Home About us Current issue Ahead of Print Back issues Submission Instructions Advertise Contact Login   

Search Article 
  
Advanced search 
 
Saudi Journal of Kidney Diseases and Transplantation
Users online: 912 Home Bookmark this page Print this page Email this page Small font sizeDefault font size Increase font size 
 

Table of Contents   
ORIGINAL ARTICLE  
Year : 2016  |  Volume : 27  |  Issue : 4  |  Page : 710-716
Comparative evaluation of efficacy and safety profile of rhubarb and α-keto analogs of essential amino acids supplementation in patients with diabetic nephropathy


1 Department of Pharmacology, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
2 Department of Medicine, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India

Click here for correspondence address and email

Date of Web Publication5-Jul-2016
 

   Abstract 

To determine the efficacy and safety profile of rhubarb and α-keto analogs of essential amino acids supplementation in patients of diabetic nephropathy (DN), we studied 96 patients of DN attending a tertiary care center of the North India. The patients were randomly divided into three equal interventional groups. Group I (control) that received conservative management along with placebo, Group II (rhubarb) that received conservative management along with rhubarb capsule (350 mg, thrice daily), and Group III [keto amino acid (KAA)] that received conservative management along with α-keto analogs of essential amino acids (600 mg, thrice daily). The treatment was continued for 12 weeks. Clinical and biochemical parameters were assessed at 0, 4, 8, and 12 weeks of treatment. A progressive improvement in clinical features and biochemical parameters was seen in all three groups after 12 weeks of treatment. The KAA group showed more marked improvement in clinical features as well as biochemical parameters compared to the rhubarb group. There was a reduction in blood glucose, blood urea, serum creatinine, and 24 h total urine protein. There was an increase in hemoglobin, 24 h total urine volume, and glomerular filtration rate. There was no statistical difference between the rhubarb and KAA groups with respect to side effects (P > 0.05). Our study suggests that KAA is more effective than rhubarb as add-on therapy with conservative management in patients of DN.

How to cite this article:
Khan IA, Nasiruddin M, Haque SF, Khan RA. Comparative evaluation of efficacy and safety profile of rhubarb and α-keto analogs of essential amino acids supplementation in patients with diabetic nephropathy. Saudi J Kidney Dis Transpl 2016;27:710-6

How to cite this URL:
Khan IA, Nasiruddin M, Haque SF, Khan RA. Comparative evaluation of efficacy and safety profile of rhubarb and α-keto analogs of essential amino acids supplementation in patients with diabetic nephropathy. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2021 Oct 19];27:710-6. Available from: https://www.sjkdt.org/text.asp?2016/27/4/710/185227

   Introduction Top


Diabetic nephropathy (DN) is a clinical syndrome characterized by persistent albuminuria (>300 mg/day or >200 μg/min) that is confirmed on at least two occasions three to six months apart, progressive decline in the glomerular filtration rate (GFR), and elevated arterial blood pressure. [1] DN is the leading cause of end-stage renal disease (ESRD) worldwide and it is estimated that ~20% of type 2 diabetic patients reach ESRD during their lifetime. [2] The pathophysiology for the development and progression of DN is not clear but it has been suggested that DN is influenced by some genetic factors such as apolipoprotein E, [3] the overexpression of glucose transporter 1 (GLUT 1) in mesangial cells, [4],[5] and the over-activity of the hexosamine pathway. [6] Low protein diet (0.6 g/kg BW/day) as well as very low protein diet (0.3 g/kg BW/day) decreases the accumulation of nitrogen waste products while maintaining an adequate nutritional status. [7],[8] The ideal treatment for DN and ESRD is renal replacement therapy which includes renal transplantation and maintenance dialysis. These modalities are costly, require lifelong therapy, not suitable for many patients, and associated with many complications and out of reach of 95-99% of patients; they are managed on conservative therapy. [9]

Rhubarb belongs to genus Rheum in the family Polygonaceae. Important derivatives from rhubarb are anthraquinones such as rhein, emodin, and aloe-emodin. [10] Rhein and rhaponticin are potential hypoglycemic agents. [11] Rhein decreases the lipid level and protects against DN progression. [12] Emodin decreases the gluconeogenesis of renal tubular cells and diminishes the ATP content of epithelial mitochondria. Both the Na + /K + ATPase and Ca [2]+ ATPase activities of the epithelial cell were attenuated during the administration of emodin in an in vitro study. [13] Rhubarb supplementation improved the conservative management in patients of chronic kidney disease. [14]

α-keto analogs of essential amino acids/keto amino acids (KAAs) are nitrogen-free analogs of essential amino acids. The use of KAA in association with a low or very low protein diet allows a reduced intake of nitrogen while avoiding the deleterious consequences of inadequate dietary protein intake and malnourishment. [15],[16],[17],[18],[19],[20],[21] α-KAA reduced proteinuria and improved renal function and nutritional status in diabetic nephropathy patients. [22] KAA halted progression of type 2 DN by regulating inflammatory mediators such as tumor necrosis factor-α (TNF-alpha), C-reactive protein (CRP), and adipo-nectin. [23]

The aim of our study was to compare the efficacy and safety profile of rhubarb and α-keto analogs of essential amino acids supplementation in patients with diabetic nephropathy.


   Materials and Methods Top


This study is a randomized, prospective, double-blinded, and parallel group study conducted in patients of DN attending Renal Clinic of a tertiary care center of the North India from June 2012 to September 2013. The diagnosis of DN was made on the basis of detailed clinical history, physical examination, and investigations. The study was approved by our Institutional Ethics Committee and Registered under Clinical Trial Registry of India with Registration Number CTRI/2012/09/002947 (Registered on: 03/09/2012). Written informed consent was taken from all patients enrolled in the study.

Patients having DN (Stage 1-4), age 20-60 years and of either sex were included in the study. Patients with nondiabetic nephropathy, ESRD, dialysis, pregnancy, terminal illness, immunodepression, and severe renal pathology such as malignancy were excluded from the study.

A total of 120 patients were assessed; out of them 105 patients were enrolled in the study. Nine patients (three from each group) were excluded from the study as they failed to report on subsequent visits. Enrolled patients were randomized into three groups at a ratio of 1:1:1 using a table generated by random with allocation software. Patients were included in the study after final diagnosis, applying inclusion and exclusion criteria. Group I (control) patients received conservative management along with a placebo, Group II (rhubarb) patients received conservative management along with rhubarb capsule (350 mg) thrice daily, and Group III (KAA) received conservative management along with KAA (600 mg) thrice daily. All the three groups received treatment for 12 weeks. Conservative management included renal diet, telmisartan (40 mg OD), and insulin. All the enrolled patients were regularly followed with investigations at 0, 4, 8, and 12 weeks of treatment. The assessed biochemical parameters included hemoglobin (Hb), fasting blood glucose, postprandial blood glucose, blood urea, serum creatinine, 24 h total urine protein (TUP), 24 h total urine volume (TUV), and GFR.

All adverse events experienced by patients or observed by the investigators were recorded on standard adverse drug reaction (ADR) reporting forms of CDSCO at each visit. ADRs causality assessment was done using Naranjo's Scale [24] and severity assessment by Modified Hartwig and Siegel Scale. [25] Physical examination including vital signs was performed at the start of study and at each visit. Additional routine laboratory safety test such as liver function tests, electrocardiogram, and chest X-ray were performed wherever required.


   Statistical Analysis Top


Statistical analysis was done using SPSS version 20 software (IBM, Armonk, NY, USA). The values were expressed as a mean ± standard deviation. Statistical significance between pre-and post-treatment values in each group was calculated using Student's paired t-test. Statistical significance between groups was calculated using ANOVA followed by post hoc Dunnett's test. P <0.05 was considered significant.


   Results Top


The patients in the subgroups included 32 (18 male, 14 female) patients with a mean age of 45 years (range: 22-58 years) in Group I, 32 (19 male, 13 female) patients with a mean age of 45 years (range: 21-59 years) in Group II, and 32 (18 male, 14 female) patients with a mean age of 45 years (range: 22-59 years) in Group III. The distribution of patients was almost similar and no significant difference (P >0.05) was seen between the groups. None of the patients required dialysis and there was no mortality in any group. As per GFR, patients belonged to Stage 3 (13, 14, and 14 in Group I, II, and III, respectively) and Stage 4 (19, 18, and 18 in Group I, II, and III, respectively) DN. In our study, baseline clinical features were almost similar in all the three groups. There was a gradual improvement in clinical features in all the three groups after 12 weeks of treatment but it was more marked in the KAA group as compared to the rhubarb group [Table 1].
Table 1: Signs and symptoms of the study patients.

Click here to view


There was a progressive decrease in both systolic and diastolic blood pressure (SBP and DBP) toward normal in all the three the groups. The KAA group showed the most significant decrease in both SBP and DBP [Table 2].
Table 2: Comparison of blood pressure, hemogram and renal function tests between rhubarb and α-keto analogs of essential amino acids (keto amino acid ) groups before and after 12 weeks of treatment.

Click here to view


The total leukocyte count, differential leukocyte count, platelet count, serum sodium, potassium, and calcium remained within normal limits at the end of 12 weeks of treatment in all the three groups.

There was a progressive improvement in various biochemical parameters in all the three groups. The KAA group showed maximum improvement among the three groups. As compared to the control group, the KAA group showed a significant increase in Hb (P <0.05), decrease in fasting and postprandial blood glucose (P <0.01), decrease in blood urea (P <0.05), decrease in serum creatinine (P <0.05), decrease in TUP (P <0.05), increase in TUV (P <0.001), and increase in GFR (P <0.01) than rhubarb group after 12 weeks of treatment [Table 2].

The ADRs occurrence was not significantly different between the rhubarb and the KAA groups. According to Modified Hartwig and Siegel Scale, the ADRs were mild (no hospitatalization, no change of therapy, and no additional treatment). On Naranjo's Scale, the ADRs were possible (score = 1-4) in seven cases and probable (score = 5-8) in five cases within the rhubarb group, while possible (score = 1-4) in six cases and probable (score = 5-8) in four cases within the KAA group [Table 3].
Table 3: Comparison of adverse drug reactions between rhubarb and α-keto analogs of essential amino acids (KAA) groups.

Click here to view



   Discussion Top


Conservative management is very important to prevent CKD and delay its progression to ESRD. Search for newer cost-effective treatment modalities, which can halt nephron damage and delay the development of ESRD continues.

The previous studies have reported a beneficial effect of rhubarb in CKD patients. [26],[27] Rhubarb contains various phytoconstituent among which rhein and emodin are important. Rhein inhibits cell hypertrophy and extracellular matrix accumulation by decreasing transforming growth factor-beta 1 (TGF-β1) and fibronectin expression in renal tissue. [12] TGF-β1 stimulates the glucose uptake in mesangial cells through the upregulation of GLUT 1 expression. Emodin has an inhibitory effect on the expression of c-myc mRNA and hence cell cycle down regulation in cultured rat mesangial cells, which might be the reason why emodin inhibits mesangial cell proliferation. [28] Rhubarb suppresses production of various cytokines from macrophages and human mesangial cells. [29],[30] Rhubarb also has a laxative effect, which increases excretion of nitrogenous wastes from the body. [31],[32] Rhubarb showed beneficial effects in nephropathy patients at a dose of 1000 mg/day; [27] therefore, rhubarb dose used in our study was 350 mg TDS daily.

Richards et al suggested that KAA might be useful in the treatment of uremia. [33] KAA is transaminated by taking nitrogen from nonessential amino acids, thereby, it can decrease the formation of urea by re-using the amino group. [17] KAA can also reduce protein degradation and urinary protein excretion. Previous studies suggested that KAA supplementation can reduce plasma urea, urea synthesis, and urea excretion and an improvement in nitrogen balance in CKD patients. [34] Further studies showed that KAA can control blood glucose, improve insulin sensitivity, and reduce hyperinsulinemia. [18] Chen et al showed a significant reduction in TNF-α, CRP, and adiponectin by KAA in type 2 DN. [23] KAA had beneficial effects in CKD Stage 4, 5 at a dose of 60 mg/kg BW/day; [19] KAA dose used in our study was 600 mg TDS daily.

In our study, the results showed that the incidence of ADRs was not significantly different between the rhubarb and the KAA-treated groups. According to Ye et al, there was no ADRs of rhubarb administration at a dose of 8-12 g/day for three weeks in thirty patients with nephropathy. [26] Walser et al showed that KAA supplementation at a dose of 6-14 g/day for 15-60 days in ten patients with severe uremia was not associated with toxicity. [20] Mitch et al found no ADRs or toxicity of KAA supplementation in patients with nephropathy. [21] Therefore, the ADRs in our study might have reflected more manifestations of underlying renal pathology or due to other co-administered drugs than drug-related effects.

The findings in our study are in accordance with those reported in earlier studies. Hence, supplementation of rhubarb or KAA along-with conservative management produces improvement in clinical features as well as biochemical parameters in CKD patients. The data from this study suggest that KAA 600 mg TDS was more effective than rhubarb 350 mg TDS in patients with diabetic nephropathy. The limitation of this study is its short duration. Longer duration of follow-up is needed in further studies to determine the long-term effect of rhubarb and KAA in DN patients.


   Conclusion Top


We conclude that supplementation of rhubarb or α-keto-analogs of the essential amino acids along with conservative management produces safe improvement in clinical features and biochemical parameters in patients with DN.

Conflict of Interests: None declared

 
   References Top

1.
Reutens AT, Prentice L, Atkins R. The epidemiology of diabetic kidney disease. In: Ekoe J, ed. The Epidemiology of Diabetes Mellitus. 2nd ed. Chichester: John Wiley & Sons Ltd.; 2008. p. 499-518.  Back to cited text no. 1
    
2.
Ayodele OE, Alebiosu CO, Salako BL. Diabetic nephropathy - A review of the natural history, burden, risk factors and treatment. J Natl Med Assoc 2004;96:1445-54.  Back to cited text no. 2
[PUBMED]    
3.
Eto M, Saito M, Okada M, et al. Apolipoprotein E genetic polymorphism, remnant lipoproteins, and nephropathy in type 2 diabetic patients. Am J Kidney Dis 2002;40:243-51.  Back to cited text no. 3
[PUBMED]    
4.
Brosius FC, Heilig CW. Glucose transporters in diabetic nephropathy. Pediatr Nephrol 2005; 20:447-51.  Back to cited text no. 4
[PUBMED]    
5.
Wang Y, Heilig K, Saunders T, et al. Transgenic overexpression of GLUT1 in mouse glomeruli produces renal disease resembling diabetic glomerulosclerosis. Am J Physiol Renal Physiol 2010;299:F99-111.  Back to cited text no. 5
[PUBMED]    
6.
Zheng JM, Zhu JM, Li LS, Liu ZH. Rhein reverses the diabetic phenotype of mesangial cells over-expressing the glucose transporter (GLUT1) by inhibiting the hexosamine pathway. Br J Pharmacol 2008;153:1456-64.  Back to cited text no. 6
[PUBMED]    
7.
Sakhuja V, Sud K. End-stage renal disease in India and Pakistan: Burden of disease and management issues. Kidney Int Suppl 2003;83:S115-8.  Back to cited text no. 7
[PUBMED]    
8.
Fouque D, Laville M, Boissel JP. Low protein diets for chronic kidney disease in non diabetic adults. Cochrane Database Syst Rev 2006;2:CD001892.  Back to cited text no. 8
[PUBMED]    
9.
Bargman JM, Skorecki K. Chronic Kidney Disease. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J ed. by. Harrison's Principles of Internal Medicine. 18th ed. New York: The McGraw-Hill Companies, Inc; 2012.  Back to cited text no. 9
    
10.
Gao LL, Xu XD, Nang HJ, Yang JS, et al. Chemical constituents in Rheum tanguticum. Chin Tradit Herb Drugs 2011;42:443-6.  Back to cited text no. 10
    
11.
Choi SB, Ko BS, Park SK, Jang JS, Park S. Insulin sensitizing and alpha-glucoamylase inhibitory action of sennosides, rheins and rhaponticin in Rhei Rhizoma. Life Sci 2006; 78:934-42.  Back to cited text no. 11
[PUBMED]    
12.
Gao Q, Qin WS, Jia ZH, et al. Rhein improves renal lesion and ameliorates dyslipidemia in db/db mice with diabetic nephropathy. Planta Med 2010;76:27-33.  Back to cited text no. 12
[PUBMED]    
13.
Zhou XM, Chen QH. Studies on Chinese Rhubarb: XXII, inhibitory effect of anthraxquinone derivatives on Na+-K+-ATPase of rabbit renal medulla and their diuretic action. Acta Pharmacol Sin 1988;23:17-20.  Back to cited text no. 13
    
14.
Khan IA, Nasiruddin M, Haque SF, Khan RA. Evaluation of Rhubarb supplementation in stages 3 and 4 of chronic kidney disease: A Randomized clinical trial. Int J Chronic Dis 2014;2014:789340.  Back to cited text no. 14
[PUBMED]    
15.
Chang JH, Kim DK, Park JT, et al. Influence of ketoanalogs supplementation on the progression in chronic kidney disease patients who had training on low-protein diet. Nephrology (Carlton) 2009;14:750-7.  Back to cited text no. 15
[PUBMED]    
16.
Khan IA, Nasiruddin M, Haque SF, Khan RA. Clinical evaluation of efficacy and safety of αketo analogs of essential amino acids supplementation in patients of chronic kidney disease. Int J Basic Clin Pharmacol 2014;3:484-9.  Back to cited text no. 16
    
17.
Teplan V. Supplements of keto acids in patients with chronic renal failure. Nefroloji Derg 2004;13:3-7.  Back to cited text no. 17
    
18.
Aparicio M, Gin H, Potaux L, Bouchet JL, Morel D, Aubertin J. Effect of a ketoacid diet on glucose tolerance and tissue insulin sensitivity. Kidney Int Suppl 1989;27:S231-5.  Back to cited text no. 18
[PUBMED]    
19.
Chen JB, Cheng BC, Kao TW. A comparison of progression of chronic renal failure: Low dose vs. standard dose ketoacids. Kidney Res Clin Pract 2012;31:A24.  Back to cited text no. 19
    
20.
Walser M, Coulter AW, Dighe S, Crantz FR. The effect of keto-analogues of essential amino acids in severe chronic uremia. J Clin Invest 1973;52:678-90.  Back to cited text no. 20
[PUBMED]    
21.
Mitch WE, Abras E, Walser M. Long-term effects of a new ketoacid-amino acid supplement in patients with chronic renal failure. Kidney Int 1982;22:48-53.  Back to cited text no. 21
[PUBMED]    
22.
Qiu HY, Liu F, Zhao LJ, et al. Comparison of the effects of alpha-keto/amino acid supplemented low protein diet and diabetes diet in patients with diabetic nephropathy. Sichuan Da Xue Xue Bao Yi Xue Ban 2012;43:425-8.  Back to cited text no. 22
[PUBMED]    
23.
Chen N, Jin Y, Ren H, et al. Anti-inflammatory effects of low protein diet supplemented with keto-amino acid in the treatment of type 2 diabetic nephropathy. Kidney Res Clin Pract 2012;31:A24.  Back to cited text no. 23
    
24.
Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.  Back to cited text no. 24
[PUBMED]    
25.
Hartwig SC, Siegel J, Schneider PJ. Preventability and severity assessment in reporting adverse drug reactions. Am J Hosp Pharm 1992;49:2229-32.  Back to cited text no. 25
[PUBMED]    
26.
Ye R, Li Y, Sun D. Clinical study of the therapeutic effects of rhubarb as a main drug in the treatment of chronic renal failure. Chin J Integrated Tradit West Med 1995;1:104-7.  Back to cited text no. 26
    
27.
Sanada H. Study on the clinical effect of rhubarb on nitrogen-metabolism abnormality due to chronic renal failure and its mechanism. Nihon Jinzo Gakkai Shi 1996;38:379-87.  Back to cited text no. 27
[PUBMED]    
28.
Liu ZH, Li LS, Hu WX, Zhou H. Effect of Emodin on c-myc proto-oncogene expression in mesangial cells. J Nephrol Dial Transplant 1992;1:27-30.  Back to cited text no. 28
    
29.
Hu WX, Li LS, Yao J. Rheum officinale inhibited the production of interleukin 1 and tumor necrosis factor by macrophages. Bull Jinling Hosp 1991;4:404-7.  Back to cited text no. 29
    
30.
Liu ZH, Li LS, Hu WX, Zhou H. Effect of IL-6 on c-myc proto-oncogene expression in human mesangial cells and the down regulation by Emodin. J Nephrol Dial Transplant 1993;2:58-61.  Back to cited text no. 30
    
31.
Li L. End stage renal disease in china. Kidney Int 1996;49:287-301.  Back to cited text no. 31
[PUBMED]    
32.
Li F, Wang SC, Wang X, et al. Novel exploration of cathartic pharmacology induced by rhubarb. China J Chin Mater Med 2008;33:481-4.  Back to cited text no. 32
    
33.
Richards P, Metcalfe-Gibson A, Ward EE, Wrong O, Houghton BJ. Utilisation of ammonia nitrogen for protein synthesis in man, and the effect of protein restriction and uraemia. Lancet 1967;2:845-9.  Back to cited text no. 33
[PUBMED]    
34.
Ell S, Fynn M, Richards P, Halliday D. Metabolic studies with keto acid diets. Am J Clin Nutr 1978;31:1776-83.  Back to cited text no. 34
[PUBMED]    

Top
Correspondence Address:
Irfan Ahmad Khan
Department of Pharmacology, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh - 202 002, Uttar Pradesh
India
Login to access the Email id


DOI: 10.4103/1319-2442.185227

PMID: 27424687

Rights and Permissions



 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

Top
   
 
 
    Similar in PUBMED
    Search Pubmed for
    Search in Google Scholar for
    Email Alert *
    Add to My List *
* Registration required (free)  
 


 
    Abstract
   Introduction
    Materials and Me...
   Statistical Analysis
   Results
   Discussion
   Conclusion
    References
    Article Tables
 

 Article Access Statistics
    Viewed2812    
    Printed21    
    Emailed0    
    PDF Downloaded363    
    Comments [Add]    

Recommend this journal