Guideline sources The following summarized guidelines for the evaluation and management of diabetic nephropathy (DN) are prepared by our editorial team based on guidelines from the American Diabetes Association (ADA 2023), the Kidney Disease: Improving Global Outcomes Foundation (KDIGO 2022), and the Canadian Cardiovascular Society (CCS 2022). 1 2 3 4 4 4 4 Definition DN is a chronic microvascular complication of diabetes characterized by glomerular hyperfiltration, progressive albuminuria, and reduced GFR. 4 Epidemiology DN is caused due to hyperfiltration and reduction of GFR mainly due to hyperglycemia, systemic hypertension, and obesity. 4 Disease course Clinical manifestations of DN include microalbuminuria, macroalbuminuria, hyperglycemia, refractory hypertension, diabetic retinopathy, nephrotic or nephritic syndrome, anemia, bone and mineral metabolism complications. Disease progression may lead to CVD, infections, end-stage renal disease, and death. 4 https://web.pathway.md/diseases/rectlsnLmFenRaCjN 1/6 6/29/23, 10:16 PM Diabetic nephropathy Pathway Prognosis and risk of recurrence 1-year mortality of patients on dialysis is around 21.5% in the United States. 4 Pathway Diabetic nephropathy Diagnosis and management Guidelines 1. Diagnostic investigations Urinary albumin testing: Assess urinary albumin (such as spot urinary albumin-to-creatinine ratio) and eGFR at least annually in all patients with T2DM regardless of treatment. B Monitor urinary albumin (such as spot urinary albumin-to-creatinine ratio) and eGFR 1-4 times per year depending on the stage of the disease in patients with established diabetic kidney disease. B 2. Medical management General principles: treat patients with diabetes mellitus and CKD with a comprehensive strategy to reduce risks of kidney disease progression and CVD. B Show 3 more Goals of treatment: reduce urinary albumin by 30% to slow CKD progression in patients with CKD with 300 mg/g of urinary albumin. B Glycemic control: optimize glucose control to slow the progression of CKD. A Blood pressure control: optimize BP control and reduce BP variability to reduce the risk or slow the progression of CKD. A Metformin: initiate metformin in patients with T2DM, CKD and an eGFR 30 mL/min/1.73 m . B Show 4 more GLP-1 receptor agonists: initiate long-acting GLP-1 receptor agonists in patients with T2DM and CKD not achieved individualized glycemic targets despite use of metformin and SGLT-2 inhibitor treatment or unable to use these medications. B Show 5 more Landmark trials: LEADER In patients with T2DM who had a glycated Hgb level of 7.0% and high cardiovascular risk, liraglutide was noninferior to placebo with respect to death due to cardiovascular causes. https://web.pathway.md/diseases/rectlsnLmFenRaCjN 2/6 6/29/23, 10:16 PM Diabetic nephropathy Pathway Marso SP et al. N Engl J Med. 2016 Jul 28. SGLT2 inhibitors: As per ADA 2023 guidelines, initiate SGLT-2 inhibitors in patients with an eGFR 25 mL/min/1.73 m and urinary albumin 300 mg/g creatinine to reduce CKD progression and cardiovascular events in patients with T2DM and diabetic kidney disease. A Show 2 more Landmark trials: CREDENCE In patients with T2DM and kidney disease, canagliflozin was superior to placebo with respect to the incidence of ESRD, doubling of creatinine, renal death, or CV death. Perkovic V et al. N Engl J Med. 2019 Jun 13. As per CCS 2022 guidelines, initiate SGLT-2 inhibitors to reduce the composite of significant decline in eGFR, progression to end-stage kidney disease, or kidney death, all-cause and cardiovascular mortality, nonfatal myocardial infarction, and hospitalization for HF in adult patients with CKD (urine albumin-to-creatinine ratio > 20 mg/mmol and eGFR 25 mL/min/1.73 m ). B As per KDIGO 2022 guidelines, initiate SGLT-2 inhibitors in patients with T2DM, CKD and an eGFR 20 mL/min/1.73 m . B Show 7 more RAAS blocker therapy: As per ADA 2023 guidelines, do not use ACEIs or ARBs for the primary prevention of CKD in patients with diabetes with normal BP, normal urinary albumin-to-creatinine ratio (< 30 mg/g creatinine), and normal eGFR. D Show 5 more As per KDIGO 2022 guidelines, initiate an ACEI or an ARB in patients with diabetes, hypertension and albuminuria and titrate the medications to the highest approved dose that is tolerated. B Show 13 more 3. Nonpharmacologic interventions Dietary protein intake: aim to a target level of 0.8 g/kg body weight/day of dietary protein intake in patients with nondialysis-dependent stage 3 CKD. A Consider allowing higher levels of dietary protein intake in patients on dialysis since protein energy wasting is a major problem in some patients on dialysis. B Smoking cessation: Advise patients with diabetes mellitus and CKD to quit using tobacco products. B Counsel patients with diabetes mellitus and CKD to reduce secondhand smoke exposure. B https://web.pathway.md/diseases/rectlsnLmFenRaCjN 3/6 6/29/23, 10:16 PM Diabetic nephropathy Pathway 4. Specific circumstances Pediatric patients: consider obtaining annual screening for albuminuria with a random (morning sample preferred to avoid effects of exercise) spot urine sample for albumin-to- creatinine ratio in patients with T1DM at puberty or at age > 10 years, whichever is earlier, once the patient has had diabetes for 5 years. C Show 2 more 5. Preventative measures Primary prevention (glycemic control): optimize glucose control to reduce the risk of CKD. A Primary prevention (blood pressure control): optimize BP control and reduce BP variability to reduce the risk or slow the progression of CKD. A Primary prevention (RAAS blockers): do not use ACEIs or ARBs for the primary prevention of CKD in patients with diabetes with normal BP, normal urinary albumin-to-creatinine ratio (< 30 mg/g creatinine), and normal eGFR. D 6. Follow-up and surveillance Indications for specialist referral: Refer patients for evaluation by a nephrologist if urinary albumin levels are continuously increasing and/or eGFR is continuously decreasing or is < 30 mL/min/1.73 m . A Refer patients promptly to a nephrologist for uncertainty about the etiology of kidney disease, difficult management issues, and rapidly progressing kidney disease. A Serial laboratory monitoring: monitor serum creatinine and potassium levels periodically for the development of increased creatinine or changes in potassium when ACEIs, ARBs, or mineralocorticoid receptor antagonists are used, or hypokalemia when diuretics are used. B Clinical findings Symptoms Past medical history Ankle swelling Hypertension Frothy urine Poorly controlled diabetes Generalized pruritus Ocular exam Polyuria Poor appetite Eyelid swelling Puffy eyelids Vascular exam Leg edema Lab findings https://web.pathway.md/diseases/rectlsnLmFenRaCjN 4/6 6/29/23, 10:16 PM Diabetic nephropathy Pathway Hyperkalemia serum cholesterol serum creatinine urine microalbumin to creatinine urine protein Studies 2021 FIGARO-DKD In patients with T2DM and CKD treated with a renin-angiotensin system inhibitor at the maximum dose, finerenone was superior to placebo with respect to death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for HF. Bertram Pitt et al. N Engl J Med. 2021 Dec 9. 2013 VA-NEPHRON D In patients with T2DM, a urinary albumin-to-creatinine ratio of at least 300, and an eGFR of 30.0 to 89.9 mL/min/1.73 m of body-surface area, combined angiotensin inhibition was not superior to monotherapy with respect to decline in eGFR (by 30 mL/min if eGFR 60-90 at baseline, or by 50% eGFR 30-60 at baseline), ESRD, or death. Fried LF et al. N Engl J Med. 2013 Nov 14. Show 2 more References 1. Steven E. Kahn, Cheryl A.M. Anderson, John B. Buse et al. Standards of Care in Diabetes 2023. Diabetes Care. 2023 Jan;46 Supplement_1 S1 S291. Open 2. Kidney Disease: Improving Global Outcomes KDIGO Diabetes Work Group. KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int. 2022 Nov;102 5S S1 S127. Open 3. G B John Mancini, Eileen O'Meara, Shelley Zieroth et al. 2022 Canadian Cardiovascular Society Guideline for Use of GLP 1 Receptor Agonists and SGLT2 Inhibitors for Cardiorenal Risk Reduction in Adults. Can J Cardiol. 2022 Aug;38 8 1153 1167. Open 4. Radica Z Alicic, Michele T Rooney, Katherine R Tuttle. Diabetic Kidney Disease: Challenges, Progress, and Possibilities. 2017 Dec 7;12 12 2032 2045.2017 Dec 7;12 12 2032 2045. Open 5. American Diabetes Association. Standards of Medical Care in Diabetes-2019 Abridged for Primary Care Providers. Clin Diabetes. 2019 Jan;37 1 11 34. Open 6. Perkovic V, Jardine MJ, Neal B et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019 Jun 13;380 24 2295 2306. Open 7. American Diabetes Association. 11. Microvascular Complications and Foot Care: Standards of Medical Care in Diabetes 2019. Diabetes Care. 2019 Jan;42 Suppl 1 S124 S138. Open https://web.pathway.md/diseases/rectlsnLmFenRaCjN 5/6 6/29/23, 10:16 PM Diabetic nephropathy Pathway 8. Radica Z. Alicic, Michele T. Rooney, and Katherine R. Tuttle. Diabetic Kidney Disease Challenges, Progress, and Possibilities. Clin J Am Soc Nephrol. 2017 Dec 7; 12 12 2032 2045. Open 9. Bertram Pitt, Gerasimos Filippatos, Rajiv Agarwal et al. Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes. N Engl J Med. 2021 Dec 9;385 24 2252 2263. Open 10. Kidney Disease: Improving Global Outcomes KDIGO Diabetes Work Group. KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int. 2020 Oct;98 4S S1 S115. Open 11. Japanese Society of Nephrology. Essential points from Evidence-based Clinical Practice Guidelines for Chronic Kidney Disease 2018. Clin Exp Nephrol. 2019 Jan;23 1 1 15. Open https://web.pathway.md/diseases/rectlsnLmFenRaCjN 6/6