Preclinical and Clinical Evaluation of the efficacy of Siddha Classical decoction formulation Aavarai Kudineer in Management of Diabetic Nephropathy

Diabetes can be defined as a chronic, metabolic disease characterized by elevated levels of blood glucose (or blood sugar), which lead over time to severe damage to the heart, blood vessels, eyes, kidneys and nerves . Diabetes mellitus (DM) has been increasing at an upsetting rate since the beginning of the 21st century, driven by health determinants that are largely related to lifestyle changes and their consequences, such as obesity and sedentary life. The burden of diabetes has besieged many healthcare systems, particularly those of low and middle-income countries.

Globally, 1 among 11 adults has diabetes. 1 in 5 of the people with diabetes in the world comes from South-East Asia. 1 among 6 adults with diabetes in the world comes from India. 1 in 2 people who are having diabetes remain undiagnosed and are at a higher risk of developing harmful complications. 1.2 million Deaths are accountable to diabetes - the second highest number of deaths of all International Diabetes Federation (IDF) Regions. Diabetic Kidney Disease (DKD) or Diabetic nephropathy (DN) one of the major complications of diabetes is defined as diabetes with albuminuria (ratio of urine albumin-to-creatinine ≥30 mg/g), impaired glomerular filtration rate (<60 mL/min/1.73 m 2), or both and is now recognised as the strongest predictor of mortality in patients with diabetes. However, current statistics regarding the incidence of DKD in India is lacking, the results of the study conducted by Unnikrishnan et al in 2007 suggests that in urban Asian Indians, the prevalence of overt nephropathy and microalbuminuria was 2.2 and 26.9% respectively. Duration of diabetes, A1C, and systolic blood pressure were the common risk factors for overt nephropathy and microalbuminuria In Allopathic System of medicine, DKD is treated by controlling the blood sugar, blood pressure, blood lipids, and reducing urine protein, with no effective ways to thwart the progression of DKD. A Cross Sectional Analysis on Clinical Trials on Diabetic Nephropathy depicts no improvement on renal outcome parameters, such as proteinuria/albuminuria and/or GFR, was reported for most medications

In Siddha System of Medicine Diabetes and its complications are more or less analogically corelated with diagnostic terms Madhumegham(MM)and Piramegam. One of the salient features of MM being polyuria with variant nature of urine quality in terms of its colour, odour, consistency, nature of froth, sedimentation etc is a hallmark diagnostic prediction for the progressing Diabetic Kidney Diseases (DKD). Features of DKD such as frothy urine are stated in ancient Siddha literature under the headings Mega Neer, Madhumegam, Piramegam.

Avarai Kudineer (AK) is a commonly used, tried and true Siddha anti-diabetic formulation. It is a polyherbal concoction consisting of seven ingredients. The formulation has been taken from the classical Siddha Literature “Theraiyar Kudineer” and it is also found in the Siddha literature “Gunapadam mooligai vaguppu” (Siddha Materia medica). An in vitro study conducted by Samiraj et al proved the proficiency of Avirai Kudineer to stimulate basal glucose uptake in differentiated L-6 myotubes. A study conducted by Bhavapriya et al demonstrated the anti-diabetic efficacy of this formulation, which was studied using alloxan-induced diabetic and normal rats. Glucose tolerance was observed within an hour in AK-treated rats (10 ml/kg body) as compared to control. A significant reduction in the severe hyperglycaemia characteristic of alloxan diabetic rats was noted after 15 days of AK treatment. Further AK treatment reversed the elevated urea, creatinine, cholesterol and it even decreased protein values to near normal levels, which give a clue to its nephroprotective potential. Assay of glycogen content and chief carbohydrate-metabolizing enzymes, viz. hexokinase, glucose-6-phosphatase and fructose 1,6 diphosphatase in the liver of diabetic and AK-treated diabetic rats clearly ascertains the hypoglycaemic efficacy of this formulation.Five among the seven ingredients of AK is having nephro protective activity , The ethanol extract of the roots of Cassia auriculata showed marked renal free radical-scavenging effects against gentamicin-induced renal injury in rats as per the study done by Annie et al  It was found that bromobenzene induced noteworthy nephrotoxicity reflected by an increase in levels of BUN and creatinine that was dose dependently prevented by extract of Cassia fistula fruit. The nephroprotective effect of the same was confirmed by the histological examination of the kidneys. This gives evidence to nephroprotective effect of second ingredient of AK. In the same way Nephroprotective effect of aqueous extract of S. cumini seed powder in STZ diabetic rats was studied by Swadhin Ranjan Behera et al, which revealed STZ administered rats had acute dysfunction as evidence by increase in Creatinine and urea levels. Treatment with aqueous extract of S. cumini seed powder 500mg/kg for 120days appreciably decrease the blood levels of Creatinine. Similarly, the ethanol-soluble fraction from Costus spicatus has significant nephroprotective effects against rhabdomyolysis-induced Acute Kidney Injury in rats. Likewise, Terminalia Arjuna bark has immense antioxidant potential which to be used in the areas of pharmacotherapy and as well as a prospective source of valuable drugs which were used for treating acetaminophen induced nephrotoxicity and oxidative stress as per study conducted by Nandi et al. The above-mentioned evidences suggest AK enbloc may have nephroprotective activity. In addition, a pilot study (unpublished) data conducted in National Institute of Siddha with AK showed hopeful results in preventing the progression of DKD moreover after searching through databases such as Pub Med, Cochrane library, Shodh ganga etc no such studies exists. In this context the proposal is put forward for preclinical and clinical evaluation of Avarai Kudineer.