Pathophysiology in CKD 31

Pathophysiology of protein energy wasting in chronic kidney disease

Madhusudan Vijayan1,Georgi Abraham2

1Kilpauk Medical College, Chennai, India,

2Madras Medical Mission Hospital, Chennai, India; Pondicherry Institute of Medical Sciences, Pondicherry, India



rotein energy wasting (PEW) is highly prevalent in chronic kidney disease (CKD) patients. It is estimated that malnutrition is present in about 42-77% of the end stage renal disease (ESRD) population in developing countries(!). PEW is associated with morbidity, mortality, impaired physical performance and impaired quality of life, as various vital functions are endangered in the setting of malnutrition(2). It has been referred to as malnutrition inflammation arteriosclerosis (MIA) syndrome or

malnutrition inflammation complex syndrome (MICS) (3).

Malnutrition is often ignored in the management of CKD patients, especially in resource poor settings. The most common symptom is weight loss, which may be masked by fluid retention. As the disease worsens, it is followed by fatigue and reduction in physical stamina. On examination, there is wasting of muscle mass and subcutaneous fat. Skeletal muscle breakdown occur due to a hypercatabolic state, reduced physical activity and resistance to anabolic hormones (4,5). In extreme cases, there may be edema and/ or ascites due to hypoalbuminemia (6).

Two types of MIA syndrome have been proposed: type 1 and type 2(3). Type 1 MIA is due to uremia per se and excessive dietary restrictions with not much significant comorbidities, where serum albumin and C-reactive protein (CRP) are normal or mildly deranged. Type 2 MIA is due to chronic systemic inflammation with predominantly pro inflammatory cytokines, associated with multiple comorbidities and patients have low serum albumin and high CRP levels. Type 2 MIA is not alleviated by nutritional therapy.

Thepathogenesis of malnutrition in CKD ismultifactorial and involves chronic inflammation, alterations in hypothalamic signaling pathways and dietary insufficiencies.


CKD patients have reduced appetite because of accumulation of pro inflammatory cytokines such as Interleukin-6 and

tumour necrosis factor-alpha and dysregulation of orexigenic and non orexigenic compounds (7). The hypothalamus controls food intake and energy expenditure, with two distinct set of neurons, one producing neuropeptide Y which stimulates food intake and the other producing melanocortin peptides, which suppresses appetite(8). Aberrations in leptin and melanocortin signaling have been documented in animal models with uremia(9,10). Since leptin is cleared by the kidney, it accumulates in CKD and binds to leptin receptor in the arcuate nucleus of hypothalamus. It may mediate cachexia by influencing melanocortin signaling pathways in the hypothalamus. Leptin increases expression of melanocortins and inhibits expression of Agouti-related peptide(AGRP) which is an endogenous antagonist of melanocortin receptors 3 and 4 (MCR-3 and MCR-4). These melanocortin receptors are involved in control of energy intake and energy expenditure. Here, in CKD, the overactivity of MCR-3 and MCR-4 suppresses appetite and increases energy expenditure, thereby leading to cachexia (9,10). Reduced renal clearance of des-acyl ghrelin lead to its accumulation in CKD and this could also be involved in the pathogenesis of anorexia in CKD patients, as it suppresses food intake as well(8,11).

Dietary restrictions

CKD patients are subject to dietary recommendations to control hyperphosphatemia, hyperkalemia, calcium balance and sodium and water retention, which inadvertently leads to PEW. The European Best Practice Guidelines (EBPG) recommend a protein intake of at least 1.1 g/kg/day among maintenance hemodialysis (MHD) patients(12). The Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines suggest a protein intake of 1.2 g/ kg/day body weight, with at least 50% being high biological value (HBV) protein. We did a study on 290 patients(males 201/females 89) in which the mean protein intake was 0.98 mg/kg/day among lower socioeconomic class haemodialysis patients and 0.71 mg/kg/day among higher socioeconomic class stage 3-4 CKD patients(13) . The percentage of HBV protein varied


from 22.576 % to 31.306 % in our patients. The energy intake in the higher and lower socioeconomic groups were

22.576 kcal/kg/day and 31.306 kcal/kg/day respectively. The recommended energy intake by EBPG is about 30- 40kcal/kg/day adjusted to age, gender and level of physical activity(12). These values suggest that the dietary protein and energy intake among Indian HD patients is inadequate and urgent nutritional counseling is required to prevent the complications of PEW.

KDOQI recommendations to prevent pew

Before diagnosing PEW due to CKD, it is important to rule out other causes of malnutrition such as liver disease, gastrointestinal disease, worm infestations and chronic diarrhea.PEW can be prevented by ensuring adequate


decreased hospitalization and mortality, and small changes in SGA score are associated with improved clinical outcomes.

Anthropometric measurements to be used include body mass index, skinfold thickness, estimated percent body fat and mid arm circumference. Body composition monitoring using multifrequency BIA and dual energy xray absorptiometry can be used as useful measures to assess the nutritional status of the patients.

It is important to give supplements to malnourished patients who are unable to maintain adequate nutritional intake. Depending on the degree of malnutrition, the support may be given in the form of oral nutritional supplements, tube feeding, intradialytic parenteral nutrition or intraperitoneal amino acids.

nutritional counseling. Owing to the complexities of

prescribing diet patterns for CKD patients, dietetic services by qualified renal dietitians are required in tertiary health centers in developing countries. The KDOQI guidelines state that an individual dietitian should cater to around 100 MHD patients but not more than 150 patients to ensure that adequate dietary counseling is offered to patients(14). Consultation with dietitians should take place at least 3 times yearly and more often as required in malnourished patients(!). It is important to have nutritional assessment and individualized nutritional counseling to prevent the complications of PEW.

Nutritional assessment should be done using a panel of anthropometric and biochemical parameters, subjective global assessment, dietary interviews and diaries(14). Biochemical parameters include albumin, prealbumin, haemoglobin, creatinine, creatinine index and serum cholesterol. Serum albumin is a useful measure of visceral protein stores and low levels are strongly associated with increased mortality. Elevated serum CRP is an indicator of inflammation and is associated with mortality.

Monitoring of daily protein and energy intake by using dietary interviews and/or diaries is recommended. Patients should maintain 3-day dietary records followed by dietary individuals conducted by individuals trained in conducting interviews and calculating nutrient intakes. The recommended intake is 1.2g/kg/day of protein with at least 50% high biological value protein for MHD patients, and

0.6 g/kg/day for stage 3-4 CKD patients. The recommended energy intake is 35 kcal/kg/day for MHD patients less than 60 years of age and 30-35 kcal/kg/day for MHD patients 60 years or older.

Protein equivalent of total nitrogen appearance (PNA) is calculated using interdialytic changes in urea nitrogen concentration of serum, urine and dialysate. It is useful measure of estimating protein intake and protein balance, and should be used in conjunction with other indicators in assessing nutritional status.

Subjective global assessment (SGA) should be done using the 4 item, 7 point scale used in the CANADA- USA (CANUSA) study. Higher SGA scores are associated with


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