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Ketoalfa-DS, The First Globally Approved Double Strength Alpha Ketoanalogues In The Management Of Nitrogenous Waste Of CKD Patients

Author: Dr. Sanjeev Kumar A. Hiremath

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

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Abstract

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]:

  • Reduction of "uremic intoxication"
  • Retardation of progression of renal failure
  • Reduction of proteinuria and amino aciduria
  • Amelioration of metabolic acidosis
  • Reduction of growth retardation in CRF children
  • Reduction of hyperphosphatemia
  • Amelioration of hyperparathyroidism
  • Decrease in oxygen radical generation
  • Improvement of tubular functions
  • Preservation of nitrogen balance
  • Improvement of nutritional status
  • Increases in plasma concentrations of essential amino acids
  • Improvement of plasma protein concentrations (albumin)
  • Improvement of glucose metabolism and insulin sensitivity Improvement in lipid metabolism

Patients who will benefit from a Low or Very Low Protein Diet Supplemented (sLPD/sVLPD) with Alpha Ketoanalogue:

  • CKD patients with advanced disease who wish to delay dialysis
  • All CKD stage 4-5 patients
  • CKD stage 3 patients with a progressive decline in GFR
  • Patients with nephrotic syndrome being considered for a low protein diet
  • Post kidney transplant patients with CKD stage 3-5 or those with proteinuria
  • Dialysis patients (PD or incremental HD) with residual renal function

 

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

  • High chances of missing dose
  • Poor medication adherence to therapy
  • Increased pill burden
  • Decreased patient compliance
  • Increased medication error
  • Increased intake of water to take high number of tablets

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:

  • Pill burden
  • Lower serum albumin
  • Increasing age
  • Greater co-morbidity
  • Higher total number of medications

 

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:

  • Increased mortality
  • Poor quality of life
  • Increased healthcare costs
  • Pill burden

 

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]:

  • Intradialytic cramping and hypotensive episodes
  • Treatment related fatigue and dizziness
  • Lower-extremity oedema
  • Ascites
  • Left ventricular hypertrophy and congestive heart failure
  • Hypertension
  • Shortness of breath
  • Pulmonary vascular congestion or acute pulmonary oedema

 

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.

 

References

  1. Thomas, R., Kanso, A., & Sedor, J. R. Chronic Kidney Disease and Its Complications. Primary Care: Clinics in Office Practice, 2008; 35(2), 329–344. doi:10.1016/j.pop.2008.01.008
  2. GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Lancet. 2016 Oct 8; 388(10053):1545-1602. doi: 10.1016/S0140-6736(16)31678-6
  3. Zhang, QL., Rothenbacher, D. Prevalence of chronic kidney disease in population-based studies: Systematic review. BMC Public Health 2008; 8:117. doi:10.1186/1471-2458-8-117
  4. Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, de Jong PE, Coresh J, Gansevoort RT. Chronic Kidney Disease Prognosis Consortium. Lancet. 2010 Jun 12; 375(9731):2073-81. doi: 10.1016/S0140-6736(10)60674-5
  5. Wu, C.-H., Yang, Y.-W., Hung, S.-C., Kuo, K.-L., Wu, K.-D., Wu, V.-C. Ketoanalogues supplementation decreases dialysis and mortality risk in patients with anemic advanced chronic kidney disease. PLOS ONE, 2017; 12(5): e0176847. doi: 10.1371/journal.pone.0176847
  6. Mims philippines Rhea Ketoanalogue 14 june 2021, https://www.mims.com/philippines/drug/info/rhea%20ketoanalogue
  7. Vladimir Teplan. Supplements of Keto Acids in Patients with Chronic Renal Failure Turkish J Nephrol. 2004; 13: 3-7
  8. Khan IA, Nasiruddin M, Haque SF, Khan RA. Clinical evaluation of efficacy and safety of α-keto analogs of essential amino acids supplementation in patients of chronic kidney disease. Int J Basic Clin Pharmacol 2014; 3:484-9 doi: 10.5455/2319-2003.ijbcp20140614
  9. Li, A., Lee, H.-Y., & Lin, Y.-C. The Effect of Ketoanalogues on Chronic Kidney Disease Deterioration: A Meta-Analysis. Nutrients, 2019; 11(5), 957. doi:10.3390/nu11050957
  10. Bellizzi, V., Calella, P., Hernández, J. N., González, V. F., Lira, S. M., Torraca, S., … Montúfar Cárdenas, R. A. Safety and effectiveness of low-protein diet supplemented with ketoacids in diabetic patients with chronic kidney disease. BMC Nephrology, 2018; 19(1). doi:10.1186/s12882
  11. Brunori, G., Viola, B. F., Parrinello, G., De Biase, V., Como, G., Franco, V., … Cancarini, G. C. Efficacy and Safety of a Very-Low-Protein Diet When Postponing Dialysis in the Elderly: A Prospective Randomized Multicenter Controlled Study. American Journal of Kidney Diseases, 2007; 49(5), 569–580. doi: 10.1053/j.ajkd.2007.02.278
  12. Garneata, L., Stancu, A., Dragomir, D., Stefan, G., & Mircescu, G. Ketoanalogue-Supplemented Vegetarian Very Low-Protein Diet and CKD Progression. Journal of the American Society of Nephrology, 2016; 27(7), 2164–2176. doi:10.1681/asn.2015040369
  13. Ikizler, T. A. Safety of Low-Protein Diets and Ketoanalogue Supplementation in CKD. Kidney International Reports, 2018; 3(3), 510–512. doi: 10.1016/j.ekir.2018.02.004
  14. David, C., Peride, I., Niculae, A., Constantin, A. M., & Checherita, I. A. Very low protein diets supplemented with keto-analogues in ESRD predialysis patients and its effect on vascular stiffness and AVF Maturation. BMC Nephrology, 2016; 17(1). DOI 10.1186/s12882-016-0347-y
  15. Shah, A. P., Kalantar-Zadeh, K., & Kopple, J. D. Is There a Role for Ketoacid Supplements in the Management of CKD? American Journal of Kidney Diseases, 2015; 65(5), 659–673. doi: 10.1053/j.ajkd.2014.09.029
  16. Chiu, Y.-W., Teitelbaum, I., Misra, M., de Leon, E. M., Adzize, T., & Mehrotra, R. Pill Burden, Adherence, Hyperphosphatemia, and Quality of Life in Maintenance Dialysis Patients. Clinical Journal of the American Society of Nephrology, 2009; 4(6), 1089–1096. doi:10.2215/cjn.00290109
  17. Parker, K., Nikam, M., Jayanti, A., & Mitra, S. Medication burden in CKD-5D: impact of dialysis modality and setting. Clinical Kidney Journal, 2014; 7(6), 557–561. doi:10.1093/ckj/sfu091
  18. Burnier, M., Pruijm, M., Wuerzner, G., & Santschi, V. Drug adherence in chronic kidney diseases and dialysis. Nephrology Dialysis Transplantation, 2014; 30(1), 39–44. doi:10.1093/ndt/gfu015
  19. T Siva Kala, Arepalli Sreedevi, M V Hari Prasad, P N Jikki Int J Med Sci Public Health. 2019; 8(3): 223-229doi: 10.5455/ijmsph.2019.0101523012019
  20. Seng JJB, Tan JY, Yeam CT, Htay H, Foo WYM. Factors affecting medication adherence among pre-dialysis chronic kidney disease patients: a systematic review and meta-analysis of literature. Int Urol Nephrol. 2020 May; 52(5):903-916. doi: 10.1007/s11255-020-02452-8
  21. Beerendrakumar N, Ramamoorthy L, Haridasan S. Dietary and Fluid Regime Adherence in Chronic Kidney Disease Patients. J Caring Sci. 2018 Mar 1; 7(1):17-20. doi: 10.15171/jcs.2018.003. PMID: 29637052; PMCID: PMC5889793.
  22. Geldine Chironda*, Busisiwe Bhengu Engagement with Fluid and Dietary restriction among Chronic Kidney Disease (CKD) patients in Selected Public Hospitals of KwaZulu-Natal (KZN) Province, South Africa Health Science Journal. 2016; 10(5):4 doi: 10.4172/1791-809X.1000100504

 

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