Renal Mechanism of SGLT2 Inhibition

Prior treatment

• Prior treatment with SGLT2 inhibitors and unable to perform a wash-out.
• Hematuria of unknown etiology. Prior to entry into the study, any participant with hematuria should be evaluated, the etiology established and documented, and treatment rendered as appropriate.
• Currently receiving a drug regimen that includes steroids, immunosuppressants, or investigational new drugs not associated with this trial.

Other illness

• Renovascular or malignant hypertension; uncontrolled hypertension (systolic blood pressure ≥150 or diastolic ≥90 mm Hg)
• Chronic debilitating disorders with or without treatment (e.g., systemic lupus erythematosus \[SLE\], cancer, amyloidosis, and chronic infection) that would interfere with the assessment of kidney function or that might reduce the chances of survival for a sufficient length of time to evaluate the efficacy of treatment.
• Known hypersensitivity to canagliflozin or iodine.
• Non-diabetic kidney disease - based on clinical history or kidney biopsy examination.
• History of osteoporotic fracture.
• Conditions likely to interfere with informed consent or compliance with the protocol.
• Single kidney; any condition with a single kidney

Lab values

• Clinically significant disorders of the liver \[cirrhosis, portal hypertension, hepatitis, increased bilirubin (≥1.5 mg/dl), active or uncontrolled cardiovascular disease, symptomatic peripheral vascular disease, (i.e. intermittent claudication), pulmonary diseases (including uncontrolled asthma and restrictive or obstructive lung disease requiring therapy), renal-urinary disorders (calculi, urinary tract obstruction, glomerulonephritis, chronic infection), gastrointestinal disorders (nausea, vomiting, diarrhea or anorexia sufficient to cause weight loss or wasting), or hematocrit levels ≤30 percent in women or ≤35 percent in men.
• Pregnancy. SGLT2 inhibitors are not recommended during the second or third trimester of pregnancy. Moreover, we do not wish to expose pregnant women to conscious sedation that is used during the kidney biopsies or to the intravenous filtration markers iohexol and p-aminohippurate needed for the renal clearance studies. Women of childbearing potential must have a negative pregnancy test prior to entry and every 2 months during the study and agree to using an effective form of contraception throughout the study, such as the oral contraceptive pill or an intrauterine device. Women who are planning a pregnancy in the next three years will be excluded.
• Bleeding disorders or requirements for anticoagulation or platelet inhibitors which cannot be safely interrupted, since kidney biopsies cannot be performed safely in these individuals.

Other

• Massive obesity with body mass index ≥45 kg/m². Kidney biopsies are more technically difficult with massive obesity.
• Kidney cortex \<1 cm (both kidneys)
• Kidney length \<8 cm (both kidneys)

• Aged 18-80 years. The lower age limit was set so renal function test results would not reflect changes associated with growth.
• Diagnosis of type 2 diabetes for ≥ 3 years.
• Estimated GFR \>45 and \< 90 ml/min/1.73m2 as determined from the CKD-EPI equation using serum creatinine (Levey et al., 2009).
• A screening urinary albumin-to-creatinine ratio \<3000 mg/g.
• Willingness to participate after receiving a thorough explanation of the study.
• Participants receiving a RAAS inhibitor must have been receiving the drug at maximum tolerable dose for at least 3 months prior to the study baseline examination.
• Participants receiving a GLP-1 receptor agonist must have been receiving the drug for at least 3 months prior to the study baseline examination.