Clinical study on the deceleration of disease progression of chronic kidney disease by Ayurvedic management - A quasi-experimental study

**Background:**End Stage Renal Disease (ESRD) is the advance stage of Chronic Kidney Disease which develops from stage I within a course of few years. Its incidence in worldwide as well as in India is increasing day by day. Globally, more than 100 countries (with a combined population of more than 1 billion) have no provisions for chronic maintenance dialysis or kidney transplantation and thus, more than 1 million people die annually from ESRD on a global scale. Data suggests that about 220,000–275,000 new patients need a renal replacement therapy (RRT) every year in India and Pakistan. It is estimated that there are about 55,000 dialysis patients in India, and this population is growing at the rate of 10–20 percent annually because of the increasing incidence (increase nearly doubled from 2003 to 2013). Hemodialysis cost in India is also high in comparison to income level. Hence, efforts are needed to develop strategies which decelerate the progression of CKD. A 10 or a 20 percent improvement in the eGFR decreases the need of renal replacement therapy and estimated cumulative savings may be of 25 and 55 percent respectively. Studies suggest that the cumulative economic impact of slowing the progression of CKD, even by 10 percent, would be staggering. The acceleration of disease progression of CKD can be judged by observing changes in eGFR within a 6 months period. Some preliminary scientific evidence exists, suggesting beneficial effects of Ayurvedic treatments in signs and symptoms as well as in renal function tests of CKD patients. Findings of one pilot study conducted in P D Patel Ayurveda Hospital, Nadiad revealed that the Ayurvedic treatment might be effective to reduce the disease progress of CKD and postpone renal transplant as well as the need of dialysis. This may be a valuable addition to conventional medicine. However, it was a pilot study, conducted in non-dialysis patients of stage IV-V of CKD with data of sixty-four participants.

Patient come to the Ayurveda intentionally for the Ayurveda treatment. Hence, randomization or controlled trial creates ethical issues which can’t be resolved and hence, randomization and taking control group is difficult for research in this type of disease especially for exploring the Ayurveda treatment effect. Hence, this study protocol is projected to evaluate the effects of Ayurvedic treatment on the deceleration of the disease progress of all stages of CKD patients with more number of participants by comparing the mean changes of eGFR and renal function tests (RFT) at three different time points (TP) i.e. six months before the beginning of the Ayurvedic treatment (TP-6), at baseline (TP0) and six months after baseline (TP+6). In this specific design, mean changes of TP0 and TP-6 would become control for the mean changes between the TP0 and TP+6.

Objectives:

a. Primary:

To compare the mean changes of eGFR at different time points i.e. TP-6, TP0 and TP+6 in the patients of CKD.

b. Secondary:

1. To evaluate the grade score changes of signs and symptoms before and after the administration of intervention

2.To evaluate the effect of ayurvedic treatment on renal function tests as well as the mean changes of grade score of signs and symptoms at different time points i.e. TP-6, TP0 and TP+6.

3. To evaluate the change in Quality of life of CKD patients managed with Ayurvedic treatment by extended versions adapted for specific use in kidney patients (KD-QoL)

4. To evaluate the safety of Ayurvedic treatment in the management of CKD

To assess the occurrence of AE/ADR if any.

Study design:

This study will be an open labelled, quasi-experimental clinical study with Dependent Pretest and Post test Samples using a Double Pretest

Inclusion criteria:

i.          Participants of both genders aged 18–65 years

ii.          Participants who are non-dialysis dependent known patients of  CKD (up to stage 4) with or without

·  diagnosed as DM and on medication,

·  diagnosed as hypertensive and on medication.

Exclusion criteria:

1.     Patients with cystic and tubulointerstitial nephropathy, Left ventricular hypertrophy, and dilated cardiomyopathy conditions associated with hyporeninemic hypoaldosteronism, and renal diseases that preferentially affect the distal nephron, such as obstructive uropathy and sickle cell nephropathy.

2.     Patients diagnosed as having later stages of CKD with prolonged bleeding time, decreased activity of platelet factor III, abnormal platelet aggregation and adhesiveness, and impaired prothrombin consumption, clinically increased tendency to bleeding and bruising, prolonged bleeding from surgical incisions, menorrhagia, and GI bleeding.

3.     Patients diagnosed as having recent acute kidney injury (more than 50 percent increase in serum creatinine in the preceding 30 days)

4.     Patients on chronic dialysis therapy or had episode(s) of dialysis in the last 3 months; had renal replacement therapy in the prior 3 months; had renal transplants or planning renal transplantation during the trial period

5.     Known case of amyloidosis, HIV nephropathy, a genetic disorder that causes many cysts to grow in the kidneys, polycystic kidney disease (PKD) that has reached some degree of renal failure with enlarged kidneys and  multiple cysts

6.     Patients diagnosed as having heritable form of CKD Alport or Fabry disease, cystinosis

7.     Known case of Secondary or Malignant Hypertension, clinically significant cardiac arrhythmias, severe aortic stenosis, unstable angina pectoris, myocardial infarction, percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG) surgery, symptomatic congestive heart failure (HF), atrial fibrillation (AF), acute coronary syndrome (ACS), increased risk of major adverse cardiac events (MACE), HF and arrhythmogenic cardiomyopathy (ACM), with atherosclerotic cardiovascular disease and stroke.

8.     Known case of uncontrolled Type 1 and Type 2 Diabetes Mellitus whose diabetes has not been stable and controlled for the previous three months and with HbA1c value more than 8%

9.     Known case of abnormal Liver Function Test with values more than 3 times the upper limit of normal

10.  Known case of autoimmune diseases such as lupus and underlying infectious etiologies such as hepatitis B and C and HIV; IgA glomerulonephritis, Anti-GBM (Goodpasture’s) disease, IgA vasculitis, renal artery stenosis

11.  Known case having any drugs such as nonsteroidal anti-inflammatory agents, cyclooxygenase-2 (COX-2) inhibitors, antimicrobials, chemotherapeutic agents, antiretroviral agents, proton pump inhibitors, phosphate-containing bowel cathartics, and lithium.

12.  Known case of heavy metal poisoning, such as lead poisoning

13.  Female patients who are pregnant, lactating or planning to concieve  during the trial period.

14.  Known case as Chronic smoker, alcoholic or drug abuse suspected.

15.  Patients with medical history of oncological conditions since last 2 years.

16.  Patients who have participated in other clinical trials within 6 months prior to the screening examination.

17.  Known case of hypersensitivity to any of the trial formulations/ingredients.

18.  Patients contraindicated for niruhabast i.e having anorectal disorders, diarrhoea, severe debility, hypokalemia, ascites etc.

19.   Patients who are not willing to participate in the study

20.   Any other condition that PI thinks may jeopardize the study

Study protocol and timeline:

Methods:

Masking:                Open label

Control:                  Not controlled

Timing:                   Prospective

End point:              Efficacy and Safety

No. of Groups:        One

**Sample size:**130

Milestone with deliverables:

Timelines:

Total Study Period 24 months

Pre-trial preparation 3 months

Recruitment, Follow up and protocol publication 19 months

Statistical Analysis 2 months

**Washout period:**6 months prior to initiation of treatment

Treatment duration for the patient 06 months (01 month in IPD and 05 months OPD)

Follow-up visit schedule during treatment:

All the enrolled patients will be hospitalized for a period of one month. They will be assessed with signs and symptoms and laboratory investigations on the day of hospitalization. After the period of one month of the above treatment, patients will be relieved from the hospital and instructed to take all medicaments (without niruhabasti) and food regimen at home as per the schedule. They will be instructed to come every month for the check-up for next 5 months. Total duration of the treatment period will be 6 months.

Preparation of Trial Medicine:

All the medicaments will be prepared by Sundar Ayurveda Pharmacy, Nadiad under the expert supervision. This pharmacy is a GMP certified and supervised by RS&BK department of J S Ayurved Mahavidyalaya, Nadiad. This Pharmacy supplies the medicaments to the P D Patel Ayurveda hospital (where this research study will be performed) only and not selling any medicine to elsewhere. Hence, maintaining of quality is possible.

The raw material will be authenticated by the expert of Dravyaguna and RS-BK department of J S Ayurveda College, Nadiad. Necessary test related to quality control of trial medicaments will be performed in QC lab.

Outcomes and measurements:

Renal functions tests (eGFR, serum creatinine, blood urea, serum electrolytes, serum calcium) and the hemoglobin level will be recorded 6 months before baseline (+/- 5 days) (TP-6). The same investigations will be performed in the laboratory of the study institute at the date of starting Ayurvedic treatment (TP0, baseline). The final assessment with laboratory investigations will be performed 6 months after completion of Ayurveda treatment in the same laboratory (TP+6).

CRF specific signs and symptoms will be assessed by using a grade score (Table 1), which was adopted from a previously published research article. Changes in signs and symptoms, eGFR, albuminuria, serum creatinine, blood urea, serum electrolytes, serum calcium and hemoglobin level will be observed. For the calculation of eGFR the DaVita Glomerular Filtration Rate calculator will be used, which applies the 2009 CKD-EPI creatinine equation, recommended by the KDIGO Clinical Practice Guidelines for Management of Chronic Kidney Disease.

Table – 1: Grade score of signs and symptoms

**Signs and
symptoms**

Grade 0

Grade 1

Grade 2

Grade 3

|Oedema

No oedema

Slight oedema in lower legs

Severe oedema in lower legs

Anasarca

|General weakness

No weakness

Mild weakness

Moderate weakness

Severe weakness

|Loss of appetite

Good appetite

Mild loss of appetite

Moderate loss of appetite

Complete loss of appetite

|Nausea / Vomiting

Absent

Occasional

Once or twice a week

Daily

|Muscle cramps

Absent

Occasional

Once or twice a week

Daily

|Breathlessness

Absent

On fast walking or climbing stairs

Sometimes at rest

Generally, occurs at rest.

|Hiccup

Absent

Occasional

Once or twice a week

Daily

|Pruritus

Absent

Mild

Moderate

Severe

Primary Outcome Measure

Change in eGFR

Secondary Outcome Measure

1. Change in UACR

2. Change in BUN and electrolytes with serum calcium.

3.Change in Serum Creatinine

4. Change in Cystatin C

5. Changes in CBC, C Reactive Protein

6. Improvement in USG whole abdomen

7.Change in Kidney Disease Quality of Life (KDQOL-SFTM) Version 1.3

8.Change in Grade score of signs and symptoms before and after the administration of intervention

9. Change in safety laboratory parameter LFT

10. Incidence rate of AE/ SAE

 Assessment Criteria:

1.KFT **(**eGFR, serum creatinine, blood urea, serum electrolytes, serum calcium)

2.Urine albumin-to-creatinine ratio (UACR)

3.Serum Cystatin C

4.C-reactive protein

5.CBC

6. FBS and HbA1C

7.LFT

8.Kidney Disease Quality of Life (KDQOL-SFTM) Version 1.3

9.specific signs and symptoms by using a grade score (Table 1), which is adopted from a previously published research article

Serum Cystatin C, UACR and HbA1C will be performed on initial visit, after 3 months and on last visit (after 6 months) of the patients. USG – whole abdomen will be performed at initial and last visit of the patients. All other laboratory tests will be done on every visit of the patients.

Laboratory investigations will be performed in the clinical pathology laboratory of NABH accredited Mahagujarat Medical General Hospital which is parent organization of J S Ayurveda College (research site), Nadiad.