Chronic Kidney Disease Identification and Management Amy L. Hazel, CNP Kidney & Hypertension Consultants

Chronic Kidney Disease One in 10 Americans have Chronic Kidney Disease

Chronic Kidney Disease Chronic Kidney Disease is most common in those > 70 years old

Chronic Kidney Disease Incidence of Chronic Kidney Disease is increasing most rapidly in people 65 years and older

Chronic Kidney Disease Kidney disease is the 8TH leading cause of death in the United States

Chronic Kidney Disease People with Chronic Kidney Disease are 16-40 times more likely to die than reach End-Stage Renal Disease

Chronic Kidney Disease The 1-year mortality for heart attack patients without identified Chronic Kidney Disease is 36% , compared with 51% for patients with stage 3 to 5 CKD

Chronic Kidney Disease Early detection and education can help prevent the progression of kidney disease to kidney failure

Chronic Kidney Disease Objectives Define Chronic Kidney Disease Classify the disease by Glomerulofiltration rate, and amount of proteinuria Discuss stages of disease and its risk factors Treatment in hypertensive and diabetic renal disease Consequences of disease Medications in ckd patient We will NOT be discussing Renal Replacement therapies including transplant Acute Kidney Injury

Chronic Kidney Disease KDOQI (Kidney Disease Outcomes Quality Initiative) 2002 National Kidney Foundation classification system Stages of Chronic Kidney Disease KDIGO (Kidney Disease: Improving Global Outcomes) Updated, more clearly defined (2004) Classified based on cause, GFR category and albuminuria category (2012)

Chronic Kidney Disease Defined Abnormalities in structure or function > 3 months with implications for health eGFR < 60 ml/min/1.73m A loss of half or more of the adult level of normal kidney function albuminuria or proteinuria Casts or blood in urine Structural Hydronephrosis, small kidneys, congenital kidneys, polycystic kidney disease History of kidney transplant

Chronic Kidney Disease What is GFR? GFR (glomerular filtration rate) is equal to the total of the filtration rates of the functioning nephrons in the kidney. In young adults it is approximately 120-130 mL/min/1.73 m2 and declines with age.

Chronic Kidney Disease MDRD (Modification of Diet in Renal Disease) Preferred method for estimating GFR using the 4-variable equation based on Serum Creatinine, age, gender, and ethnicity. Includes body surface area eGFRs per 1.73m2 May be the best estimate for eGFR in older population Current gold standard More accurate than measured creatinine clearance from 24-hour urine collections or estimated by the Cockroft-Gault formula

Chronic Kidney Disease Stages of disease Limitations of CR Age < 18 or >70 Gfr > 60 Extreme body size Severe malnutrition Paraplegia or quadriplegia Does not adjust for Hispanic or Asian populations Tends to overestimate gfr Urinary creatinine excretion is lower in ckd, therefore overestimating gfr from serum creatinine.

Chronic Kidney Disease Cockroft-Gault Formula Does not includes body weight, reflecting muscle mass….main determinant of creatinine generation. May overestimate individuals having ckd after age of 70 yrs, obese or edematous pts Less accurate than mdrd and ckd-epi

Chronic Kidney Disease CKD-Epidemiology Collaboration (CKD-EPI) Uses the 4 variables found in MDRD equation, with addition of serum cystatin C to provide more accurate eGFR than MDRD in gfr >60 May raise the number of older individuals with ckd CKD-EPI and MDRD Study equations can therefore be applied to determine level of kidney function, regardless of a patient’s size.

Chronic Kidney Disease To use the free GFR calculator on the NKF web site: Go to www.kidney.org/gfr To download NKF’s new GFR calculator to your smartphone: Go to www.kidney.org/apps

Chronic Kidney Disease Because of greater cardiovascular disease risk and risk of disease progression at lower eGFRs, CKD Stage 3 is sub-divided into Stages 3A (45–59 mL/min/1.73 m2) and 3B (30–44 mL/min/1.73 m2).

Chronic Kidney Disease Proteinuria Proteinuria (most important marker of disease progression) Ratio of the concentrations of urine albumin (mg/dl) to that of urine creatnine (g/dl) on a spot untimed specimen (or early morning?????) Mg albumin/g creatinine (UACR) Normal <30 mg albumin/g creatinine Microalbuminemia > 30-300 mg albumin /g creatinine Macroalbuminemia > 300 albumin/ g creatinine Ckd if 2 of 3 tests are abnormal

Chronic Kidney Disease Proteinuria Albuminuria Presence of excessive amounts of the protein albumin in urine Microalbuminuria UACR 2.5-25mg/mmol in men UACR 3.5-35mg/mmol in women Macroalbuminuria UACR > 25mg/mmol in men UACR > 35mg/mmol in women (Urinary creatinine excretion is influenced by muscle mass, urinary creatinine excretion higher in men, on average, than women) The preferred method: urinary albumin-to-creatinine ratio (UACR) in first void. Spot urine is acceptable if first void not practical.

Chronic Kidney Disease Proteinuria Presence of excessive amounts of proteins in urine Includes: albumin, low-molecular weight immunoglobulin's, lysozyme, insulin and microglobin Total protein (mg/dl) to creatinine (g/dl) on a spot urine sample Normal < 200 mg/g Urine pr mg/dl 200 Urine cr mg/dl 100 Ratio 200/100 = 2gm protein/24hours Increased excretion of protein leads to progression of ckd and increases cvd risks Albuminuria and proteinuria are related, but not interchangeable.

Chronic Kidney Disease Proteinuria Persistant microalbuminemia: Tx lipid disorders and /or htn Retest in 6mo Affect urinary albumin excretion UTI High protein diet Acute febrile illness Heavy exercise within 24 hrs Menstruation Drugs (NSAIDS, ACEI, ARB)

Chronic Kidney Disease Stage 1 and 2 new guidelines American College of Physicians 2013 Do not recommend screening for ckd in asymptomatic adults without risk factors for ckd False positive test results, disease labeling No benefit of early treatment Treat hypertension in stage 1-3 ckd with acei or arb No need to test urine for protein in adults with or without diabetes if currently taking acei or arb Manage elevated LDL in pt with stage 1-3 ckd

Chronic Kidney Disease Risk Factors Diabetes 44% of new cases of ckd Hypertension 28% of new cases of ckd Cardiovascular disease Obesity High cholesterol Lupus Family history of CKD UTI/urinary stones Systemic infections Recovery from Acute Kidney Injury (AKI) Exposure to certain drugs Socio-demographic groups Elderly minority population African American, Native American, Hispanic, and Asian. Low income/education

Chronic Kidney Disease Diabetic Nephropathy Diabetic Kidney Disease Glomerulosclerosis 5-7 yr after dx Hypertrophy and hyperfiltration in glomerulus Strict glycemic control ACEi ARB

Chronic Kidney Disease Diabetic Nephropathy Blood pressure control Goal Diabetic or Non diabetic with Albumin-to-creatinine ratio > 30 mg/g <130/80 Diabetic or Non diabetic with albumin-to-creatinine ratio < 30gm/g <140/90 Protein restriction, individualize Smoking cessation

Chronic Kidney Disease Diabetic Nephropathy Hypoglycemics Agents Sulfonylureas, biguanides, DPP-4 inhibitors, GLP-1 agonists, and insulin require dose adjustments All second generation sulfonylureas can be used in ckd pts Glyburide not recommended with crcl < 50% Glipizide, no adjustment

Chronic Kidney Disease Diabetic Nephropathy Hypoglycemic Agents Metformin Lactic Acidosis Avoid in gfr < 30 ml/min/1.73m2 Insulin Thiazolidinediones Decreased renal glucogenesis Decreased renal clearance of sulfonylureas

Chronic Kidney Disease Hypertensive Nephropathy Hypertensive Kidney Disease Both a cause and consequence of the disease Primarily: Inappropriate sodium reabsorption Activation of RAAS Erythropoietin administration RAS Extracellular fluid Calcified arterial tree Cardiovascular disease Antiplatelet agents are recommended BNP in gfr <60, interpret with caution

Chronic Kidney Disease Hypertensive Nephropathy Management RAAS blockade Reduce proteinuria Lowers systemic BP and intraglomerular pressure More difficult d/t increase in vascular resistance and increased blood volume Low sodium diet (DASH diet not recommended in CKD stage 3-5) Combination of ace/arb significantly slowed disease progression, greater reduction in proteinuria Use of non-dihydropyridine CCB have shown to decrease proteinuria (if failed ace/arb)

Chronic Kidney Disease Hypertensive Nephropathy Goals Diabetic or Non-diabetic with Albumin-to-creatinine ratio > 30 mg/g <130/80 Diabetic or Non-diabetic with albumin-to-creatinine ratio < 30gm/g <140/90 Delay progression of disease Reduce cardiovascular risk

Chronic Kidney Disease Hypertensive Nephropathy Diuretics Enhances antihypertensive therapy Decreasing tubular sodium reabsorption, increasing sodium excretion, reversing ECF volume expansion and lowering bp. Thiazides (qd) for gfr > 30 (stage 1-3) Loops (qd-bid) for gfr < 30 (stages 4 & 5) Potassium sparing diuretics Risk of hyperkalemia, esp with ACEI/ARB

Chronic Kidney Disease Complications Chronic Kidney Disease-Metabolic Bone Disorder (CKD-MBD) Systemic disorder Renal osteodystrophy Extraskeletal (vascular) calcification Increases in morbidity and mortality of ckd pts Abnormalities in Calcium Phosphorus Parathyroid Hormone Vitamin D 25(OH)D 1,25(OH)2D Osteoporosis (ckd 1-3) versus renal osteodystrophy (later stages)

Chronic Kidney Disease Complications GFR falls Rise in phosphorus decrease in calcium decreased production of calcitriol Triggers increase in Parathyroid hormone (PTH) production Increased absorption of Phosphorus in kidneys Normalize phosphorus with high PTH

Chronic Kidney Disease Complications Treat complications High phosphorus Low Phosphorus diet Phosphorus Binders Correct low Vitamin D levels Ergocalciferol/cholecalciferol Watch for high Calcium Active Vitamin D to suppress PTH Seen more in late stages of disease

Chronic Kidney Disease Complications Anemia (hgb < 13g/dL in males, < 12g/dL in females) A decline in production of erythropoietin (EPO) Not measured, assumed Check red cell indices, absolute reticulocyte count, vitamin B12 and folate levels, and iron panel Goal Hemoglobin??? Serum transferrin saturation (TSAT) > 30% Serum ferritin <500ng/ml Acute phase reactant, elevated with infection/inflammation

Chronic Kidney Disease Complications Anemia Treatment Iron therapy Most common cause of anemia in ckd Oral vs IV Erythropoiesis-stimulating Agents (ESA) Prevent need for transfusions Improve QOL? Based on weight Not recommended in hgb > 10g/dL Treat <10g/dL on individual basis

Chronic Kidney Disease Complications Metabolic acidosis Result of decreased production of ammonia by the kidney Seen in stages 3-5 Treatment: supplement Bicarbonate Complications Bone loss Anorexia Hypoalbuminemia Insulin resistance Muscle wasting

Chronic Kidney Disease Diet Sodium Restriction reduces blood pressure and may reduce albuminuria Dash diet, not rec. for ckd stage 3-5 High sodium diet limits effectiveness of ACEi/ARBs Potassium Low: loop diuretics High: Common in stage 4/5 & aldactone/ACEi/ARB/BB/NSAIDS Diet? Salt substitutes? Constipation Treatment Kayexlate education

Chronic Kidney Disease Diet Phosphorus High levels contribute to vascular calcification High phosphorus is risk factor for cvd high phosphorus leads to a more rapid decline in kidney function Phosphate salts added to processed foods in form of additives and preservatives These are > 90% absorbed versus 40-60% absorption from organic phosphorus (ie: beans, peas, nuts) Beverages (clear) Nutrition labeling Treatment: Low phosphorus diet, phosphorus binders with meals

Chronic Kidney Disease Diet Protein Restriction should not be used in severe ckd Restriction among selected patients Restriction, controversial 0.6-0.8g/kg per day Provide a small reduction in rate of decline of gfr Follow body weight, serum albumin, pre-albumin in advanced ckd Monitored by dietician

Chronic Kidney Disease & Medications Pharmacokinetics Bioavailability of oral meds can be increased or decreased Changes in gastric pH Increases in metabolism Decreases in absorption

Chronic Kidney Disease & Medications Pharmacokinetics Distribution affected by hypoalbuminemia, uremia and alterations in protein binding sites Possibility leading to toxicity of unbound drug

Chronic Kidney Disease & Medications Pharmacokinetics Metabolism of drugs may be increased, decreased or unchanged. Reduced activity of cytochrome P-450

Chronic Kidney Disease & Medications Pharmacokinetics Elimination of drugs may cause accumulation of drug and prolong its action, active metabolites may have toxic effects

Chronic Kidney Disease & Medications Diabetic meds Sulfonylureas metabolized by liver, however GLYBURIDE AND GLIMEPIRIDE produce active metabolites and may contribute to hypoglycemia. Glyburide not recommended. Glipizide, no decrease needed. Biguinides, metformin eliminated unchanged by kidney. Contraindicated risk of lactic acidosis. Hold in women cr >1.4 men 1.5mg/dl per package insert Inctretins are eliminated by kidney, so not recommended in crcl < 30ml/min Insulin, with 40-50% elimination by kidneys, dose reductions are recommended

Chronic Kidney Disease & Medications Statins Metabolized by liver, however, active metabolites renally eliminated. Not atorvastatin (lipitor) Inc risk of myopathy with inc doses and declining gfr

Chronic Kidney Disease & Medications Antibiotics (ATN) Most penicillins, cephalosporins, and all fluroquinolones except moxifloxacin are eliminated by kidneys. Require reduction Aminoglycosides (gent, tobra) can cause nephrotoxicity especially when used with vancomycin Nitrofurantoin (macrobid). Excreted by kidneys. contraindicated in crcl <60 Sulfamethoxazole-trimethoprim (bactrim). Nephrotoxicity. Dose reduction of ½ in CrCl 15-30 and avoid in < 15.

Chronic Kidney Disease & Medications Analgesics (prerenal) NSAIDS Inhibit the synthesis of prostaglandin leading to vasoconstriction and reduced renal blood flow to kidneys Cause a decline in gfr and impaired sodium, water, potassium and hydrogen excretion COX-2 inhibitors work similarly to NSAIDS in that they inhibit synthesis of prostaglandin production

Chronic Kidney Disease & Medications Antihypertensives All ACEi have some renal elimination. Use lower doses. High risk for high k+, increase in serum creatinine and hypotension All ARBs are metabolized by liver, however, watch k+, serum creatinine and blood pressure in ckd BetaBlockers Many eliminated by kidney. Dose adjustments are recommended and follow hr and blood pressure

Chronic Kidney Disease & Medications Diuretics Thiazide are recommended in those with gfr >30 Loop are recommended in those with gfr <30 Potassium-sparing should be used with caution in those with gfr < 30

Chronic Kidney Disease & Medications Gabapentin (neurontin). Primarily removed by the kidneys. Use with caution. Stage 3 400-1400 in two divided doses Stage 4 200-700 once daily Stage 5 100-300 once daily Gout medications CKD patient at increased risk for hypersensitivity reactions from drug. Use of low dose colchicine or xanthine oxidase inhibitors (uloric, allopurinol) Inject glucocorticoids for flare Avoid NSAIDs

Chronic Kidney Disease & Medications Cancer therapies (ATN) Toxicity, impaired gfr Immunosuppressive agents (ATN) Antithrombotics Many not studied in renal population Diagnostic agents (ATN) Use of low osmolar contrast (but still problem with high risk pts) less nephrotoxic Hold potentially nephrotoxic agents before and after procedure Adequately hydrate with saline before, during and after procedure Avoid gadolinium-containing contrast in gfr < 15

Chronic Kidney Disease & Medications Over-the-counter Medications Pseudoephedrine Nsaids Magnesium Bismuth Phosphorus-containing enemas Sodium bicarbonate PPI Zantac Calcium-based reflux meds Salt substitutes Herbal remedies and dietary supplements

Questions? Thank You!

References Willems, J.M, et al Performance of Cockroft-Gault, MDRD, and CKD-EPI in estimating prevalence of renal function and predicting survival in the oldest old. BioMed Central 2013 National Kidney and Urologic Diseases Information Clearinghouse Matzke, G. R, et al. Drug dosing consideration in patients with acute and chronic kidney disease-a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney International 2011 Qassem, A. Screening, Monitoring, and Treatment of Stage 1 to 3 Chronic Kidney Disease: A clinical practice guideline from the clinical guidelines committee of the American College of Physicians. American College of Physicians. 2013 Perazella, M. A. Core Curriculum in Nephrology. Toxic Nephropathies: Core Curriculum 2010. American Journal of Kidney Disease. Feb 2010 Zuber, K., et al. Medication dosing in patients with chronic kidney disease. Journal of the American Academy of Physician Assistants. 2013 Liles, A. M., Medication considerations for patients with chronic kidney disease who are not yet on dialysis. Nephrology Nursing Journal, May-June 2011 Johnson, D. W., Chronic kidney disease and measurement of albuminuria or proteinuria: a position statement. Medical Journal of Australia, August 2012 Eknoyan, G, et al. Proteinuria and other markers of chronic kidney disease: A position statement of the National Kidney Foundation (NKF) and the National Institute of Diabetes and Kidney Diseases (NIDDK) Bakris, G. L., Slowing Nephropathy Progression: Focus on Proteinuria Reduction. American Society of Nephrology, 2008 James, P. A., 2014 Evidence-Based Guidelines for the Management of High Blood Pressure in Adults: Report From the Panel Members Appointed to the Eight Joint National Committee (JNC 8). Journal of American Medical Association, 2013 National Kidney Foundation: Kidney Disease Outcomes Quality Initiative Guidelines Summary of Recommendation Statements. Kidney Disease International Supplement, 2012 Ferrari, P. Serum iron markers are inadequate for guiding iron repletion in chronic kidney disease. American Society of Nephrology, 2011 Kopple, J. D., Risks of chronic metabolic acidosis in patients with chronic kidney disease. Kidney International, Supplement, 2005.