Healthcare e-Compendium
A joint initiative of DPSRU & DRSC
Healthcare e-Compendium
A joint initiative of DPSRU & DRSC
Author: Dr. Sanjeev Kumar A. Hiremath
MD (Int. Med), DM (Nephrology, Mumbai), Sanjeev Clinic, Bengaluru
download ArticleAbstract
Diet is an important factor of care during Chronic Kidney Disease (CKD). Nutritional interventions, has been under debate for decades specifically, a restricted protein diet. Nitrogen-free ketoacid analogues (KAs) supplementation have been proposed in order to reduce the risk of nutritional disorders in Very-Low Protein Diets (VLDP). This review is aimed to summarize the potential effects of KA supplemented diet therapy on renal function, nutritional and metabolic parameters, uremic toxins levels, and propose future directions. Uremic toxins production seems to reduce by VLPD + KAs but the impact on intestinal microbiota remains unexplored. Reduction of phosphorus, acidosis, and possibly sodium intake is observed in all studies, while still providing adequate calcium intake. The current evidence suggests that, as part of the clinical recommendations for both the metabolic management of CKD and nutritional prevention, KAs supplemented Low Protein Diet (LPD) diets should be included. The purpose of this paper is also to identify the challenges that come with ketoanalogues dosing. A CKD patient is burdened with a high pill intake and with ketoanalogues dosage being 6-9 tablets/day adds to the burden. The present article focuses on the importance of ketoanalogues in delaying the progression of CKD. But, also reviewing the challenges of pill burden and compliance among patients, understanding the gap in therapy and need of double strength ketoanalogues. The objective is to reduce pill burden and ensure better patient compliance.
Keywords: Alpha Ketoanalogues, Ketoalfa-DS, Chronic Kidney Disease, Low protein diet, Pill burden, fluid restriction
Introduction
Chronic Kidney Disease (CKD) occurs when the damaged kidney cannot filter blood properly [1]. CKD is a complex disease involving various organs [1]. Progression of CKD is associated with a number of serious complications, including increased incidence of cardiovascular disease, hyperlipidaemia, anaemia, metabolic bone disease, nitrogenous waste and morbidity and mortality (figure 1).
Figure 1: Interplay of processes secondary to Chronic Kidney Disease leading to cardiovascular disease and death
CKD – Affecting a Significant Population
Increasing noncommunicable diseases (NCDs) and other risk factors are adding to the burden of CKD which is increasing worldwide. CKD affects approximately 10% of the world's adult population [2]. Various conditions such as diabetes, hypertension, cardiovascular disease and glomerulonephritis are known to cause CKD. Because of the high prevalence of infections, besides the above known causes, in low income countries interstitial nephritis and glomerulonephritis are the cause for most cases of CKD. Although CKD affects all age groups and sexes, it is more prevalent in aged individuals. It is estimated that the worldwide prevalence to be 23–36% in people aged ≥64 [3]. CKD is a global public health problem and is associated with impaired quality of life and substantially reduced life expectancy at all age groups. Other conditions such as diabetes, infection, cancer and excess risk for cardiovascular disease is also associated with it [4].
Dietary Protein Restriction
Dietary protein restriction in CKD patients plays a pivotal role in delaying the progression of CKD [5]. Low Protein Diet (LPD) is generally recommended to patients with CKD. It ameliorates uremic symptoms and slows the progression of renal dysfunction. Low protein diet also reduces the quantities of sulfates, phosphates, potassium, and sodium ingested, thus leading to a more favorable metabolic profile. Generally, nutritional management of CKD requires balancing the intake of energy, protein, sodium, potassium, phosphorus, and fluid with biochemical markers and weight change. Dietary protein restriction preserves renal function and improves survival in animals with varied glomerulopathies. Conversely, it was suggested that prolonged protein restriction preceding dialysis may induce protein malnutrition and thus confer a poor prognosis during dialysis.
Alpha Ketoanalogues
Alpha Ketoanlogues (KA) are the Nitrogen-free Analogues of Essential Amino Acids (EAA) [5]. Prevalence of protein-energy wasting in early to moderate CKD is 20–25% and increases as CKD progresses. Mitch and colleague, in 1980s, found that progression of renal insufficiency in CKD patients slowed or halted by using KA to supplement a LPD. The decrease in Glomerular Filtration Rate (GFR) and maintained body mass index is alleviated by LPD supplemented with KA. “Ketodiet” is a diet which refers to a variety of KA and LPDs (0.6 g/kg per day) or Very-Low-Protein Diets (VLPDs; 0.3–0.4 g/kg per day). While avoiding the deleterious consequences of inadequate dietary protein intake and malnourishment, Ketodiet allows a reduced intake of nitrogen. These diets have been proven effective in reducing renal death in selected, well-nourished, progressive CKD patients with proven diet adherence and low-comorbidity. Alpha Ketoanalogue is part of the conservative treatment of patients with CKD. In combination with a protein-restricted diet KA is an excellent tool to treat CKD in the pre-dialysis period.
How Alpha Ketoanalogues Works?
Alphaketoanalogues work by reducing nitrogen intake while preventing the deleterious consequences [6]. Keto-analogues are transaminated to the corresponding essential amino acids by taking nitrogen from non-essential amino acids thereby decreasing the formation of urea by re-using the amino group. Hence, accumulation of uremic toxins is reduced. Ketoanalogues do not induce hyper-filtration of the residual nephrons and exerts a positive effect on renal hyperphosphatemia and secondary hyperparathyroidism. Ketoanalogues supplementation has also shown positive effects in improving Renal osteodystrophy. Use of amino acid ketoanalogue in combination with a VLPD allows to reduce nitrogen intake while preventing the deleterious consequences of inadequate dietary protein intake and malnutrition.
Benefits of Alpha Ketoanalogues
Following potential beneficial effects of ketoanalogue supplements can be seen in patients with chronic renal failure on a low protein diet [7]:
Patients who will benefit from a Low or Very Low Protein Diet Supplemented (sLPD/sVLPD) with Alpha Ketoanalogue:
Safety and Efficacy of Alpha Ketoanalogues
Alpha Ketoanalogues supplementation along with conservative management is efficacious and safe in preventing the progression of disease in patients of CKD [8]. A restricted protein diet supplemented with KAs could delay the progression of CKD, prevent hyperphosphatemia and hyperparathyroidism, and benefit blood pressure control without causing malnutrition [9]. In CKD patients a LPD supplemented with ketoacids improves uremia and diabetes, causes sudden decline of body weight which remains stable over time and does not have a negative effect on muscle wasting. In diabetic CKD patients the LPD-KA is safe and the nutritional impact is the same as in nondiabetics CKD [10]. For patients on sVLPD, the start of dialysis treatment can be delayed for about 1 year without increasing their risk of either death or hospitalization [11]. Ketoanalogues, allow for a nutritionally safe, more severe reduction in protein intake. Furthermore, the calcium content of ketoanalogues preparations and their phosphate binder capabilities allow for even better correction of mineral metabolism abnormalities [12].
Data suggest that protein-restricted diets supplemented with keto/amino acids result in a significant decrease in urea production and a beneficial effect on insulin resistance and oxidative stress in humans [13]. In an observational study, malnourished advanced CKD patients treated with a KA supplement had increased body weight, body mass index, serum albumin levels, and alleviated Subjective Global Assessment Scores and Appetite Scores [5]. VLPD supplemented with KA/EAA appear to improve the native arteriovenous fistula (AVF) primary outcome, decreasing the initial vascular stiffness, possible by preserving vascular wall quality in CKD patients through a better serum phosphate levels control and the limitation of inflammatory response [14]. It is proved that a VLPD supplemented with KA/EAA produces decreased levels of toxic metabolic substances and lowers the catabolic tendency of CKD, protecting against oxidative stress [14]. KA/EAA supplements commonly contain substantial amounts of 4-methyl-2-oxovaleric acid, the KA analogue of leucine (ketoleucine), which may suppress protein degradation. In contrast, leucine may increase protein synthesis in muscle; hence, both leucine and ketoleucine and possibly also KA/EAA supplements may promote net protein anabolism and suppress urea formation [15]. Improves nitrogen balance and provides relief from the symptoms of uremia while maintaining good nutrition [7].
Challenges of Conventional Dosage Regimen
Dosage / Administration:
For Oral Use. 6-9 tablets three times a day during meals. To be swallowed whole. This dosage applies to adults (70kg body weight).
Poor Health-related Quality of Life (HR-QOL) is a common sight in CKD patients. CKD patients encounter high pill burden with approximately >20 pills a day (figure 2) [16].
Lowered physical component of HR-QOL were associated with:
Figure 2: Percentage of pill burden from different classes of medications
High Pill Burden in CKD Patients
Pill burden on everyday basis in dialysis patients is one of the highest reported to date in any chronic disease state. Higher pill burden is associated with lower HR-QOL [16]. High burden of co-existing diseases, depression, and a high symptom burden explain, in part, the significant impairment in HR-QOL in dialysis patients. According to reports an average dialysis patient is expected to take 10 to 12 different types of medications. One study found maintenance haemodialysis patients had a median pill burden of >20 pills/day. Complex medication regimes with high pill burden are shown to impair adherence in chronic conditions [17].
Poor Medication Adherence in CKD Patients
In earlier stages of CKD, patients are treated with a mean of 6–12 types of medications, totalling approximately >25 medications daily [18] as expected, such a high pill burden is inevitably associated with major problems of drug adherence, the number of drugs being an important determinant of long-term drug adherence in chronic diseases (figure 3). Poor drug adherence is a major obstacle to achieve treatment goals and increases the risk of morbidity, mortality and hospitalization (figure 4) [19].
Figure 3: Percentage of poor drug adherence in different stages of CKD
Figure 4: Sunburst chart showing the frequencies of sub-factors affecting medication adherence investigated in studies
Review by Ghmire et al. found that the medication non-adherence rates ranged from 12.5 to 98.6% [20]. For dosing regimen factors, high pill burden and taking more types of medication were the most common sub factors that reduced medication adherence. Similarly, developing medication-related side effects and fear of medication adverse effects were associated with poorer medication adherence (table 1).
Table 1: Reasons for non-adherence to medication in patients of CKD (n=158)
Poor adherence has been reported as a cause of:
Fluid Restriction - Must for all CKD Patients
CKD patients have to be under strict dietary and fluid restriction, but due to high pill burden they are bound to take fluid to swallow those pills. Excessive fluid overload contributes to an increased morbidity and high mortality in CKD patients [21]. Fluid restriction is considered the most difficult to accomplish and this remains a major clinical problem in individuals with CKD contributing to severe complications which include [22]:
Increasing Dosage Compliance and Patient Convenience by Reducing Pill Burden – Ketoalfa-DS
CKD Patients needs to take >20 pills/day which leads to increase pill burden and an increased pill burden leads to a fluid overload. To overcome the challenges of pill burden, medication adherence and fluid restriction, Alniche Lifesciences has developed World’s first CDSCO approved Ketoalfa-DS, a double strength tablet of Alpha Ketoanalogues for Patients’ Convenience and Dosage Compliance. Ketoalfa-DS was introduced with the main objective of reducing the pill burden, hence improving patient and dosage compliance. Conventional tablets of Ketoanalogues adds to the daily pill burden (6-9 tablets per day), increased fluid intake of CKD patients and chances of non-compliance. Double strength tablets of Ketoanalogues (Ketoalfa-DS) decrease the daily pill burden (3-4 tablets per day) and fluid intake, with similar dosage, safety and efficacy profile.
Same Form and Dosage of Alpha Ketoanalogues:
The conventional dosage of Ketoanalogue tablet is 2 tablets/meal which is equal to 1260 mg of alpha-ketoanalogues and dosage of Ketoalfa-DS tablet is 1 tablet/meal which is equal to 1260 mg of alpha-ketoanalogues, therefore, the dosage (in mg) remains same. As the form and quantity of dosage is same, hence, the safety and efficacy profile of Ketoalfa-DS remains unchanged (table 2).
Table 2: Comparison of Alpha Ketoanalogues Double Strength Tablet with Conventional Tablet
|
Equivalent to Essential Amino-acid |
Conventional (mg) |
Double Strength (mg) |
|
Isoleucine |
67 |
134 |
|
Leucine |
101 |
202 |
|
Phenylalanine |
68 |
136 |
|
Valine |
86 |
172 |
|
Methionine |
59 |
118 |
|
L-Lysine acetate USP |
105 |
210 |
|
L-Threonine USP |
53 |
106 |
|
L-Tryptophan USP |
23 |
46 |
|
L-Histidine USP |
38 |
76 |
|
L-Tyrosine USP |
30 |
60 |
|
Nitrogen content per tab |
36 |
72 |
|
Calcium content per tab |
50 |
100 |
|
Dosage (approx. no. of tablets): |
6-9 tabs per day |
3-4 tabs per day |
Ketoalfa-DS comes with a rationale of reducing pill burden, maintaining fluid restriction and improving patient and dosage compliance without compromising on the safety and efficacy of ketoanalogues. Ketoalfa-DS comes in double strength which reduces the dosage to half in comparison to conventional ketoanalogues. The reduced dosage adds to patient compliance. The pharmacokinetics and pharmacodynamics of Ketoalfa-DS is unchanged (table 3).
Table 3: Comparison of Alpha Ketoanalogues Double Strength Tablet with Conventional Tablet
|
Parameters |
Conventional |
Double strength |
|
Recommended Dosage (1 tablet/ 10kg body weight) |
6 to 9 tablets daily |
3 to 4 tablets daily |
|
Pill burden |
Increased |
Decreased |
|
Fluid intake |
Overloaded |
Balanced |
|
Safety and Efficacy profile |
Similar safety and efficacy |
|
Conclusion
Chronic Kidney Disease is a worldwide public health problem and is associated with impaired quality of life and substantially reduced life expectancy at all ages. Dietary protein restriction in CKD patients plays a pivotal role in delaying the progression of CKD. Low protein diet (LPD) is usually recommended to patients with CKD. It ameliorates uremic symptoms and slows the progression of renal dysfunction. Ketoanalogues supplementation with a LPD slowed or halted the progression of renal insufficiency in CKD patients. Alpha Ketoanalogue is part of the conservative treatment of patients with CKD. In combination with a protein-restricted diet, Alpha Ketoanalogue is an excellent tool to treat CKD in the pre-dialysis period. Alpha ketoanalogues have shown proven and potential benefits in CKD patients and have significant results in delaying the progression of CKD. Although Ketoanalogues are safe and efficacious but the high dose regimen adds to patient’s discomfort, leading to challenges like increased pill burden and fluid intake and reduced adherence and compliance which affects the quality of life. To overcome these challenges Ketoalfa-DS, a double strength tablet of Alpha Ketoanalogues for Patients’ Convenience and Dosage Compliance was introduced. Double strength ketoanalogue comes with the main objective of reducing the pill burden, hence improving patient and dosage compliance. Conventional tablets of Ketoanalogues adds to the daily pill burden (6-9 tablets per day), increased fluid intake of CKD patients and chances of non-compliance. Double strength tablets of Ketoanalogues (Ketoalfa-DS) decrease the daily pill burden (3-4 tablets per day) and fluid intake, with similar dosage, safety and efficacy profile.
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