Chronic Kidney Disease DR. SANJAY PANDEYA MD. FRCPC.

Objectives Review CKD and its implications for the family physician Review the relevance of CKD and ESRD, its complications and management issues in the patient on dialysis for the family physician

CKD Classification Stage Description GFR 1 Kidney Damage with normal or increased GFR >=90 2 Kidney Damage with mild decrease GFR 60-89 3 Moderate decrease in GFR 30-59 4 Severe decrease in GFR 15-29 5 Kidney Failure <15 or RRT

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Detection Test with egfr and urine ACR If egfr < 60, repeat in 3 months or sooner If urine ACR > 3 mg/mmol, repeat 1-2x over next 3 months Always consider reversible factors

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Detection Box C: If egfr > 60 and urine ACR < 3 mg/mmol Patient does not have CKD Test annually Box A: If egfr < 30 and/or urine ACR > 60 Patient has CKD For low egfr GFR: CBC, lytes, Ca, Phos, Alb, PTH, urine R+M ACR: Urine R+M, electrolytes Refer to Nephrologist

Detection Box B: If egfr 30-59 and/or urine ACR 3-60 Patient has CKD See Management box (to come) Check urine R+M, lytes Follow egfr, UACR q6 months If egfr stable x 2 years, check annually Refer to Nephrologist egfr < 60 and decline > 5 ml/min within 6 months * egfr < 30 or UACR > 60 egfr <45 and urine ACR 30-60 BP control K+ disorders, RBC casts or hematuria (>20 RBC/hpf)

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Manage CV Risk Factors Lifestyle modification, smoking cessation Lipid management for patients with CKD If with diabetes treat with a statin If without diabetes, age 50 treat with a statin If without diabetes, age <50, with risk such as having known coronary artery disease, prior stroke, or 10-year Framingham risk >10% treat with a statin (+/- ezetemibe if egfr<60) see KDIGO guidelines for further details For patients with diabetes, target HbA1c to appropriate level (see CDA guidelines)

Manage Minimize further kidney injury If possible, avoid nephrotoxins such as NSAIDs, IV and intra-arterial contrast, etc. (if egfr < 60) If contrast is necessary, consider oral hydration, withholding diuretics Sick Day Medication List (SADMAN) Sulfonylureas ACEI Diuretics Metformin ARB NSAIDS

Manage Slow Progression Measures BP and RAAS blockade (repeat creatinine and potassium 2 weeks after initiation of ACEI or ARB use): If with diabetes, target BP < 130/80, otherwise target BP < 140/90 * If with diabetes and with ACR > 3, start use of an ACEI or ARB as first-line therapy. If BP already < 130/80, use ACEI or ARB cautiously, monitoring for signs and symptoms of hypotension If without diabetes, ACR > 30 and BP > 140/90, start use of an ACEI or ARB as first-line therapy

BP CONTROL AND REDUCING PROTEINURIA

Recommended Office BP Treatment Targets Treatment consists of health behaviour ± pharmacological management Population SBP DBP High Risk 120 NA Diabetes < 130 < 80 All others* < 140 < 90 * Target BP with AOBP < 135/85 16

Cardio-renal continuum:the ultimate treatment goal is to reduce mortality Regress Retard Prevent Macroalbuminuria (>300 mg/d) Worsening nephropathy Reduce Microalbuminuria (30-300 mg/d) Mortality Adapted from Dzau VJ, et al. Circulation. 2006;114;2850-2870.

Studies of Primary Prevention of Microalbuminuria (MAU) Regress Retard Prevent Macroalbuminuria Worsening nephropathy Reduce Microalbuminuria ROADMAP (olmesartan) BENEDICT (trandolapril) ADVANCE (perindopril) DIRECT (candesartan) MICRO-HOPE (ramipril) Mortality Adapted from Dzau VJ, et al. Circulation. 2006;114;2850-2870.

Studies of Secondary Prevention of Micro- and Macroalbuminuria Regress Retard Prevent Macroalbuminuria Worsening nephropathy Reduce Microalbuminuria Mortality IRMA-2 (irbesartan) ADVANCE (perindopril) ONTARGET (telmisartan, ramipril) TRANSCEND (telmisartan) Adapted from Dzau VJ, et al. Circulation. 2006;114;2850-2870.

Studies of Reduction in Risk of Renal Events and Worsening Nephropathy Regress Retard Prevent Macroalbuminuria Worsening nephropathy Reduce Microalbuminuria IDNT (irbesartan) IRMA-2 (irbesartan) RENAAL (losartan) ADVANCE (perindopril) ONTARGET (telmisartan, ramipril) TRANSCEND (telmisartan) ACCOMPLISH (benazapril, amlodipine) ROADMAP (olmesartan) Mortality Adapted from Dzau VJ, et al. Circulation. 2006;114;2850-2870.

ACE-inhibitor in T1DM with Macroalbuminuria Reduces Renal Outcomes Lewis EJ et al. N Engl J Med 1993;329:1456-62. guidelines.diabetes.ca 1-800-BANTING (226-8464) diabetes.ca Copyright 2013 Canadian Diabetes Association

Reduced Risk of Renal Events Study Treatment Renal events vs control (RRR) IDNT 1 (n=1715) Irbesartan 300 mg vs placebo 20%* (P=0.02) RENAAL 2 (n=1513) IRMA 2 3 (n=590) ADVANCE 4 (n=11240) ONTARGET 5 (n=25620) TRANSCEND 6 (n=5927) Losartan 50-100 mg vs placebo 16%* (P=0.02) Irbesartan 150 mg vs placebo -44%**, (P=0.05) Irbesartan 300 mg vs placebo 68%**, (P<0.001) Perindopril 4 mg / Indapamide 1.25 mg vs placebo 21%** (P=0.006) Telmisartan 80 mg vs ramipril 10 mg +0% (NS) Telmisartan 80 mg vs placebo +29% (NS) Primary Endpoint? Yes, as a composite Yes, as a composite * Composite of doubling of serum creatinine, end-stage renal disease, and all-cause mortality; ** nephropathy Adjusted for baseline levels of microalbuminuria and the BP achieved during the trial; Composite renal outcome of dialysis or doubling of serum creatinine, changes in estimated glomerular filtration rate (GFR), and changes in albuminuria 1. Lewis EJ, et al. N Engl J Med 2001;345(12):851-60. 4. de Galan BE, et al. J Am Soc Nephrol 2009;20(4):883-92. 2. Brenner BM, et al. N Engl J Med 2001; 345:861-869. 5. Mann JF, et al. Lancet 2008;372(9638):547-53. 3. Parving HH, et al. N Engl J Med 2001;345(12):870-8. 6. Mann JF, et al. Ann Intern Med 2009;151(1):1-10. Table adapted from García-Donaire JA, et al. Blood pressure.2011; 20: 322 334. No No; secondary Yes, as a composite Yes, as a composite

Lowering Blood Pressure Reduces Renal Events in Type 2 Diabetes n =11,140 ADVANCE Collaborative group J Am Soc Nephrol, 2009.

Studies of Reduction in Risk of Mortality Regress Retard Prevent Macroalbuminuria Worsening nephropathy Reduce Microalbuminuria IDNT (irbesartan) RENAAL (losartan) IRMA-2 (irbesartan) DIRECT (candesartan) ADVANCE (perindopril) ROADMAP (olmesartan) ONTARGET (telmisartan, ramipril) TRANSCEND (telmisartan) ACCOMPLISH (benazapril, amlodipine) Mortality Adapted from Dzau VJ, et al. Circulation. 2006;114;2850-2870.

Cochrane Meta-analysis: Reduction of All-Cause Mortality 26 Significant effect for ACE inhibitors vs. placebo Treatment Mortality RRR vs placebo ACE inhibitors* -16% [0.73, 0.97] Studies included in the analysis: ADVANCE, BENEDICT, EUCLID, HOPE, Kvetny 2001, RASS, Ravid 1998, Tuominen 1998. No significant effect for ARBs vs. Placebo ARB +12% NS Studies included in the analysis: DIRECT, Perrin 2008, RASS, ROADMAP, TRANSCEND. No significant effect for ACE inhibitors vs. ARBs ACE inhibitors -2% NS Studies included in the analysis: ON-TARGET, RASS 2002 Adapted from Lv J, et al. Cochrane Database of Syst Rev. 2012;12:CD004136. doi:10.1002/14651858.cd004136.pub3.

GLYCEMIC CONTROL

When to Consider Other Causes of CKD Known duration of DM >5 years DM: Diabetes mellitus; egfr: Estimated glomerular filtration rate guidelines.diabetes.ca 1-800-BANTING (226-8464) diabetes.ca Copyright 2013 Canadian Diabetes Association 30

DCCT: Reduction in Albuminuria Primary Prevention Secondary Intervention 34% RRR (p<0.04) 43% RRR (p=0.001) 56% RRR (p=0.01) Solid line = risk of developing microalbuminuria Dashed line = risk of developing macroalbuminuria RRR = relative risk reduction CI = confidence interval The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986.

EDIC: Early Glycemic Control Reduces Long-term Risk of Impaired GFR Risk reduction with intensive therapy 50% (95% CI 18-69; p=0.006) DCCT/EDIC Research Group. N Engl J Med 2011;365:2366-76.

UKPDS: Post-trial Monitoring Legacy Effect After median 8.5 years post-trial follow-up Aggregate Endpoint 1997 2007 Any diabetes related endpoint RRR: 12% 9% P: 0.029 0.040 Microvascular disease RRR: 25% 24% P: 0.0099 0.001 Myocardial infarction RRR: 16% 15% P: 0.052 0.014 All-cause mortality RRR: 6% 13% Holman R, et al. N Engl J Med 2008;359. P: 0.44 0.007

Metformin (K/DOQI guidelines) 34 egfr < 30 = STOP egfr 30-45 = REDUCE dose Metformin does NOT cause kidney problems egfr 45 = USE FULL DOSE egfr = estimated glomerular filtration rate in ml/min/1.73m 2 National Kidney Foundation. KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 update. Am J Kidney Dis 2012;60(5):850-86.

Prevention of Diabetic Nephropathy Optimal glycemic control in type 1 and type 2 diabetes has been shown to reduce the development and progression of nephropathy

LIPID LOWERING THERAPY

Lipid reduction and the progression of renal disease Fried, L, Kidney Int 59:260-269,2001

Reducing LDL cholesterol with simvastatin 20mg and ezitimibe 10 mg/day in CKD patients stage 3-5, reduced adverse cardiovascular but not renal events over 4.9 years Lancet 2011; 377: 2181 92

Lipid-Lowering in HD patients 4D Trial 1255 DM patients on HD; Atorvastatin v. placebo Avg decline in LDL 3.1 to 1.9 No difference at 4y Post-hoc analysis reduction in those with LDL > 3.76 AURORA 2776 HD patients not on statin; Crestor 10 mg v. placebo No difference in composite CV outcome at 3.8 y SHARP 3023 pts; 1/3 on HD; Simvistatin+Ezetrol v. placebo Trend toward NS in reduction in atherosclerotic events

Lipids Recommendations Lipid management for patients with CKD If with diabetes treat with a statin If without diabetes, age 50 treat with a statin If without diabetes, age <50, with risk such as having known coronary artery disease, prior stroke, or 10-year Framingham risk >10% treat with a statin (+/- ezetemibe if egfr<60) see KDIGO guidelines for further details

ANEMIA

Anemia in CKD has multiple causes insufficient erythropoietin iron deficiency chronic inflammation hyperparathyroidism blood loss ACEi/ARB aluminum toxicity other causes of anemia McGonigle, KI, 25:437-444, 1984

Hemoglobin (g/dl) 15 14 13 Evolution of Anemia in CKD EPO level (mu/ml) 100 12 11 Expected EPO levels 50 10 30 9 8 20 7 N= 6 5 59 29 18 18 34 18 100-70 70-40 40-25 25-15 15-10 <10 Creatinine Clearance (ml/min) 10 Adapted from Radtke HW et al Blood 1979;54:877 and Erslev AJ. N Engl J Med 1991;324:1339

Hemoglobin targets for CKD revised CHOIR: RCT to Hb 11.3 v 13.5 in 1432 with GFR 15-50 Adverse CV outcomes in 13.5% (Hb 11.3) v 17.5% (Hb 12.6) No change in QOL measures Singh et al, NEJM 2006; 355:2085-98 CREATE: RCT to Hb 10.5-11.5 v 13-15 in 603, GFR 15-35 No difference in time to first CV event (but underpowered) Better QOL (vitality score SF36) in high Hb group Drueke et al NEJM 2006:355:2071-84 TREAT: DM RCT in 4000 CKD (GFR 20-60), DM2, Hb < 11; Intervention: darbepoietin v placebo; Goal: Hb 13 g/dl or rescue if < 9 g/dl; Outcome: all cause mortality, CV morbidity no different but higher rate of stroke and thrombolic events JASN 21: 2 6, 2010.

ESA Treatment prior to initiating treatment: control BP (< 160/90 mmhg) ensure adequate B12, folate, Fe (% saturation > 20) CSN Target: hemoglobin 95-115 g/l (as per symptoms) Ongoing monitoring

Bicarbonate Supplementation

Metabolic Acidosis CKD Association (AASK) trial, renal event rates were approximately three times higher in patients whose serum bicarbonate was <20 as compared with >25 meq/l. After controlling for other factors, a serum bicarbonate of 28 to 30 meq/l was associated with the lowest risk for renal events. (UMC) 5422 patients, those whose serum bicarbonate was 22 as compared with 25 to 26 meq/l had a significantly increased risk for progression of renal disease (CRIC) Among 3939 patients in the CRIC study mentioned above, lower serum bicarbonate was significantly associated with a higher risk of (adjusted hazard ratio 0.97 for every 1 meq/l lower serum bicarbonate)

Metabolic Acidosis Mortality Association veterans with non-dialysis dependent CKD, those whose serum bicarbonate was <22 meq/l had a significantly higher risk of mortality as compared with those whose bicarbonate was 26 to 29 meq/l CKD stages 2-4, the four-year mortality rate was higher among those with a serum bicarbonate less than or equal to 22 as compared with greater than 26 meq/l (approximately 3 versus 2 percent) = NS maintenance hemodialysis, the two-year mortality rate was lowest among those whose serum bicarbonate was 17 to 19 meq/l normal bicarbonate concentrations usually reflect reduced protein intake and malnutrition

Bicarbonate Supplementation Bicarbonate supplementaion slows progression of CKD (JASN 2009) N=134, egfr 16-30, baseline HCO3 16-20mEq/L Rx: 600 mg tid (1.8 g or about 0.4 teaspoon baking soda a day) x 2yr; Outcome: lower mean rate of decline of creatinine clearance compared with the control group (1.88 versus 5.93 ml/min/1.73 m 2 per year 6.5% v 33% reached ESRD Daily oral sodium bicarbonate preserves glomerular filtration rate by slowing its decline in early hypertensive nephropathy (Kidney International 2010) RCT n=120 hn + albuminuia, egfr 75.6 ml/min, S.bicarbonate 26. Rx: NaHCO3 v NaCl v placebo: 0.5 meq/kg (2.9g or about 0.6 teaspoon baking soda a day) x 5 yr Outcome: egfr 67.6 v 65.2 v 64.0 ml/min (-1.5 v. 2 v 2.1 ml/min/1.73m2)

Bicarbonate Supplementation HCO3 < 22 mmol/l associated with higher risk of worsening renal function. in part to the adaptive response of surviving nephrons to the loss of their neighboring nephrons an increase in ammonia production Activation of the complement system, RAAS and endothelin-1 Rx: maintain bicarbonate levels > 22 mmol/l No evidence of deleterious effects

Metabolic Bone Disease

Hyperphosphatemia A tendency toward phosphate retention begins early in renal disease due to the reduction in the filtered phosphate load phosphate retention is intimately related to the common development of cardiovascular disease risk in chronic kidney disease

CVD Arch Intern Med. 2007;167:879-885 West et al, CJASN 2010; 5:S41-47

Vit D 2 or D 3 reduce P in diet< 1 g/day Vit D 1,25 sterols P binders Ca carbonate Ca acetate sevelamer lanthanum carbonate nicotinamide PTH X Calcimimetics

Prevalence of CAC with CKD not on Dialysis

Hyperphosphatemia Rx Dialysis Patient Phos goal 1.13 1.78 Stage 3 to 5 (not on dialysis) Phos goal normal Dietary restriction Phosphate binders Aluminum based avoided except short term 4 weeks Calcium based Non-Al, Non-Ca based (especially in hypercalcemic0 Renagel Sevalamer Fosrenol Lanthanum Carbonate

Hyperparathyroidism - Rx In addition to therapy of hyperphosphatemia Vitamin D Rx initiated if vitamin D deficiency exists Low levels of 25(OH)D; cholecalciferol (D3) Vitamin D analogues calcitriol (Rocaltrol) alfacalcidiol (One-Alpha) Other Calcimimetics (Cinacalcet) and EVOLVE Increased incidence of achieving target PTH, Phos, Ca But cinacalcet did not decrease the risk of death or major cardiovascular events among hemodialysis patients Parathyroidectomy

Protein intake

Other Considerations

Dialysis Modality Dialysis Modality HD v. PD Independent/Home Modality

Other Considerations Dialysis Access AVF v. AVG v. Tunnelled Catheter preferred type of access is a native fistula because a mature fistula has the lowest risk of complications, lowest need for intervention, and the best long-term patency Vein preservation measures

Transplantation Transplant options DD v LD Extended Criteria Paired Exchange High Sensitivity (National)

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