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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2013  |  Volume : 24  |  Issue : 4  |  Page : 737-742
Comparative evaluation of fosinopril and herbal drug Dioscorea bulbifera in patients of diabetic nephropathy


1 Department of Nephrology, Institue of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
2 Department of Pathology, Institue of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
3 Faculty of Ayurveda, Institue of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India

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Date of Web Publication24-Jun-2013
 

   Abstract 

Worldwide, diabetic nephropathy is one of the leading causes of end-stage renal failure. This hospital-based single-center prospective open-label randomized case-control interventional study was performed to evaluate and compare the native drug Dioscorea bulbifera with fosinopril in the management of diabetic nephropathy. Patients with diabetic nephropathy with proteinuria >500 mg/day or albuminuria >300 mg/ day, S Cr ≤2.5 mg/dL and hypertension controlled with a single drug were included into the study and were divided into three groups according to the interventional drugs that they were given; group A (n = 46) on fosinopril (5-40 mg/day), group B (n = 45) on Dioscorea bulbifera (500 mg BD) and group C (n = 46) on neither of these drugs. All necessary laboratory investigations needed to assess the effect of both the drugs were carried out. Patients were followed-up for six months. The study included 137 patients (M:F 2.61:1) with an age range of 19-76 years. At the sixth-month follow-up, a significant decrease in the systolic blood pressure was noted in all three groups whereas the diastolic blood pressure decreased significantly only in group B. There was significantly better control of both systolic and diastolic blood pressures in group B than in the other groups. Although fasting blood sugar was poorly controlled in the initial visit in all three groups, there was a significant decrease at the sixth-month follow-up in all three groups. Moreover, the decrease was significantly more pronounced in group B than in the other two groups. Low-density lipoprotein decreased significantly only in group B. Proteinuria, serum transforming growth factor-β, interleukin-6 (IL-6) and C-reactive protein decreased in both group A and group B, more so in the latter, but the differences between the groups were not statistically significant. Importantly, proteinuria and serum IL-6 showed an increasing trend in group C. It can be concluded that Dioscorea bulbifera was more effective than fosinopril in controlling blood pressure, glycemia, cholesterolemia and inflammatory state in diabetic nephropathy. Both agents decreased proteinuria. However, creatinine clearance significantly decreased with both the drugs, more so with Dioscera, and thus further evaluation with a larger trial is needed.

How to cite this article:
Singh R G, Rajak M, Ghosh B, Usha, Agrawal A, Dubey G P. Comparative evaluation of fosinopril and herbal drug Dioscorea bulbifera in patients of diabetic nephropathy. Saudi J Kidney Dis Transpl 2013;24:737-42

How to cite this URL:
Singh R G, Rajak M, Ghosh B, Usha, Agrawal A, Dubey G P. Comparative evaluation of fosinopril and herbal drug Dioscorea bulbifera in patients of diabetic nephropathy. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2019 Oct 19];24:737-42. Available from: http://www.sjkdt.org/text.asp?2013/24/4/737/113866

   Introduction Top


Diabetes mellitus, resulting in diabetic nephropathy, is one of the leading causes of end-stage renal failure (ESRD) worldwide. The number of adults with diabetes in the world is expected to rise from 135 million in 1995 to 300 million in 2025. [1] In India, there were an estimated 40 million persons with diabetes in 2007. This number is predicted to rise to almost 70 million people by 2025 and, therefore, India is going to be the diabetes capital of the world. [2],[3] Diabetic nephropathy is one of the most serious long-term complications of diabetes mellitus and is the leading cause (25-45%) of ESRD all over the world. Combined with the significant micro- and macrovascular complications that accompany the disease, these patients are at an increased risk of morbidity and mortality. Strategies to decrease proteinuria and control imbalance in the metabolic milieu have been shown to retard the progression of diabetic nephropathy. The angiotensin converting enzyme inhibitor (ACE-I), fosinopril, has been well tried in this regard. [4],[5],[ 6] The herbal drug, Dioscorea bulbifera, has been shown to have antiproteinuric, anti-diabetic and cholesterol-lowering properties, and may offer a cheaper alternative to strategies to slow the progression of diabetic nephropathy. [7],[8],[9]

In the present study, a comparative evaluation of fosinopril and the herbal drug Dioscorea bulbifera was undertaken as a possible strategy to retard the progression of renal disease in overt proteinuric patients with diabetic nephropathy.


   Materials and Methods Top


The study was carried out in the Department of Nephrology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India. One hundred and thirty-seven patients of diabetic nephropathy were included in this hospital-based single-center prospective open-label randomized case-control interventional study after taking informed consent. The study was authorized by the institutional ethical committee.

We included diabetic patients with evidence of nephropathy defined as urinary excretion of >500 mg/day of protein or >300 mg/day of albumin in the absence of other renal disease, urinary tract infection or heart failure. We excluded patients who were already taking ACEI or angiotensin receptor antagonist or had any kind of allergic history with the trial drugs, advanced renal failure (serum creatinine >2.5 mg/dL), acute on chronic renal failure (CRF), hypertension requiring multiple drugs and bilateral renal artery stenosis. Termination criteria were rapid decline in renal function requiring renal replacement therapy, death of the patients due to any cause, acute on CRF and patient's completion of six months follow-up, whichever occurred first.

The patients were randomized into one of three groups. One group (group A) consisted of 46 patients who received fosinopril in a dose of 5-40 mg/day for six months. The second group (group B) consisted of 45 patients who received capsules of Dioscorea bulbifera in a dose of 500 mg BD for a period of six months. The third group (group C) consisted of 46 patients who did not receive either of the above drugs but were treated with standard antidiabetic and other drugs as appropriate.

The 24-h urinary protein excretion, creatinine clearance, complete blood count, liver function tests, fasting blood sugar, and serum levels of cholesterol [total, low-density lipoprotein (LDL), high-density lipoprotein(HDL) and very low-density lipoprotein(VLDL)], creatinine, transforming growth factor-β (TGF-β), C-reactive protein (CRP) and IL-6 were estimated using standard laboratory techniques.

Safety and efficacy were assessed by comparing these baseline investigations with those repeated after three and six months. Adverse events were recorded at each visit and classified as mild (transient and easily tolerated), moderate (caused patient discomfort but did not interrupt activities) or severe (caused severe disruption of usual activities).

Statistical analysis was performed using the software SPSS version 12.0 and the mean values were compared using t-test and ANOVA, taking P <0.05 as significant.


   Results Top


One hundred and thirty-seven patients (M:F, 2.61:1) of diabetic nephropathy were included in the study and their age ranged from 19 to 76 years. There was no significant difference in age, sex ratio, baseline blood pressure, fasting blood sugar, lipid profile, proteinuria, creatinine clearance and inflammatory markers among the three groups at presentation [Table 1] and [Table 2].
Table 1: Demographic profile of patients in the three groups at the initiation of the study.

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At the sixth month, the systolic blood pressure (SBP) decreased significantly in all three groups but the diastolic blood pressure (DBP) decreased significantly only in group B [Table 2]. The decrease in SBP was significantly higher in group B than in group A (P = 0.016).

Glycemia was poorly controlled at the initial visit, with fasting blood glucose in groups A, B and C being 182.4 mg/dL, 182.6 mg/dL and 186.2 mg/dL, respectively. However, it decreased significantly in all the groups at the sixth month of follow-up [Table 2]. There was no significant difference in these values between groups A and B, either initially or at the sixth month. However, compared with group C, there was a significantly better glycemia control in group B and not in group A.

Initially, the serum LDL levels in groups A, B and C were 142.8 mg/dL, 138.6 mg/dL and 148.4 mg/dL, respectively. At the sixth month, there was a significant decrease in the LDL level only in group B [Table 2].

The 24-h urinary protein excretion decreased in both groups A and B, but the difference did not reach statistical significance. Proteinuria increased in group C [Table 2], although this was not statistically significant.

Creatinine clearance decreased in all groups, but the decrease was more pronounced in group B (P <0.05).

At the sixth month, there was a significant decrease in the serum levels of CRP, IL-6 and TGF-β from the initial values in both groups A and B, while the serum levels increased in group C [Table 2]. Also, the levels of CRP and IL-6 at the sixth month were significantly lower in both groups A and B as compared with group C. However, the serum level of TGF-β at the sixth month was significantly lower in group B only but not in group A when compared with group C.


   Discussion Top


The effect of hyperglycemia in the development of diabetic nephropathy may be mediated by several pathogenic mechanisms, including generation of mitochondrial reactive oxygen species (ROS), accumulation of advanced glycosylation end products (AGEs) and activation of intracellular signaling molecules such as protein kinase C (PKC). [10],[11],[12],[13],[14] The AGEs cause increased cross-linking of structural proteins, dysregulation of enzyme systems and abnormalities in the ability of certain proteins to bind regulatory molecules. [11] In addition, the binding of AGE to receptors on macrophages may result in activation of platelets and release of a variety of factors such as nitric oxide and interleukins, which may play a role in tissue response to diabetes mellitus. [11] It has been proposed that many abnormalities in diabetic nephropathy are due to the altered interactions between the glomerular endothelium and the mesangium. [15] There is strong evidence that growth hormone or its effector molecule, insulin-like growth factor-1, plays a pathogenic role in diabetic nephropathy. [16] In both experimental diabetic glomerulopathy and glomerulonephritis, TGF-β 1 causes expansion of the extracellular matrix by inducing the synthesis of several matrix components. [17] Cytokines such as interleukin-1 have been shown to cause mesangial cell proliferation in vitro. [18] It is increasingly appreciated that there may be important interactions between metabolic pathways and various hemodynamic factors, including vaso-active hormones such as angiotensin-II, in mediating renal injury in diabetes. [19],[20],[21],[22] Angiotensin-II may contribute to diabetic nephropathy by inducing glomerular hypertension, promoting mesangial cell growth and producing extracellular matrix proteins as well as altering the filtration properties of the glomerular barrier. Thus, interventions aimed at controlling either the dysregulated metabolic/inflammatory milieu or blood pressure have been the focus of research to retard the progression of diabetic nephropathy. While controlling hyperglycemia, hyperlipidemia and raised blood pressure along with rennin angiotensin system (RAS) blockade are well-recommended approaches. [23],[24]

Recent trials targeting pathogenetic mechanisms such as ROS, TGF-β 1 , PKC, AGEs and glycosaminoglycan are promising. [25],[26],[27],[28],[29]

In the present study, although glycemic control was very poor initially in all three groups, good control was achieved with treatment during the study period in all the groups. The better glycemic control achieved in group B might be due to the intrinsic antidiabetic property of Dioscorea bulbifera, which possesses antidiabetic property by inhibiting N-acetly-β-D glucoseminidase. [7] However, this trial drug was given as an add-on therapy to other anti-diabetics like OHA and insulin and thus was not evaluated for its antidiabetic property.

While there were significant changes in SBP in all the groups, the DBP fell significantly only in group B. Thus, reduction of both SBP and DBP with Dioscorea bulbifera might be helpful in retarding the progression of diabetic nephropathy and can prevent cardiovascular disease-related mortality and morbidity in diabetic nephropathy.

Both Dioscorea and fosinopril decreased the 24-h urinary protein excretion at the sixth month of follow-up while proteinuria increased in patients in group C taking neither of these drugs. As proteinuria is an independent risk factor for the progression of kidney disease as well as cardiovascular morbidity and mortality, this finding is significant from a prognosis and management point of view. Although the decrease was not significant statistically, it may be because of the short duration of follow-up, and a significant difference might be evident in longer follow-up as has been well documented with RAS blockade. [19],[20],[21],[22],[23],[24] Importantly, the decrease in proteinuria was more pronounced with Dioscorea than with fosinopril.

There was a significant decrease in the serum levels of inflammatory markers IL-6 and CRP along with TGF-β in group B receiving Dioscorea. Thus, it was evident that Dioscorea could reset the altered cytokine and growth factor milieu that was responsible for the relentless progression of nephropathy and loss of kidney function in diabetic nephropathy.

However, creatinine clearance decreased after treatment with both fosinopril and Dioscorea bulbifera, more so with the latter. This is a cause for concern with the use of this drug. Further studies are needed to evaluate this issue.

In summary, Dioscorea bulbifera was more effective than fosinopril in controlling blood pressure, hyperglycemia, hypercholesteremia and inflammatory state in diabetic nephropathy. Both agents decreased proteinuria. It remains to be seen if improvement in these intermediate outcomes could be translated to the hard outcomes of retarding or reversing the progression of nephropathy or improving patient survival. However, creatinine clearance decreased with both the drugs, more so with Dioscera and, hence, we feel that further evaluation with a larger trial is needed.

 
   References Top

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2.Mohan V, Sandeep S, Deepa R, Shah B, Varghese C. Epidemiology of type 2 diabetes: Indian scenario. Indian J Med Res 2007;125: 217-30.  Back to cited text no. 2
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3.Joshi SR, Das AK, Vijay VJ, Mohan V. Challenges in Diabetes Care in India: Sheer numbers, lack of awareness and inadequate control. J Assoc Physicians India 2008;56;443-50.  Back to cited text no. 3
    
4.Huang YH, Wang HT, Zhu QZ, Zhang H, Shen W, Wang Y. Combination therapy with losartan and fosinopril for early diabetic nephropathy. Di Yi Jun Yi Da Xue Xue Bao 2003;23:963-5.  Back to cited text no. 4
    
5.Villa E, Rábano A, Ruilope LM, García-Robles R. Effect of cicaprost and fosinopril on progression of rat diabetic nephropathy. Am J Hypertens 1997;10:202-8.  Back to cited text no. 5
    
6.Asselbergs FW, Diercks GF, Hillege HL, et al; Prevention of Renal and Vascular End stage Disease Intervention Trial Investigators Effects of Fosinopril and Pravastatin on Cardiovascular. Events in Subjects With Microalbuminuria. Circulation 2004;110:2809-16.  Back to cited text no. 6
    
7.Ahmed Z, Chishti MZ, Johri RK, Bhagat A, Gupta KK, Ram G. Antihyperglycemic and antidyslipidemic activity of aqueous extract of Dioscorea bulbifera tubers. Diabetol Croat 2009;38:63-72.  Back to cited text no. 7
    
8.Choudhary K, Singh M, Pillai U. Ethnobotanical Survey of Rajasthan - An Update. Am Eurasian J Bot 2008;1:38-45.  Back to cited text no. 8
    
9.Chakraborty A, Mitra MN, Chakraborty D. Saponin from India-Dioscorea bulbifera. YAMS Calcutta Sch. Trop Med 1963;11:20.  Back to cited text no. 9
    
10.Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001; 414:813-20.  Back to cited text no. 10
    
11.Kiritoshi S, Nishikawa T, Sonoda K, et al. Reactive oxygen species from mitochondria induce cyclooxygenase-2 gene expression in human mesangial cells: Potential role in diabetic nephropathy. Diabetes 2003;52:2570-7.  Back to cited text no. 11
    
12.Forbes JM, Cooper ME, Oldfield MD, Thomas MC. Role of advanced glycation end products in diabetic nephropathy. J Am Soc Nephrol 2003;14(8 Suppl 3):S254-8.  Back to cited text no. 12
    
13.Oldfield MD, Bach LA, Forbes JM, et al. Advanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE). J Clin Invest 2001 ;108:1853-63.  Back to cited text no. 13
    
14.Gorin Y, Block K, Hernandez J, et al. Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney. J Biol Chem 2005;280:39616-26.  Back to cited text no. 14
    
15.Hayden MR, Sowers JR, Tyagi SC. The central role of vascular extracellular matrix and basement membrane remodeling in metabolic syndrome and type 2 diabetes: The matrix preloaded. Cardiovas Diabetol 2005;4:9.  Back to cited text no. 15
    
16.Lupia E, Elliot S J, Lenz O, et al. IGF-1 Decreases Collagen Degradation in Diabetic NOD Mesangial Cells Implications for Diabetic Nephropathy. Diabetes 1999;48:1638-44.  Back to cited text no. 16
    
17.Rutledge JC, Ng KF, Aung HH, Wilson DW. Role of triglyceride-rich lipoproteins in diabetic nephropathy. Nat Rev Nephrol 2010; 6:361-70.  Back to cited text no. 17
    
18.Moriwaki Y, Yamamoto T, Shibutani Y, et al. Elevated Levels of Interleukin-18 and tumor necrosis factor-« in serum of patients with type 2 diabetes mellitus: Relationship with diabetic nephropathy. Metabolism 2003;52:605-8.  Back to cited text no. 18
    
19.Ruggenenti P, Cravedi P, Remuzzi G. The RAAS in the pathogenesis and treatment of diabetic nephropathy. Nat Rev Nephrol 2010;6 :319-30.  Back to cited text no. 19
    
20.Cooper ME. Interaction of metabolic and haemodynamic factors in mediating experimental diabetic nephropathy. Diabetologia 2001;44:1957-72.  Back to cited text no. 20
    
21.Thomas MC, Tikellis C, Burns WM, et al. Interactions between renin angiotensin system and advanced glycation in the kidney. J Am Soc Nephrol 2005;16:2976-84.  Back to cited text no. 21
    
22.Wassef L, Langham RG, Kelly DJ. Vasoactive renal factors and the progression of diabetic nephropathy. Curr Pharm Des 2004;10:3373-84.  Back to cited text no. 22
    
23.Agha A, Amer W, Anwar E, Bashir K. Reduction of microalbuminuria by using losartan in normotensive patients with type 2 diabetes mellitus: A randomized controlled trial. Saudi J Kidney Dis Transpl 2009;20:429-35.  Back to cited text no. 23
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24.Atins RC, Zimmet P. Diabetic kidney diseased: Act now or pay later. Saudi J Kidney Dis Transpl 2010;21:217-21.  Back to cited text no. 24
    
25.Sadiq S, Nagi AH, Shahzad M, Zia A. The reno-protective effect of aqueous extract of Carum carvi (Black zeera) seeds in streptozotocin induced diabetic nephropathy in rodents. Saudi J Kidney Dis Transpl 2010;21: 1058-65.  Back to cited text no. 25
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26.Zhu Y, Usui HK, Sharma K. Regulation of transforming growth factor beta in diabetic nephropathy: Implications for treatment. Semin Nephrol 2007;27:153-60.  Back to cited text no. 26
    
27.Tuttle KR, Bakris GL, Toto RD, McGill JB, Hu K, Anderson PW. The effect of ruboxistaurin on nephropathy in type 2 diabetes. Diabetes Care 2005;28:2686-90.  Back to cited text no. 27
    
28.Coughlan MT, Thallas-Bonke V, Pete J, et al. Combination therapy with the advanced glycation end product cross-link breaker, alagebrium, and angiotensin converting enzyme inhibitors in diabetes: Synergy or redundancy? Endocrinology 2007;148:886-95.  Back to cited text no. 28
    
29.Gambaro G, Kinalska I, Oksa A, et al. Oral sulodexide reduces albuminuria in microalbuminuric and macroalbuminuric type 1 and type 2 diabetic patients: The Di.N.A.S. randomized trial. J Am Soc Nephrol 2002;13:1615-25.  Back to cited text no. 29
    

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Correspondence Address:
B Ghosh
Department of Nephrology, Institute of Medical Sciences, Banaras Hindu University, Varanasi - 221 005, Uttar Pradesh
India
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DOI: 10.4103/1319-2442.113866

PMID: 23816723

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