MIA :causes in HD patients

1. Ekbal Mhamed Abo-Hashem (MD)
Professor of Clinical Pathology,Faculty of Medicine
Mansoura University -Egypt
The Malnutrition ,Inflammation ,and Atherosclerosis (MIA)
Syndrome in Haemodialysis Patients :Pathogenesis and
Laboratory Workup

3. INTRODUCTION
Moderate and severe malnutrition is endemic in much of the
developing countries . The presence of low socio-economic
status can negatively impact on well-being of the population,
and more so in those with chronic diseases. Malnutrition affects
up to 75% of patients with end-stage renal disease (ESRD).
Malnutrition begins as renal function decreases, and patients
with chronic kidney disease (CKD) are known to have a
progressive decrease in both protein and total caloric intake as
glomerular filtration rate decreases .
Malnutrition in HD patients

4. The nutritional requirements of patients with worsening
kidney function are altered and sometimes lead to
ineffective energy production despite adequate intake of
protein and carbohydrate substrates. This is because
malnutrition in chronic renal failure is due to multiple
factors such as metabolic acidosis, hormonal changes, co-
morbidities and hospitalizations, dialytic nutrient losses,
dialysis-induced catabolism and infection in addition to
inadequate protein/caloric intake and increased energy
expenditure. There is adequate evidence to suggest that
poor nutritional status prior to dialysis increases patient
morbidity and mortality after initiating renal replacement
therapy [RRT] .

5. Dialysis patients are commonly depleted of protein and energy stores .
The degree to which protein and energy depletion is the result of
deficient nutrition or, alternatively, protein and energy wasting is
unclear. In 2009, the International Society of Renal Nutrition and
Metabolism (ISRNM) recommended the terminology protein-energy
wasting (PEW) syndrome to describe the loss of body protein mass and
fuel reserves in patients with end-stage renal disease (ESRD) .
The assessment of nutritional status is a routine part of the care of
maintenance dialysis patients in order to allow early recognition and
treatment of PEW syndrome. Markers of PEW are among the strongest
predictors of morbidity and mortality in ESRD patients .

6. Malnutrition in the form of protein energy wasting (PEW) is highly prevalent in maintenance
hemodialysis (HD) patients and associated with adverse clinical outcomes, hospitalization,
higher morbidity and mortality rates . A number of factors could disturb nutritional and
metabolic status in these patients. Uremic state, inflammation, depression, inability to
prepare food, low quality of life, unfavorable restricted diets, dialysis procedure itself and
concurrent catabolic illnesses lead to anorexia in hemodialysis patients and finally poor
nutrient intake. Malnutrition and associated chronic inflammation are responsible for
cardiovascular mortality in dialysis patients . The more severe the malnutrition is, the poorer
the quality of life of HD patients would be .

7. Nutritional status of HD patients could be assessed by different methods,
such as subjective global assessment (SGA), malnutrition inflammation
score (MIS), markers of body composition measured by bioelectrical
impedance analysis (BIA), predialysis serum creatinine, albumin , and
interdialytic weight gain (IDWG)
Nutritional status markers are strong predictors of health-related quality of
life in HD patients; thus, identification of nutritional barriers and targeting
them through nutritional strategies would result in better health outcomes
.

8. Compliance with fluid restriction and calorie and protein intake could be
assessed by IDWG . Dialysis adequacy is an important factor in
maintaining good nutritional status. Low-dose dialysis was associated with
malnutrition . Anorexia is a prevalent characteristic in HD patients , which
aggravates the disease due to higher inflammation . Nutritional education
programs aimed to improve dietary knowledge could be useful in
treating malnutrition and decreasing mortality in patients on hemodialysis
. Depression is an important risk factor affecting mortality rate in HD
patients in the same way of other medical risk factors .

9. Decreased intake of protein and calories is a major contributor to
malnutrition in renal failure . Maintenance of a neutral nitrogen
balance is therefore important for the preservation of nutritional
health in patients with chronic renal impairment. Patients with a
glomerular filtration rate (GFR) <60 mL/min/1.73 m2 should
undergo assessment of dietary protein and energy intake and
nutritional status . Pre-dialysis patients with protein intake of <
0.7 g/kg/day may already have malnutrition originating prior to
initiating RRT. A low protein intake of less than 0.75 g/kg/day is
an early warning sign for the development of uraemic
malnutrition. It has been demonstrated that nutritional markers,
serum albumin and creatinine improve during the first half year of
haemodialysis , implying that there is an improvement in
nutritional status after initiation of dialysis .

10. There is no single measurement of malnutrition. Several
nutritional markers can be used to assess the nutritional
status of renal failure patients. Serum albumin is a reliable
indicator of visceral protein and is the most extensively
studied of the nutritional markers. Low levels of serum
albumin are highly predictive of poor clinical outcomes in all
stages of CKD and, therefore, serum albumin is considered a
reliable marker of general clinical status . However, non-
nutritional causes of hypoalbuminaemia, such as tissue
injury, hepatic disease, renal losses, gastrointestinal
disorders and volume overload, can affect the specificity of
this marker.
Serum pre-albumin (transthyretin) is a sensitive marker for
assessing subtle changes in visceral protein stores due to its
low body pool and fairly rapid turnover of two to three days.
Levels <30 mg/dL suggest protein depletion. Prealbumin
levels are inversely related to mortality .

13. The half-lives of pre-albumin, transferrin and retinol
binding protein are considerably shorter than that of
albumin, therefore changes in nutritional status will be
reflected more promptly in levels of these three than in
albumin . These proteins act as negative acute-phase
reactants, ie their serum concentrations decrease in
response to systemic inflammation and in a roughly
proportional degree to the severity of the inflammatory
response. This effect severely curtails their reliability as
indicators of protein energy malnutrition in the acutely ill
patient.

14. Blood urea nitrogen (BUN) and creatinine are also
simple markers of nutritional status. Patients with stage 5
CKD in whom the serum creatinine concentration is <880
^mol/L (<10 mg/dL) should be evaluated for muscle wasting
as a result of poor nutrition. Also, serum cholesterol
concentrations less than 150 mg/dL (3.9 mmol/L) can
indicate low levels of dietary and energy intake. Low or
declining serum total cholesterol levels are predictive of an
increased mortality risk .

15. Several studies suggest that serum insulin growth
factor-1 (IGF-1) concentrations may have a better
correlation with body composition than serum albumin and
transferrin. in patients with ESRD, interleukin (IL-6) and
hsCRP levels were independently associated with
malnutrition whilst serum albumin was not . Interleukin,
serum albumin and fetuin A, however, better predicted
mortality in multivariate analyses .

16. The analysis of a patient's body composition also
provides important nutritional information. Malnutrition
associated with obesity is closely related to morbidity and
mortality in the dialysis population possibly due to the
increase in visceral fat. Anthropometric studies (oedema-
free weight, body mass index (BMI), assessment of arm fat
and muscle) have been used to estimate body composition
and nutritional adequacy. However, reproducibility of
anthropometric measurement is poor and is dependent
upon the skill of the observer . It has been found to be
unreliable in the haemo-dialysis setting.

17. Nutritional Assessment
The nutrition-focused physical examination (NFPE) is an
essential component for diagnosing malnutrition. Focusing on
general characteristics such as edema, muscle wasting and
subcutaneous fat loss to specific micronutrient related
deficiencies, the NFPE is very sensitive for assessing nutritional
status. The SGA is a well-validated tool for assessing
malnutrition, especially in hospitalized patients. It includes
several physical examination assessments such as muscle
wasting and subcutaneous fat loss .

18. Subjective global assessment (SGA) :
Historically, the SGA was proposed to predict postoperative infectious
complications. However, since the 1980s, it has transitioned into the
gold-standard tool for complete nutritional assessment in patients
undergoing hemodialysis and organ transplantation as well as
patients diagnosed with gastrointestinal and gynecological
malignancies and chronic kidney disease. The value of the SGA for
nutritional assessment is the inclusion of the physical examination in
its scoring system.

19. The Subjective Global Assessment (SGA) can adequately assess
nutritional status in patients on dialysis (peritoneal and haemo). It
uses several components of a medical history, such as weight
change, dietary intake, gastrointestinal symptoms, functional
capacity and nutritional requirement and relation to disease. It can
give an overview of nutritional intake and body composition,
including a rough assessment of both muscle mass and fat mass,
and it correlates with mortality rates. A focussed history and
physical examination are used to categorize patients as :
* well nourished (category A),
* having mild or moderate malnutrition (category B),or
* having severe malnutrition (category C).

21. The Subjective Global Assessment (SGA) was evaluated in different studies as
an adequate tool for the assessment of nutritional status in dialysis patients.
However, its subjective evaluation and semi-quantitative scale consisting of
only three discrete severity levels has been suggested to restrict its reliability
and precision. Therefore, in later years, another version of SGA was developed,
initially called the modified quantitative SGA and subsequently known as the
Dialysis Malnutrition Score (DMS).

22. The DMS consisted of 7 variables:
weight change, dietary intake, gastrointestinal symptoms, functional
capacity, comorbidity, subcutaneous fat and signs of muscle wasting.
Each component was assigned a score from 1 (normal) to 5 (very
severe). This tool was reported to be more reliable than the conventional
SGA in several studies. The DMS was reported to correlate with age,
years of dialysis therapy, and the combination of mid-arm muscle
circumference (MAMC), BMI, serum albumin concentration, and total
iron-binding capacity (TIBC) which were markers of malnutrition and
inflammation.

23. The Malnutrition Inflammation Score (MIS) was developed
with addition of three new components to the DMS which
were the BMI, serum albumin, and serum TIBC. The MIS has
total score ranging from 0 to 30 with higher scores denoting
presence of malnutrition risk. Unlike the DMS, no cut-offs
have been proposed for the MIS to classify the severity of
malnutrition. The MIS was found to significantly correlate
with hospitalisation, mortality, and indices of nutrition,
inflammation, and anemia.

24. Guidelines
The American Society for Parentral and Entral Nutrition (A.S.P.E.N.)
guidelines for diagnosing malnutrition, which looked at six
characteristics, were first proposed in 2009 . At least two of the six
characteristics are needed for the diagnosis of malnutrition. If two or
more characteristics are met, the malnutrition can then be
categorized first by severity and further by acuity. For example,
weight loss > 2% per week is classified as acute severe malnutrition,
while loss of 1–2% per week is considered to be moderate severity .

25. The American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) is an interdisciplinary society whose
vision is to ensure that every patient receives safe, efficacious, and high-quality nutrition care. The society has
produced clinical guidelines to assist practitioners in enteral and parenteral nutrition decision making.

26. There is a strong association between malnutrition,
inflammation and atherosclerosis (MIA syndrome) in
patients on dialysis and those with chronic kidney
disease . This suggests that chronic inflammation
leads to accelerated atherosclerosis and
malnutrition. Inflammation is defined as elevated
hsCRP above 5-10 mg/L. There is, however, no
consensus with regard to the optimal "cut-off" point
of CRP used to define the presence of inflammation
in CKD patients .

27. cardiovascular diseases are responsible for 40%-50% of the deaths
among dialysis patients and cause a mortality rate 5-20 times higher
than that in the general population . Even the presence of classical risk
factors of cardiovascular diseases in these patients cannot justify such a
high mortality rate. In fact, it is now evident that systemic inflammation
plays an important role in the development of atherosclerosis .
Cardiovascular diseases (CVDs) are the leading cause of morbidity and
mortality in patients with end-stage renal disease (ESRD), and
atherosclerosis is a fundamental reason for the majority of CVDs in these
patients.
Inflammation and atherosclerosis in HD patients

28. The accelerated atherosclerotic process of ESRD may involve
several interrelated processes, such as oxidative stress,
endothelial dysfunction and vascular calcification, in a milieu
of constant low-grade inflammation. The cause(s) of
inflammation in ESRD are multifactorial and, while it may
reflect underlying CVD, an acute-phase reaction may also be
a direct cause of vascular injury via several pathogenetic
mechanisms.

29. The prevalence of inflammation has been reported as 35%-65%
among hemodialysis patients ., C-reactive protein (CRP), a positive
acute phase protein produced in the liver, is an inflammatory
biomarker whose levels increase in response to inflammation . High
serum CRP is a strong predictor of death, especially due to
cardiovascular disease, in hemodialysis patients and high levels have
been reported in 30%-50% of the patients .
The cause(s) of inflammation in HD patients is multifactorial and includes both
dialysis-related (such as graft and fistula infections, bioincompatibility, impure
dialysate, and back-filtration) and dialysis-unrelated factors.

30. A low concentration of serum albumin has been identified
as a strong predictor of death due to cardiovascular
diseases in patients with chronic renal failure , i.e. every 1 g/
dL decrease in serum albumin increases the patients’ risk of
mortality by seven times . Moreover, every 10-unit increase
in the dialysis malnutrition score (DMS) and malnutrition
inflammation score (MIS) has been found to increase the
risk of mortality by 7.7 and 10.0 times, respectively .

31. Pathogenesis of atherosclerosis in hemodialysis (HD) patients is
complex and involves both traditional and non-traditional risk
factors. There is a significant role of inflammation in
pathogenesis of atherosclerosis in general population.
Hypertension, hyperlipidemia, hyperglycemia,
hyperhomocysteinemia, infections, and smoking are
arthrogenous factors which, if acting long enough, cause subtle
endothelial injury leading to cell dysfunction.

32. Cell dysfunction is manifested by intracellular overproduction of
selective adhesion molecules (VCAM-1, vascular cellular
adhesion molecule-1; ICAM-1, intercellular adhesion molecule-1)
and their exposure on the cell surface. ICAM-1 is an
endothelial adhesion molecule belonging to immunoglobulin
superfamily, which serves as a ligand for leukocyte integrins
enabling leukocyte adhesion and migration across the cell wall.
Similarly, VCAM-1 is an adhesion molecule belonging also to the
immunoglobulin superfamily that facilitates adhesion of
lymphocytes, monocytes, and eosinophiles .

34. tunica intima. Undergoing transformation into macrophages in tunica
intima, they start phagocytosing enormous loads of lipoproteins,
particularly oxidized low-density lipoproteins (LDLs). As a consequence
of extensive phagocytosis of oxidized LDLs, foam cells arise. Foam cells
are an important source of cytokines that attract new inflammatory
cells into inflamed areas of cell wall. Particularly important among
cytokines are tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-
6). Both of them are proinflammatory cytokines and mediate immune
response.

35. that are involved in the expression of selective adhesion molecules.
Moreover, TNF-α facilitates the activation and recruitment of inflammatory
cells, as well as IL-6,which stimulates liver synthesis of acute phase
proteins, especially CRP and fibrinogen.
The C-reactive protein (CRP) is an acute phase protein for which
concentrations rise several fold during inflammatory process and function
as an opsonin on antigens. Additionally, it facilitates the removal of
necrotic cells by binding to their chromatin remnants. With sensitive
methods, virtually normal CRP values can detect slight, but significant
deviations indicating an atherosclerotic process.

36. Moreover, inflammatory cells in an advanced plaque are an
important source of proinflammatory cytokine interleukin-2 (IL-2),
which is being synthesized by Th1 subpopulation of CD4+
lymphocytes. The binding of IL-2 to the IL-2 receptor (IL-2R), which
is bound on the surface of T-cells, facilitates the proliferation of T-
cells as well as the proliferation of natural killer T cells. The
inflammatory process can be asymptomatic for a long time, but
due to a persisting initial triggering event progresses and causes
atherosclerotic arterial lesions .

37. Available data suggest that pro-inflammatory cytokines play a central role in the
genesis of both malnutrition and CVD in ESRD. Thus, it could be speculated that
suppression of the vicious cycle of malnutrition, inflammation and
atherosclerosis (MIA syndrome) would improve survival in dialysis patients.
Recent evidence has demonstrated strong associations between inflammation
and both increased oxidative stress and endothelial dysfunction in ESRD
patients. As there is not yet any recognized, or even proposed, treatment for
ESRD patients with chronic inflammation it would be of obvious interest to study
the long-term effect of various anti-inflammatory treatment strategies on the
nutritional and cardiovascular status as well as outcome of these patients.

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42. Thank you…