Nutrition and Inflammation in CKD
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This document discusses inflammation and its link to malnutrition in chronic kidney disease (CKD) patients. It provides definitions and epidemiology around inflammation in CKD, noting that 30-60% of dialysis patients have elevated C-reactive protein (CRP) levels. CRP is a popular marker for monitoring inflammation. The pathophysiology section explains how inflammation can lead to protein-energy wasting (PEW) through decreased appetite and increased muscle breakdown. Interventions to break this link include optimizing renal replacement therapy, treating comorbidities like acidosis and diabetes, nutritional support through oral or parenteral supplements, and anti-inflammatory therapies targeting inflammatory sources or pathways. Future research needs include large intervention studies identifying specific treatment targets and
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Nutrition and Inflammation in CKD
- 2. Overview Epidemiology of Inflammation Pathophysiology Link to Malnutrition Clinical recognition Therapy Future
- 3. “Inflammario”- set on fire
- 4. 2 Pathways of inflammation Inciting Agent Inflammation removes it Healing Inciting Agent Inflammation can’t remove agent Systemic damage CKD
- 5. Definition of inflammation in CKD Elevation of CRP levels > 5mg/L for 3 months 30-60% of Dialysis patients in Europe and US Asians have a slightly lower incidence ! Am J Kidney Dis. 2000;35(3):469.
- 6. Why CRP is a popular choice? Stable with half life > 15 hours Easy to measure Produced by liver under IL-6 stimulus Binds to multiple phosphocholine ligands and aggregates them This in turn stimulates Alternate complement pathway Monitoring treatment Independent risk factor for mortality in CKD
- 9. More inflamed patients Progressed Faster through CKD stages
- 10. Markers of inflammation From the above, altered levels of CRP (>5mg/lit), IL6 (>7.2pg/ml) & albumin (<4g/dl) have been associated with increased mortality. In the setting of hypoalbuminemia, raised CRP & IL6 helps distinguish inflammation from malnutrition. Similarly, ferritin levels in excess of 800ng/ml with normal TSAT can help distinguish inflammation from iron overload.
- 11. 46 Markers and counting…… Broadly divided into Positive Negative CRP Albumin Transferrin IL-6 Ferritin
- 12. Why are CKD patients Inflamed?
- 14. Low S.Albumin Low Muscle mass Weight loss or Low BMI Protein Energy Wasting
- 15. Making a diagnosis of PEW in CKD… • Sr.Albumin < 3.8gms/dl • BMI < 23kg/m2 or >5% weight loss over 3 months • Deficient dietary intake • <0.8g/kg/day of protein for atleast 2 months in dialysis patients • <25kcal/kg/day for atleast 2 months ___________________________________________________________________________________ • The above values are mostly based on observational studies from western population. Lower cutoffs may be more suitable in Indian patients. • Scoring systems like SGA & MIS scores have been devised to bring more uniformity to the dx process. • These usually incorporate dietary intake, weight change, functional capacity, comorbities, albumin levels, symptoms & signs of wasting.
- 17. IL-6 , CRP increase muscle protein catabolism
- 19. Leptin Serotonin Neuropeptide –Y IL-6 TNF a IL-1beta Ghrelin Orexin Anorexia due to Inflammation Depression Cachexia
- 20. Inflammation PEW YES MIS/SGA score predicts Basic science evidence on TNF a,IL-6 Dialysis patients have intact Appetite . But weight loss Low Cholesterol level linked to High inflammatory markers in Dialysis NO Correlation Coefficient between albumin And CRP not precise [ <0.5] Non fluctutating S.Albumin levels unlike CRP S.Albumin directly reflects protein intake Independent of inflammation. S.Albumin improves with nutritional support
- 22. Interventions to Break the Unholy Nexus
- 23. Prevention & Rx of PEW in CKD Periodic Nutritional Screening & counselling • Weight • BMI • Albumin, • CRP • MIS score Optimizing RRT • Kt/V monitoring • Biocompatible dialyzers • Ultrapure water • Hemdodiafiltration Treating comorbidities • Acidosis correction • CHF Rx • Depression • DM management Removing inflammatory sources Nutritional Interventions • Oral nutritional supplements • IDPN Adjunct measures • Anabolic hormones • Antiinflammatory drugs • Orixogenics • Excercise Central venous catheters Rejected Grafts Clotted AVG
- 24. 1. Dietary intake in CKD Recommended dietary intake of proteins for patients (preferably from plant sources to restrict phosphorus intake): • 0.6-0.8g/kg/day in non dialysis CKD • 1.2g/kg/day in HD & PD patients Caloric intake of 30-35kcal/kg/day (including calories from PD fluids in PD patients). Sodium of 80-100mmol/day. Potassium <1mmol/kg/day (if elevated) Phosphorus 800-1000mg/day
- 25. 2. Optimization of RRT NCDS showed an association between higher time averaged urea levels & lower protein intake, suggesting a link between underdialysis & anorexia. These patients also had poorer outcomes Subequent studies (HEMO & ADEMEX) did not show a nutritional benefit for higher Kt/V. No benefit were reported for either more frequent HD (FHN trials) or with high flux dialyser (HEMO trial) In contrast, trials of hemodiafiltration did show positive signd (CONTRAST in terms of reduction in CRP & IL6 levels. RISCAVID in terms of improved cumulative survival)
- 26. 3. Treating comorbidities Metabolic acidosis • It increases protein catabolism via suppression of IGF1 signaling, activation of ubiquitin-proteasome pathways & stimulation of glucocorticoids. • In an RCT of 134 patients with stage 4 CKD, bicarbonate levels of 24mmol/l compared to 20mmol/l showed improved dietary protein & energy intake, mid-arm muscle circumference, serum albumin levels and slower progression of CKD. Diabetes • Secondary to insulin resistance/deprivation, more muscle protein breakdown. Especially important in PD patients due to extra glucose from the dialysate. • Diabetic gastroparesis might further decrease intake
- 27. 5. Oral & Parenteral nutrition When standard preventive measures fail, nutritional supplements can be tried. Response depends upon the baseline severity of PEW. Underlying inflammation DOES NOT hinder the beneficial effects of nutritional supplements. Route of administration doesn’t have a significant effect on the response to therapy (FineS trial) Optimal targets for protein & energy intake is >1.2g/kg/day & >35kcal/kg/day. Albumin is usually used to assess the response
- 30. IF Targeted Approaches Pathways Drug manipulation of cell response Source reduction of ligands Direct Suppression
- 31. Therapetics Cell response RAS blockade Anti inflammatory Statins CRP inhibition Vitamin D,E,Omega FA Anti oxidant, RAS inhibition Bardoxalone Nrf2 pathway inhibits NF-KB Growth Hormone Anabolism
- 32. Therapeutics Source redn P Inulin, Probiotics Reduction of endotoxin, IR,p Cresyl, Indole Sevelamer Binds adsorbs endotoxins Visit to Dentist Dental Plaques harbour infl.bacteria Visit to Psychiatrist IL-6 CRP associated with depression
- 33. Therapeutics Direct suppression Megesterol Acetate IL-1,6, TNF a inhibition, Improves appetite Etranercept Anti – TNF Pentoxyfyllin Inhibits TNF transcr Anakinra IL-1R antagonist
- 35. Future Large Scale intervention studies needed Specific targets should be identified Genetic influences to be uncovered Life style modifications important though difficult on long term basis
Editor's Notes
- To summarize, elevated circulating levels of TNF-α and fibrinogen and decreased SAlb are independent predictors of progression of CKD. These biomolecules could be useful in risk stratification and also, could be potential therapeutic targets. The associations of inflammatory biomarkers and kidney outcomes were stronger at higher levels of eGFR and thus, could possibly represent an opportunity for early intervention.
- Chronic kidney disease-induced protein degradation by the UPS. An initial step in the degradation cascade involves cleavage of the complex structure of muscle protein by caspase-3, which produces substrates for degradation. Protein substrates are conjugated to Ub by an ATP-dependent process involving the enzymes E1, E2 and E3. The selectivity of protein substrates principally depends on recognition of the protein to be degraded by specific E3 Ub-ligases (for example, TRIM63 for muscle proteins). After five Ub proteins are attached to the protein substrate, the complex can be recognized by the 26S proteasome, which releases Ubs, unfolds the protein substrate and ‘injects’ it into the 20S CP in which proteins are degraded to peptides. At this stage, caspase-3 also cleaves the 26S protease regulatory subunit 4 and 26S protease regulatory subunit 8, which are specific subunit proteins of the 19S proteasome RP. This reaction stimulates degradation of proteins in the 20S proteasome CP. Peptides released into the cytoplasm are degraded into amino acids. Abbreviations: CP, core particle; RP, regulatory particle; Ub, ubiquitin; UPS, ubiquitin–proteasome system
- Figure 2Patients survival curve showing CDV mortality adjusted for age, gender, and diabetes in 310 CKD stage 5 patients divided according to the presence of wasting (subjective global assessment – SGA≥2) and inflammation (CRP≥10 mg/l) at start of the dialysis treatment.