Clinical trial NCT05748925
Conditions: SLE Lupus Nephritis SGLT2 Inhibitors
Sponsor: Mansoura University
Start date: 2022-10-01; Completion date: 2024-01-01
Enrollment: 84 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study aims to assess sodium glucose linked transoprter inhibitors(SGT2i) role in regression of ongoing kidney and cardiac diseases among lupus nephritis patient either diabetic or non-diabetic under different immunosuppressive therapy.

The main objective of this study is to:

To compare use of sodium glucose linked transoprter inhibitors (SGLT2i) versus standard care in regression of chronic kidney disease in patient with lupus nephritis (LN).

To study the safety and efficacy of this drug group with use of immunosuppression and possible interaction.

Patients with an estimated glomerular filtration rate (eGFR) \>30 ml/min/1.73m2 will be randomized into two groups Study group will receive SGLT2i inhibitor as add on drug or replace another drug according to patient clinical situation, Dapagliflozin 10 mg and 25 mg will be used once daily with or without food.

Control group will be maintained on placebo.We will follow up all patients for 12 months and compare their results.

Detailed description:
Study sitting:

Nephrology and renal transplant unit at urology and nephrology center in Mansoura University.

It will include 100 patients with lupus nephritis, Diagnosis of glomerulonephritis was performed by renal biopsy, and all of the renal biopsies were carried out at urology and nephrology center.

Patients with an estimated glomerular filtration rate (eGFR) \>30 ml/min/1.73m2 will be randomized into two groups Study group will receive SGLT2i inhibitor as add on drug or replace another drug according to patient clinical situation, dapagliflozin 10 mg and 25 mg will be used once daily with or without food.

Control group will be maintained on placebo. The primary endpoint will be sustained decline in eGFR ≥50%, ESKD, or kidney or cardiovascular death We will follow up all patients for 12 months and compare their results.

2\. Inclusion criteria: Patients aged more than 16 year. Willing to sign informed consent. Diagnosis of Systemic Lupus Erythematosus (SLE) according to american college of rheumatology (ACR) classification criteria.

Renal biopsy showed lupus nephritis. Patient with eGFR \> 30 ml/min/1.73m2 by cockcroft-gault equation. 3. Exclusion criteria: Patients with eGFR \<30 ml/min per 1.73 m2. Current pregnancy or lactation. Medical history of chronic disease (CLD, cancer, severe respiratory distress, gastrointestinal tract lesions).

Patients refusing to participate in the study or lost follow up. Evidence of urinary obstruction of difficulty in voiding at screening. Patients who are receiving high dose diuretics or combined Angiotensin converting enzymes inhibitors(ACEI) and Angiotensin II receptor blockers (ARBS).

Patients who have frequent hypotensive episode or systolic blood pressure (SBP) \<100 mmHg.

Operational design:

Study Protocol:

Patients included in the study will treated with dapaglifilozin initiated at a total daily dosage of 10 mg/kg per day.

Study design:

Type of the study: randomized controlled study.

The following data will be gathered and evaluated for all patients:

I-before intervention:

Serum creatinine, Creatinine clearance. 24 hour urine protein, urine protein/creatinine ratio. Urine analysis. HBA1c. Hemoglobin (HGB). Uric acid and lipid profile. Lupus serology.

II-after intervention: All patients will be evaluated monthly regarding:

Serum creatinine, creatinine clearance. 24 hour proteinuria, protein/creatinine ratio. Fasting, random and postprandial glucose levels. calcineurin inhibitors (CNI) trough level if used. Urine analysis. HGB level. Uric acid, lipid profile. Lupus serology.

Cardiovascular assessment:

Echocardiogram. Atherosclerosis and vascular calcification incidence (NCCT model). Regular measurement of blood pressure each visit

ll patients will be evaluated at 12 month regarding:

1. erythropoetin level
2. Hepcidin level.

Arms: arm 1: study group: will receive SGLT2i as add on drug or replace another drug according to the patient clinical situation, Dapagliflozin 10 mg will be used once daily with or without food for one ye arm 2: Control group: will receive placebo as add on drug once daily with or without food for one year.
Interventions: intervention 1: dapagliflozin intervention 2: placebo
Intervention descriptions: intervention 1: The patients will be randomized into two groups Study group: will receive SGLT2i as add on drug or replace another drug according to the patient clinical situation, Dapagliflozin 10 mg will be used once daily with or without food. intervention 2: Control group: will be maintained on their medication

Protocol documents:
Prot_000.pdf: 
Study Protocol 
Official Title: 
Study of the Cardio Renal Effects of SGLT2 Inhibitors Among Diabetic and Non-diabetic 
Lupus Nephritis Patients 
ClinicalTrials.gov Identifier (NCT Number): 
NCT05748925 
Date of Document: 
May 11, 2024 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Internal Medicine Department 
Faculty of Medicine – Mansoura University 
 
 
Study of the cardio renal effects of SGLT2 inhibitors among 
diabetic and non-diabetic lupus nephritis patients. 
 
 
 
Thesis submitted as partial fulfillment of M.D in Nephrology 
By 
Nour Elsabah Mohamed Elbialy 
(Nour M. Elbialy) 
M.B.B.ch, MSC 
Specialist of Nephrology, 
Urology and Nephrology center- Mansoura University 
 
Under supervision of 
Prof. Dr. Mohamed Abdel-Kader Sobh 
(Mohamed A. Sobh) 
Professor of internal medicine (Nephrology), 
Urology & Nephrology Center, 
Faculty of Medicine- Mansoura University,Egypt. 
 
 
 
Prof. Dr. Ayman Fathi Refaie 
(Ayman F. Refaie) 
Consultant of internal medicine (Nephrology), 
Urology & Nephrology Center 
Faculty of Medicine –Mansoura University, Egypt. 
 
 
Dr. Kareem Nagaty Zayed 
 
 
1


 
(Kareem N. Zayed) 
lecturer of internal medicine (Nephrology), 
Faculty of Medicine- Mansoura University, Egypt. 
 
 
 
2021 
 
 
 
 
 
 
Introduction 
 
Sodium-glucose cotransporter 2 inhibitors have been the recent 
 
focus in a large number of diseases, not only type 2 diabetes but also 
congestive heart failure and chronic kidney disease. (1) 
 
Latest studies show that sodium-glucose cotransporter 2 inhibitors 
originally approved for glycemic control in patients with type 2 diabetes 
(2). 
 
 
SGLT2i also exert protective renal effects independently from their 
effects on blood glucose level (2). 
 
Recently it is obvious that SGLT2i treatment can be effective in 
 
patients with non-diabetic chronic kidney disease, including primary and 
secondary glomerular diseases. (3) 
 
Glomerular diseases can result from either immune or nonimmune 
mediated damage, it appears that SGLT2i would not target the mechanism 
of immune-mediated glomerular diseases; it may improve the source of 
injury from the original glomerular damages. (4) 
 
 
It is still not obvious at what point of the mechanism of specific 
glomerular diseases (either immune or nonimmune mediated) SGLT2i can 
be beneficial. So, more studies targeting nondiabetic primary and 
 
2


 
secondary glomerular diseases are ensured to assess the efficacy and safety 
of SGLT2i in patients with glomerular diseases. (4) 
 
SLE is a chronic inflammatory disease that has renal effect in about 
 
half of patients. Lupus nephritis is a major risk factor for morbidity and 
mortality in patients with SLE, and in spite of strong anti-inflammatory 
and immunosuppressive therapies still ends in CKD or ESRD. (5) 
 
Based on this observation, we aim to determine the effect of SGLT2i 
 
treatment in patients with glomerulonephritis secondary to SLE who either 
is diabetic or non-diabetic. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aim of the work 
 
 
This study aims to assess SGT2i role in regression of ongoing kidney and 
cardiac diseases among lupus nephritis patient either diabetic or non-
diabetic under different immunosuppressive therapy. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients and methods 
 
 
Technical design: 
 
 
Study sitting: .1 
 
 
Nephrology and renal transplant unit at urology and nephrology center 
in Mansoura University. 
 
It will include 100 patients with lupus nephritis, Diagnosis of 
glomerulonephritis was performed by renal biopsy, and all of the renal 
biopsies were carried out at urology and nephrology center. 
 
Patients with an estimated glomerular filtration rate (eGFR) >30 
ml/min/1.73m2 will be randomized into two groups 
 
Study group will receive SGLT2i inhibitor as add on drug or replace ● 
another drug according to patient clinical situation, Dapagliflozin 10 
mg and 25 mg will be used once daily with or without food. 
 
 
Control group will be maintained on placebo. ● 
 
The primary endpoint will be sustained decline in eGFR ≥50%, ESKD, 
or kidney or cardiovascular death 
 
We will follow up all patients for 12 months and compare their results. 
 
 
 
 
 
 
 
5


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. Inclusion criteria: 
 
Patients aged more than 16 year. .1 
 
 
Willing to sign informed consent. .2 
 
 
Diagnosis of SLE according to EULAR/ACR classification .3 
criteria. 
 
Renal biopsy showed lupus nephritis. .4 
 
 
Patient with eGFR > 30 ml/min/1.73m2 by cockcroft-gault .5 
equation. 
 
3. Exclusion criteria: 
 
Patients with eGFR <30 ml/min per 1.73 m2. .1 
 
 
Current pregnancy or lactation. .2 
 
 
Medical history of chronic disease (CLD, cancer, severe .3 
respiratory distress, gastrointestinal tract lesions). 
 
Patients refusing to participate in the study or lost follow up. .4 
 
 
Evidence of urinary obstruction of difficulty in voiding at .5 
screening. 
 
 
 
6


 
Patients who are receiving high dose diuretics or combined .6 
ACEI, ARBS. 
 
Patients who have frequent hypotensive episode or SBP .7 
<100 mmHg. 
 
 
 
 
 
 
 
Operational design: 
 
 
Study Protocol: 
 
 
Patients included in the study will treated with dapaglifilozin ● 
initiated at a total daily dosage of 10 mg/kg per day. 
 
Study design: 
 
 
Type of the study: randomized controlled study. 
 
 
The following data will be gathered and evaluated for all  
 
patients: 
 
 
I-before intervention: 
 
Serum creatinine, Creatinine clearance. .1 
 
24 hour urine protein, urine protein/creatinine ratio. .2 
 
Urine analysis. .3 
 
HBA1c. .4 
 
HGB. .5 
 
Uric acid and lipid profile. .6 
 
Lupus serology. .7 
 
 
7


 
 
 
 
II-after intervention: All patients will be evaluated monthly regarding: 
 
Serum creatinine, creatinine clearance. .1 
 
24 hour proteinuria, protein/creatinine ratio. .2 
 
Fasting, random and postprandial glucose levels. .3 
 
CNI trough level if used. .4 
 
Urine analysis. .5 
 
HGB level. .6 
 
Uric acid, lipid profile. .7 
 
Lupus serology. .8 
 
Cardiovascular assessment: .9 
 
ECCHO. 
 
Atherosclerosis and vascular calcification incidence (NCCT model). 
 
Regular measurement of blood pressure each visit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Outcomes: 
 
Effect of dapagliflozin compared to placebo on eGFR. .1 
 
Effect of dapagliflozin compared to placebo on systolic/diastolic blood .2 
pressure. 
 
Effect of dapagliflozin compared to placebo on body weight. .3 
 
Safety of dapagliflozin vs. placebo - the number of hypoglycemia .4 
episodes between groups and serious adverse events. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical Analysis: 
 
 
Qualitative data were displayed in cross tabulations, and 
quantitative data were described in terms of arithmetic mean ± SD. 
Bivariate techniques were used for initial evaluation of contrasts. Thus, 
the chi-square and Fisher's exact tests were used for comparisons of 
frequencies of qualitative variables; the Mann-Whitney test and the 
unpaired t-test were used for comparisons of means of two quantitative 
variables. A p-value <0.05 was considered significant. Graft and patient 
survival rates were assessed using the Kaplan-Meier method. All 
analyses were carried out using the computer package SPSS for 
windows, release 16 SPSS Inc. Chicago, III, USA. 
 
 
 
 
 
Administrative design ● 
 
Informed consent will be obtained from all subjects and the approval will 
be obtained from institutional review board (IRB) in Faculty of Medicine, 
Mansoura University. There is no funding. 
 
 
10


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research question 
 
 
The main research question is: Does use of SGLT2i will show 
 
superiority over conventional lines of treatment of lupus nephritis patient as 
regard efficacy and safety. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rationale and justification 
 
 
The rational of this study is that SGLT2i are now one of the common 
 
lines in regression of chronic kidney disease either is diabetic or not. 
 
 
Large trials on this issue exclude patient with glomerulonephritis, so 
 
we will study its renal efficacy in patient with secondary glomerulonephritis 
to SLE to prove their efficacy and safety in this group of patients. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Objectives 
 
 
The main objective of this study is to: 
 
 
 
To compare use of SGLT2i versus standard care in regression of ● 
chronic kidney disease in patient with LN. 
 
To study the safety and efficacy of this drug group with use of ● 
immunosuppression and possible interaction. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypothesis 
 
 
SLE is the one of the leading causes of secondary 
 
glomerulonephritis. 
Despite 
the 
use 
immunosuppressive 
and 
 
antiproteinuric drugs, a number of patients are at risk of progressing to 
end-stage kidney disease. Additional therapies to slow kidney function 
decline are highly desired. The DAPA-CKD trial demonstrated that the 
sodium glucose co-transporter 2 inhibitor dapagliflozin significantly 
reduced the risk of kidney failure and prolonged survival in participants 
with chronic kidney disease with and without type 2 diabetes. The 
DAPA-CKD population excluded patients with lupus nephritis, so we 
determined the long-term efficacy and safety of dapagliflozin on major 
kidney and cardiovascular outcomes in these patients. 
 
 
 
 
 
 
 
 
 
 
 
 
 
14


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
References 
 
 
James Matera, DO. SGLT2 Inhibitors and CKD in 
-1 
2021. Consultant360. Published online May 25, 2021. 
 
Dan Xu, Owain Chandler, Cleo Wee, et al. Sodium- 
-2 
 
Glucose Cotransporter-2 Inhibitor (SGLT2i) as a Primary 
Preventative Agent in the Healthy Individual: A Need of 
August 2021 
 
Hiddo J.L. Heerspink, Ph.D., Bergur V. Stefánsson, et 
-3 
al. Dapagliflozin in Patients with Chronic Kidney Disease. 
N Engl J Med 2020; 383:1436-1446. 
 
 
Kana N. Miyataa, Shao-Ling Zhanga John S.D. Chana 
-4 
. The Rationale and Evidence for SGLT2 Inhibitors as a 
Treatment 
for 
Nondiabetic 
Glomerular 
Disease. 
CJASN May 2017, 12 (5) 825-835. 
 
 
Salem 
Almaani, Alexa 
Meara and Brad 
H. 
-5 
Rovin. Update 
on           Lupus 
Nephritis           Clin 
PharmacolTher 2007;81:228-34. 
10.1038/sj.clpt.6100039. 
 
15 

SAP_001.pdf: 
 
 
Statistical Analysis Plan 
Document Control 
 
    Title: Statistical Analysis Plan for the Study of SGLT2 Inhibitors in Lupus Nephritis 
Patients 
    Protocol ID: [NCT05748925] 
    Version: 1.0 
    Date: [11/3/2024] 
    Principal Investigator: [Nourelsabah Mohamed Elbialy] 
    Statistician: [Nourelsabah Mohamed Elbialy] 
    Approval Signatures: 
        Principal Investigator: Nourelsabah Mohamed Elbialy  
        Statistician:  Nourelsabah Mohamed Elbialy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Table of Contents 
1. Introduction 
2. Study Design 
3. Study Objectives 
4. Endpoints 
5. Sample Size Justification 
6. Statistical Methods 
7. Handling of Missing Data 
8. Interim Analysis 
9. Safety Analysis 
10. 
Data Quality and Management 
11. 
Software 
12. 
Appendices 
 
 
 
 
 
 
 
 
 
 
 
1. Introduction 


 
 
 Purpose of the SAP: This document outlines the statistical 
approach for analyzing data from the clinical trial studying 
the effects of SGLT2 inhibitors on renal, cardiovascular, and 
hematological outcomes in lupus nephritis patients. 
2. Study Design 
    Design: Randomized, double-blind, placebo-controlled clinical trial. 
    Study Duration: Conducted from September 2022 to November 2023 
Randomization: Patients were randomly assigned to either dapagliflozin 
(10 mg once daily) or placebo groups using computer-generated random tables 
in a 1:1 ratio stratified by age and gender. 
Blinding: The study was double-blinded, and all trial staff and participants 
remained unaware of individual treatment assignments until study completion. 
3. Study Objectives 
    Primary Objective: To evaluate the impact of SGLT2 inhibitors on renal, 
cardiovascular, and hematological parameters in lupus nephritis patients. 
    Secondary Objective: To explore changes in body weight, BMI, and other 
echocardiographic and iron profile parameters over 12 months. 
 
 
 
 
 
 
4. Endpoints 
Primary Endpoints 
    Renal Function: Serum creatinine, eGFR, and 24-hour urine protein 


 
 
Cardiovascular Health: BNP levels and coronary calcification via NCCT 
Hematological Parameters: Hemoglobin and erythropoietin levels 
Hepcidin Level: Measured before and after intervention 
Secondary Endpoints 
    Body Weight and BMI: Assessed at baseline and follow-up visits. 
    Echocardiographic Findings: Assessed pre- and post-intervention. 
    Iron Profile: Serum ferritin and TSAT 
5. Sample Size Justification 
    Calculation: A sample size of 100 patients was targeted, accounting for potential 
dropouts, to provide sufficient power (80%) at a significance level of 0.05 to detect 
differences between the two groups. 
6. Statistical Methods 
General Considerations 
    Significance Level: A two-sided alpha level of 0.05 will be used for all primary 
analyses. 
    Analysis Populations: 
        Intent-to-Treat (ITT): All randomized patients will be analyzed according to their 
assigned group. 
        Per-Protocol (PP): Only patients completing the study without major protocol 
violations. 
Primary Endpoint Analysis 
    Renal Outcomes: ANOVA for repeated measures for serum creatinine and eGFR if 
normally distributed, and the Friedman test for non-normally distributed data. Post-hoc 
tests using Bonferroni correction. 
    Cardiovascular Outcomes: Mann-Whitney U test for BNP levels and coronary 
calcification between groups. 
    Hematological Outcomes: Paired t-test for hemoglobin and erythropoietin levels if 
data is normally distributed; otherwise, Wilcoxon signed-rank test. 
Secondary Endpoint Analysis 


 
 
    Body Weight and BMI: Compared over time using ANOVA for repeated measures. 
    Echocardiographic Parameters: Analyzed with paired t-tests, adjusted with 
Bonferroni correction. 
    Iron Profile: Analyzed pre- and post-intervention using ANOVA or Kruskal-Wallis for 
non-normally distributed variables. 
Categorical Variables 
    Chi-Square Test: For between-group comparisons of categorical data (e.g., 
presence of diabetes, hypertension). 
7. Handling of Missing Data 
    Imputation: Last observation carried forward (LOCF) for data missing at random; 
multiple imputation for extensive missing data. 
    Sensitivity Analysis: Conducted to evaluate the robustness of primary endpoint 
findings against different missing data assumptions. 
8. Interim Analysis 
    Timing: An interim analysis is planned at the halfway point (6 months). 
    Stopping Rules: An O’Brien-Fleming approach will be applied to adjust the 
significance threshold for interim testing, allowing for an earlier stop for efficacy or safety 
concerns. 
9. Safety Analysis 
    Adverse Events (AEs): Summarized by type, frequency, and severity. Fisher’s exact 
test will be used to compare AE rates between groups. 
    Specific Safety Parameters: Monitoring for hypotension, electrolyte imbalances, 
and kidney function. 
 
10. Data Quality and Management 
    Data Quality Measures: Includes data verification, regular audits, and query 
resolution. 
    Database Lock: Data will be locked and verified prior to the final analysis. 
11. Software 


 
 
    Statistical Software: All analyses will be conducted using SPSS (Version 25). 
12. Appendices 
Table (1): Demographics and associated medical disorders: 
 
Control group. 
(n= 41) 
Study group. 
(n= 38) 
P value 
Age (years) Mean ± 
SD 
36.6 ± 9.6 
38 ± 9.8 
0.8  
Sex No. (%) 
- 
Male 
- 
Female 
 
7 (17.1%) 
34 (82.9%) 
 
4 (10.5%) 
34 (89.5%) 
 
0.5  
Body weight (Kg) 
mean ± SD 
78.9 ± 14 
90 ± 15 
0.5  
Body mass index 
(Kg/m2) mean ± SD 
30.6 ± 10.5 
33 ± 5.7 
0.6  
Hypertension No. 
(%) 
37 (90.2%) 
38 (100%) 
0.1  
Diabetes No. (%) 
7 (17.1%) 
11 (28.9%) 
0.2 
(Student T test or Mann-Whitney) for continuous data, and chi-square test for categorical data. Continuous data are 
expressed as mean (SD) or median (minimum – maximum). Categorical data are expressed as number (percentage), 
Level of significance < 0.05. 
 
 
 
 
 
Table (2): SLE characteristics: 
 
Control group. 
(n= 41) 
Study group. 
(n= 38) 
P value 
Disease duration (years) 
Median (min, max) 
6 (1, 20) 
7(1,19) 
0.3  


 
 
Lupus nephritis class No. 
(%) 
- 
Class I 
- 
Class II 
- 
Class III 
- 
Class IV 
- 
Class V 
- 
Class VI 
 
 
1 (2.4%) 
2 (4.9%) 
11 (26.8%) 
26 (36.4%) 
5 (2.4%) 
0 (0%) 
 
 
1 (2.6%) 
7 (18.4%) 
8 (21.1%) 
16 (42.1%) 
1 (13.2%) 
1 (2.6%) 
0.1    
Activity index Median 
(min, max) 
6 (0, 19) 
6 (0, 21) 
0.8  
Chronicity index Median 
(min, max) 
2 (0, 8) 
5 (0, 14) 
0.2 
Anti- phospholipid No. 
(%) 
6 (14.6%) 
3 (7.9%) 
0.4 
Immunosuppressive 
medications No. (%) 
- 
Steroid + MMF 
- 
Steroid + CNI 
- 
Steroid + CNI + MMF 
- 
Steroid + Azathioprine 
- 
Steroid 
 
27 (65.9%) 
5 (12.2 %) 
2 (4.9 %) 
7 (17.1%) 
0 (0%) 
 
 
18 (47.4%) 
4 (10.5%) 
1 (2.6%) 
14 (36.8%) 
1 (2.6%) 
0.2  
Cyclophosphamide No. 
(%) 
7 (17.1%) 
5 (13.2%) 
0.7  
 
Other medications No. (%) 
- 
Aspirin 
- 
Statins 
- 
Allopurinol 
- 
ACEI/ARBS 
- 
Diuretics 
 
15 (36.6%) 
30 (73.2%) 
10 (24.4%) 
26 (63.4%) 
14 (34.1%) 
 
18 (34.4%) 
24 (63.2%) 
14 (36.8%) 
27(71.1%) 
16 (32.1%) 
 
0.3 
0.4 
0.3 
0.4 
0.3 
- 
MMF: mycophenolate mofetil; CNI: calcineurin inhibitors; ACEI/ARBS: angiotensin converting enzyme 
inhibitors/angiotensin receptor blockers; (Student T test or Mann-Whitney) for continuous data, and chi-
square test for categorical data. Continuous data are expressed as mean (SD) or median (minimum – 
maximum). Categorical data are expressed as number (percentage).; Level of significance < 0.05. 
 
Table (3): Baseline laboratory investigations: 
 
Control group. 
(n= 41) 
Study group. 
(n= 38) 
P value 
Consumed C3 & C4 
No. (%) 
5 (12.2%) 
2 (5.3%) 
0.4  


 
 
S. creatinine 
(mg/dL) Median 
(min, max) 
0.8 (0.4, 2.7) 
0.8 (0.4, 2.6) 
0.8  
24- hour urinary 
protein (g/24 hours) 
mean ± SD 
0.4 (0.06-3.6) 
0.6 (0.07-3) 
0.3  
eGFR (ml/min/m2) 
mean ± SD 
114 ± 51 
128 ± 59.7 
0.6  
Cholesterol mg/dL 
mean ± SD 
185 ± 46 
172 ± 40.7 
0.5  
Albumin (g/dL) 
mean ± SD 
3.7 ± 0.4 
3.7 ± 0.3 
0.4  
Random blood 
sugar (mg/dL) 
Median (min, max) 
89 (66, 568) 
92.5 (64, 243) 
0.4  
Uric acid (mg/dL) 
mean ± SD 
6.2 ± 2.1 
6.5 ± 1.7 
0.2  
Alanine 
aminotransferase 
(IU/L) Median (min, 
max) 
17 (2, 84) 
17 (7, 82) 
0.8  
Aspartate 
aminotransferase 
(IU/L) Median (min, 
max) 
21(9, 66) 
19 (12,72) 
0.4  
Sodium (mEq/L) 
mean ± SD 
137 ± 3.1 
136 ± 3 
0.5  
Potassium (mEq/L) 
mean ± SD 
3.9 ± 0.4 
4 ± 0.4 
0.3  
eGFR: estimated glomerular filtration rate; (Student T test or Mann-Whitney) for continuous data, and chi-
square test for categorical data. Continuous data are expressed as mean (SD) or median (minimum – maximum). 
Categorical data are expressed as number (percentage). Level of significance < 0.05. 
 
 
 
 
Table (4): Baseline hematological findings: 


 
 
 
Control group. 
(n= 41) 
Study group. 
(n= 38) 
P value 
Hemoglobin (g/dL) 
Mean ± SD 
11.9 ± 1.9 
11.7 ± 1.7 
0.5  
MCV (FL) Mean ± 
SD 
82 ± 7 
84 ± 6.9 
0.9  
MCH (Pg) Mean ± 
SD 
25.4 ± 2.9 
26.3 ± 2.9 
0.9  
Ferritin 
(mg/dL) 
Median (min, max) 
60 (13, 1113) 
33.5 (3, 1460) 
0.09  
TSAT (%) Median 
(min, max) 
23.8 (7, 64) 
18 (6, 74) 
0.05  
Erythropoietin 
level (IU/L) Mean ± 
SD 
11.6 ± 2.1 
11.3 ± 1.4 
0.1 
Hepcidin 
level 
(ug/L) 
Mean ± SD 
198 ± 74 
182 ± 76 
0.3 
Platelet count (*103) 
Mean ± SD 
288 ± 71 
300 ± 79 
0.7  
MCV: Mean corpuscle volume; MCH: Mean corpuscular hemoglobin; TSAT: Transferrin saturation test; 
(Student T test or Mann-Whitney) for continuous data, and chi-square test for categorical data. Continuous data are 
expressed as mean (SD) or median (minimum – maximum). Categorical data are expressed as number (percentage).; 
Level of significance < 0.05. 
 
 
 
 
 
 
 
 
Table (5): Baseline Cardiac evaluation: 
 
Control group. 
Study group. 
P value 


 
 
(n= 41) 
(n= 38) 
Coronary 
calcification No. 
(%) 
3 (7.3%) 
11 (28.9%) 
0.012  
Coronary 
calcification 
severity No. (%) 
- 
No 
- 
Minimal 
- 
Mild 
- 
moderate 
 
 
38 (92.7%) 
1 (2.4%) 
1 (2.4% 
1 (2.4%) 
 
 
27 (71.1%) 
3 (7.9%) 
7 (18.4%) 
1 (2.6%) 
0.04  
BNP 
(ng/L) 
Median 
(min, 
max) 
52 (40, 557) 
52 (34, 90) 
0.8  
Echocardiographic finding 
EF % Mean ± SD 
65.4 ± 9.3 
64.6 ± 5.4 
0.6  
LAD (ml) Mean ± 
SD 
24.2 ± 7.6 
24.9 ± 7.6 
0.6 
Aortic diameter 
(ml) Mean ± SD 
24.7±7.4 
24.8±7.1 
0.9 
ESV 
(ml/m) 
Median 
(min, 
max) 
38±13.6 
41±13.9 
0.4  
EDV 
(ml/m) 
Mean ± SD 
98±35.7 
111.5±31.6 
0.08 
BNP: Brain natriuretic peptide; EF: Ejection fraction; LAD: Left atrial dimension; ESV: End- systolic volume; EDV: End diastolic 
volume; (Student T test or Mann-Whitney) for continuous data, and chi-square test for categorical data. Continuous data are 
expressed as mean (SD) or median (minimum – maximum). Categorical data are expressed as number (percentage).; Level of 
significance < 0.05. 
 
 
 
 
 
 


 
 
Table (6): Comparison between study and control groups as regard effect of intervention on 
disease activity and renal affection at different time points 
 
Grouping 
Baseline 
3 
months 
6 months 
9 months 
12 months 
P value* 
Consumed C3 & C4 
No. (%) 
 
Control 
5 (12.2%) 
5 
(12.2%) 
4 (9.8%) 
6 (14.6%) 
10 (24.4%) 
0.1  
Study 
2 (5.3%) 
5 
(13.2%) 
2 (5.3%) 
6 (15.8%) 
6 (15.8%) 
0.1 
P value** 
0.4 
0.9 
0.3 
1 
0.4 
 
S. creatinine (mg/dL) 
Median (min, max) 
 
Control 
0.8 (0.4, 
2.7) 
0.9 (0.4, 
3.1) 
0.9 
(0.3-
3.1) 
0.9 (0.6, 4) 
0.9 (0.6, 5) 
0.1  
Study 
0.8 (0.4, 
2.6) 
0.9 (0.6, 
2.6) 
0.9 
(0.5, 
3.1) 
1 (0.5, 
4.2) 
a 
0.9 (0.5, 5) 
0.01 
 
P value** 
0.8 
0.8 
1 
0.5 
0.8 
 
eGFR 
(ml/min/m2) 
Mean ± SD 
 
Control 
114±51 
104±45 
a 
107±53.8 
99±47 
a 
100.3±44.5 
a 
0.003 
 
Study 
128±59.7 
115±47 
A 
118±50 
A 
109±44.5 
a, c 
115.7±48 
a 
0.001 
 
P value** 
0.6 
0.9 
0.8 
0.2 
0.9 
 
24- hour urinary 
protein (g/24 hours) 
Median (min, max) 
Control 
0.4(0.06-
3.6) 
0.6 
(0.03-5) 
0.6 (0.03-
7) 
0.6 (0.02, 
5) 
0.5 
(0.02, 
8) 
0.06 
 
Study 
0.6 
(0.07-3) 
0.7 
(0.01-4) 
0.8 (0.02, 
4.8) 
0.6 (0.05, 
4.7) 
0.5 
(0.02, 
4) 
0.07 
 
P value** 
0.3 
0.9 
0.8 
0.6 
0.6 
 
Albumin (g/dL) 
Mean ± SD. 
 
Control 
3.7±0.4 
3.7±0.4 
3.6±0.4 
3.8±0.4 
c 
3.9±0.3 
a, b, c 
0.001 
 
Study 
3.7±0.3 
3.7±0.5 
3.7±0.3 
3.8±0.3 
c 
3.9±0.8 
a, c 
0.04 
 
P value** 
0.4 
0.9 
0.1 
0.7 
0.8 
 
(*) Within group analysis (repeated measure ANOVA). 
(**) Between group analysis (Student T test or Mann-Whitney) for continuous data, and chi-square test for categorical data. Post-hoc analysis; 
(a) significance against baseline <0.05; (b) significance against 3 months level <0.05, (c) significance against 6 months level <0.05, (d) 


 
 
significance against 9 months level <0.05. Continuous data are expressed as mean (SD) or median (minimum – maximum). Categorical data 
are expressed as number (percentage). 
 
 
Table (7): effect of intervention on hematological findings between both groups at different 
time points: 
 
Grouping 
Baseline 
3 months 
6 months 
9 months 
12 months 
P value* 
Haemoglobin 
(g/dL) Mean ± 
SD 
 
Control 
11.9±1.9 
12.2±1.9 
11.8±2.5 
12±1.9 
12.2±1.9 
0.08 
 
Study 
11.8±1.8 
 
12.3±1.7 
12±2.5 
11.9±2.2 
12±2 
 
0.06 
 
P value** 
0.5 
0.7 
0.7 
0.3 
0.6 
 
MCV 
(FL) 
Mean ± SD 
 
Control 
82±7 
83±7 
84±7 
84.6±7.9 
81.5±13 
0.1 
 
Study 
84±6.9 
80±14 
83±10 
83.2±10.8 
84±7 
0.3 
 
P value** 
0.9 
0.1 
0.5 
0.5 
0.4 
 
MCH 
(Pg) 
Mean ± SD 
Control 
25.4±2.9 
27.3±9.8 
28.5±9 
26.9±3.2 
26.9±3.1 
0.08 
 
Study 
26.3±2.9 
27.3±9.5 
27±3 
26.6±3.5 
27.1±3.4 
0.8 
 
P value** 
0.9 
0.9 
0.4 
0.4 
0.5 
 
(*) Within group analysis (repeated measure ANOVA). 
(**) Between group analysis (Student T test or Mann-Whitney) for continuous data, and chi-square test for categorical data. 
Continuous data are expressed as mean (SD) or median (minimum – maximum). Categorical data are expressed as number 
(percentage). 
MCV: Mean corpuscle volume; MCH: Mean corpuscular haemoglobin. 
 
 
 
 
 
Table (8): other hematological findings differences between both groups: 


 
 
 
 
Grouping 
Baseline 
12 months 
P value* 
Ferritin 
(mg/dL) 
Median (min, max) 
 
Control 
60 (13, 1113) 
75 (6, 2127) 
0.5  
Study 
33.5 (3, 1460) 
64 (3, 1311) 
0.8  
P value** 
0.09 
0.4 
 
TSAT (%) Median 
(min, max) 
 
Control 
23.8 (7, 64) 
28 (5, 62) 
0.1  
Study 
18 (6, 74) 
20 (6, 66) 
0.9  
P value** 
0.05 
0.1 
 
Erythropoietin 
level IU/L Mean ± 
SD 
 
Control 
11.6±2.1 
12.8 ± 3.5 
0.08  
Study 
11.3±1.4 
12.4 ± 3.5 
0.1  
P value** 
0.1 
0.6 
 
Hepcidin level ug/L 
Mean ± SD 
Control 
198 ± 74 
128 ±63 
0.001  
Study 
182±76 
116±15 
0.001  
P value** 
0.3 
0.2 
 
Platelet count 
(×103) Mean ± SD 
Control 
288 ± 71 
283 ± 74 
0.6 
Study 
300 ± 79 
276 ± 65 
0.01 
P value** 
0.7 
0.5 
 
(*) Within group analysis (paired t test). 
(**) Between group analysis (Student T test or Mann-Whitney) for continuous data, and chi-square test for 
categorical data. 
Continuous data are expressed as mean (SD) or median (minimum – maximum). Categorical data are 
expressed as number (percentage). 
TSAT: Transferrin saturation test 
 
 
 
 
 
 
 
 
Table (9): Cardiac evaluation differences between both groups after 12 months: 


 
 
 
Control group 
Study group 
P value 
Coronary calcification 
No. (%) 
1 (2.4%) 
11 (28.9%) 
0.001  
Coronary calcification 
severity No. (%) 
- 
No 
- 
Minimal 
- 
Mild 
- 
moderate 
 
 
40 (97.6%) 
0 
0 
1 (2.4%) 
 
 
27 (71.1%) 
9 (23.7%) 
2 (5.3%) 
0 
 
 
 
0.002  
BNP ng/L Mean ± Sd 
66 ± 22.1 
65.8±21 
0.9 
Echocardiographic finding 
EF % Mean ± SD 
65.5±5.8 
64.9±5.2 
0.8  
LAD ml Mean ± SD 
26.7±7.6 
28.2±8.6 
0.4 
Aortic 
diameter 
ml 
Mean ± SD 
26.6±6.5 
25.5±6.2 
0.4 
ESV ml/min  
Mean ± SD 
39.5±18 
36.3±9.3 
0.3 
EDV ml/min  
Mean ± SD 
108±29.6 
109±19.3 
0.9 
BNP: Brain natriuretic peptide; EF: Ejection fraction; LAD: Left atrial dimension; ESV: End- systolic volume; EDV: 
End diastolic volume; Chi square test; Student t- test; Man, Whitney test; Level of significance < 0.05. 
 
 
 
 
 
 
 
 
 
 
Table (10): Comparison between both groups as regard post intervention side effects 


 
 
 
Control group. 
(n= 41) 
Study group. 
(n= 38) 
P value 
AKI episodes No. 
(%) 
- 
No 
- 
once 
- 
twice 
 
 
 
38 (92.7%) 
1 (2.4%) 
2 (4.9%) 
 
 
31 (81.6%) 
5 (13.2%) 
2 (5.3%) 
 
 
0.17  
UTI No. (%) 
- 
No 
- 
once 
- 
more 
than 
once 
 
 
35 (85.4%) 
4 (9.8%) 
2 (4.9%) 
 
31 (81.6%) 
5 (13.2%) 
2 (5.3%) 
 
 
0.8  
Gynecological 
infection No. (%) 
1 (2.4%) 
2 (5.3%) 
0.6  
Viral infection No. 
(%) 
1(2.4%) 
1 (2.6%) 
1  
MMF 
intolerance 
No. (%) 
1 (2.5%) 
2 (5.3%) 
0.6  
Renal biopsy No. 
(%) 
2 (4.9%) 
1 (2.6%) 
0.6  
Increase 
steroid 
dose No. (%) 
7 (17.1%) 
4 (10.5%) 
1  
UTI: urinary tract infection episodes; AKI: acute kidney injury; chi-square test for categorical data. Categorical data 
are expressed as number (percentage).; Level of significance < 0.05. 
 
 
 
 


 
 
 
 
figure1: flow chart of participating populations 


 
 
 
 
 
Figure (2) shows difference between individual which had improved eGFR or not as regard to their 
basal eGFR in total cohort, which found that improving eGFR had been occurred in patients with lower eGFR 
(107±50 vs 137±58 ml/min/m2  
 
 


 
 
 
 
Figure (3) show no significant difference between the drug and placebo groups (p=0.857). as 
regard incidence of anemia before intervention, the drug group has 23 anemic participants 
(60.5%) versus 24 participants (58.5%) in the placebo group, while post intervention, In the 
anemia category, the drug group has 16 participants (42.1%), while the placebo group has 22 
participants (53.7%) with non-significant differences (p = 0.3) 
Figure (4) differences in body weight between both groups at different time points:
 
 


 
 
Glossary of Terms and Abbreviations 
AA 
Amino Acids 
ABIN 
A20 Binding Inhibitor Of NF-Κb  
ACE 
Angiotensin-Converting Enzyme Inhibitors  
ACR 
American College of Rheumatology  
AKI 
Acute Kidney Injury 
ALCAM 
Activated Leucocyte Adhesion Molecule  
ALP 
Alkaline Phosphatase 
AMP 
Adenosine Monophosphate 
AMPK 
Amp-Activated Protein Kinase  
ANA 
Antinuclear Antibodies 
ANG II 
Angiotensin 2 
ANOVA 
Analysis Of Variance 
ANTI-DSDNA 
Anti Double Stranded Deoxyribonucleic Acid 
Antibodies 
ANTI-SM  
Anti-Smith Antibodies 
APLS 
Antiphospholipid Syndrome  
ARBS 
Angiotensin 2 Receptor Blockers  
ATN 
Acute Tubular Necrosis 
ATP 
Adenosine Triphosphate 
BAFF 
B-Cell-Activating Factor 
BLISS 
B Lymphocyte Stimulator Inhibitor Belimumab 
Plus Standard Therapy 
BMI 
Body Mass Index 
BNP 
 Brain Natriuretic Peptide 
BP 
Blood Pressure 
CAC 
Coronary Artery Calcification  
CAD 
Coronary Artery Disease  


 
 
CAMK 
Ca2+/Calmodulin-Dependent Protein Kinase  
CASR 
Serine/Threonine Kinase Camk4 
CCS 
Coronary Calcium Score  
CD163 
Macrophage-Specific Protein 
CD4 T-CELLS 
Helper T-Cells  
CD8 T-CELLS 
Cytotoxic T-Cells  
CI 
Confidence Interval 
CKD 
Chronic Kidney Disease 
CKD-MBD 
Chronic Kidney Disease-Mineral Bone Disorders 
CLD 
Chronic Liver Disease 
CMV 
Cytomegalovirus 
CNI 
Calcineurin Inhibitors 
CT 
Computed Tomography 
CVD 
Cardiovascular Disease 
CYC 
Cyclophosphamide 
DAPA-HF 
The Dapagliflozin and Prevention of Adverse 
Outcomes in Heart Failure  
DCGF 
Death-Censored Graft Failure 
DECLARE-TIMI 58 
Dapagliflozin Effect on Cardiovascular Events–
Thrombolysis in Myocardial Infarction 58 
DELIGHT 
Delay Of Impaired Glucose Tolerance by A 
Healthy Lifestyle Trial 
DM 
Diabetes Mellitus 
DNA 
Deoxyribonucleic Acid 
EBV 
Epstein Bar Virus 
EDV 
End Diastolic Volume 
EF 
Ejection Fraction 
EGFR 
Estimated Glomerular Filtration Rate 
EMPA-REG 
Empagliflozin-Removing Excess Glucose 


 
 
EPO 
Erythropoietin 
EPOR 
Erythropoietin Receptors 
ESRD 
End-Stage Renal Disease 
ESV  
End- Systolic Volume 
EULAR 
The European League Against Rheumatism 
FDA 
Food And Drug Administration 
FEUA 
Fractional Excretion of Uric Acid 
FGF 
Fibroblast Growth Factor 
FN1 
Fibronectin 1  
GCS 
Glucocorticoids 
H2 O2 
Hydrogen Peroxide 
HBA1C 
Glycated Hemoglobin  
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HD 
Hemodialysis 
HIF 
Hypoxia-Inducible Factor  
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leucocytic Antigen 
HPT 
Hyperparathyroidism 
HR 
Hazard Ratio 
HR-PQCT 
High-Resolution Peripheral Quantitative 
Computer Tomography 
HUS 
Hemolytic Uremic Syndrome 
HZ 
Herpes Zoster 
IFTA 
Interstitial Fibrosis and Tubular Atrophy 
IGG 
Immunoglobulin G 
IL-6 
Interleukin-6 
IPTH 
Intact Parathyroid Hormone 
ITP 
Immune Thrombocytopenic Purpura 


 
 
KDIGO 
Kidney Disease Improving Global Outcomes 
LAD 
Left Atrial Dimension 
LDL 
Low-Density Lipoprotein 
LUMINA 
Lupus In Minorities; Nature Vs. Nurture 
LV 
Left Ventricle 
MCH 
Mean Corpuscular Hemoglobin 
MCP1 
Monocyte Chemoattractant Protein-1 
MCV 
Mean Corpuscular Volume  
MDCT 
Multidetector CT 
MMF 
Mycophenolate Mofetil 
MPAA 
Mycophenolic Acid Analogue 
MRI 
Magnetic Resonance Imaging 
NGAL 
Neutrophil Gelatinase-Associated Lipocalin 
NH3 
Na+/H+ Exchanger 3 
NHS 
National Health Service 
NLR 
Nucleotide-Binding Oligomerization Domain-
Like Receptor  
NSAIDS 
Non-Steroidal Anti-Inflammatory Drugs 
PD 
Peritoneal Dialysis 
PET 
Positron Emission Tomography 
PGC-1Α 
Peroxisome Proliferators-Activated Receptor 
Gamma Coactivator-1α 
QCT 
Quantitative Computer Tomography 
RAAS 
Renin-Angiotensin-Aldosterone 
RBG 
Random Blood Glucose 
RCTS 
Randomized Controlled Trials 
RNA 
Ribonucleoside Antibodies 
ROS 
Reactive Oxygen Species  


 
 
RPS/ISN 
The Renal Pathology Society/International 
Society of Nephrology 
RRT 
Renal Replacement Therapy 
SBP 
Systolic Blood Pressure 
SELENA-SLEDAI 
Safety Of Estrogens in Lupus Erythematosus 
National Assessment–SLE Disease Activity 
Index  
SGLT2 
Sodium-Glucose Cotransporter 2 
SGLT2 inhibitors  
Sodium-Glucose Cotransporter 2 Inhibitors 
SIRT1  
 
Sirtuin Type 1.  
 
SLE 
Systemic Lupus Erythematosus 
SLEDAI 
Systemic Lupus Erythematosus Disease Activity 
Index  
SLICC 
The Systemic Lupus International Collaborating 
Clinics  
SNS 
Sympathetic Nervous System 
T2DM 
Type 2 Diabetes Mellitus 
TLRS 
Toll-Like Receptors  
TNF 
Tumor Necrosis Factor 
TSAT 
Transferrin Saturation 
UTI 
Urinary Tract Infection 
VCAM-1 
Vascular Cell Adhesion Molecule-1