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CKD and Diabetes: Tips & Tricks
No, the combination of an ACE inhibitor and an ARB is not generally recommended for patients with diabetes and CKD. Some key points: - There is no evidence that combining an ACEi with an ARB provides additional renal protection compared to monotherapy in patients with diabetes and CKD. - Combining the two classes of drugs increases the risk of hyperkalemia and acute kidney injury without proven additional benefit over monotherapy. - Current guidelines recommend using either an ACEi or an ARB as first-line therapy for albuminuria, but do not recommend combining the two classes of drugs. So in summary, while ACEis and ARBs are both reasonable first-line options, combining
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CKD and Diabetes: Tips & Tricks
- 1. CKD and Diabetes:Tips & Tricks Usama Ragab Youssif, MD Lecturer of Medicine
- 2. Case Question 1 A50-year-old female was diagnosed with type 2 diabetes at age 30. She has taken medications as prescribed since diagnosis. The fact that she has confirmed diabetes puts this patient at: A. Higher risk for kidney failure and CVD B. Higher risk for kidney failure only C. Higher risk for CVD only D. None of the above
- 3. CKD-CVD- Diabetes Link: CKD is aDisease Multiplier
- 4. CKD Risk Factors* Modifiable •Diabetes • Hypertension • History of AKI • Frequent NSAID use Non-Modifiable • Family history of kidney disease, diabetes, or hypertension • Age 60 or older (GFR declines normally with age) • Race/U.S. ethnic minority status *Partial list AKI, acute kidney injury
- 5. Diabetes and hypertension are leading causes ofkidney failure ESRD, end stage renal disease USRDS ADR, 2007 Incident ESRD rates, by primary diagnosis, adjusted for age, gender, & race.
- 6. *ASVD was definedas the first occurrence of AMI, CVD/TIA, or PVD. Incidence/100 Patient-Yr x 2.8 x 2.3 x 1.7 x 2.1 x 2.0 x 2.5 Risk for Cardiovascular Events Is Greatest When Both Diabetes and CKD Are Present Retrospective analysis of 5% of US Medicare population 1990-1999 (N = 1,091,201) Foley. J Am Soc Nephrol. 2005;16:489. Slide credit: clinicaloptions.com 0 10 20 30 40 50 60 CHF AMI CVA/TIA PVD ASVD* Death No diabetes/no CKD Diabetes/no CKD No diabetes/CKD Diabetes/CKD
- 7. Patients (%) *Relative to diabetesalone. 15.7 32.3 29.5 T2D, No CKD No T2D, CKD T2D, CKD No T2D, No CKD 10.3 Mortality Among Medicare Patients Mortality Risk Doubles* in Comorbid T2D and CKD Retrospective analysis of US Medicare enrollees 1996-2000 (N = 1.1 million) Collins. Kidney Int. 2003;64:S24. Slide credit: clinicaloptions.com 0 10 20 30 40
- 8. So… Diabetes + CKD= CVD Diabetes + CKD = Mortality Detect Early Treat Early
- 9. Definitions Clinical syndrome characterized by↑ in UAE, ↑ BP up to ESRD with progressive rise in CV risk. The earliest evidence of diabetic kidney disease is the appearance of albuminuria, ≥30mg/day
- 10. Natural History of DiabeticNephropathy: Hyperglycemia Causes Hyperfiltration, Followed by Albuminuria and Decreased GFR Reference: Adapted from Friedman, 1999
- 11. And to bemore precise… *Kidney complications: anemia, bone and mineral metabolism, retinopathy, and neuropathy. Alicic. CJASN. 2017;12:2032. Slide credit: clinicaloptions.com Diagnosis Yr 2 5 10 20 30 Hyperglycemia Cellular injury Mesangial expansion glomerulosclerosis, tubulointerstitial fibrosis, and inflammation Microalbuminuria Macroalbuminuria GFR High Normal Low ESRD Hypertension Kidney complications* Cardiovascular disease, infections, death
- 12. Mechanistic Links BetweenPrediabetes, Diabetes, DKD, and End-Stage Kidney Disease Prediabetes, Diabetes Chronic hyperglycemia, metabolic syndrome, dyslipidemia, increased fatty acid metabolism Hemodynamic Inflammation cytokines, chemokines Oxidative stress ROS Apoptosis/autophagy Mitochondrial dysfunction mitophagy Diabetic nephropathy Extracellular matrix accumulation Glomerular nodular sclerosis Glomerular basement membrane thickening Glomerular hyalinosis podocytopathy End-stage kidney disease Nicholas. NephSAP. 2020;19:110. Slide credit: clinicaloptions.com
- 13. Structural Changes inDiabetic Kidney Disease Alicic. CJASN. 2017;12:2032. Reproduced with permission. Normal Kidney Glomerulus Diabetic Kidney Glomerulus Slide credit: clinicaloptions.com
- 14. Diabetic Glomerulopathy Alicic. CJASN.2017;12:2032. Reproduced with permission. Slide credit: clinicaloptions.com Normal Glomerulus Diffuse mesangial expansion Nodularity, mesangiolysis Kimmelstiel-Wilson nodules Dilated capillaries- microaneurysms Obsolescent glomerulus
- 15. Electron Microscope Imagesof Diabetic Glomerulopathy Alicic. CJASN. 2017;12:2032. Reproduced with permission. Slide credit: clinicaloptions.com
- 16. How to AssessThe risk
- 17. KDIGO: Composite Rankingfor Relative Risks by GFR and Albuminuria 17 Levey. Kidney Int. 2011;80:17-28. Slide credit: clinicaloptions.com Composite ranking for relative risks by GFR and albuminuria (KDIGO 2009) Albuminuria stages, description, and range (mg/g) A1 A2 A3 Optimal and high-normal High Very high and nephrotic <10 10-29 30-299 300-1999 ≥2000 eGFR Stages, Description, and Range (ml/min/1.73m 2 ) G1 High and optimum >105 90-104 G2 Mild 75-89 60-74 G3a Mild-moderate 45-59 G3b Moderate-severe 30-44 G4 Severe 15-29 G5 Kidney failure <15
- 18. So… ACR ≥30 mg/gmand / or eGFR <60 mL/min/1.73 m2 CKD in Diabetes means
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- 21. PERSONAL USE ONLY Bewareof Transient Albuminuria
- 22. What is thefrequency of monitoring for CKD in patients with diabetes? At least annually, urinary albumin (e.g., spot uACR) and eGFR. B Patients with diabetes and uACR ≥300 mg/g and/or eGFR 30–60 mL/min/m2 should be monitored twice annually. B Standards of Medical Care in Diabetes - 2022. Diabetes Care 2022;45(Suppl. 1):S144-S174
- 23. Case • A 68-year-oldman with >60 years of type 1 DM, no retinopathy and no history of albuminuria is found to have 1.2 grams of proteinuria on routine check after complaining of bodyache. His creatinine is 1.0 mg/dL. He is already on enalapril and HCZ and his BP levels average 110/70. His A1C is 7%. At this point you should 1. add valsartan 2. order CTUT 3. order UPEP, SPEP, ANA, CRP 4. Refer to nephrology
- 24. Be Aware ofCKD of other causes
- 25. PERSONAL USE ONLY Beware ofOther Causes of CKD CKD, chronic kidney disease
- 26. PERSONAL USE ONLY 2018Diabetes Canada CPG – Chapter 29. Chronic Kidney Disease in Diabetes When to consider other causes of CKD CKD, chronic kidney disease
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- 28. Kidney damage and normal or GFR Kidney damage and mild GFR Severe GFR Kidney failure Moderate GFR Stage 1 Stage 2 Stage 3 Stage 4 Stage 5 Nephrologist Primary Care Practitioner The Patient (always) and other subspecialists (as needed) GFR 90 60 30 15 Who Should be Involved in the Patient Safety Approach to CKD? Patient safety Consult?
- 29. When to refer https://doi.org/10.2337/dci22-0027 Patients shouldbe referred for evaluation by a nephrologist if they have an estimated glomerular filtration rate <30 mL/min/1.73 m2. A Promptly refer to a nephrologist for uncertainty about the etiology of kidney disease, difficult management issues, and rapidly progressing kidney disease. A
- 30. CKD Patient SafetyIssues Fink JC, Brown J, Hsu, VD, et al. Am J Kidney Dis 2009;53:681-668. Medication errors • Toxicity (nephrologic or other) • Improper dosing • Inadequate monitoring Electrolytes • Hyperkalemia • Hypoglycemia • Hypermagnesemia • Hyperphosphatemia Miscellaneous • Multidrug-resistant infections • Vessel preservation/dialysis access
- 31. CKD Patient SafetyIssues (cont.) Diagnostic tests • Iodinated contrast media: AKI • Gadolinium-based contrast: NSF • Sodium Phosphate bowel preparations: AKI, CKD CVD • Missed diagnosis • Improper management Fluid management • Hypotension • AKI • CHF exacerbation AKI = acute kidney injury; CHF = congestive heart failure; NSF = nephrogenic systemic fibrosis. Fink JC, Brown J, Hsu, VD, et al. Am J Kidney Dis 2009;53:681-668..
- 32. Also, refer early if… Chronic,progressive loss of kidney function ACR persistently >60 mg/mmol eGFR <30 mL/min/1.73 m2 Unable to remain on renal-protective therapies due to adverse effects such as hyperkalemia or a >30% increase in serum Cr within 3 months of starting ACEi or ARB Unable to achieve target BP (could be referred to any specialist in hypertension) 2018 Diabetes Canada CPG – Chapter 29. Chronic Kidney Disease in Diabetes
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- 34. Optimize blood glucose • Optimize glucosecontrol to reduce the risk or slow the progression of chronic kidney disease. A Standards of Medical Care in Diabetes - 2022. Diabetes Care 2022;45(Suppl. 1):S144-S174
- 35. What are the preferred antidiabetic drugsin patients with CKD?
- 36. ADA. Diabetes Care.2021;44:S1. Slide credit: clinicaloptions.com COMPELLING NEED TO MINIMIZE WEIGHT GAIN OR PROMOTE WEIGHT LOSS SGLT2i2 +HF Particularly HFrEF (LVEF <45%) To avoid therapeutic inertia reassess and modify treatment regularly (3-6 months) FIRST-LINE Therapy is Metformin and Comprehensive Lifestyle (including weight management and physical activity) INDICATORS OF HIGH-RISK OR ESTABLISHED ASCVD, CKD, OR HF† NO CONSIDER INDEPENDENTLY OF BASELINE A1C OR INDIVIDUALIZED A1C TARGET, OR METFORMIN USE* +ASCVD/Indicators of High Risk GLP-1 RA with proven CVD benefit1 If A1C above target SGLT2i with proven benefit in this population5,6,7 COMPELLING NEED TO MINIMIZE HYPOGLYCEMIA DPP-4i GLP-1 RA SGLT2i TZD If A1C above target If A1C above target If A1C above target If A1C above target SGLT2i OR TZD SGLT2i OR TZD GLP-1 RA OR DPP-4i OR TZD SGLT2i OR DPP-4i OR GLP-1 RA If A1C above target GLP-1 RA with good efficacy for weight loss10 GLP-1 RA with good efficacy for weight loss8 SGLT2i EITHER/OR If A1C above target COST IS A MAJOR ISSUE9-10 SU4 TZD12 TZD12 SU4 If A1C above target If A1C above target IF A1C ABOVE INDIVIDUALIZED TARGET PROCEED AS BELOW Established ASCVD Indicators of high ASCVD risk (age ≥55 years with coronary, carotid, or lower extremity artery stenosis >50%, or LVH SGLT2i with proven CVD benefit1 Either/or If further intensification is required or patient is unable to tolerate GLP- 1 RA and/or SGLT2i choose agents demonstrating CV benefit and/or safety: For patients on a GLP-1 RA, consider adding AGLT2i with proven CVD benefit and vice versa TZD2 DPP-4i if not on GLP-1 RA Basal insulin3 SU4 +CKD PREFERABLY SGLT2i with primary evidence of reducing CKD progression OR SGLT2i with evidence of reducing CKD progression in CVOTs5,6,8 OR GLP-1 RA with proven CVD benefit1 if SGLT2i not tolerated or contraindicated DKD and Albuminuria6 For patients with T2D and CKD8 (e.g., eGFR <60 mL/min/1.73 m2) and thus at increased risk of cardiovascular events NO GLP-1 RA with proven CVD benefit1 SGLT2i with proven CVD benefit1 Either/or Continue with addition of other agents as outlined above If A1C above target Consider the addition of SU4 OR basal insulin: Choose later generation SU with lower risk of hypoglycemia Consider basal insulin with lower risk of hypoglycemia9 If A1C above target Insulin therapy basal insulin with lowest acquisition cost OR Consider other therapies based on cost If quadruple therapy required, or SGLT2i and/or GLP-1 RA not tolerated or contraindicated, use regimen with lowest risk of weight gain PREFERABLY DPP-4i (if not on GLP-1 RA) based on weight neutrality If DPP-4i not tolerated or contraindicated or patient already on GLP-1 RA, cautious addition of: ▪ SU4 ▪ TZD2 ▪ Basal Insulin ADA Clinical Practice Guidelines: Glucose-Lowering Medications in T2D
- 37. What are issues tobe considered while treating CKD in patients with diabetes In patients with chronic kidney disease who have ≥300 mg/g urinary albumin, a reduction of 30% or greater in mg/g urinary albumin is recommended to slow chronic kidney disease progression. B Optimization of blood pressure control and reduction in blood pressure variability to reduce the risk or slow the progression of chronic kidney disease is recommended. A
- 38. Just reduction of albuminuria is asuccess Clinical Journal of the American Society of Nephrology. 2015 Jun 5;10(6):1079-88.
- 39. ACEi and ARBs •In nonpregnant patients with diabetes and hypertension, either an ACEi or an ARB is recommended for those with modestly elevated urinary albumin-to-creatinine ratio (30–299 mg/g creatinine) B and is strongly recommended for those with urinary albumin-to creatinine ratio ≥300 mg/g creatinine and/or estimated glomerular filtration rate <60 mL/min/1.73 m2. A • Monitor serum creatinine and potassium levels for the development of increased creatinine or changes in potassium when ACEi, ARBs, or diuretics are used. B
- 40. Is ACEi +ARBs combination is recommended ? 2018 Diabetes Canada CPG – Chapter 29. Chronic Kidney Disease in Diabetes
- 41. What about primaryprevention of CKD? • An ACE inhibitor or an angiotensin receptor blocker is not recommended for the primary prevention of chronic kidney disease in patients with diabetes who have normal BP, normal uACR (<30 mg/g), and normal eGFR. A
- 42. Quiz 52 Year oldfemale, diabetes, hypertension, albuminuria eGFR 55 ml/min She was prescribed ramipril 2 weeks later, her cousin text you and tell you that the GFR is now 50 and he is concerned with the nephrotoxic effect of this group of drug? ADA SoC 2022: Do not discontinue renin-angiotensin system blockade for minor increases in serum creatinine (<30%) in the absence of volume depletion. A KDIGO Practice Point: Continue ACEi or ARB therapy unless serum creatinine rises by >30% within 4 weeks following initiation of treatment or an increase in dose.
- 43. Ann Intern Med.doi:10.7326/M20-5938
- 44. Residual Risk orunable to use SGLT2i • In patients with chronic kidney disease who are at increased risk for cardiovascular events or chronic kidney disease progression or are unable to use a sodium–glucose cotransporter 2 inhibitor, a nonsteroidal mineralocorticoid receptor antagonist (finerenone) is recommended to reduce chronic kidney disease progression and cardiovascular events. A
- 45. Finerenone: Novel, Nonsteroidal,Selective Mineralocorticoid Receptor Antagonist 1. Kolkhof. Handb Exp Pharmacol. 2017;243:271. 2. Kolkhof. J Cardiovasc Pharmacol. 2014;64:69. 3. Grune. Hypertension. 2018;71:599. N H H2 N N N Bulky, nonsteroidal molecule1 Unique structure results in selective and potent interaction with the MR and regulation of gene expression1 Exhibits antifibrotic and anti-inflammatory effects2,3 Slide credit: clinicaloptions.com
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- 48. Don’t ban everything •For people with non-dialysis dependent stage 3 or higher chronic kidney disease, dietary protein intake should be a maximum of 0.8 g/kg body weight per day (the recommended daily allowance). A • For patients on dialysis, higher levels of dietary protein intake should be considered, since malnutrition is a major problem in some dialysis patients. B
- 49. Don’t forget Reference: DeZeeuw et al. Kidney Int 2004; 65(6):2309–2320. Control • Control blood pressure Reduce • Reduce sodium intake Achieve • Achieve good control of diabetes early; may help prevent albuminuria Reduce • Reduce weight, if obese Achieve • Achieve tobacco cessation
- 50. PERSONAL USE ONLY Ifthe patient get sick, what advice you offer him? 2018 Diabetes Canada CPG – Chapter 29. Chronic Kidney Disease in Diabetes
- 51. Make sure ofdiagnosis
- 52. 65–year–old man withT2D for 25 years and Retinopathy He may have diabetic kidney disease: he has long term diabetes, and both retinopathy and albuminuria.
- 53. 69–year–old Woman withDM 2 for 15 years, without Retinopathy, Lupus for 4 years Probably not, she has normal urine albumin and no retinopathy.
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- 57. Metformin recommendations forpatients with T2D and CKD from ADA and KDIGO ADA SoC 2022 • First-line therapy depends on comorbidities, patient-centered treatment factors, and management needs and generally includes metformin and comprehensive lifestyle modification (A). KDIGO • We recommend treating patients with T2D, CKD, and an eGFR >30 mL/min/m2 with metformin (1B). • Adjust the dose of metformin when the eGFR is <45 mL/min/m2, and for some patients when the eGFR is 45–59 mL/min/m2.
- 58. GLP1A recommendations forpatients with T2D and CKD from ADA and KDIGO ADA SoC 2022 • Among patients with T2D who have established ASCVD or established kidney disease, an SGLT2i or GLP-1 receptor agonist with demonstrated CVD benefit is recommended as part of the comprehensive CV risk reduction and/or glucose-lowering regimens (A). KDIGO • In patients with T2D and CKD who have not achieved individualized glycemic targets despite use of metformin and SGLT2i treatment, or who are unable to use those medications, we recommend a long-acting GLP-1 receptor agonist (1B).
- 59. SGLT2i recommendations for patients with T2Dand CKD from KDIGO • An SGLT2i with proven kidney or cardiovascular benefit is recommended for patients with T2D, CKD, and eGFR >20 mL/min/1.73 m2. Once initiated, the SGLT2i can be continued at lower levels of eGFR.
- 60. Considerations for selectingglucose-lowering agents in patients with T2D and CKD
- 62.