The nutritional status of patients with chronic kidney disease is generally compromised and requires dietary adjustments. This review considers several aspects of the nutritional management of chronic kidney disease in adults.

https://www.nejm.org/doi/suppl/10.1056/NEJMra1700312/suppl_file/nejmra1700312_appendix.pdf

Nutritional Management of Chronic Kidney Disease

Chronic inflammation is a non-traditional risk factor for cardiovascular mortality in the chronic kidney disease (CKD) population. In recent years, the gastrointestinal tract has emerged as a major instigator of systemic inflammation in CKD. Postmortem studies previously discovered gut wall inflammation throughout the digestive tract in chronic dialysis patients. In CKD animals, colon wall inflammation is associated with breakdown of the epithelial tight junction barrier ('leaky gut') and translocation of bacterial DNA and endotoxin into the bloodstream. Gut bacterial DNA and endotoxin have also been detected in the serum from CKD and dialysis patients, whereby endotoxin levels increase with the CKD stage and correlate with the severity of systemic inflammation in the dialysis population. The CKD diet that is low in plant fiber and symbiotic organisms (in adherence with low potassium, low phosphorus intake) can alter the normal gut microbiome, leading to overgrowth of bacteria that produce uremic toxins such as cresyl and indoxyl molecules. The translocation of these toxins from the 'leaky gut' into the bloodstream further promotes systemic inflammation, adverse cardiovascular outcomes and CKD progression. Data are lacking on optimal fiber and yogurt consumption in CKD that would favor growth of a more symbiotic microbiome while avoiding potassium and phosphorus overload. Prebiotic and probiotic formulations have shown promise in small clinical trials, in terms of lowering serum levels of uremic toxins and improving quality of life. The evidence points to a strong relationship between intestinal inflammation and adverse outcomes in CKD, and more trials investigating gut-targeted therapeutics are needed.

/pdf/the-gut-as-a-source-of-inflammation-in-chronic-kidney-1myexu30nr.pdf

The Gut as a Source of Inflammation in Chronic Kidney Disease

The accurate definition and staging of chronic kidney disease (CKD) is one of the major achievements of modern nephrology. Intensive research is now being undertaken to unravel the risk factors and pathophysiologic underpinnings of this disease. In particular, the relationships between the kidney and other organs have been comprehensively investigated in experimental and clinical studies in the last two decades. Owing to technological and analytical limitations, these links have been studied with a reductionist approach focusing on two organs at a time, such as the heart and the kidney or the bone and the kidney. Here, we discuss studies that highlight the complex and systemic nature of CKD. Energy balance, innate immunity and neuroendocrine signalling are highly integrated biological phenomena. The diseased kidney disrupts such integration and generates a high-risk phenotype with a clinical profile encompassing inflammation, protein-energy wasting, altered function of the autonomic and central nervous systems and cardiopulmonary, vascular and bone diseases. A systems biology approach to CKD using omics techniques will hopefully enable in-depth study of the pathophysiology of this systemic disease, and has the potential to unravel critical pathways that can be targeted for CKD prevention and therapy.

/pdf/the-systemic-nature-of-ckd-1sywd5l5xl.pdf

The systemic nature of CKD

Role of the Gut Microbiome in Uremia: A Potential Therapeutic Target

Background and objectives The generation of key uremic nephrovascular toxins, indoxyl sulfate (IS), and p-cresyl sulfate (PCS), is attributed to the dysbiotic gut microbiota in CKD. The aim of our study was to evaluate whether synbiotic (pre- and probiotic) therapy alters the gut microbiota and reduces serum concentrations of microbiome–generated uremic toxins, IS and PCS, in patients with CKD. Design, setting, participants, & measurements Predialysis adult participants with CKD (eGFR=10–30 ml/min per 1.73 m2) were recruited between January 5, 2013 and November 12, 2013 to a randomized, double–blind, placebo–controlled, crossover trial of synbiotic therapy over 6 weeks (4-week washout). The primary outcome was serum IS. Secondary outcomes included serum PCS, stool microbiota profile, eGFR, proteinuria-albuminuria, urinary kidney injury molecule-1, serum inflammatory biomarkers (IL-1β, IL-6, IL-10, and TNF-α), serum oxidative stress biomarkers (F2-isoprostanes and glutathione peroxidase), serum LPS, patient-reported health, Gastrointestinal Symptom Score, and dietary intake. A prespecified subgroup analysis explored the effect of antibiotic use on treatment effect. Results Of 37 individuals randomized (age =69±10 years old; 57% men; eGFR=24±8 ml/min per 1.73 m2), 31 completed the study. Synbiotic therapy did not significantly reduce serum IS (−2 μmol/L; 95% confidence interval [95% CI], −5 to 1 μmol/L) but did significantly reduce serum PCS (−14 μmol/L; 95% CI, −27 to −2 μmol/L). Decreases in both PCS and IS concentrations were more pronounced in patients who did not receive antibiotics during the study (n=21; serum PCS, −25 μmol/L; 95% CI, −38 to −12 μmol/L; serum IS, −5 μmol/L; 95% CI, −8 to −1 μmol/L). Synbiotics also altered the stool microbiome, particularly with enrichment of Bifidobacterium and depletion of Ruminococcaceae. Except for an increase in albuminuria of 38 mg/24 h (P=0.03) in the synbiotic arm, no changes were observed in the other secondary outcomes. Conclusion In patients with CKD, synbiotics did not significantly reduce serum IS but did decrease serum PCS and favorably modified the stool microbiome. Large–scale clinical trials are justified.

Synbiotics Easing Renal Failure by Improving Gut Microbiology (SYNERGY): A Randomized Trial

Reduced GFR in patients with CKD causes systemic accumulation of uremic toxins, which has been correlated with disease progression and increased morbidity. The orally administered spherical carbon adsorbent AST-120 reduces systemic toxin absorption through gastrointestinal sequestration, which may slow disease progression in these patients. The multinational, randomized, double-blind, placebo-controlled Evaluating Prevention of Progression in CKD (EPPIC)-1 and EPPIC-2 trials evaluated the effects of AST-120 on the progression of CKD when added to standard therapy. We randomly assigned 2035 adults with moderate to severe disease (serum creatinine at screening, 2.0–5.0 mg/dl for men and 1.5–5.0 mg/dl for women) to receive either placebo or AST-120 (9 g/d). The primary end point was a composite of dialysis initiation, kidney transplantation, and serum creatinine doubling. Each trial continued until accrual of 291 primary end points. The time to primary end point was similar between the AST-120 and the placebo groups in both trials (EPPIC-1: hazard ratio, 1.03; 95% confidence interval, 0.84 to 1.27; P=0.78) (EPPIC-2: hazard ratio, 0.91; 95% confidence interval, 0.74 to 1.12; P=0.37); a pooled analysis of both trials showed similar results. The estimated median time to primary end points for the placebo groups was 124 weeks for power calculations, but actual times were 189.0 and 170.3 weeks for EPPIC-1 and EPPIC-2, respectively. Thus, disease progression was more gradual than expected in the trial populations. In conclusion, the benefit of adding AST-120 to standard therapy in patients with moderate to severe CKD is not supported by these data.

/pdf/randomized-placebo-controlled-eppic-trials-of-ast-120-in-ckd-2jzbetops5.pdf

Randomized Placebo-Controlled EPPIC Trials of AST-120 in CKD

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Randomized Placebo-Controlled EPPIC Trials of AST-120 in CKD