Diabetic Kidney Disease in the Primary Care Clinic

Diabetic Kidney Disease in the Primary Care Clinic Jess Wheeler, DO Nephrology 2015 Outline: 1. CKD/DKD is a growing problem 2. Diagnosis of Chronic Kidney Disease (CKD) 3. Diagnosis of Diabetic Kidney Disease (DKD) 4. Management Issues Focus on early stages 5. When to refer to a nephrologist Cardiovascular risk >> Dialysis concern

Diabetic Kidney Disease: Epidemiology Chronic Kidney Disease (CKD) 13.1 14.2% of the U.S. population. Diabetic Kidney Disease (DKD): Responsible for 38 45% of all CKD in the US The leading cause of ESRD in the US ESRD: Medicare expenditures of $33.5 billion/year ~0.2% US Population 6% annual budget CDC Annual Report 2012 Am J Kidney Dis. 2009;53:S8 S374 NHANES 2003 2006 USRDS 2012 Annual Data Report CKD: Epidemiology We project that the number of Americans 30 years or older with CKD will reach 28 million in 2020 and nearly 38 million in 2030. This increase suggests that CKD health care costs and qualityof life loss will increase accordingly and further emphasizes the need to develop new interventions to slow the onset and progression of CKD Am J Kidney Dis. 2015; 65(3): 403 4011

CHRONIC KIDNEY DISEASE (CKD) Am J Kidney Dis. 2009; 53:S4 16

Chronic Kidney Disease: Diagnostic Criteria Kidney damage for > 3 months Defined by structural or functional abnormalities of the kidney Pathological Abnormal blood or urine markers of kidney function (e.g., albuminuria) GFR < 60 ml/min for > 3 months GFR Stage of Chronic Kidney Disease Stage Description GFR (ml/min/1.73 m2) 1 Kidney damage w/ normal or GFR > 90 2 3 4 5 Kidney damage w/ mild GFR 60 89 Moderate GFR 30 59 Severe GFR 15 29 Kidney failure < 15 (or dialysis) 3A egfr 45 59 Lower risk of progression 3B egfr 30 44 Higher risk of progression American Journal of Kidney Diseases, Vol 42, No 4, Supple 3 (2003): S10 S11

Source: United States Renal Data System. USRDS 2007 Annual Data Report Screening for Chronic Kidney Disease (CKD) Risk Factors Diabetes Hypertension Cardiovascular disease Hyperlipidemia Obesity Metabolic syndrome Smoking HIV or HCV Malignancy Treatment with potentially nephrotoxic drugs Family history of kidney disease Testing for CKD Urinalysis Creatinine to estimate GFR Urine alb:crratio **Screening the general population is not recommended. **KDIGO Conference: all patients over age 60 years.

DIABETIC KIDNEY DISEASE (DKD) Diabetic Kidney Disease: Risk Factors Longer duration of diabetes Poor glycemic control HTN Proteinuria Other risk factors: Race (AA, Mexican American, Native American, Pima Indians) Advanced age Male Smoking Obesity Genetic susceptibility NKF KDOQI Clinical Practice Guidelines. Am J Kidney Dis 49: S1 S180, 2007 (suppl 2)

Diabetic Kidney Disease: Diagnostic Criteria Inclusion Diabetes, Impaired Fasting Glucose Persistent albuminuria, proteinuria Elevated creatinine decreased GFR Normal to large kidneys Retinopathy Neuropathy Exclusion Alternative systemic process Rapid increase in proteinuria nephrotic syndrome Rapid decrease in GFR Active urinary sediment Refractory HTN Greater than expected drop in GFR with ACEs/ARBs NKF KDOQI Clinical Practice Guidelines. Am J Kidney Dis 49: S1 S180, 2007 (suppl 2) DKD: Monitoring Type 2 DM At time of diagnosis: Creatinine/eGFR Urinalysis Urine A/C ratio Confirm by two or more samples over 3 6 months. Annual: Urine A/C ratio Creatinine/GFR Type 1 DM Begin evaluating and monitoring 5 years after diagnosis. Diabetes Care. 2005 Jan; 28(1): 164 76 Am J Kidney Dis. 2000; 35: S117 131

Management of DKD HTN (< 140/90) Proteinuria Slow Progression Diet Protein: 0.8 g/kg/d (egfr <30) Salt: <2 g per day Glycemic control Hgb A1 c < 7.0% Anemia Hgb 10 to 11 g/dl Dyslipidemia LDL goal <100 mg/dl Uric Acid Aspirin Smoking cessation Weight Avoid NSAIDs and nephrotoxic substances Medication dosing appropriate to kidney function (i.e., CrCl formula) Avoid unnecessary IV contrast studies Albuminuria: Definitions Term Nephrotic Range Proteinuria Macroalbuminuria New terms: Very High Albuminuria Severely Increased Microalbuminuria New terms: High Albuminuria Moderately Increased Normal ACR albumin:creatinine ratio (aka UMAR) > 3,500 mg/g > 300 mg 30 300 mg/g 0 30 mg/g Increased ESRD risk Increased CV Risk Urine albumin:creatinine ratio Confirm with two or more samples over 3 6 months

Albuminuria: Transient causes Inflammation Infection Fever Exercise Poor glycemic control Uncontrolled HTN Elevated LDL Heart failure Periodontal disease DKD: CKD stages using egfr + Albuminuria

CKD and Cardiovascular Risk Factors Menon et al, Kidney Int 68:1413 1418 [Figure 1], 2005. Diabetes Medications and CKD Stage 3 5 CKD* Decreased clearance Insulin Some oral hypoglycemic agents Impaired kidney gluconeogenesis. * GFR < 60 ml/min Increased risks for hypoglycemia KDOQI guidelines (AJKD 2007)

Potential Complications of Diabetes Medications in Moderate to Severe CKD Medication Class (example) Sulfonylurea (Glimepiride) α glucosidase Inhibitors (Acrabose) Biguanide (Metformin) TZD (Pioglitazone) Megltidine (Nateglinide) Incretin Mimetics (Exenatide) DPP 4 Inhibitors (Sitagliptin) Insulin Complication Hypoglycemia Possible hepatic toxicity Lactic acidosis Volume retention Hypoglycemia If egfr <30, GI side effects and possible acute kidney injury Hypoglycemia Hypoglycemia KDOQI clinical practice guidelines Am J Kidney Dis 49:S1 S180, 2007 Clinical Diabetes Volume 25, Number 3, 2007 Kerri L. Cavanaugh, MD DKD: Nephrology consult? Co management (PCP and Nephrologist) 43% of pts started dialysis without ever having seen a nephrologist Referral: (generally) egfr < 45 UMAR > 300 mg/g (or UPCR > 0.5 g/g) Call anytime USRDS Annual Report 2012

More information www.usrds.org www.kidney.org KDIGO Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney International Supplements; Vol 3, Issue 1, January 2013 ADA Guidelines: J Clin and Applied Research and Edu, January 2015; Vol 38, suppl 1 www.diabetes.org/diabetescare SUPPLEMENTAL INFORMATION Pathophysiology Treatment 1. Albuminuria/Proteinuria 2. Glucose Control

Natural History of T2DM and Risk for Complications Post-meal glucose Fasting glucose PG 200 mg/dl PG 126 mg/dl Meets ADA diagnostic criteria for T2DM Macrovascular disease risk Other risk e.g. cancer; NAFLD Microvascular disease risk Insulin Resistance Beta-cell Function DeFronzo R. Diabetes Care. 1992;15:318-368. Haffner S, et al. Diabetes Care. 1999;22:562-568. Haffner S, et al. N Engl J Med. 1998;339:229-234. American Diabetes Association. Diabetes Care. 2003;26:S33-S50. Time (years) Slide courtesy of Dr. Bergenstal, International Diabetes Center. Park Nicollet Clinic Diabetic Kidney Disease: Natural Course NephSAP 2012

Albuminuria Management in CKD KDOQI 2012 Consensus statement Management of Albuminuria Treatments that produce a long lasting decrease in urinary albumin excretion may slow the progression of DKD even in the absence of hypertension. Recommendations: DM without HTN and without albuminuria: Recommend not using an ACEi or ARB for primary prevention of DKD. DM and UAE > 30 mg/g at high risk for DKD or its progression: Suggest treating with an ACEi or ARB. KDOQI Diabetic Guidelines: 2012 Update AJKD Vol 60, No 5, November 2012 DKD: Albuminuria Therapy RAS blockade Initial treatment of choice in patients with proteinuria (DKD and non DKD patients) ACEi or ARB Strictly speaking: ARB for DM2 patients with CKD (RENAAL and INDT) ACEi for DM1 pts with CKD. Some evidence that ARB may delay the development of DM in patients at risk. Collaborative Study Group. N Engl J Med 329: 1456 1462, 1993 Collaborative Study Group. N Engl Jj Med 345, 851 860, 2001 RENAAL. N Engl J Med 345: 861 869, 2001 IRMA2 trial and INDT trials J ClinHypertens13(4), 290 295, 2011 Diabetes Care 31(suppl 1): 12 54, 2008.

DKD: Dual RAS Blockade Combination therapy (ACEi + ARB) Meta analysis: Ann Intern Med 148: 30 48, 2008 improved reduction in proteinuria. Most studies were small, uncertain endpoints. ONTARGET (Telmisartan + Ramipril) Failed to show benefit with dual blockade. Showed increased incidence of AKI and hyperkalemia VA NEPHRON D study: ongoing 1850 pts, DM, CKD, Proteinuria. Losartan + lisinopril. No large RCT that have proven benefit of dual blockade. Currently, there is insufficient evidence to recommend dual RAS blockade in patients with diabetic kidney disease. DKD and HTN: Direct Renin Inhibitors Aliskiren (trade name Tekturna) 1. AVOID Trial DM 2 pts with microalbuminuria Aliskiren + Losartan lowered UMAR by an additional 20% in pts already taking losartan. 2. ALTITUDE Trial: DM and CKD cohort Aliskiren + [ACEi or ARB] Stopped early hypotension, hyperkalemia, and nonfatal strokes. ** Dual blockade with a direct renin inhibitor added to either an ACEi or ARB cannot be recommended. KDIGO 2012 guidelines **FDA (April 2012): Contraindicated J Clin Hypetension 11(2) pp. 89 93, February 2009 Heart Wire http://theheart.org/article/1331173.do

What if there is still proteinuria? Aldosterone Rc blockade (e.g., spironolactone) Mineralocorticoid receptors Expressed on many tissues There may be direct effects of aldo blockade on podocytes Inhibition of podocyte MR attenuates proteinuria. Addition of spironolactone to maximal ACEi significantly lowered proteinuria in patients with DM and proteinuria. Spironolactone + [ARB or ACEi] Lowered proteinuria more than ARB or ACEi alone. Increased risk of hyperkalemia Monitor. Consider low potassium diet, and or potassium wasting diuretics. J Am Soc Nephrol 20:2641 2650. 2009 Hormon Metab Res 37 (Suppl 1) 4 8, 2005 Diabetic Kidney Disease: Glycemic Control Hgb A1c lower than expected in patients with CKD. reduced RBC lifespan, transfusions, hemolysis, ESAs. Improved glycemic control Renal protection especially during early stages of DM1 and DM 2. Insufficient data to recommend a target Hgb A1c in patients with stage 3 5 CKD. Hyperglycemia (even brief) renal injury cumulative damage N Engl J Med 365: 2366 2376, 2011

Diabetes Management and CKD KDOQI 2012 Consensus statement Management of Hyperglycemia and General Diabetes Care in CKD Intensive treatment of hyperglycemic prevents elevated albuminuria and delays progression Attempts to achieve near normal glycemia may increase risk of severe hypoglycemia Recommendations: Target HgbA1c of ~7.0% to prevent or delay progression of microvascular complications of diabetes, including DKD. Not treating to a HgbA1c < 7.0% in patients at risk for hypoglycemia Suggest target HgbA1c be extended above 7.0% in individuals with co morbidities or limited life expectancy and risk of hypoglycemia. KDOQI Diabetic Guidelines: 2012 Update AJKD Vol 60, No 5, November 2012 DKD: Smoking Cessation Smoking: Risk factor for development and progression of DKD Smokers who quit slowing of DKD progression Diabetes Care 1994;17(2):126 131 Neph Dial Transplant 2000;15(10):1509 1511 Diab Res Clin Pract. 2009: 85, (1): 4 13 World J Diabetes 2012:3(12):186 195