Protocol on Comparative Efficacy of Bruhatyadi Kwath as Compared to Furosemide for Improving e –GFR and Albuminuria in Chronic Kidney Disease- A Randomized Controlled Study

Background: The steady decrease of kidney function is referred to as chronic kidney disease. The kidney function is measured by Glomerular Filtration Rate (GFR). According to Ayurveda the CKD can be correlated to Mutraghatabecause of similarity of symptoms. In Ayurveda Mutraghata is described under Mutrarogawhich comes under Mutravahastrotas (urinary system). Objective: To assess and compare the efficacy of Bruhatyadikwath, Furosemide and Bruhatyadikwath along with Furosemide on symptoms, eGFR, and Albuminuria in various stages of Chronic Kidney Disease. Study Protocol Shankarpure et al.; JPRI, 33(63A): 175-182, 2021; Article no.JPRI.80087 176 Methodology: Total 90 patients will be divided in 3 equal groups. Patients in group A will be treated with Bruhatyadikwatha, group B patients will be treated with Furosemide and patients in group C will be treated with Bruhatyadikwatha and Furosemide for 90 days. Follow up will be taken after every 30 days. Expected Results: Furosemide along with Bruhatayadikwath will show better improvement in eGFR and Albuminurea as compared to only treated with Bruhatyadikwath and Furosemide. Assessment of subjective criteria like edema, anorexia, weakness and vomiting will be done on day 0, 30, 60 and 90 whereas assessment of Serum creatinine, Blood Urea, Sr. Sodium, Sr. Potassium, eGFR (Cockcroft formula) and Albuminuria will be done before and after treatment (on 0 and 90th day). Result: Subjective and objective outcomes will be assessed by statistical analysis. Conclusion: It will be drawn from the result obtained.


INTRODUCTION
Chronic Kidney Disease (CKD) is a progressive, permanent decline in kidney function that usually occurs over months to years. It begins as a biochemical aberration, but when the kidney's excretory, metabolic, and endocrine functions deteriorate, clinical signs and symptoms of renal failure, commonly known as uraemia, develop. End Stage Renal Disease (ESRD) is a term used to describe a condition in which mortality is likely without RRT (Renal Replacement Therapy) (CKD stage 5) [1].
Chronic Kidney Disease (CKD) is becoming a major chronic disease worldwide. One reason is that the global incidence of diabetes and hypertension is quickly growing. Given India's population of over one billion people, the increased frequency of CKD is projected to cause severe challenges in the future for both healthcare and the economy. Indeed, the ageadjusted incidence rate of end-stage renal illness in India has recently been estimated to be 229 per million people, with more than 100,000 additional patients entering renal replacement programmes each year [2]. Only 10% of Indian patients with end-stage renal disease receive any renal replacement therapy due to a lack of funding.
Therefore, exploration of a safe and alternative cost-effective therapy is highly required, which proves to be helpful in reducing requirement or frequency of dialysis and in postponing the renal transplantation.
Chronic kidney disease (CKD) is a kind of kidney disease in which kidney function gradually deteriorates over months to years.
Kidney function is a measure of the kidney's health and its contribution to renal physiology.
The Glomerular Filtration Rate (GFR) is a metric for measuring kidney function.
The Glomerular Filtration Rate (GFR) is the rate at which filtered fluid flows through the kidneys. Without Chronic Kidney Disease, a Glomerular Filtration Rate (GFR) of 60 ml/min/1.73 m2 is considered normal [3] .Chronic Kidney Disease is characterised as having a GFR of less than 60 ml/min/1.73 m2 for three months. In CKD we get changes in blood, urine and imaging studies. In blood there is raised Serum Creatinine and Urea even than normal Albuminuria in urine is the oldest and widely used marker for kidney dysfunction, Albumin is the most prevalent plasma protein, and its urine excretion is determined by the combined effects of glomerular filtration and renal tubular processing. It's also used to track CKD progression. On the basis of GFR, Chronic Kidney Disease (CKD) is divided into five stages.
The majority of patients with slowly progressive illness are asymptomatic until their GFR drops below 30 ml/min/1.73 m2, and others can be asymptomatic even with significantly lower GFR values.
Symptoms and indicators are typical when GFR goes below 15-20 ml/min/1.73m2, and they can influence practically all physiological systems [4]. Tiredness or shortness of breath, as well as lower limb swelling, can all be signs of renal anaemia or fluid overload.
Patients with worsening renal function may have pruritus, anorexia, weight loss, nausea, vomiting, and hiccups.
Due to significant metabolic acidosis, the patient's respiration may be exceptionally deep (Kussmaul breathing) in very severe renal failure and muscle twitching, fits, sleepiness, and coma are all possible side effects [5].
Ayurvedic management has proved its potential as an alternative medicine for the treatment of a variety of ailments in recent years, and it continues to be a key source for the discovery of new medications, which has gotten more attention recently. Ayurvedic therapy is also becoming more popular for enhancing healthcare and preventing Chronic Kidney Disease, according to data (CKD). Chronic Kidney Disease is not described in Ayurveda but due to similarity of symptoms it can be correlated with Mutraghata, which is one of the most important Mutraroga as described in ancient Samhitas. There are a variety of formulations available that target urinary system problems and have a variety of activities. Brihatyadikwatha is one of them described in Sushruta Samhita [6]. It contains Gokshur, Brihati, Patha, Indrayava, Kantakari and Yashtimadhu as shown in Table 1. All these herbs have Mutral (Diuretic) property. In Sushruta Samhita BruhatyadiGana is mainly described for the management of Mutrakruccha where as in Sahastryogam it is indicated in the management of all Mutravikara [7]. It possesses Rasayana property which is helpful in regeneration of damaged kidneys. Deepan-Pachan property of these drugs reduces production of Aam as well as Kleda. It corrects Mansa and Medadhatwagni by its Katu, Tikta Rasa and Ushna Veerya thus reduces production of Kha-Mala.

Rationale of the Study
Chronic Kidney Disease (CKD) is a global health problem that costs health systems a lot of money, and it's also a risk factor for cardiovascular disease (CVD).
CKD is linked to an increased risk of cardiovascular morbidity, premature mortality, and/or a lower quality of life at all stages. In modern science management of Chronic Kidney Disease mainly includes supportive treatment, use of diuretics and in severe cases dialysis or renal transplant. But all these treatments have their own limitations like high cost, adverse effects as well as complications. In Ayurveda many herbal formulations having Mutral (diuretic) and Rasayana (rejuvenating) properties are recommended in the management of Mutravikar as like Mutraghata (Chronic Kidney Disease). Various research studies conducted on herbal drugs in Mutravikaras are available showing their efficacy [8,6,9]. BruhtyadiKwath possesses diuretic, rejuvenating, antibacterial and antiinflammatory properties. Research studies are conducted on Bruhatyadikwath in the management of Mutrakruchra but no study is conducted on Mutraghata [10]. So for early stage prevention and to check further progression this study is planned along with Furosemide to evaluate the efficacy of Bruhtyadikwath for improving e-GFR and Albuminuria in Chronic Kidney Disease.

Aim
Comparative efficacy of Bruhatyadikwath as compared to Furosemide for improving e -GFR and Albuminuria in Chronic Kidney Disease.

Case Definition
Patients having age ≥ 20 to 70 years of either sex having eGFR ≥ 90 to 30 (Cockcroft formula) that is Chronic Kidney Disease of stage 1 to 3 with Albuminuria will be included in the study.

Research Question
Whether Brihatyadikwath along with Furosemide is effective as compared to Brihatyadikwath and Furosemide given separately in improving e-GFR and Albuminuria in Chronic kidney Disease?

Hypothesis (a) Null Hypothesis (H0):
Bruhatyadikwath along with Furosemide may not be more effective than Bruhatyadikwath and Furosemide given separately in improving the e-GFR and Albuminuria in Chronic Kidney Disease (CKD)

(b) Alternative Hypothesis (H1):
BruhatyadiKwath along with Furosemide may be more effective than

Study Formulation (Bruhtyadi kwatha) Contents
Bruhtyadikwatha will be freshly prepared each time by Standard operating procedure as per the reference of Sharangadhar Samhita (Madhyam Khanda 2/1 and 8/1). In coarse powder of raw material 16 parts of water will be added and it will be heated to reduce to 1/8 part. Mixture will be filtered and decoction will be obtained.

Sample Size
For calculating sample size with desired error of margin-

Statistical Analysis
The observations will be analyzed by using chi square test and student unpaired t test.
Time duration till follow up: The patient will be treated for a total 90 days and will be followed up on day 30, 60, 90.

Time schedule of enrolment, interventions:
Drug will be given from 0 to 30 days Recruitment: Patients will be recruited by Computerised algorithm for random allocation into three groups of 90 (30 patients in each group).

Data collection methods: Assessement criteria
Subjective Criteria:
2. Blood Urea 3. Sr. Sodium 4. Sr. Potassium will be done before and after treatment 5. eGFR (Cockcroft formula) 6. Albuminuria Data management: The data entry coding will be done by PI

DISCUSSION
In Chronic kidney disease, the kidney functions gradually go on decreasing due to various pathologies. It reduces excretion of waste products formed during metabolism, increases leakage of proteins and electrolytes due to damage of nephrons. This loss of proteins, electrolytes depletion and accumulation of nitrogenous waste products produces symptoms. As per Ayurveda, Mutraghata means retention of urine along with pain in supra pubic region are observed due to obstructive pathology, there is deranged function of Vatadosha, particularly apanavata which is the prime causative factor also vitiating Kaphadosha, affecting to mutravahastrotas and derangements occurs in Basti which results in Mutraghata. In this study patients will be divided in three equal groups and will be given interventions as shown in Table 2 [12]. Due to Rasayana property it will promote and boost cell growth and their function. It acts as a Kaphaghna because of Tiktakatu rasa. It also acts as Kledashoshak because of the Grahiguna of Indrayava and Brihati. Srotovishodhana as it contains Patha and Kantakari and lastly it has Mutral property because of Gokshur. In this way Brihatyadikwath helps in breaking pathogenesis.
Furosemide is a loop diuretic that is used to treat hypertension and edema in people with congestive heart failure, liver cirrhosis, renal illness, and high blood pressure. Diuretics enhance urine salt and water excretion by inhibiting sodium reabsorption in particular renal tubules. It is a drug used in CKD. The subjective criteria as shown in Table 3 and objective criteria will be assessed before and after treatment.

CONCLUSION
Conclusion will be drawn after statistical analysis.

RECOMMENDATION
Furosemide is a known loop diuretic drug used in CKD, if BruhatyadiKwath is given along with it may be found effective in alleviating the subjective and objective parameters. So the use of two drugs in combination will have a significant effect on preventing progression of CKD and correcting albuminuria in early stages.

LIMITATIONS
This study will not be conducted on major systemic diseases like uncontrolled diabetes mellitus, hypertension, malignance and immunocompromised disorders and also in advanced stages of stage 4 and 5.

CONSENT
The written consent will be taken from the patient before starting the study. During the study the confidentiality of each patient will be maintained. With all the information consent form and other related documentation will be given to participants.

DISSEMINATION POLICY
The data will be disseminated by paper publication.