Effects of Low Carbohydrate Diet (LCBD) on Weight and Renal Outcome in Patients With Diabetic Kidney Disease (DKD)- A Pilot Study
Phase: NA
Conditions: Type 2 Diabetes Mellitus, Diabetic Kidney Disease, Obesity
Sponsor: Universiti Teknologi Mara

PROTOCOL 
TITLE PAGE 
Effects of Low Carbohydrate Diet (LCBD) on Weight 
and Renal Outcome in Patients with Diabetic Kidney 
Disease (DKD)- A pilot study 
Primary Investigator: 
Associate Professor Dr Rohana Abdul Ghani 
 
Co-investigators: 
Prof Dr Nafeeza bt Hj Mohd Ismail 
Dr Aisyah bt Zainordin  
Dr Ahmad Azhar bin Abdul Rahim  
Cik Fatin Aqilah 
 
Date of document preparation: 8th Oct 2018  
Amended date: 10th Jun 2021 

 
2 
Effects of Low Carbohydrate Diet (LCBD) on Weight and Renal Outcome in 
Patients with Diabetic Kidney Disease (DKD)- A pilot study 
Investigator-initiated, single center, randomized, controlled, clinical trial in Type 2 
diabetes mellitus patients.  
INTRODUCTION 
The current population of type 2 diabetes mellitus worldwide is over 200 million and 
Malaysia contributes to 1.2% of that number1. Type 2 diabetes mellitus is a 
progressive disease associated with debilitating microvascular and macrovascular 
complications. The prevalence of T2DM in Malaysia has approximately tripled over 
the last three decades from 6.3% in 1986 to 17.5% of the adult population in 2015 2. 
The prevalence of chronic kidney disease (CKD) in Peninsular Malaysia was high at 
9.1% of the adult population in 2011. Among these, 4.2% patients were in CKD stage 
1, 2.0% in CKD stage 2, 2.3% in CKD stage 3, 0.2% in CKD stage 4, and 0.4% 
in CKD stage 53. Diabetes is the leading cause of renal failure for patients 
commencing dialysis, increasing from 53% of new dialysis patients in 2004 to 61% 
in 20134. Therefore, diabetic kidney disease (DKD) is a debilitating complication 
which not only imposes significant health problems but also confers financial burden 
on affected patients. There has been increasing amount of understanding in the 
complexity of the relationship between T2DM and obesity. As the prevalence of both 
conditions continue to demonstrate a parallel rise, the influence of obesity on T2DM 
is further marked. Thus, this has led to greater emphasis on weight loss in the 
management of T2DM. More recent anti-diabetic medications including SGLT-2 
inhibitors and GLP1 agonists demonstrated greater efficacy in improving glycaemic 
control and their ability to produce weight reduction. In addition, there has been more 
interest in the effects of these drugs on retardation of renal disease progression. The 
mechanism is unclear, either attributed by direct drug effects on renal glomerular-
tubular structures, through the Renin-Angiotensin-Aldosterone-System (RAAS), or 
other pathways. Another plausible explanation is the significant weight loss, which 
has been shown to have a significant effect of attenuation of renal disease.  
Weight reduction programs have long been a complex and tedious treatment plan 
which has inconsistent, non-duplicable and unpredictable outcomes. Most programs 

 
3 
emphasized on medical nutrition therapy and lifestyle changes. There have been 
many different dietary plans which share a common goal ie to reduce calorie intake 
whilst increasing energy expenditure. Few have been successfully reproducible, 
limited by either patient adherence or modest outcome.  
Low carbohydrate diet is a diet plan which stresses on reducing carbohydrate intake 
to less than 20g daily. Numerous studies have shown that weight loss could be 
obtained by reduction of calorie intake in either the form of carbohydrate or fat. CKD 
patients are recommended to consume low protein diet of less than 0.6-0.7g/kg/day 
with little emphasis on calorie or carbohydrate intake. 
This study, thus, aims to evaluate the effects of low carbohydrate and moderate fat 
(LCBD) in addition to low protein diet on renal disease in patients with DKD. 
Objectives 
1. To evaluate the effects of LCBD in comparison to low protein diet (LPD) alone 
on renal outcome in patients with DKD 
2. To evaluate the effects of LCBD in comparison to low protein diet (LPD) alone 
on anthropometric and other metabolic parameters in patients with DKD  
3. To determine the associations between renal outcome and metabolic 
parameters in patients with DKD who received LCBD and standard therapy. 
 
 
OUTCOME MEASURES 
Primary Outcome 
1. Proteinuria as assessed by UACR 
2. Rise in serum creatinine, reduction in eGFR  
Secondary Outcomes 
1. Weight loss, blood pressure 
2. Metabolic parameters- lipid profile and inflammatory markers including 
hsCRP, IL-6 
 
HYPOTHESES 

 
4 
LCBD reduces proteinuria and improves renal function compared to standard 
treatment in patients with DKD. 
LCBD causes significant weight loss and improvement in other metabolic 
parameters compared to standard treatment in patients with DKD. 
 
 
 

 
5 
Study Design 
This is an investigator-initiated, single centre, randomized, controlled, clinical trial in 
Type 2 diabetes mellitus patients, comparing 12-weeks of LCBD compared to 
standard medical therapy in patients with DKD.  
Patient Selection 
Recruitment would be conducted at the Endocrinology and Nephrology clinics of 
UiTM. Patients with Type 2 Diabetes Mellitus undergoing follow-up in these clinics 
who meet the inclusion and exclusion criteria will be invited to participate in the study. 
Inclusion Criteria 
1. Diagnosed with Type 2 DM of more than 5 years  
2. Diagnosis of stable CKD of more than 6 months 
3. HbA1c of 7% - 10.5% 
4. Patient age between 40-75 years old 
5. Able to sign informed consent 
 
Exclusion Criteria 
1. Type 1 DM 
2. Frequent hypoglycemia 
3. Persistent elevations of serum liver transminase 
4. Heart failure (New York Heart Association functional class III–IV), active 
systemic inflammatory disease, chronic renal failure requiring hemodialysis, 
active hepatic disease and collagen disease 
5. Malignancy 
6. Recent hospital admission for acute within the past 3 months  
7. Pregnant women, breastfeeding or planning to conceive within the next year 
All patients who fulfilled the inclusion and exclusion criteria will be offered to 
participate in the study and written consent will be obtained.  
 
 
SAMPLE SIZE CALCULATION 

 
6 
This is a single centre, interventional, randomised, controlled clinical trial. This will 
be a pilot study involving 20 patients per arm. However, considering a 20% 
dropout, we would be recruiting 24 patients per arm. 
 
STATISTICAL ANALYSIS 
The SPSS program will be used for the statistical analysis. Differences between 
before and after intervention will be analyzed by employing one-way ANOVA, 
following unpaired t-test. A Pearson’s correlation analysis would be carried out to 
determine the correlation of the changes of proteinuria, creatinine, weight loss, and 
other variables. levels and surrogate endothelial function marker.  
 
STUDY PROTOCOL 
Following informed consent, patients would be randomised to either LCBD or low 
protein Diet (LPD) group.  
All recruited patients will be given the standard dietary and exercise advice which 
will include low protein of 0.6-0.7g/kg/day and low salt diet. 
In addition, patients within the LCBD will be given a prescription diet of 20g of 
carbohydrate daily. This will be supplemented by visual aids on carbohydrate counts 
of various local food. Patients would be given the option to choose their most 
appropriate food types which will amount to the carbohydrate count given. Patients 
on oral anti-diabetic treatment including insulin will advised on titrations of their 
medications to avoid hypoglycaemia. 
The control arm will not be given any additional advice. 
All patients will be required to fill in a 3day food diary during their scheduled visits 
which will be at 6 weeks and 12 weeks. 
Clinical assessments include blood sampling which will be done at baseline and at 
study end. 
 
 
 
ULTRASOUND FOR FATTY LIVER 

 
7 
Ultrasound is widely used as a first-line investigation for hepatic steatosis. It provides 
a qualitative assessment of fatty infiltration of the liver. Grading of diffuse hepatic 
steatosis can demonstrate the extent of fatty changes in the liver. A senior consultant 
radiologist who has previous experience in such studies will perform abdominal 
ultrasound. Each case will be graded as normal, mild fatty liver, moderate fatty liver 
or severe fatty liver. The liver will be assessed to be normal if the texture is 
homogeneous, exhibits fine-level echoes, or is minimally hyperechoic or isoechoic 
compared with normal renal cortex and if there is no posterior attenuation of the 
ultrasound beam. Mild steatosis is seen as a slight increase in liver echogenicity. In 
moderate steatosis, visualization of intrahepatic vessels and the diaphragm is 
slightly impaired, and increased liver echogenicity is present. Severe steatosis is 
recognized as a marked increase in hepatic echogenicity, poor penetration of the 
posterior segment of the right lobe of the liver, and poor or no visualization of the 
hepatic vessels and diaphragm5.  
 
Dual energy x-ray absorptiometry (DEXA) SCAN6 
Dual energy x-ray absorptiometry (DEXA) was once used for determining bone 
density however it has now evolved into a technique for also estimating body 
composition. DEXA can measure bone mineral content (BMC), bone mineral density 
(BMD), fat-free mass (FFM), and can also provide estimates of percent body fat. It 
is widely regarded as one of the most proven and reliable technologies for measuring 
body composition. DEXA works by measuring the body's absorbance of x-rays at 
two different energies.  Fat, bone mineral, and fat-free soft tissue have different 
absorption properties.  The amount of radiation exposure during a DEXA scan varies 
based on the region of the body scanned and is much lower than standard plain 
radiography examinations. DEXA scan is less than two days’ exposure to natural 
background radiation (NBR). In comparison, a plain radiograph of the chest is 
equivalent to approximately three days of exposure to NBR, and a transatlantic flight 
is approximately a week’s exposure to NBR. Improved technology has dramatically 
decreased scan times to 5-10 minutes making this method convenient and non-
invasive. DEXA allows accurate and comprehensive measurements of total body fat 
percentage, and also segmental body fat distribution in regions such as arms, legs, 
waist and hips. Another advantage of DEXA is it can measure the visceral fat content 
in the waist region. Visceral fat is of particular concern as it is a key player in many 

 
8 
preventable diseases. It is extremely valuable in research as it can be used to obtain 
an initial body composition assessment and to understand how body is changing 
over time, that is, how much lean and fat tissue changes over time therefore 
measuring the impact of training or dietary programs. The scan is a quick and 
painless procedure whereby the patient lies on the back of the DEXA table. No 
special preparation is needed before the scan. Analysis of the results is done by the 
DEXA computer software. 
 
References: 
1. Feisul MI, Azmi S. (Eds). National Diabetes Registry Report, Volume 1, 
2009-2012. Kuala Lumpur; Ministry of Health Malaysia; 2013 Jul. 
2. National Health and Morbidity Survey 2015 (NHMS 2015). Ministry of 
Health, Kuala Lumpur, Malaysia(2015) 
3. L.S. Hooi, L.M. Ong, G. Ahmad, et al.A population-based study measuring 
the prevalence of chronic kidney disease among adults in West Malaysia. 
Kidney Int, 84 (2013), pp. 1034-1040. 
4. B. Goh, L. Ong, Y. LimTwenty First Report of the Malaysian Dialysis and 
Transplant 2013. Malaysian Society of Nephrology, Kuala Lumpur, 
Malaysia (2014) 
5. Strauss S, Gavish E, Gottlieb P, KatsnelsonL . Inter-observer and Intra-
observer Variability in the Sonographic Assessment of Fatty Liver. AJR:189, 
December 2007 W320–W323) 
6. Australian Radiation Protection and Nuclear Safety Agency. Ionizing 
Radiation 
and 
Health. 
Updated 
3 
December 
2003. 
https://www.legislation.gov.au/Details/F2019C00829 
 
  
 
 

 
9 
FLOWCHART 
 
 
 
 
 
 
 
 
 
Patient randomization 
LCBD 
N: 24 
Patient recruitment 
N : 48 
Inform consent obtained 
LPD 
N: 24 
Week 0 
2-Weekly visits 
Week 12 
Final Visit: Hba1c, FBS, FSL, LFT, RP, Urine microalbuminuria 
Surrogate markers: hsCRP, Insulin, IL-6 
USS for fatty liver 
DEXA Scan for body fat 
Data analysis 
Assessments of adherence, medication adjustments and adverse events 
BMI, waist and hip circumference measurement 
Heart rate, blood pressure measurement 
Blood sample taken (HbA1c, FBS, FSL, LFT, RP, Urine 
microalbuminuria 
Surrogate markers: hsCRP, Insulin, IL-6) 
USS for fatty liver 
DEXA Scan for body fat 

 
10 
Effects of Low Carbohydrate Diet (LCBD) on Weight and Renal Outcome in 
Patients with Diabetic Kidney Disease (DKD)- A pilot study  
Revised Budget 
 
No 
Item 
Price per item 
(RM) 
Quantity 
Total 
(RM) 
1 
Fasting plasma glucose 15 
96 
1,440 
2 
HbA1c 
25 
96 
2,400 
3 
Lipid profile 
15 
96 
1,440 
4 
Liver profile 
15 
96 
1,440 
5 
Renal profile 
15 
96 
1,440 
6 
UPCI 
15 
96 
1,440 
6 
ELISA kits for surrogate 
markers hsCRP 
2000/kit 
2 
4,000 
7 
ELISA kits for IL-6 
3000/kit 
2 
6,000 
8 
Insulin (for 100 tests) 
2,350 
1 
2,350 
9 
Glucometer and strips  
200 
48 
9,600 
10 
Patient reimbursement 
50/ visit 
50 x 9 x 24 = 
50 x 7 x 24 
10,800 
+ 
8,400 =  
19,200 
11 
USS (Fatty liver) 
50 
96 
4,800 
12 
Dexa 
190 
96 
19,200 
10 
Stationery + Visual Aids 50/patient 
48 
2,400 
 
 
 
TOTAL 
76,950 
 
 
 
 

 
11 
Gaant Chart 
See Appendix A 
 
 

 
12 
Key Milestones 
 
 
 
 
 
Milestone 
Timeline 
Milestone description 
Ethics Approval 
Sept 2018 
Starting of recruitment 
Patient Recruitment 
Dec 2018 
50% recruitment 
March 2019 
 
100% recruitment 
Patient randomisation 
Dec 2018 
Blood 
sampling 
and 
other measurements 
50% 
April 2019 
100% randomised 
Data Compilation 
Jul 2019 
100% data compilation 
Data 
Analysis 
and 
interpretation 
Sept 2019 
Completed 
data 
collection 
and 
performing 
Statistical 
analysis 
Report Writing 
Dec 2019 
Completed report writing 
Submission report 
Feb 2020 
Submission completed 

 
Appendix  A
Research 
Activities 
April 
2018 
May 
2018 
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2020 
Literature Review 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Proposal 
Development 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Proposal Defense 
and Approval 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ethical Approval 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient 
Recruitment and 
randomisation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data Collection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data Entry and 
Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Report Writing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Submission of 
Report 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Patient Information Sheet 
 
 
Dear Sir / Madam, 
Thank you for your consideration to participate in this trial. Enclosed is a brief introduction and 
outline of the study.  
 
What is the name of the study? 
Effects of Low Carbohydrate Diet (LCBD) on Weight and Renal Outcome in Patients with Diabetic 
Kidney Disease (DKD)- A pilot study 
 
Why are we doing this study? 
Diabetes mellitus is a progressive disease and associated with many complications. Kidney failure 
is one of the serious and debilitating disease. Besides good glycaemic control, previous studies 
have shown reducing protein in your diet and weight loss may help slow the progression of kidney 
disease. Weight loss is difficult but reducing calori intake, particularly carbohydrate in your diet, 
may produce significant results. 
Thus, this study aims to determine the effects of low carbohydrate diet on renal outcome in 
patients with DKD. 
 
 Why have I been chosen? 
You are a patient with diabetes with mild to moderate diabetic kidney disease.  
 
Do I have to take part? 
It is up to you whether or not to take part. If you decide to take part, you will be given this 
information sheet to keep and be asked to sign a consent form.  
 
What will happen to me if I take part? 
If you agree to participate in the study, you will undergo some routine blood tests. You will be 
given standard dietary and exercise advice. You will be then randomised into 2 groups. If you are 
included in the intervention group you will be asked to reduce your carbohydrate content in your 
diet an amount of 20g/ day. You will be given clear instructions on how you would be able to 
achieve this. If you are in the control group you will not receive any additional advice. You will 
bemonitored in the next 12 weeks, at the end of which another battery of blood tests will be 
performed at no added cost. You will be given a limited supply of glucometer and strips throughout 
the study period.   
 
What do I have to do? 
You are required to adhere to your dietary prescription and provide a 3-day food diary for the 
required study visits. You are also required to perform regular blood sugar monitoring at home. 
You are also required to undergo an ultrasound test to detect fatty liver. This test is completely 
harmless and will not cause any pain to you. A bone densitometry test will also be performed to 
look at your body fat. This test has the radiation of 1/10th of a normal chest-XRay. These 
investigations will be conducted without any cost to you. 
 
What kind of monitoring is offered during the study? 
Blood test will be obtained at baseline (before start of trial) to assess your kidney function, liver 
function, fasting lipids, glucose, insulin, HbA1c and 2 other inflammatory markers ie hsCRP and 
IL-6. 
 
What are the possible disadvantages and risks of taking part? 
You might experience mild discomfort during blood taking. Other than that, the dietary 
prescriptions may result in some symptoms of lethargy with possibility of episodes of 
hypoglycaemia. Thus, the need for regular home blood glucose monitoring (HBGM).  
 
 

 
2 
 
What are the possible benefits of taking part? 
You will be given appropriate dietary advise, which may result in significant weight loss and 
subsequently improve your diabetes control. You will obtain an USS for fatty liver and a bone 
densitometry for free. 
 
What if new information becomes available? 
We will let you know as soon as possible and re-obtain your consent (should you agree to 
continue) after discussing with you any new findings appear during the trial.  
 
What happens when the research study is terminated before the study end date? 
We will notify you immediately and provide you with proper follow-up. 
 
Will my taking part of this study be kept confidential? 
Yes. Your name will never be released to the public. If and when a publication of this study is 
submitted/published, your participation in this study will remain anonymous. 
Thank you for your interest and your time. We will be happy to answer any questions that you 
have.  
If you have any queries please do not hesistate to call our clinic at the following numbers: 
+60361265131 
 
Prof Dr Rohana Abdul Ghani 
Prof Dr Nafeeza bt Hj Mohd Ismail 
Dr Aisyah bt Zainordin  
Dr Ahmad Azhar bin Abdul Rahim  
Cik Fatin Aqilah 
 
Confidentiality 
Your medical information will be kept confidential by the researcher and will not be disclosed 
unless it is required by law. 
By signing this agreement form, you authorize the records research, analysis and data usage of 
this study. 
 
 
 

 
3 
Consent Form 
 
Effects of Low Carbohydrate Diet (LCBD) in Patients with Diabetic Kidney Disease (DKD)  
 
To become a subject in the research, you or your legal guardian is advised to sign this Consent 
Form. I herewith confirm that I have met the requirement of age and am capable of acting on 
behalf of myself /* as a legal guardian as follows: 
1.  I understand the nature and scope of the research being undertaken. 
2.  I have read and understood all the terms and conditions of my participation in the   research. 
3.  All my questions relating to this research and my participation therein have been answered to 
my satisfaction. 
4.  I voluntarily agree to take part in this research, to follow the study procedures and to provide all 
necessary information to the investigators as requested. 
5.  I may at any time choose to withdraw from this research without giving reasons. 
6.  I have received a copy of the Subjects Information Sheet and Consent Form. 
7.  Except for damages resulting from negligent or malicious conduct of the researcher(s), I hereby 
release and discharge  UiTM and  all participating researchers from all liability associated with, 
arising out of, or related to my participation and agree to hold them harmless from any harm or 
loss that may be incurred by me due to my participation in the research. 
 
 
________________________________________________________________________ 
Name of Subject/Legal Guardian                                             Signature 
________________________________________________________________________ 
I.C No                                                                                       Date 
________________________________________________________________________ 
Name of Witness                                                                       Signature 
________________________________________________________________________ 
I.C No                                                                                        Date 
________________________________________________________________________ 
Name of Consent Taker                                                             Signature 
________________________________________________________________________ 
I.C No                                                                                        Date