Nephrology Hypertension

Chronic Kidney Disease: Malnutrition & Inflammation Complex

Does this patient have malnutrition and inflmmation complex from chronic kidney disease?

A 78-year-old Caucasian male patient with end stage renal disease (ESRD) has been on maintenance hemodialysis three times/week for the past 3 years. He was using a forearm loop arteriovenous graft (AVG) as dialysis access. During a routine evaluation in the dialysis unit, the patient reports decreased energy, low appetite and weight loss. These symptoms have been going on for the past few months.

Past medical history includes type 2 diabetes mellitus (DM), hypertension (HTN), coronary artery disease (CAD) (3v disease, status post coronary artery bypass graft (CABG 2 years ago), chronic obstructive pulmonary disease (COPD), diabetic retinopathy, anemia of ESRD, and secondary hyperparathyroidism. Medications include aspirin, lisinopril, carvedilol, insulin, simvastatin, tiotropium inhaler, erythropoetin, lanthanum carbonate and paricalcitol.

Physical exam shows blood pressure (BP) 138/55 mmHg, heart rate (HR) 82, afebrile, weight 61 kg, body- mass index (BMI) 22.1 kg/m2. Head and neck exam shows temporal muscle wasting. Chest exam negative except thoracotomy scar. Cardiovascular exam shows a grade 2/6 systolic ejection murmur. Abdomen exam negative. Extremities reveal moderate muscle wasting. Neurological exam is non-focal and negative except for mild decrease in muscle strength.

Key history, symptoms pertaining to malnutrition and inflammation: Typically vague and non-specific. Low appetite, low energy, and weight loss. The typical patient has multiple comorbidities. The malnutrition-inflammation-calhexia syndrome (MICS) often occurs after an acute illness or hospitalization, but can present as a chronic problem without an identifiable underlying cause.

Key signs: low or low-normal, or seemingly ideal body weight-BMI and abdominal circumference. Signs of muscle wasting and sarcopenia.

Most important aspect of differential diagnosis is to identify underlying conditions that offer an opportunity for therapeutic intervention. DDX includes acute and chronic conditions accompanied by inflammation: infections, malignancies, advanced liver and cardiac disease, ESRD or non-dialysis–dependent chronic kidney disease (CKD). Consider depression, which is seen quite often in ESRD and can present with the same symptoms.

What tests to perform?

Lab testing

The most commonly used lab test to identify MICS is serum albumin. However, it is not worth checking more often than once a month. Be aware that normal range depends on lab assay used to measure it (BCG vs. BCP). In terms of prognostic value serum albumin is associated with poorer outcomes in a linear fashion (the lower the level, the worse the outcome), without a threshold value.

Other tests that could offer more insight are serum prealbumin <30 mg/dl (aka transthyretin; has no relationship to albumin in spite of the name) which has a shorter half life and is hence better suited to monitor short term changes in MICS (like during recovery from an acute illness or during a nutritional intervention). Serum C-reactive protein (CRP), especially if >3.0 mg/l (or >0.3 mg/dl) is a specific marker of inflammation and could offer additional insight into the underlying pathophysiology; elevated CRP levels have also been associated with increased mortality in ESRD.Several routinely available lab tests are considered non-specific markers of MICS: elevated white blood cell count (WBC), low percentage of lymphocytes in white blood cell count , low serum transferrin or low blood cholesterol. Finally, a low serum creatinine level in dialysis patients is usually a reliable marker of sarcopenia.

The interpretation of these tests has to take into consideration the other conditions that could affect their values. Abnormal values of essentially all of the listed biochemical tests have been associated with adverse outcomes such as increased mortality in dialysis patients and in patients with earlier stages of CKD. It remains unclear if therapies that lead to improvements in these lab values can lead to better outcomes, since there have been no clinical trials to test such a hypothesis. These tests should be used for diagnostic purposes and to monitor for the effects of therapies (nutritional or anti-inflammatory).

An important aspect of MICS is low nutrient intake, which is both a symptom and a cause; hence the measurement of the amount of protein and energy intake can be helpful in diagnosis and in guiding nutritional interventions. The normalized protein catabolic rate (nPCR), aka normalized protein nitrogen appearance (nPNA) is routinely calculated in hemodialysis patients on a monthly basis. Unfortunately similar measurements are not available in non-dialysis patients, in whom the amount of daily protein intake can be estimated from 24 hour urine collections (by measuring urine urea nitrogen).

An nPCR of 1.1-1.3 is considered desirable in chronic dialysis patients; the same value in non-dialysis dependent CKD patients is 0.6-0.8 g/kg/day. Lower values should prompt an evaluation for causes and consideration of nutritional interventions. It remains unclear, though if such interventions can have a beneficial impact on clinical outcomes such as mortality, since there have been no clinical trials to test such a hypothesis.

Other diagnostic tests to consider in routine practice include anthropometric measurements (weight, height, BMI, waist circumference, waist-height ratio) and measures of muscle mass (mid-arm muscle circumference or urinary creatinine appearance). Skin fold thickness is a simple way of quantifying subcutaneous fat; it requires a special caliper. There are numerous tests that measure body composition, such as dual-emission X-ray absorptiometry (DEXA), bioimpedance and near-infrared interactance, or more elaborate imaging techniques such as computed tomography (CT) or magnetic resonance imaging (MRI) used to quantify visceral and/or muscle fat and lean body mass; these are mainly used in research studies.

Similar to the previously listed other types of diagnostic tests, measurements of body composition and body mass are also used for diagnostic and prognostic reasons, and their longitudinal follow-up can be useful to monitor the effects of therapies; but it is unclear if improvements in their values can result in better clinical outcomes. Differentiation of increased or decreased body fat from increased or decreased muscle mass (both can present with increased or decreased BMI) may offer clues about prognosis and guidance about best therapeutic interventions.

Imaging studies

These can be used to measure body composition (see above under Diagnostic tests), but the use of such tests (CT and MRI) is not common in clinical practice.

Muscle biopsies

Some research centers have been performing muscle biopsies, but there is no consensus as to what muscle strcuture or what markers to examine.

Abnormal test results

Abnormal blood tests (in particular low serum albumin level) are very robust indicators of poor clinical outcomes, most importantly increased mortality.

Controversies in diagnostic testing

It remains unclear what the actual role of the detected abnormalities is. Are they surrogate markers of an underlying pathologic process? Or are any of them somehow in a direct causal relationship with the downstream clinical events (typical example is CRP, which may be representing more severe underlying atherosclerosis but could also be causally involved in downstream vascular events though complement activation or other mechanisms)? Such controversy could be resolved by clinical trials that target a specific abnormality; but such trials are not currently available.

How should patients with Malnutrition and Inflammation Complex be managed?

The most important step is to identify and treat any potential underlying cause (occult or manifest infections, chronic inflammatory conditions, malignancies, etc.). Besides treating the underlying comorbidities, specific treatment measures directed at MICS include nutritional interventions to address the malnutrition component and anti-inflammatory measures, or a combination of the two.

Nutritional interventions are meant to address the fact that the amount of protein and energy intake in patients with MICS is inadequate; this could be both a cause and a consequence of MICS. Interventions include nutritional counseling, nutrient supplementation and/or appetite stimulants. Nutrient support can be through oral or through parenteral route. Both of these interventions are equally effective at improving serum albumin and prealbumin levels and a randomized controlled trial did not find a survival benefit from adding intradialytic parenteral nutrition (IDPN) to oral supplements; hence, it is advised to favor the simpler/cheaper approach with less potential side effects as the initial step, which means oral supplements if the patient is able to ingest and absorb food.

The administration of oral nutritional supplements (either concentrated nutritional beverages, powders or simply meals) should be considered during the hemodialysis procedure, as this can not only add to the overall protein intake of a patient, but can also offset the acute catabolic effect of the dialysis procedure and assure that patients will not use the supplements as a substitute for their usual meals. The administration of meals during hemodialysis is not routinely practiced in the US, mainly due to concerns related to hygiene, safety and cost; it is, however, routine practice in other countries in which its cost is subsidized.

Enteral tube feeding is another option that can be used in anorexic patients who otherwise have a functioning gastroinestinal (GI) tract. This type of intervention has not been studied extensively in adults, but has been proven to be useful in pediatric patients. Advantages include the utilization of the gastrointestinal tract (including benefits related to nutrients' contact with the intestinal mucosa and stimulation of gut hormones) and a full control over the amount and composition of the administered nutrients. Potential complications include risk of aspiration, fluid overload, esophagitis (if using a nasogastric tube) or other surgical complications (if using a gastrostomy or jejunostomy tube).

Parenteral nutrition can be prescribed for chronic hemodialysis patients as intradialytic parenteral nutrition (IDPN, administered three times a week during dialysis sessions, as a nutritional supplement), or as total parenteral nutrition if a patient is unable to take any oral nutrition (typically in the acute setting) .

The IDPN solution usually consists of amino acids (typically 8.5%) and lipids (optional) diluted in 50% dextrose solution, with electrolyte content adjusted to the individual patient's serum electrolytes. Regular insulin may be added and adjusted based on patient's blood sugar level and water soluble vitamins may also be added. The IDPN solution is infused continuously during the HD session in the venous drip chamber. Potential side effects include cramps, hyperglycemia, hypoglycemia (immediately following the discontinuation of the infusion), infections (with prolonged use of IDPN), hyperlipidemia and increase in fat tissue (rather than dry weight). The infused amino acids also provide an added catabolic load so it's typical to see a decrease in KT/V of approximately 0.2 while administering IDPN.

Total parenteral nutrition is administered continuously to patients to whom the previous interventions cannot be applied. It typically consists of 70% dextrose, a mix of essential and non-essential amino acids, lipids (available in 10% or 20% solution), electrolytes, vitamins and trace elements. The TPN prescription has to be adjusted according to the complex needs of patients who are often critically ill. It is beyond the scope of this text to provide an in-depth account of all the potential issues arising in this context, which are available in specialized reviews.

In general, IDPN appears more effective when serum albumin is exceptionally low (eg, <3.0 g/dl). Some specific issues pertinent to patients with kidney disease and on TPN involve the following: (1) total amount of volume, which should be restricted if possible in patients with no kidney function; (2) sodium and chloride content, also in order to limit volume overload. Typical sodium level should be close to physiologic (140 mmol/L) in patients receiving CRRT, but much lower (40-80 mmol/L) in patients on intermittent hemodialysis; (3) the concentration of all electrolytes should be monitored frequently and the composition of TPN adjusted as needed.

Intraperitoneal infusion of amino acids is possible in peritoneal dialysis patients. It has been shown to improve protein anabolism and serum protein levels. Solutions usually contain a mixture of essential and non-essential amino acids, and are infused in the long dwell (night-time dwell in CAPD and long daily dwell in CCPD) to maximize absorption. The osmotic effect of a 1% amino acid solution is similar to a 2% dextrose solution. Potential complications include nausea/vomiting, decreased appetite, and an increase in blood urea nitrogen concentration.

Another nutrition-related intervention aimed at decreasing the catabolic effect of uremia includes treatment of metabolic acidosis. The administration of alkali in ESRD patients has been shown to improve nutritional parameters, and in non-dialysis CKD patients it has been shown to cause an attenuation of the progression of CKD.

Adequate dialysis is also considered a possible treatment of MICS, based on the potential role that retention of uremic toxins play in its development. It remains unproven, though that high dose dialysis could result in improvement in nutrition/resolution of MICS. In a recent randomized controlled trial frequent dialysis has not resulted in improved serum albumin levels.

Anorexia is a typical feature of MICS; hence, appetite stimulants can be considered to enhance nutrient intake. Megestrol acetate is a synthetic progesterone which stimulates appetite in part through central hypothalamic effects and in part by suppressing inflammation. There is very limited clinical trial data on the effectiveness of megestrol acetate in ESRD; the single available randomized double blind clinical trial was small and showed no effect of megestrol acetate administration on serum albumin or lean body mass.

Side effects of megestrol acetate are common and can be serious (eg, hypertension, edema, thromboembolism, uterine bleeding, diarrhea, hyperglycemia). Antidepressants such as mirtazapine may be useful by virtue of their side effect of causing an increase in appetite, but there is no safety and efficacy data on its use to this effect in CKD or ESRD. Other orexinogenic agents such as ghrelin agonists are the subject of ongoing research studies.

Anabolic agents are currently not approved to treat MICS in adult ESRD or CKD patients. Clinical trials in ESRD showed improved nutritional parameters after treatment with human growth hormone and with nandrolone decanoate. There is no data on the long-term impact of these interventions on clinical outcomes.

Antioxidant and antiinflammatory medications are currently not approved to treat the inflammatory component of MICS, even though there are large numbers of agents that could potentially exert such an effect. Short of large clinical trials we cannot recommend the use of any such therapies at this time.

What happens to patients with malnutrition and inflammation complex?

MICS starts developing relatively early during the course of CKD, and shows gradual worsening until ESRD is reached. Mechanisms responsible include on the one hand factors related to low glomerular filtration rate (GFR), on the other hand factors related to the dialysis procedure itself (in ESRD). GFR-related factors include decreased clearance of pro-inflammatory cytokines, volume overload, oxidative stress, carbonyl stress and decreased antioxidant levels, and a high level of comorbid conditions, including occult infections.

Dialysis-related factors that play a role in MICS include exposure to dialysis tubing, non-biocompatible membranes, back-filtration of contaminants from dialysate, foreign bodies (catheters, AV grafts, failed transplants), peritonitis and exposure to peritoneal dialysate (in PD). MICS is associated with a significant increase in mortality in ESRD and CKD patients, irrespective of which component of MICS is used to predict such outcomes.

Most of the data implicating MICS in adverse outcomes is observational in nature, hence there is no conclusive proof that MICS is actually a cause of the observed higher mortality. Indeed, it may merely be a surrogate marker of more significant underlying comorbid conditions. Nevertheless, it is possible that some or all components of MICS may play a causal role in various pathophysiologic processes and thereby directly contribute to higher mortality. The complex nature of MICS makes it difficult to discern which components may be causally involved and which may be merely surrogate markers of other pathologic states.

Some of the putative mechanisms whereby the various aspects of MICS could be directly harmful include effects on the immune system (immune deficiency causing increased susceptibility to infections), muscle wasting (with resultant decreased cardiac and respiratory muscle function, increased circulating actin with decreased gelsolin levels, decreased antioxidant capacity), decreased fat mass (decreased adiponectin levels, decreased energy stores, decreased sequestration of uremic toxins), altered lipid profile, direct effects of inflammatory cytokines (endothelial dysfunction, atherosclerotic plaque formation), hematologic effects (anemia, increased platelet activation), altered nutrient intake (decreased levels of high value proteins, vitamins, antioxidants, trace elements and vitamin D leading to pro-atherogenic effects, oxidative stress, calcification) and the gastrointestinal system (decreased intestinal secretion, altered gut flora and atrophy of intestinal lining leading to decreased absorption and harboring of infections).

Pharmacologic considerations. Direct pharmacologic treatment of the inflammatory component of MICS is possible, but currently not approved. Potential interventions include specific anti-inflammatory agents with well-described mechanisms of action (inhibitors of TNF-alfa, IL-1, IL-6, IL-15 and IL-18, costimulation blockade and B-cell depletion) and the use of medications with complex and/or unclear mechanisms of action (PPAR-gamma agonists, non-steroidal antiinflammatory agents, statins, ACE-inhibitors and angiotensin receptor blockers, sevelamer, megestrol acetate, heparin, vitamin C, vitamin E and acetylcysteine). Clinical trial data on these agents in ESRD and CKD is scant to none, hence their routine use for anti-inflammatory purposes at this point cannot be recommended.

How to utilize team care?

  • Specialty consultations - Depends on underlying comorbidities.

  • Nurses - Supervised nutrient administration during dialysis. Frequent emphasis on importance of good nutrition. Patient examinations for detection of occult infections (eg, diabetic foot exams, access exams).

  • Pharmacists - Involvement in preparation of IDPN, TPN.

  • Dietitians - Regularly scheduled nutritional evaluations. Tailored recommendations regarding amount and composition of diet. Prescription of IDPN, TPN.

  • Therapists (physical, occupational, speech, other) - Implementation of physical exercise programs to improve muscle strength, etc.

Are there clinical practice guidelines to inform decision making?

Guidelines

Kidney Disease Outcomes Quality Initiative (KDOQI) guideline on Nutrition in Renal Failure. Am J Kidney Dis 35(6) Suppl 2 , 2000. Provides mostly evidence based recommendations on diagnostic tests and desirable nutritional goals in dialysis and non-dialysis patients with CKD. Appendices offer detailed information on various methodological issues. Separate adult and pediatric guidelines.

Limitations

No recommendations on treatments. These KDOQI guidelines are now 12 years old. Hence, more recent information has not been considered or incorporated.

Other considerations

  • DRG code - 297

  • Typical lengths of stay - not directly applicable

What is the evidence?

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