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Complipro - 1st Innovative And Patented Intra-Dialytic Protein Supplement For Patients On Dialysis

Author: Dr. Sanjeev Kumar A. Hiremath

MD (Int. Med), DM (Nephrology, Bombay), Sanjeev Clinic, Bengaluru

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Abstract

Chronic Kidney Disease (CKD) is a progressive disorder associated with decreased Glomerular Filtration Rate (GFR) and/or increased urinary albumin excretion. In advanced kidney disease, dialysis leads to disturbance of nutritional and metabolic arrangement of the body. Protein-energy wasting (PEW) is increasingly becoming a clinical problem in maintenance hemodialysis patients and guidelines call for nutritional interventions. The complications make it a problem with high prevalence and treatment cost. The present article focuses on the various aspects of dialysis, its requirement, advantages and disadvantages, nutritional loss and their management, intradialytic nutrition, its advantage and recently developed new product which could be beneficial to the dialysis patients in replenishing protein and nutritional requirements.

Keyword: Complipro, Intra-dialytic nutritional supplement, Chronic kidney disease, Hemodialysis, Protein supplement

 

Introduction

Chronic kidney disease (CKD) is a progressive disorder associated with the decreased glomerular filtration rate (GFR) and/or increased urinary albumin excretion [1]. Its global prevalence is considered as 8% to 16% [1]. The complications associated with CKD make it a problem with high prevalence and treatment cost [2]. The situation in India is not different from world and many factors directly contribute to high prevalence of CKD.

The core contributors to the CKD include:

  • Low birth weight
  • Malnutrition and hypovitaminosis A [3]
  • Congenital anomalies and obstructive or reflux nephropathy
  • Environmental factors and nephrotoxins
  • Growing incidences of hypertension and diabetes mellitus
  • Family history [4]

Chronic kidney disease refers to the 5 stages of kidney damage starting Stage 1 (eGFR > 90) to Stage 5 (eGFR < 15). A patient needs dialysis when he/she develops end stage kidney failure, that is loss of 85% to 90% kidney function and a GFR below 15 (Stage 5).

Dialysis is a process of eliminating excess solutes and toxins from the blood in patients whose kidneys fail to perform the functions naturally. Dialysis can be used as a temporary measure in either acute kidney injury or in patients due for kidney transplant and as a permanent measure for patients ruled out for transplant [5]. The kidneys perform an important task of maintaining the body's internal equilibrium of water and minerals while produce erythropoietin, calcitriol, and rennin, function as a part of the endocrine system. Dialysis does not correct the compromised endocrine functions of the kidney but replaces few of the functions through diffusion and ultrafiltration [6] while using highly purified water [7]. Advanced kidney disease and its dialysis lead to disturbance of nutritional and metabolic arrangement of the body.

 

Dialysis and its Prevalence

The global burden of CKD continues to rise, enabling the need for cost-effective treatment along with it. According to the Global Burden of Disease (GBD) 2015 study, 12 lakh deaths, 1.8 crore years of life and 1.9 crore disability-adjusted life-years were lost from cardiovascular diseases, directly attributing to reduced glomerular filtration rates [8, 9]. The Global Burden of Disease (GBD) 2015 study also estimated around 1.2 million deaths from kidney failure, with an increase of 32% in 10 years [9]. In 2010, 2.3–7.1 million deaths were estimated in people with end-stage kidney disease due to no access to chronic dialysis [10]. World Health Organization (WHO) estimated around 1.7 million deaths per year due to acute kidney injury [11]. According to WHO, 2.62 million patients received dialysis globally in 2010, and the need for dialysis was projected to double by 2030 [10]. The greatest increase in peritoneal dialysis utilization was reported in China, Thailand, and the USA in the past decade and it decreased in European parts and Oceania [12]. Asian countries have reported the largest absolute growth in patients on dialysis [12].

In India, GBD 2015 ranks chronic kidney disease as the eighth leading cause of death [13]. It is estimated that the population requiring dialysis is increasing at 10-20% annual rate with only 55,000 patients on dialysis in India [14].

As of 2017, over 1, 30,000 patients were reported to receiving dialysis and the number is increasing by about 232 per million populations [15]. In countries like India, the screening of CKD patients is quite challenging and due to poor access to healthcare facilities, around 50% CKD patients are first reported when GFR is 15 ml/min per 1.73 m2 [15]. This is an alarming situation and there is an immediate need of robust screening of CKD patients.

 

Protein Loss in Dialysis Patients

In case of kidneys failure, the patient will need to start dialysis or have a kidney transplant to survive. Each treatment has its pros and cons. The decision to choose the treatment is based on the medical conditions, lifestyle, and personal preference.

The major pros of dialysis include maintenance of fluid balance, removal of wastes, and control of blood pressure while major disadvantage associated with dialysis is loss of 6-15 g amino acids [16] during each session and the loss of amino acids exert a great influence on hemodialysis membranes (fig. 1).

 

Malnutrition in Dialysis Patient

The CKD patients are prone to risk of malnutrition manifested by protein energy wasting and micronutrient deficiency. The various studies revealed high prevalence of malnutrition in paediatric and adult CKD patients in both developing and developed countries [17]. The paediatric CKD patients are stunted and malnutrition is considered responsible for growth failure in this population [18]. Based on subjective global assessment scale, a study reported that almost 31% adults with CKD (including dialysis and non-dialysis patients) had protein energy wasting [19].

The pathogenesis of nutritional loss or malnutrition during dialysis depends on various factors. Though it is not fully understood, the common pathway for all the nutritional and metabolic derangements is considered to be related to extensive protein degradation and a reduced rate of protein synthesis. The various etiological factors include reduced protein and energy intake due to anorexia, high protein catabolism, decreased anabolism, chronic inflammation, metabolic acidosis and hormonal imbalances [20-23]. Chronic inflammatory state in CKD result in resting energy expenditure, which in turn promotes catabolism of protein and reduced anabolism. The published studies revealed that during dialysis, resting energy expenditure increase (12-20%) [24], resulting increased demand for protein and energy intake.

High protein losses through dialysis, protein catabolism, and reduced albumin synthesis result in negative nitrogen balance and muscle wasting [20, 25]. If the loss of amino acids continues in CKD patient, it can lead to weight loss, muscle wasting, and reduced ability to fight against infections, which can ultimately lead to high mortality rates in hemodialysis patients. Reduced intake of dietary nutrients is a common aspect of advanced CKD. The epidemiologic published literature shows that prevalence of increased levels of inflammatory markers is high in CKD patients. Malnutrition is considered to exert serious consequences in patients with ESRD treated with maintenance dialysis and they are advised to be managed vigorously.

Description: C:\Users\LENOVO\Desktop\PEW-392x360.png

Figure 1: Cycle of protein loss and malnutrition in dialysis patients.

 

Current Management of Nutrition in Dialysis Patients

In CKD patients, malnutrition treatment requires a multidisciplinary, multifaceted and individual customized approach. Evaluation of the nutritional status is a key criterion to initiate the supplementation as per requirement. A clinically meaningful evaluation of the nutritional status can identify the risks and underlying causes and can help in choosing the possible benefits from the nutritional interventions [26]. For management of CKD during dialysis, nutrient intake through dietary supplements is increased. These supplements can be given by oral route or by parenteral route. The oral therapy includes intradialytic meals, oral nutritional supplements outside dialysis sessions, and tube feeding. If no improvement is reported then management can be done by intradialytic parenteral nutrition, intraperitoneal nutrition, and total parenteral nutrition.

 

Challenges Faced in the Current Nutritional Loss Management

Most of the appetite stimulating agents (megestrol acetate, dronabinol, cyproheptadine, melatonin, thalidomide and ghrelin) are available but the published data in CKD patients is not available; however, these agents are used in other catabolic illnesses [27]. Short and long-term benefits of oral nutritional supplements include improvement in whole-body and skeletal muscle protein balance [28]. The current nutritional supplements have risk of hypotension, quality of protein which may disrupt dialyzer settings, overall low quality profile with deleterious potential, and low compliance due to poor acceptability. The risk of hypotension may frighten nephrologists to recommend these supplements. Apart from low blood pressure, the other disadvantages reported were risk of aspiration and other respiratory complications; infectious control and hygiene issues; logistics constraints; and availability of a fraction of required meal [29]. The artificial flavors, certain additives have deleterious potential while powders requiring reconstitution and taste problems may compromise with acceptability. The benefits of nutritional supplements include corrections of intra-and post dialysis catabolism; an improvement in control of dietary phosphorus, potassium, salt and fluid; enhanced adherence to hemodialysis; and improved quality of life.

High protein dietary intake may result in higher intraglomerular pressure and glomerular hyper filtration which in turn can damage glomerular structure leading to or aggravating CKD [30]. Hence, it is recommended to provide supplements with a low protein diet (LPD) of 0.6 0.8 g/kg/day for the management of CKD [30]. The LPD exerts favorable metabolic effects, which preserve kidney function and control uremic symptoms [31-33]. For rapid decline of GFR and initiation of dialysis, LPD as proper dietary regimen is recommended. In non-dialysis days, essential amino acids or their keto-analogs, along with supplemented LPD may be used for incremental transition to dialysis [30].

 

Innovative Approach to Protein Loss Management

Intradialytic Nutrition

Patients with end‐stage renal disease often experience malnutrition as a result of decreased dietary intake; inadequate dialysis; loss of nutrients into the dialysate; abnormal protein, carbohydrate, and lipid metabolism; and concomitant diseases, which may contribute to an increase in morbidity and mortality. Intradialytic parenteral nutrition (IDPN) is being used to improve nutritional status, in conjunction with other methods of nutritional supplementation. The biggest advantage of IDPN is probably its convenience since it is administered during dialysis treatment and thus does not require additional clinic visits or prolonged dialysis time. IDPN has ability to improve nutritional status and reduce morbidity and mortality in patients with end‐stage renal disease is promising.

Intradialytic nutritional support has been used for more than 30 years both in critically ill patients with acute renal failure and during maintenance hemodialysis. Present knowledge allows better estimation of its metabolic and nutritional efficacy, as well its effect on patient outcome. Recent data showed that intradialytic nutritional support is able to counteract these effects of dialysis on protein metabolism and to improve both nitrogen and energy balance. In maintenance hemodialysis patients, the improvement of nutritional status during nutritional support was shown to improve long-term survival. In critically ill patients with acute renal failure, protein sparing is one of the main therapeutic goals. The effect of nutritional support on patient outcome is not demonstrated. Recent data, however, showed that the improvement of nitrogen balance may be associated with a better outcome [34].

 

Advantages of Intradialytic Nutrition

There is a strong need of high protein product without other ingredients which could compensate amino acids losses and could also prevent the hyper catabolism. The published data suggest that use of optimal diet can prevent protein-energy wasting and enteral nutritional supports primarily targeting dietary protein intake. Intradialytic oral nutrient support can help in maintaining optimal protein preventing the muscle wasting and can enhance survival rate with reduced hospital stay. Intradialytic oral protein supplementation helps in improving outcomes of dialysis which include improved nutritional biomarkers in CKD patients, decreased missed dialysis treatments, decreased all-cause mortality rates by at least 30% in dialysis patients, decreased hospitalization rate, and increased survival rate (fig. 2) [35].

Figure 2: Total plasma amino acid concentrations by functional groups during hemodialysis (HD), comparing control, intradialytic parental nutrition (IDPN), and oral supplement (PO). Units are mol/L.*P<0.05 versus control; p<0.05 versus IDPN, BCAA, branched-chain amino acids; EAA, essential amino acids; NEAA, nonessential amino acids; TAA, total amino acids

 

COMPLIPRO: Innovative Ready-to-Drink High Protein Oral Supplementation

Intra-dialytic Protein Supplements- Right Choice, Right Proportion (COMPLIPRO)

Currently available intradialytic oral protein supplementations need reconstitution before consumption. The supplements available in powder form needs to be dispersed in calculated quantity of water which can be tedious to patients and can cause loss of nutrients while reconstitution.

Presently no marketed product is formulated or positioned as ready-to-use high protein oral supplement. Alniche, in collaboration with DPSRU, government of NCT has developed India’s first intradialytic oral nutritional supplement, Complipro.

 

Importance and Benefits

Complipro helps to compensate the intradialytic amino acids losses in dialysis patients. During dialysis, Complipro prevents the hyper-catabolism through maintaining a positive amino acid balance during the whole dialysis session. Complipro prevents high protein loss by maintaining the intradialytic plasma amino-acid balance against replenishing the protein capital post-dialysis in comparison to the current products.

Complipro contains HIGH QUALITY protein that forms spherical complex structures (SCS) of 0.04 to 0.3 µm in diameter in homogenized form in liquid form. These are porous structures that allow the water/milk to move freely in and out of these spherical structures. These SCS are stable yet dynamic structures that do not settle in solution while remain dissolved. They can be heated to boiling or cooled without adverse effects or affecting the nutritional properties of the protein. These contains all the essential amino acids in right proportion that body is unable to produce naturally. Most importantly, it provides a high amount of leucine, which initiates muscle protein synthesis.

SCS in Complipro are fairly simple in their structure, lacking the high degree of coils, turns, and folds found in many other proteins. In theory, they should move through the stomach quickly and transfer their amino acids into the bloodstream soon after ingestion. However, SCS are “Time Release Proteins” and assimilate slowly providing amino acid for longer period.

SCS, has hydrophilic (water-loving) portions of the protein on the outside of the sphere and the hydrophobic (water-fearing) portions on the inside. With hydrophilic structures on the outside, the spherical globules are soluble in water/milk. But when SCS reach the stomach, “one of the most ingenious events in nature takes place”. Chymosin is a digestive enzyme that snips one of the bonds on the exterior protein (known as the kappa subunit), leaving only the hydrophobic subunits inside. Without their outer layer, now these proteins form a semi-solid structure. Thus, by effectively turning a liquid into a semi-solid, that passed on to small intestine for absorption and is the key of better assimilation.

In comparison to fast assimilating proteins, the SCS reduced the total amount of protein burned for fuel over a four to five-hour period leading to an improved net protein balance, a key factor for muscle growth and retention in dialysis patients. SCS is anti-catabolic, reduces protein breakdown within the body due to its slow digestion rate and sustained supply of amino acids to muscle cells for longer period and absorbed from microvilli of small intestine to keep dialysis patient satiated.

PDCAAS value (Protein Digestibility Corrected Amino Acid Score) of Complipro is one. This score means after digestion of the protein; it provides per unit protein 100% or more of the indispensable amino acid required.

Protein in Complipro remains completely dissolved in liquid and are passed on to small intestine to be absorbed through microvilli. Protein in Complipro is 100% assimilated, thus, patients will not have a feeling of flatulence and heaviness.

In addition, Complipro does not contain soya, added sugar, stabilizers and preservatives which is safe, long-lasting and cost-effective product. Complipro, is patient friendly and is available in single dose (1 “Tin can” ~ 150 mL/dialysis), can be stored at ambient temperature for 6 months with burnt coffee flavor.

 

Reconstituted Protein Powder: Inconvenience to Patients

While reconstituted Protein powders when dissolved in milk or water have following problems [36]: -

  1. Incomplete dissolution: Addition of Protein powder in hot, cold or normal water/milk leads to formation of flakes or lumps because of improper wetting, sinking, dispersion and dissolving. This is due to two factors. Firstly, the surface of protein powder has hydrate-forming components forming a gel like structure around the powder preventing liquid to penetrate inside the protein powder. Secondly, hydrophobic layer or fat layer on the protein molecule prevents complete dissolution. Both these factors result in incomplete or inconsistent dissolution or even sinking of the protein powder at bottom of the glass while trying to reconstitute it.
  2. Heaviness and Formation of Gas: The undissolved or undigested protein or lumps of protein not only makes patient feel “gut heavy” or “gut discomfort”, but microbes in colon act on these lumpy undigested protein particles and try breaking them down leading to formation of fermented metabolites like thiols, phenols, ammonia, indoles, and amines, which are undesirable substances, due to which these patients have tendency to pass foul gas too frequently.
  3. Use of Agglomeration and Lecithination (Emulsifiers): These two techniques are being used, in order to make protein powers dissolve properly in water/milk. These methods have their own undesirable effects.
  • Agglomeration increases wetting property of protein powder, but repeated drying of protein powder also increases its denaturation
  • Lecithin is used to enhance the properties of instant milk powders. This involves dissolving lecithin in butter oil and spraying over the agglomerated milk powder, either internally or in a fluidized bed, and outside the dryer. It can cause some side effects including diarrhea, nausea, abdominal pain, or fullness.

 

Conclusion

The imbalance between protein synthesis and degradation seems to be the major driver for the disturbance, which can be mitigated by various anabolic strategies. Nutritional supplementation administered orally or parenterally, is an effective approach. Ready-to-use high protein oral supplement can be proven as an effective measure to prevent the amino acids loss during dialysis. The demand for dialysis and renal replacement therapy is increasing rapidly. Providing intradialytic meals or oral nutritional supplements to patients undergoing dialysis and other nutritional interventions can be one of the most promising interventions to increase serum albumin and to improve longevity and quality of life in this patient population. Ready-to-use high protein intradialytic oral nutritional supplement (Complipro) effectively helps in preventing high protein loss by maintaining plasma amino acid balance during dialysis. The current article throws light on the management of protein and energy intake in patients undergoing dialysis in a limited manner. Though these are the symptomatic preventive measures, the robust screening to detect the disease at the early stage and proper evaluation of the nutritional status of the patients undergoing dialysis are some of the key factors to manage the patients with kidney disease and government initiatives may play an important role in mitigating the disease.

 

 

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