and the intervention was carried out for a year and the results were based on 2 years of follow up. About a third of patients discontinued parenteral nutrition. There was no difference in mortality, hospitalization rate, or the reasons for hospitalizations between groups. Unfortunately, The FINE Trial did not have a true control group without nutritional supplementation, limiting the conclusions that could be drawn from the trial, except that the route of administration does not seem to alter patient outcome. 

Then coming this past fall was FrEDI, a RCT of high-protein meals versus low-protein meals provided during dialysis. 110 patients with an albumin south of 4 and who were “cleared to eat” during dialysis were enrolled.

  • The low-protein group received a meal with less than a gram of protein, less than 30 mg of phosphorus, and less than 50 Calories.
  • The high-protein group received a meal with 50-55 grams of protein, 400-450 mg of phosphorus, and 850 Calories. They also received a slug of 500-1,500 mg of lanthanum.

Meals were to be eaten in the first 60 minutes of dialysis to minimize the risk of hypotension. The primary outcome was an increase in serum albumin of ≥0.2 g/dL while maintaining a target serum phosphorus in the range of 3.5–

Of note, but not surprising, people liked the high-protein food better than the low-protein salads. The low-protein diet was also associated with increased inflammatory markers interleukin-6 and TNF-α.

This is a Dave’s Double Cheeseburger from Wendy’s. It costs $5 and has approximately as much protein as the FrEDI meal (49 grams in the burger compared to 50-55 grams in the study, 415 mg of phosphorus compared to 400-450 mg in the study). That protein consumption increased albumin of 0.2 g/dL. This increase in albumin is estimated to reduce mortality by 16-30% and hospitalization by 25%. In 2014 there were 95,000 deaths among dialysis patients, a 16% drop is 15,000 lives saved. That is for an intervention that costs $60/month. Sensipar, a drug that despite a comprehensive, double blind, randomized controlled trial showing that it does not reduce mortality, costs about $800 a month. Instead of more pills maybe we should think about ordering them a burger.

Microbiome and the Kidney

“We should think of each host and its parasites as a superorganism with the respective genomes yoked into a chimera of sorts” – late Joshua Lederberg, Nobel laureate, calling for an end to the war against microbes

I am human, or am I bacteria? Do we contain multitudes? Indeed, we all are bacteria: bacterial cells, at 100 trillion in each of us, outnumber human cells 10-fold, and encode over 3 million genes – over a 100-fold more unique genes than the human genome. There are approximately 160 different bacterial species in each of us, and a staggering 1000 to 1200 bacterial species shared across humanity. These bacteria reside throughout our body, but the highest concentration is found in our gut. From lactobacilli and helicobacter in our stomachs, staph, strep, and lactococcus in the duodenum and jejunum, bacteroides, and clostridium in the ileum, to a large variety including bacteriodetes and firmicutes in our colon, our gut is teeming with life. The fact that the microbiota weighs in at 1-2 kg, has synthetic and metabolic properties, has led some to call it another ‘organ’. The National Institute of Health has invested 170 million dollars in the Human Microbiome Project. But what do the microbes in the gut have to do with the kidneys?

How do we influence the microbiome and how does it influence us? Diet and genetics play a role, as does bacterial exposure in developmental years and antibiotic exposure. Once established though, the microbiome remains fairly stable for a particular individual. The microbiome in patients with chronic conditions (eg metabolic syndrome and diabetes, atherosclerosis, advanced CKD) is different from healthy individuals. This has led to chronic diseases being labelled as gut ‘dysbiosis’ (as against ‘symbiosis – a state of mutual harmony), with fewer and different bacterial species seen in rat and human CKD. This could be due to decreases in digestive capacity, slowing intestinal transit and secretion of ammonia and urea into the gut.

More importantly, uremic toxins, such as indoxyl sulfate, p-cresol sulfate and trimethylamine N-oxide, are generated by gut bacteria. There is breakdown of the colonic epithelial tight junctions in CKD, enabling translocation of endotoxins and other such noxious luminal contents into the intestinal wall and systemic circulation, even potentially contributing to the inflammatory state seen in CKD.

Figure 2 from Ramezani et al, AJKD, © National Kidney Foundation.

Oxalobacter formigenes is just the most well known of several oxalate-degrading microbes (eg, lactobacillus and bifidobacterium spp), the presence of which is associated with lower rates of kidney stones. Interestingly, the melamine-contaminated milk scandal, which caused nearly 300,000 infants to develop kidney stones in China in 2008, was due to melamine and its co-crystallizing chemical derivative cyanuric acid. The conversion of melamine to cyanuric acid is a microbial transformation by Klebsiella in the gut. This can be attenuated by antibiotic treatment.

To see how unexpected the role of the microbiome may play in the future of CKD one need look no further than artificial sweeteners. These add sweetness without calories by failing to be absorbed by the gut. By not being absorbed the full dose is exposed to the gut microbiome. In a clever series of experiments, Suez, et al. showed that these artificial sweeteners leads to glucose intolerance and that glucose intolerance is due to changes in the gut microbiome.

How can one modulate the microbiome and re-establish symbiosis? Several trials have been conducted with administration of prebiotics (nondigestible food ingredient that selectively stimulates growth of one or a limited number of colonic bacteria) and probiotics (live microorganisms such as Bifidobacteria spp, lactobacilli, and streptococci) in animals and human and show beneficial effects on surrogate markers for atherosclerosis and inflammation and decrease in circulating uremic toxins. Not all are positive however, and challenges include delivering the right species (fewer than 10 have been tried out of thousands of possible species) and delivering the right dose to the right place for effective colonization. Precision medicine may be important to tailor the bacterial species and dose to the individual’s existing microbiome. Another interesting approach is to wipe the slate clean by using antibiotics, and then introducing the probiotics for effective re-colonization. Lastly, there is of course, the DIY approach, with a blender and the appropriate sample.

Omega 3  Fatty Acids in CKD

This last concept is trying to take the lid off some nutrition topics that might have been flying under the radar. Take fish oil for example. Since the late 70s fringes of the nutritional science world have been beating the omega-3 fatty acid drum. There are two essential fatty acids, alpha-linolenic acid (an omega-3 fatty acid) and linoleic acid, an omega-6 fatty acid.

These are polyunsaturated fatty acids (PUFA) and are the key substrates for the synthesis of prostaglandins, leukotrienes and anadamides. The typical American diet has plenty of PUFA but there is concern that the ratio of omega-6 to omega-3 fatty acids may be non-optimal. The typical ratio is 15:1 omega-6:omega-3, with some health experts calling for ratios closer to 1-4:1. There is some evidence that omega-6 is proinflammatory and omega-3 are anti-inflammatory. Eskimos traditionally had diets rich in omega-3 fatty acids but low rates of heart disease, leading people to suspect there may be a causal relationship between the two factors. Then in 1999 the GISSI-Prevenzione Trial showed that a pill with 850 mg of omega-3 fatty acids taken daily reduced the composite of death, MI, and stroke in an unblinded RCT. Despite this being an unblinded, secondary prevention trial it kicked off the fish-oil revolution.

No one will ever forget the short but bloody fish oil revolution.

This data was replicated by the Japan Eicoapentanoic Acid Lipid Intervention Study, another open-label RCT. Then the GISSI team came back and showed a 9% reduction in total mortality with fish oil in patients with NYHA class 2-4 CHF in a blinded placebo controlled trial.  Subsequent (and blinded) data was less kind to omega-3 fatty acids and fish oil. The Alpha-Omega Trial was a double blind RCT that found no advantage in secondary prevention of major cardiovascular events. The Risk and Prevention Study Collaborative Group randomized 12,513 patients with CV risk factors to omega-3 fatty acid supplements and couldn’t find any effect even after 5 years. Same for the SU.FOL.OM3 trial, the OMEGA trial, and the ORIGIN trial all of which found no benefit of omega-3 fatty acids on cardiovascular end points. This was sealed with a meta-analysis of 20,485 patients from 14 RCT which found no benefit of fish oil in secondary prevention of cardiovascular disease.

Fish oil broke into the nephrology bubble with Donadio’s buzzerbeater in the NEJM. He randomized patients with biopsy proven IgA and 1-3 g of proteinuria to 12(!) g of fish oil or placebo daily for 2-years. The results were statistically significant and clinically compelling with reductions in disease progression (increased creatinine by 50%) and ESKD.

Donadio’s study initiated a race to replicate and verify the findings. This has not happened. A typical study is the Southwest Nephrology Pediatric Study Group. They randomized patients with IgA to prednisone, fish oil, or placebo and were unable to find any difference among the treatments.The last word on IgA nephropathy is still probably a meta-analysis by John Dillon that showed no significant treatment effect and that a difference in follow-up among trials was responsible for much of the variability in results.

Outside of IgA, fish oil and omega-3 fatty acids have poked their head into dialysis outcomes. Noori et al looked at dietary omega-3 intake and survival in a cohort of 145 HD patients. She found that as the the ratio of omega-6 to omega-3 went up, so did patient’s CRP, however even after 6 years of follow-up they could not find a significant relationship with PUFA and survival. However, Lok et al, in a trial focused on AV graft survival, did find a reduction in cardiovascular events with fish oil supplements. Additionally the blood pressure was lowered 3.61/2.17 in the fish oil group compared to a rise of 4.49/0.13 in the placebo group (P=0.01 for systolic, P=0.13 for diastolic). The reduction in blood pressure was in addition to a reduction of 1.7 blood pressure medications with fish oil versus a reduction of  0.6 medications with placebo (P<0.001).

Recently, Irish et al looked at supplementing 4 g of fish oil per day following fistula placement in an attempt to reduce fistula failure (thrombosis, abandonment, or cannulation failure). After screening they successfully randomized 284 to fish oil and 283 to a matching placebo. Patients that were not on aspirin were further randomized to either 100 mg of ASA or matching placebo. Unfortunately, there was no effect with either agent.

Of note patients with diabetes had significantly worse fistula survival if they were randomized to fish oil (p=0.03).

This builds on conflicting data on dialysis AV grafts. Schmitz et al randomized 24 patients to 4 g of fish oil or matching placebo after placement of an AV graft. The primary patency skyrocketed from 15% to 75% with the addition of the fish oil. The above-mentioned Lok trial randomized 201 patients to 4 g of fish oil or matching placebo. The larger study just missed showing an effect, 48% with fish oil versus 62% loss of native patency with placebo (RR 0.78 with fish oil; 95% CI, 0.60-1.03; P=0.06). A number of secondary outcomes of vascular access patency were significantly reduced by the fish oil.

The ongoing VITAL trial of 25,800 men and women should provide more information on the use of omega-3 fatty acids for prevention of cancer and cardiovascular disease. Regarding vascular access and other dialysis specific outcomes, the future of fish oil and omega-3 fatty acids is unclear.

– Post written and edited by Joel Topf (@kidney_boy) and Swapnil Hiremath (@hswapnil).

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