The efficacy and safety of Dapagliflozin in adult patients with Active Lupus nephritis - An exploratory non-randomised trial

·       Background and Rationale Despite therapeutic advances, lupus nephritis remains a major cause of morbidity and progression to end-stage renal disease. Current treatment strategies including corticosteroids and immunosuppressants result in low early response rates, which negatively influence long-term renal outcomes. Existing literature highlights that the rate of progression to ESRD in lupus nephritis has not significantly declined over the past decade. Therefore, there is an unmet clinical need for adjunctive agents that may improve partial or complete renal response and reduce proteinuria more effectively in the short term, thereby improving long-term outcomes. Sodium-glucose cotransporter 2 inhibitors SGLT2i,  such as dapagliflozin have demonstrated nephroprotective and cardioprotective effects across various types of chronic kidney disease including diabetic nephropathy. Recent retrospective studies in patients with lupus and coexistent diabetes suggest potential benefits, but data in biopsy-proven active lupus nephritis is lacking. Based on this, we planned a prospective cohort study to evaluate the efficacy and safety of dapagliflozin when used in conjunction with standard-of-care induction therapy in lupus nephritis. This study aims to generate preliminary data to support future randomized controlled trials. Objectives Primary Objective To evaluate the proportion of patients with active lupus nephritis achieving partial or complete renal response at 6 months in the group receiving standard-of-care with dapagliflozin compared to those receiving standard-of-care alone. Secondary Objectives 1. Proportion achieving partial renal response at 3 months 2. Trend of eGFR using CKD-EPI 2021 equation during induction 3. Proportion with more than 25 percent proteinuria reduction at 3 months and more than 50 percent at 6 months 4. Changes in cardiometabolic profile including blood pressure, heart rate, body weight, lipid profile, HbA1c and left ventricular ejection fraction 5. Changes in clinical SLEDAI at 12 weeks and SLEDAI-2K at 24 weeks 6. Frequency of adverse drug reactions including hypoglycemia, urinary tract infections, genital mycotic infections, dehydration, ketoacidosis, and acute kidney injury Study Design This is a prospective, single-centre cohort study conducted at AIIMS Rishikesh. Patients with biopsy-proven class III, IV, or V lupus nephritis according to ISN RPS 2003 criteria will be enrolled into one of two groups: Group A -Those receiving  standard-of-care with dapagliflozin 10 mg once daily Group B -Those receiving standard-of-care alone Study Setting Patients will be recruited from the outpatient and inpatient departments of General Medicine, Rheumatology, and Nephrology at AIIMS Rishikesh. Sample Size and Duration The study will enroll patients over an 6-month period with follow-up of 6 months. Based on average patient flow, approximately 120 new SLE patients are expected, of whom 60 may have lupus nephritis. With an anticipated 10 percent dropout rate, a target of at least 30 patients is kept to be enrolled in each group. Eligibility Criteria Inclusion 1.Age more than or equal to 18 years 2. Diagnosis of SLE per ACR EULAR 2019 criteria 3. Biopsy-proven active class III, IV, or V lupus nephritis within past 3 months 4. Not on induction therapy or high-dose corticosteroids more than 1 month in last 3 months Exclusion 1. Recurrent urinary tract infections that is more than one episode in 6 month 2. Current genital mycotic infection 3. eGFR less than 30 mL per min or on dialysis 4. Known diabetes mellitus Methodology Initial Assessment and Baseline Evaluation All eligible patients will undergo complete history and clinical examination. Laboratory investigations including CBC, renal and liver function tests, lipid profile, 24-hour urine protein, immunological markers, and kidney biopsy reports will be recorded. Group Allocation Patients will be assigned to Group A or B depending on consent to take study drug. Induction Therapy All patients will receive:  Intravenous methylprednisolone 500 mg daily for 3 days followed by Oral prednisolone 0.8 to 1 mg per kg with taper per KDIGO guidelines Cyclophosphamide per modified NIH protocol or MMF up to 3 g per day Ramipril up to 10 mg or Telmisartan as tolerated Hydroxychloroquine and other supportive treatments Dapagliflozin Administration Patients in Group A will begin dapagliflozin 10 mg daily from baseline. Adverse events will be monitored during monthly visits. In cases of AKI or suspected infection, the drug may be withheld or discontinued. Safety Monitoring All patients will be monitored for adverse events including UTI, hypoglycemia, AKI, and dehydration. Monthly assessments will include symptom screening, clinical exam, and investigations. Telephonic follow-up will be provided at week 2 and as needed. Management will be as per standard institutional protocols. Response Assessment Renal response either partial and complete will be assessed at week 12 and 24 based on reduction in proteinuria and stabilization or improvement in serum creatinine. Withdrawal Criteria Patients experiencing serious adverse events attributable to study drug, such as life-threatening infections, or those who wish to withdraw from study may be withdrawn. Statistical Analysis Data will be analyzed using SPSS software. Continuous variables will be expressed as mean and standard deviation. Categorical data will be presented as frequencies and percentages. Inter-group comparisons will be made using unpaired t-test and Fisher’s exact test. Intention-to-treat analysis will be applied with a significance level of 0.05.

Ethical Considerations No investigational drug is used. Dapagliflozin has a known safety profile and is approved for nephroprotection in CKD. Both groups receive standard treatment for lupus nephritis. No extra cost is imposed on patients. All routine tests are part of standard of care.

Confidentiality Patient identity and records will remain confidential. Data will be anonymized and securely stored.

Conflict of Interest There is no conflict of interest to declare. The study is not industry-sponsored and is conducted as an academic initiative. Budgetary Notes There are no additional investigations or financial incentives. All services are part of standard care.