background

Chronic kidney disease (CKD), identified by a blood test for creatinine, is a progressive loss of kidney function over months or years. Higher levels of creatinine indicate lower filtration rate which results from reduced capability of the kidneys to remove waste products. The treatments of CKD differ largely from stage 1, where just slight kidney damage noted, to stage 5, a transplant or dialysis is required. Despite recent advances in the technology of renal replacement therapy and the treatment of the uremic state, the prognosis of patients with advanced CKD remains poor. Patients with advanced CKD may have multiple nutritional or metabolic derangements as their kidney disease progresses - a condition collectively termed protein-energy wasting and present in approximately 20-50% of these patients.¹ Progression of this situation causes deterioration in mineral homeostasis, along with various abnormalities, including bone calcification and calcifications of vascular tissues which contribute to several cardiovascular diseases may occur as well.^2,3

key words: Chronic kidney disease, nutrition support, protein-energy wasting

Introduction

CKD is associated with oxidative stress and inflammation which contribute to progression of kidney disease and its numerous complications.⁴ Patients with CKD show signs of inflammation, presented by Kimmel et al.: mean concentrations of most cytokines are several-fold higher in these patients than in healthy people.¹ Other studies have shown a very high prevalence of increased concentrations of C-reactive protein (CRP).¹ Apparent disruption of the colonic epithelial barrier structure and significant alteration of the colonic bacterial flora in humans with advanced CKD was noted.⁴ The observed disintegration of the intestinal epithelial barrier complex probably result in the development of systemic inflammation by enabling influx of endotoxin and other harmful luminal contents into the systemic circulation.⁴

Hemodialysis, a procedure used to regulate chemical balance and remove free water and waste products from the blood, is a common practice for patients with advanced CKD. Hemodialysis, can be applied for inpatient or outpatient, facilitates control of hyperphosphatemia without having major effects on calcium or parathyroid hormone concentration.⁵ However, this procedure may have an adverse impact on the immunological, nutritional, and emotional status of patients,⁶ and cause vitamin D deficiency⁷ and cardiovascular disease.⁸ The hemodialysis procedure is also associated with the activation of an inflammatory cascade as evidenced by increases in CRP, IL-6 and fibrinogen synthetic rate.¹ Protein or caloric malnutrition, another problem in chronically haemodialysed patients, is an independent risk factor for increased mortality in these patients.⁹

Accordingly, constant evaluation of nutrition situation of CKD patients, and appropriate nutrition support and antiinflammatory interventions may be necessary as medical treatment options to improve the high mortality and morbidity in patients with advanced CKD.

Nutrition support

Hyperphosphatemia is a common problem for CKD patients, and more frequent and longer session length of hemodialysis, 6-8 hours a day and six times per week, may offer better control and allow more liberal and freedom from phosphorus binders.⁵ Yet hemodialysis may have negative impact on nutrition or inflammation which deters aggressive use for these patients.⁶ According to the study presented by Frazao JM et al: ¹⁰ In cases where calcium overload and vascular calcification are concerned, lanthanum carbonate and sevelamer offer equivalent lowering of serum phosphorus and often effectively achieve phosphorus targets. Vitamin D deficiency is another common issue in hemodialysis patients, and appropriate Vitamin D supplement may suppress chronic inflammation and reduce mortality as well.⁷

Limitation of ingested protein, particularly from animal sources, is crucial in order to slow the progression of CKD and impaired renal function. On the contrary, patients with CKD receiving hemodialysis or peritoneal dialysis, have an increased demand for protein.¹¹ Protein energy malnutrition is common in patients with advanced CKD, especially those receiving hemodialysis treatment.¹² Hypercatabolism in dialysis patients is related to intradialytic loss of amino acids as well as cytokine activation. ¹³ Consequently, nutrition support is critical for these patients, and intradialytic nutrient supplementation increases protein synthesis, although not attenuating muscle protein catabolism.¹³

The protein and calorie intake of patients with ESRD should meet the increased requirements after initiation of dialysis, more than 1.2 g/kg/day and 30 kcal/kg/day, respectively.¹ Oral nutritional supplement is preferred, despite parenteral administration of nutrients during the hemodialysis procedure has been shown to be a safe approach.¹ According to previous studies ¹ - oral vs. oral plus parenteral, does not have any significant effect on survival in patients with CKD having protein-energy wasting. Therefore, net anabolism during hemodialysis may be accomplished only by providing nutrients as well as inhibiting apparent inflammatory signals.¹³

Anti-inflammatory interventions

As kidney function declines, there is a progressive deterioration in mineral homeostasis, along with various abnormalities, including bone disease and vascular calcification,² oxidative stress and systemic inflammation play a major role in progression of CKD and its numerous complications.⁴ Finally, CKD results in disruption of the intestinal epithelial barrier complex and relocation of microbial flora-leading to inflammation and uremic toxicity.⁴

A bisphosphonate is useful in prevention of vascular calcification which contributes to several cardiovascular diseases³ in former studies. Pentoxifylline and resistance exercise are commonly used antiinflammatory interventions shown to have an effect on nutritional markers in patients with CKD. Another study reported that- pentoxifylline, known to block tumor necrosis factor release, modulates whole-body protein kinetics in patients with stages IV-V CKD.¹ Angiotensin- converting enzyme inhibitors, fish oil, simvastatin, vitamin E, and certain antioxidants may have similar anti-inflammatory effect in CKD patients.^1,14 In addition, combined administration of [gamma]-tocopherol and docosahexaenoic acid over 3 months resulted in significant decreases in IL-6 and white blood cell counts in patients with CKD.¹

Discussions

Moderate to advanced CKD is associated with increased oxidative stress burden which leads to formation of advanced glycosylation end-products (AGEs). The interaction of AGEs with their receptors leads to the increased production of interleukin (IL)-6 by monocytes and indirectly to the excess formation of CRP in the liver, thus participating in the genesis of inflammation.¹ Hemodialysis is commonly used to regulate chemical balance and remove free water and waste products from the blood. However, this procedure may cause vitamin D deficiency⁷ and cardiovascular disease⁸ and have an adverse impact on the patients' immunological, nutritional, and emotional status.⁶ In addition, hemodialysis is also involved in the activation of an inflammatory cascade as evidenced by increases in CRP, IL-6 and fibrinogen synthetic rate,¹ thus appropriate use of hemodialysis is essential for CKD patients.

Proinflammatory cytokines play important roles in muscle catabolism in models of inflammatory diseases, and in surgical patients with sepsis where abundant levels of proinflammatory cytokines are considered to be the feature of the disease leading to increased whole-body protein catabolism.¹ Anorexia or suppression of nutrient intake, or even a decrease in voluntary activity requiring bed rest caused by chronic inflammation are other well established metabolic effect of inflammation. ¹ The above-mentioned drugs, such as fish oil, vitamin E or simvastatin,¹⁴ are appropriate options for anti-inflammation. Parenteral nutrition, feeding a person intravenously and bypassing the usual process of eating, is commonly indicated to prevent the adverse effects of malnutrition in CKD patients who are unable to obtain adequate nutrients by oral or enteral routes. Intradialytic parenteral nutrition (IDPN) which increases protein supplementation, although not attenuate muscle protein catabolism, can be a feasible alternative. ¹³ By continuing a focus on nutrition parameters, such as albumin and body mass index,¹¹ we will be able to early identify and intervene upon those who are failing to achieve appropriate nutrition goals.

CKD patients on chronic hemodialysis have a higher incidence of protein-energy malnutrition due to two major factors: dialytic removal of amino acids averages 10-12 g per hemodialysis treatment, and low dietary protein intake of 0.94-1g/kg/day which is lower than 1.2 g/kg/day necessary to ensure positive nitrogen balance in stable patients with advanced CKD.¹² Malnutrition is a strong predictor of mortality and morbidity in this population, with the prevalence rate of about 18-70%,¹² IDPN is an effective option for management of malnutrition in these patients if oral or enteral feeding is not feasible.

Although IDPN is an effective management of malnutrition in hemodialysis patients, the perfect way for providing nutrition support in these patients is oral or enteral feeding because of lower infection risk, lower cost and convenience. According to a recent study presented by Jesse C.,¹² Criteria for initiating IDPN in hemodialysis patients include: those having severe malnutrition, with dietary intake protein < 0.8 g/kg/day and/or calorie < 25 Kcal/kg/day; serum albumin <3.4 g/dL (3 month rolling average); inability to administer or tolerate adequate food or enteral feeding; anorexia caused by the uremic state; gastroparesis; altered taste sensation; and weight loss greater than 20% of usual body weight.

According to a recent study provided by Feldt-Rasmussen et al. - administration of recombinant human growth hormone for six month results in improvements in lean body mass and serum albumin in CKD patients receiving hemodialysis treatment with protein-energy wasting.¹ However, potential side-effects of this agent were observed in these patients, and further studies are needed for its widespread use.

Conclusion

Continuous evaluation of nutrition status of CKD patients, especially those receiving hemodialysis, is one important part of medical treatment. Early identification of those suffering from malnutrition, and appropriate nutrition support and anti-inflammation intervention are essential for improving patient's health as well as saving medical costs.

References:

1. Ikizler TA: Nutrition, inflammation and chronic kidney disease. Current Opinion in Nephrology and Hypertension 2008; 17(2): 162-7.

2. Tanaka H, Komaba H, Koizumi M et al: Role of uremic toxins and oxidative stress in the development of chronic kidney disease-mineral and bone disorder. Journal of Renal Nutrition 2012; 22(1):98-101.

3. Mori H, Okada Y, Tanaka Y et al: Kidney and bone update: the 5-year history and future of CKD-MBD. Bisphosphonates treatment for chronic kidney disease-mineral and bone disorder. Clinical Calcium 2012; 22(7):1034-42.

4. Vaziri ND: CKD impairs barrier function and alters microbial flora of the intestine: a major link to inflammation and uremic toxicity. Current Opinion in Nephrology and Hypertension 2012; 21(6): 587-92.

5. Daugirdas JT, Chertow GM, Larive B et al: Effects of frequent hemodialysis on measures of CKD mineral and bone disorder. Journal of the American Society of Nephrology 2012; 23(4):727-38.

6. Wang LJ, Wu MS, Hsu HJ et al: The relationship between psychological factors, inflammation, and nutrition in patients with chronic renal failure undergoing hemodialysis. International Journal of Psychiatry in Medicine 2012; 44(2): 105-18.

7. Ogawa T, Kyono A, Sato M et al: Vitamin D receptor agonist supplementation and suppression of inflammation may have advantage for all-cause mortality in hemodialysis patients. Clinical & Experimental Nephrology 2012; 16(5): 779-85.

8. Hojs R, Bevc S, Ekart R: Biomarkers in hemodialysis patients. Advances in Clinical Chemistry 2012; 57:29-56.

9. Korzets A, Azoulay O, Ori Y et al: The use of intradialytic parenteral nutrition in acutely ill haemodialysed patients. Journal of Renal Care 2008; 34(1):14-8.

10. Frazao JM, Adragao T: Non-calcium-containing phosphate binders: comparing efficacy, safety, and other clinical effects. Nephron 2012; 120(2):108-19.

11. Ambuhl PM: Protein intake in renal and hepatic disease. International Journal for Vitamin & Nutrition Research 2011; 81(2-3): 162-72.

12. Jesse C, Mitchell HR: Intradialytic Total Parenteral Nutrition (IDPN) Evidence-Based Recommendations. Practical gastroenterology 2009; 80: 13-28.

13. Raj DS, Sun Y, Tzamaloukas AH: Hypercatabolism in dialysis patients. Current Opinion in Nephrology and Hypertension 2008; 17(6): 589-94.

14. Kirmizis D, Papagianni A, Dogrammatzi F et al: The effects of vitamin E-coated membrane dialyzer compared to simvastatin in patients on chronic hemodialysis. Renal Failure 2012; 34(9):1135-9.

背景

慢性腎臟疾病 (CKD) 以血液測試 creatinine 值證實，是一種經過數月或數年之腎功能退化情況。Creatinine 數值的提升表示低的腎臟過濾速率，導源於腎臟對於廢物排除能力的下降。不同期別 CKD 的治療方式差異性很大，從第一期僅輕微腎損傷，而第五期則需換腎或洗腎。儘管近年來在換腎技術及尿毒症狀治療有顯著的進展，可是末期 CKD 病人的癒後還是不佳。隨著腎臟疾病的惡化，末期 CKD 病人可能會有多重營養及代謝混亂的情形，此情況通稱蛋白質-能量耗損，大約佔了此類病人數的20-50%之後¹，礦物質愈來愈不恆定、絆隨著一些異常如骨頭及血管組織鈣化、最後可能演變成幾種心血管疾病^2,3。

作者

高雄長庚紀念醫院藥劑部藥師 李榮明、王鵬翔、李炳鈺

國軍左營總醫院臨床藥劑科藥師 陳立材