Wasting in chronic kidney disease

INTRODUCTION

- Wasting is prevalent among patients with chronic kidney disease (CKD)

- About 18% to 75% of adults with end-stage renal disease (ESRD) undergoing maintenance dialysis showed some evidence of wasting

- Although inadequate nutrition may contribute to wasting or cachexia, other factors including systemic inflammation, perturbations of appetite-controlling hormones from reduced renal clearance, aberrant neuropeptide signaling, insulin and insulin-like growth factor resistance, and metabolic acidosis, may be important in the pathogenesis of CKD-associated wasting

- The wasting/cachexia syndrome in CKD patients consists of anorexia, increased energy expenditure, decreased protein stores characterized by a low serum albumin, and loss of body weight and loss of muscle mass

- Importantly, the individual components of this syndrome all represent risk factors for mortality in patients with CKD, which is 100–200 times higher than the general population

- The wasting/cachexia syndrome should be distinguished from malnutrition: 

DIAGNOSTIC CRITERIA OF CACHEXIA/PROTEIN-ENERGY WASTING IN CKD 

- Cachexia was defined as “a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle, with or without loss of fat” (Evans et al., 2008)

- In the context of CKD, the term protein–energy wasting (PEW) has been proposed by The International Society of Renal Nutrition and Metabolism (ISRNM) to describe a “state of decreased body stores of protein and energy fuels (body protein and fat masses)”

- The ISRNM suggested that the term cachexia be reserved for only the most severe forms of PEW. However, there is no obvious distinction between PEW and cachexia from a pathophysiology standpoint

- Limiting the term cachexia to the extreme forms of PEW could be considered too restrictive. The term pre-cachexia has been proposed to include the milder forms of wasting in cancer patients (Fearon et al., 2011)

- Cachexia Definition (Evans et al., 2008)

- Protein-energy wasting in CKD (by ISRNM, Fouque et al., 2008)

DIAGNOSTIC CRITERIA OF CACHEXIA/PROTEIN-ENERGY WASTING IN CKD (cont’)

Anthropometric Indicators

1) BMI

- Although BMI gives little information about body composition, BMI is a useful means of assessing PEW.

- BMI is strongly correlated with LBM at the low end of the BMI spectrum, and low BMI is a consistent predictor of mortality in both adults and children on maintenance dialysis.

- However, BMI is not a very precise parameter of nutritional status in patients in whom gross imbalances in fluid homeostasis are commonly observed, such as in patients with ESRD, CHF, and liver disease.

- Furthermore, in patients with significant muscle wasting with relatively well-preserved fat mass, small changes in BMI may well be obscured by imbalances in fluid homeostasis

2) SGA

- Stenvinkel et al. analyzed 268 patients with ESRD according to their BMI and SGA,

- They found that 38% of their patients in the low BMI group had a normal SGA, whereas 45% of the patients in the normal BMI group and 17% in the high BMI group were considered to have PEW by SGA

- Low BMI has no impact on cardiovascular mortality whereas an SGA ≥2 was associated with a marked increase in cardiovascular mortality

3) Rate of weight loss

- Unintentional weight loss or reduction in weight of 5% or more over 3 months, or 10% or more over 6 months are suggested as indicators of cachexia/PEW, independent of absolute BMI

4) Growth Failure in Children

- Linear growth failure in children with CKD was highlighted as central to the diagnosis of cachexia, and has been associated with a greater mortality risk in children on maintenance dialysis

- However, the etiology of growth retardation in CKD is multifactorial, including other factors such as delayed sexual maturation, bone disease, acidosis, and growth hormone/insulin growth factor resistance.

- Growth failure may emerge as a necessary, but insufficient criterion, for PEW in children with CKD

5) Muscle mass

- Reduced muscle mass appears to be the most valid criterion for the presence of PEW in CKD, and is also emphasized in the diagnostic criteria for cachexia.

- Mid-arm circumference has been shown to correlate with quality of life and survival in adult patients on maintenance hemodialysis (HD).

- Dual X-ray absorptiometry, near-infrared interactance, and bioelectrical impedance have been used in investigations of ESRD patients [30] but these techniques have limitations in

ESRD and are not currently accepted as clinically useful tools.

- Indirect measures, such as creatinine appearance (estimated by quantification of creatinine in a 24-h urine collection and in the collected spent dialysate) have been proposed as an index of muscle mass in patients with CKD and ESRD

6) Fat mass

- Body fat mass lower than 10% of body weight is considered an additional criterion for PEW in adults with CKD due to the known association between total body fat below 10% and increased mortality risk in adult maintenance dialysis patients

- A more recent study showed that higher fat mass in dialysis patients might actually be protective in survival predictability

- Nevertheless, abdominal fat deposition was shown to be linked to inflammation and PEW, resulting in an increased mortality risk in maintenance HD patients

Biochemical Indicators

1) Albumin

- Low serum albumin is a consistent predictor of mortality in both adult and pediatirc ESRD patients.

- A low serum albumin concentration is by far the strongest predictor of mortality and poor outcomes in adult ESRD patients on maintenance dialysis when compared to any other risk factors, including traditional risk factors (hypertension, smoking, hypercholesterolemia, diabetes, and obesity) and nonconventional ones (anemia measures, oxidative stress, minerals and bone surrogates, dialysis treatment and technique)

- Dialysis patients with baseline serum albumin of even 0.2 g/dL higher or lower than other dialysis patients with similar demographic and comorbidity constellations have significantly lower or higher death risk, respectively.

- The albumin–death association is highly incremental and linear, and the mortality–predictability of serum albumin below 4.0 g/dL has virtually no cutoff level, below which the association with death would cease or reverse

2) Prealbumin

- Low serum prealbumin (e.g., <30 mg/dL) is another indicator of PEW and a strong predictor of outcomes in maintenance dialysis patients

- Even though baseline serum prealbumin may not be superior to albumin in predicting mortality in maintenance HD patients, prealbumin concentrations <20 mg/dL are associated with death risk even in normoalbuminemic patients, and a fall in serum prealbumin over 6 months is independently associated with increased death risk

- Dialysis patients with high serum prealbumin have lower proportion of body fat as well as higher proportion of muscle mass, which suggest that normal serum prealbumin is associated with reversal of the abnormal body composition in cachexia

- Dialysis patients with a baseline serum prealbumin between 20 and 40 mg/dl, a drop of 10 mg/ dl was associated with 37% increase in death risk independent of baseline markers of malnutrition inflammation score (MIS), serum albumin, and inflammatory markers

Food & Nutrition Indicator (Anorexia)

- Both subjectively reported anorexia as well as measured low protein or energy intake has been associated with increased mortality in adult ESRD patients

- Anorexia is prevalent, in 30–40% in adult maintenance HD patients, and is associated with higher concentrations of pro-inflammatory cytokines and higher levels of erythropoietin hypo-responsiveness as well as poor clinical outcome, including a fourfold increase in mortality, greater hospitalization rates, and poor quality of life.

- As male ESRD patients seem to be more prone to inflammation-associated anorexia than female patients, sex hormones may play an important role in this context.

-Anorexia is prevalent in children with fairly mild CKD can be the primary reason for growth failure

- Poor growth due to inadequate intake has been observed in children with glomerular filtration rate as high as 70 ml/min/1.73m²

- Growth of children with CKD is compromised when energy intake fall below 80% of recommended daily allowance.

Other indicators

- Serum transferrin, choleteral, inflammatory markers such as CRP, proinflammatory cytokine such as IL-6.

PATHOPHYSIOLOGY OF CACHEXIA/PEW SYNDROME IN ADVANCED CKD

- The pathophysiology of cachexia/PEW syndrome is CKD is multifactorial. An overview is summarized in Figure below. Please refer to the original paper for detailed discussion on Anorexia, Increased energy expenditure, Inflammation, Insulin resistance and Vitamin D deficiency

THERAPEUTIC STRATEGIES FOR PREVENTION AND/OR TREATMENT OF CACHEXIA/PEW IN CKD

1)  Nutritional supplementation

- There is evidence that nutritional therapy will improve PEW in adult ESRD patients, such as the use of oral nutritional supplement (ONS), Intradialytic parenteral nutrition (IDPN) --> improved serum albumin and/or prealbumin level.

- Growth of children with CKD is compromised when energy intake fall below 80% of recommended daily allowance (RDA). Increasing energy intake to 100% (but not more than 100%) of the RDA can increase weight gain and stabilize growth rates

2) Exercise & Physical Activity

- While that is evidence that patients with ESRD can improve skeletal muscle quality by exercise, longer training durations or more sensitive analysis techniques are required before this regimen can be recommended as therapy for cachexia/PEW in CKD.

- There is no data on whether exercises capacity tests can predict outcome in ESRD.

3) Appetite stimulant

- Megestrol acetate is a synthetic derivative of progesterone. Megestrol acetate may induce appetite via stimulation of hypothalamic neuropeptide Y, modulation of calcium channels in hypothalamic appetite centers or inhibition of inflammatory cytokines such as IL-1, IL-6, and TNF

-  In the only double-blinded, crossover study of 24 maintenance hemodialysis patients with anorexia, no significant increase in albumin or LBM was observed. A large number of side-effects were reported, including headaches, dizziness, confusion, diarrhea, hyperglycemia, thrombo-embolism, uterine bleeding, peripheral edema, hypertension, and adrenal insufficiency

- Thus, the current experience in ESRD patients does not support the use of megestrol acetate in clinical practice.

4) Correction of Acidosis

- There is evidence that acidosis can induce muscle protein catabolism and it could therefore be an important factor contributing to loss of muscle protein in these conditions

- Acidosis is associated with negative nitrogen balance and degradation of branched-chain amino acids and protein

- There are, however, few treatments available for correcting metabolic acidosis apart from alkali supplements such as NaHCO₃ which, in CKD patients, carry the risk of sodium loading and fluid overload

- Despite the risk, a recent study using NaHCO₃ supplementation in patients with (predialyss) CKD actually led to a slower decline in their renal function as well as improvement in their nutritional status (dietary protein and calorie intake increased, accompanied by improvements in serum albumin and LBM as assessed by mid-arm muscle circumference)

5) Growth Hormone

- Acquired resistance to the anabolic actions of growth hormone (GH) is a potential cause of the increased net protein catabolism and wasting in patients with advanced CKD.

- Studies showed that pharmacologic doses of recombinant human growth hormone (rhGH) improves whole body protein homeostasis in chronic HD patients in the short-term.

- More studies are needed to evaluate its long-term effect of rhGH on outcomes in patients with advanced CKD

6) Ghrelin agonists

- The salutary effects of ghrelin on food intake and meal appreciation suggest that it could be an effective treatment for anorexic ESRD patients

- Tolerance in appetite-regulating centres and/or other factors may override the long-term appetite-stimulating effects of ghrelin

- Ghrelin infusion acutely induces lipolysis and insulin resistance independently of GH and cortisol, thus it will be important to follow subjects for the risk of diabetes while on long-term ghrelin treatment

- A major limitation of treatment based on natural hormones is the need for parenteral administration, because of the large size of the molecule. The long-term therapeutic potential of GHS-R agonists will likely rest with orally bioavailable compounds

- Despite reports of the short- and intermediate-term success of ghrelin administration in treating anorexia and cachexia in ESRD patients, we must await results of studies on its long-term efficacy

7) Leptin and melanocortin signalling modulation

- Studies in mice shows promising results, human studies are awaited.

8) Ubiquitin-proteasome inhibitors

- Cachexia/PEW in CKD is characterized by protein catabolism. Protein synthesis is unchanged while protein degradation is increased in CKD. The daily rate of protein turnover in cells is so high that even a small increase in protein degradation will cause marked protein depletion over time.

- The mechanism of increased protein degradation in CKD is through the activation of the UPS.

- Complications of CKD, including acidosis, insulin resistance, inflammation, and increased glucocorticoid and angiotensin II production, all activate the UPS to degrade muscle protein

- Recognition of the role of the UPS in the pathogenesis of cachexia/wasting has led to the therapeutic use of bortezomib—a proteasome inhibitor—in cancer patients.

- Inhibition of the proteasome will block activation of NF-[kappa]B, which is a common final pathway for signal transduction of many cytokines, thought to be a central mechanism of cachexia/wasting in many chronic disease states including CKD

9) Dose & frequency of dialysis

- A recent randomized controlled trial failed to confirm the beneficial effects of daily HD on nutritional status in maintenance HD patients, as measured by serum albumin

CONCLUSION

- Many questions remain about the description, classification, and treatment of PEW or cachexia in children and adults with CKD.

- Whether nutritional supplementation can improve nutritional status and hence morbidity and mortality in ESRD patients remains to be tested with appropriately designed RCTs

- Most of the information on the novel strategies is currently at the experimental level and awaits confirmation by RCTs in patients with CKD-associated cachexia/PEW syndrome.

Mak et al. J Cachexia Sarcopenia Muscle 2011; 2:9–25. DOI10.1007/s13539-011-0019-5

Further Reading:

Fouque et al. A proposed nomenclature and diagnosticcriteria for protein–energy wasting in acute and chronic kidney disease. Kidney Int 2008;73:391–398 doi:10.1038/sj.ki.5002585