Chronic Kidney Disease

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Chronic Kidney Disease

  1. 1. MANAGEMENT OF THE PATIENT WITH CHRONIC KIDNEY DISEASE Medicine Housestaff Conference 2/13/2009 Margaret A Kiser MD PhD,
  2. 2. Outline  Chronic Kidney Disease  Definitions  Epidemiology  Screening for CKD  Treating Complications of Advanced CKD  Hypertension  Control of volume  Alterations in bone metabolism  Anemia  Nutrition  Hyperkalemia  Suggested K-DOQI action plan based on disease severity  When to refer and why  Slowing Progression of CKD  Evidence supporting antihypertensive use  Cardiovascular Risk Modification  Getting the word out
  3. 3. What is Chronic Kidney Disease?
  4. 4. Defining CKD  Kidney damage for 3 months as defined by structural or functional abnormalities of the kidney, with or without decreased GFR, manifest by either:  Pathological abnormalities; or  Markers of kidney damage, including abnormalities in the composition of the blood or urine, or abnormalities in imaging testing  Glomerular Filtration Rate (GFR) < 60 ml/min/1.73 m2 for 3 months, with or without structural kidney damage
  5. 5. Estimates of U.S. Chronic Kidney Disease Population in 2000 19,000,000 Chronic Kidney Disease 372,000 80,000 Dialysis Transplant
  6. 6. Stages of CKD CKD Continuum “CKD” ESRD 1 2 3 4 5 6 Kidney Mild Moderate Severe Kidney RRT Damage GFR GFR GFR Failure 90 80 70 60 50 40 30 20 <15 GFR (mL/min/1.73 m2) Proposed NKF-K/DOQI Guidelines. NKF Clinical Nephrology Meetings 2001; Orlando, Fla.
  7. 7. Prevalence of CKD GFR Prevalence in US Pop.* Stage Description (mL/min/1.73 m2) N (1,000s) % 1 Kidney damage > 90** 10,259 5.8 2 Mild GFR  60 – 89** 5,300 – 7,100 3–4 3 Moderate GFR  30 – 59*** 7,553 3.3 4 Severe GFR  15 – 29 363 0.2 5 Kidney failure < 15 or dialysis 300 0.1 12.4 – 13.4 *Population of 177 million adults age over 20 ** with presence of proteinuria or hematuria +/- structural changes *** do not need proteinuria or hematuria, just GFR <60
  8. 8. AGE AND RACE Point prevalence of ESRD Caucasian Hispanic Native African American American 1151/million 2243/million 2669/million 4863/million  Further, African Americans develop ESRD at a younger age 55.8 vs 62.2 yo  Although only 12.6% of the US population, African Americans constitute 50% of the ESRD population USRDS 2007 Annual Report AJKD 51, Suppl 1, Jan 2008
  9. 9. Familial Influences  Inherited Nephropathies  Family history is a strong risk factor for diabetic nephropathy  In all ethnic groups studied to date diabetic siblings of pts with ESRD 2/2 DM were at markedly increased risk of developing ESRD.  Particularly common in African Americans with an increased incidence rate of 4-25 fold greater than Caucasians AJKD 2008, 51 (1), 29-37
  10. 10. Etiology of Chronic Kidney Disease Other 20% Diabetes Diabetes 43% HTN GN GN 12% Other HTN 25% USRDS 2001
  11. 11. Identifying patients at risk: National Kidney Foundation Recommendations (KDOQI)  Individuals at increased risk for CKD should be tested at the time of health evaluations to determine if they have CKD. This should include patients with:-  DM  HTN  Autoimmune diseases  Chronic systemic infections  Recovery from acute renal failure  Age > 60yrs  Family history of kidney disease  Exposure to drugs or procedures associated with an acute decline in kidney function  Kidney donors and transplant recipients (AJKD, 39, 2002, pS214)
  12. 12. Relationship of Serum Creatinine to GFR
  13. 13. Estimation of GFR  GFR can be assessed by the renal clearance of a substance Clearance of substance X (Cx) = UxVx/Sx Recall GFR * Sx = UxVx (amount filtered = amount excreted) Cx = UxV/Sx Cx = GFR  Two important assumptions:  Marker neither secreted or absorbed  Steady state  Examples of markers: inulin, iothalamate, iohexol, serum creatinine, cystatin-C
  14. 14. Calculation of GFR  Methods of calculation  Cockcroft-Gault formula  MDRD formula/modified MDRD
  15. 15. The Cockcroft-Gault calculation GFR ml/min/1.73m2 = (140-age) x Lean BW Kg 72 x S creatinine mg% ( x 0.85 for Females )
  16. 16. MDRD GFR  MDRD GFR Formula* 170 x [SCr]-0.999 x [Age]-0.176 x [0.762 if female] x [1.180 if black] x [Alb]+0.318  Modified MDRD Formula 186.338 x [SCr]-1.154 x [Age]-0.203 x [1.212 if black] x [0.742 if female] (A calculator may be found at www.hdcn.org) *From Levey et al, 1999 Ann Intern Med 130: 461-470
  17. 17. 84 F 22 M 66 M 66 F • Wt (kg) 45.5 104.5 77.2 71.8 • Screat 1.2 1.2 1.2 1.2 • eGFR 26.9 142.7 66.1 52.3 (Calculated with Cockcroft-Gault)
  18. 18. Urine Protein / Creatinine Ratio  Based on the assumption that in the presence of stable GFR, urine creatinine and protein excretion constant  Ginsberg et al first demonstrated a strong correlation between single Urine P/C and 24 h urine in 46 ambulatory patients at a single center, r=0.97  Important caveats  Lean body mass  Timing of urine collection Relationship of spot and 24 urine protein Group A: Low creatinine excretion, slope=1.11 Group B: Intermediate Cr excretion, slope=0.97 Group C: High Cr excretion, slope = 0.77
  19. 19. Fig 1 Correlation between ln spot morning urine protein:creatinine ratio and log 24 hour urinary protein in 177 non-diabetic patients with chronic nephropathies and persistent clinical proteinuria
  20. 20. Physiologic Changes in Chronic Kidney Disease  Increased single nephron GFR  Afferent arteriolar vasodilation  Intraglomerular hypertension  Loss of glomerular permselectivity  Inabilty to appropriately dilute or concentrate the urine in the face of volume challenge
  21. 21. Anatomic and Histologic Features Due to Glomerular Hypertension  Glomerular hypertrophy  Focal segmental glomerulosclerosis with hyalinosis  Interstitial fibrosis  Vascular sclerosis  Epithelial foot process fusion
  22. 22. Pathogenesis of Secondary Glomerulosclerosis Primary Insult Nephron Mass Glomerular Sclerosis Glomerular Volume and and Hyalinosis Glomerular Hypertension Epithelial Cell Density and Foot Process Fusion Proteinuria
  23. 23. Hypertension in CKD
  24. 24.  Recommendations for Anti-hypertensives in Patients with Chronic Kidney Disease  Treatment is indicated at any stage of the disease  Use drugs that lower glomerular capillary pressure (ACE inhibitors, ARB, verapamil and diltiazem)  Goal is to keep the blood pressure < 130/80 mmHg (< 120 SBP in DM)
  25. 25. Effects of Various Anti-hypertensives on Glomerular Capillary Pressure Afferent Efferent Arteriole Arteriole ACE-I Pressure Vasoconstrict Vasodilate Vasodilate Pressure ARB Dihydropyridines Verapamil Nifedipine Diltiazem Felodipine Amlodipine
  26. 26. Number of Medications to Achieve Goal BP in 5 Trials of DM/Renal Disease UKPDS (<150/85 mm Hg) 2.7 ABCD (< 75 mm Hg DBP) 2.8 MDRD (<92 mm Hg MAP) 3.6 HOT (<80 mm Hg DBP) 3.3 AASK (<92 mm Hg MAP) 3.8 0 1 2 3 4 Number of BP Meds Bakris. J Clin Hypertens 1999;1:141.
  27. 27. A Hierarchy of Agents ACE-I More Preferred ARB -Blockers Thiazide Diuretics Vasodilators - Blockers Central Agents CCB’s Less Preferred
  28. 28. Volume Management-Diuretics % Filtered Na+ Site of Action Diuretic Excreted Na+-K+-2Cl- carrier Furosemide in Loop of Henle Bumetanide 20 % Torsemide Ethacrynic acid Na+-Cl- carrier Thiazides 3-5 % in the distal tubule Metolazone Na+ channel in the Amiloride 1-2 % cortical collecting Triamterene duct Spironolactone (indirect)
  29. 29. Natriuretic Response to Furosemide at Different Levels of Renal Function GFR 150 ml/min GFR 15 ml/min 1250 mEq 125 mEq 250 mEq 25 mEq
  30. 30. Diuretic Tolerance  Type I: Short-term  Decrease in the response to a diuretic after the first dose  Teleologically-- appropriate response to volume depletion  Type II: Long-term  Hypertrophy of distal nephron segments allowing greater sodium resorption
  31. 31. Algorithm for Diuretic Use Renal Insufficiency CrCl < 50 •Loop Diuretic •Determine Effective Dose: 5-10X Usual Dose •Administer as Frequently as Necessary ADD Thiazide According to CrCl < 20ml/min 20-50 > 50ml/min 50-100mg/ 50-100mg/ 25-50mg/ day day day From Brater DG Add Distal Diuretic Drug N Eng J Med 1998;339:387
  32. 32. Alterations in Bone and Mineral Metabolism
  33. 33. Hyperparathyroid Related Bone Disease Pi Ca2+ + Acidosis Impaired Absorption PTH Renal Mass + 1-alpha-hydroxylase 1-alpha-hydroxylase 25(OH)D3 1,25(OH)2D3 Osteitis Fibrosa Cystica
  34. 34. Reduced Renal Mass GFR < 65 Decreased 1,25-D <40 Hyperphosphatemia Hypocalcemia <25 Increased PTH Secretion
  35. 35. Calcium and Phosphorus Balance: National Kidney Foundation Recommendations (KDOQI)  In addition, it has become clear that CKD patients have a nutritional deficiency of 25-OH Vitamin D which itself leads to an increase in PTH secretion  Levels of 25-OH D should be measured when PTH-Intact >70pg/ml and supplementation instituted if necessary, a level of <30ng/ml is abnormal and <15ng/ml, moderate to severe  Treatment  <5ng/ml 50,000U Ergocalciferol/wk x12, then q mo x6  5-15ng/ml 50,000/wk x 4, then q mo x 6  16-30ng/ml 50,000/month x 6  Measure 25(OH)-D at 6months  Maintenance 800-1200 IU qd (AJKD, 39, 2002, pS214)
  36. 36. Calcium and Phosphorus Balance KDOQI Recommendations  Stage 3 CKD, GFR 30-59  Stage 4 CKD, GFR 15-29  Measure Ca, Phos and  Measure Ca, Phos and PTH-I every 12 months PTH-I every 3 months  Target levels  Target levels  Calcium WNL for lab  Ca preferably WNL for lab  Phos > 2.7- 4.6 mg/dL  Phos > 2.7-</= 4.6mg/dL  Ca X Phos < 55  Ca X Phos < 55  PTH-I 30-70 pg/ml  PTH-I 70-110 pg/ml
  37. 37. Calcium and Phosphorus Balance KDOQI Recommendations  How are these goals achieved ?  Control of dietary phosphorus intake to 0.8-1g/d  May need initiation of “Phosphate binders” with meals  When 25(OH)-D >30pg/ml and PTH-I > target, initiate treatment with exogenous “Active Vitamin D”  A few patients with very elevated PTH-I values may benefit from Calcimimetics (AJKD, 39, 2002, pS214)
  38. 38. Calcium and Phosphorus Balance: Limit Phosphorus intake to 0.8-1.0 g/d  High Phosphorus Foods  Dairy products (Cheese, ice cream, milk), nuts, peanut butter, biscuits, processed meats-hotdogs, chocolate, dark sodas (Coke, Pepsi), beans  Lower Phosphorus Choices  Cream cheese, sour cream, Ginger ale/sprite, sherbet, non-dairy creamer
  39. 39. Use of Phosphate binders  Given with meals, timing essential  Aluminum based medicines; (Basaljel, Amphogel)  Calcium Based  Calcium Carbonate/Magnesium Carbonate (Magnebind)  Calcium Carbonate (Tums, Calcichew, Calcimix)  Calcium Acetate (Phoslo)
  40. 40. Use of Phosphate binders  The use of calcium based binders is now falling out of favor because of the recognition of accelerated vascular calcification proposed to be associated with them (Disputed by the manufacturers of same)  Sevelamer hydrochloride (“Renagel”), cationic polymer, binds phosphate thru’ ion exchange, can promote/worsen metabolic acidosis  New product Sevelamer carbonate (“Renvela”) does not lead to acidosis  Lanthanum carbonate (“Fosrenol”), long term effects unknown  VERY EXPENSIVE (Sevelamer 800mg tab $1.93 each, dose varies 3- 9 tabs a day, $173-521 each month, Fosrenol 1000mg tab $4.87 each, dose 3 tabs daily, $438 each month)
  41. 41. Vitamin D Sterols  Several Vitamin D sterols are now available to replace naturally occurring 1,25 Vitamin - D3 , levels of which fall with declining renal mass  Rocaltrol (Calcitriol, oral)  Doxercalciferol (Hectoral , D2 prohormone, available in oral and parenteral forms)  Paracalcitol (Zemplar), oral and parenteral forms available
  42. 42. KDOQI Recommendations for use of Vitamin D sterols  In compliant patients with stable renal function,  Initiate “Active Vitamin D” (1,25-OH D3) supplements when: 25-(OH)D > 30pg/ml, PTH-I >target, Ca < 9.5, Phos > 4.6  Calcitriol 0.25-1.0 mcg po qd (Rocaltrol)  Doxercalciferol 2.5-10 mcg po tiw (Hectoral)  Paracalcitol 1-4 mcg po qd (Zemplar)  Check Ca and Phos q month x 3months then q 3 months and check PTH-I q 3 months  Monitor closely because of the significant risk of developing hypercalcemia (AJKD, 39, 2002, pS214)
  43. 43. The Calcimemetics Serum Calcium Calcium Sensing Receptor Cinacalcet (Sensitizes CaR to Ca2+) (CaR) Stimulatory Cellular Proliferation Nucleus PTH VDR Inhibitory Vitamin D The parathyroid cell
  44. 44. Treatment of Secondary Hyperparathyroidism Calcimimetic agents Vitamin D Sterols  Rapid onset (hours)  Act on genomic receptor  Inhibit PTH secretion  Slow onset (days to  Inhibit PTH synthesis weeks)  Inhibit parathyroid  Inhibit PTH synthesis cellular proliferation  Increase serum calcium  Decrease serum calcium
  45. 45. New Paradigm in Treatment of Secondary Hyperparathyroidism Phosphorus Cinacalcet Non-calcium Based Binders PTH Ca2+ 1,25(OH)2D3 (Use Cautiously)
  46. 46. Complications of Long Term Calcium and Phosphorus imbalance  Tertiary hyperparathyroidism  Renal osteodystrophy  Demineralization  Bone pain  Fractures  Systemic toxicity  Cutaneous - Calciphylaxis  Cardiovascular, accelerated vascular calcification  Nervous
  47. 47. Parathyroidectomy  Indication  Bio-Intact PTH > 800 pg/mL refractory to medical therapy  Severe hypercalcemia  Progressive high turnover bone disease  Complications  May result in excessive low PTH levels  Symptomatic hypocalcemia  Risk for injury to recurrent laryngeal nerve
  48. 48. Anemia of Chronic Kidney Disease  Develops when the GFR decreases to < 30-35 ml/min  decreasing production of erythropoietin 2/2 reduced renal mass  Uremic inhibition of bone marrow  Decreased RBC life-span  PTH induced marrow fibrosis  Iron deficiency  Aluminum related bone disease  Normochromic, normocytic
  49. 49. Why Treat Anemia? 175-Patient CKD Study 6% increase in risk of 1g/dL decrease in Hgb = LVH P = 0.0062 Levin et al. Am J Kidney Dis. 1996;27:347-354.
  50. 50. Anemia-Treatment Guidelines  Goal Hgb 11-12  Recombinant erythropoeitin  Epogen/Procrit 50-150 U/kg/wk SQ  Darbopoetin alfa (ARANESP) Start 0.45mcg/kg SQ once every 2 weeks, usually dosed every three to four weeks when patient is stable in the therapeutic range  Recent concerns re increased risk of cardiovascular events associated with an elevated Hgb in association with use of high doses of these products  Iron  Goal Ferritin >200, TSAT >20%  Oral agents  Chromagen: 33% iron  Ferrous sulfate: 20% iron  Niferex (Polysaccharide with Vit C): 150mg elemental iron  Ferrous fumurate: 33% iron  Ferrous gluconate (Fergon): 12% iron  Oral agents do not work well, primarily b/o ill tolerated GI side effects
  51. 51. Nutrition  Balancing the impact of decreased protein intake on the rate of progression of renal disease, against hypoalbuminemia and malnutrition  Can we restrict protein intake sufficiently, without leading to malnutrition, especially important in patients with eGFR < 25 ml/min
  52. 52. Serum Albumin at the Start of Dialysis in the U.S. ESRD Population 35% Mean 3.2 +/- 0.7 Median 3.3 30% 30% 25% 22% 23% 20% 15% 15% 10% 10% 5% 0% <2.5 2.6 - 3.0 3.1 - 3.5 3.6 - 4.0 4.1+ Serum Albumin (g/dL) Obrador et al. J Am Soc Nephrol 1999; 10; p. 1795
  53. 53. Serum Albumin Concentration (gm/dl) Odds Ratio of Death 14.0 Albumin 12.0 unadj. 10.0 Odds Ratio of Death Case Mix 8.0 adj. 6.0 5.0 Case Mix 4.0 + Lab adj. 3.0 2.5 2.0 1.5 Reference = p < .05 1.0 0 = p < .01 0.7 Bars without symbols are not different from 0.5 Reference < 2.5 2.5-3.0 3.0-3.5 3.5-4.0 4.0-4.5 >4.5 1994 Data Albumin (gm/dl) Lowrie, Seminars in Dialysis. Vol 10, No 2 (Mar-Apr) 1997, p. 116
  54. 54. Hyperkalemia  A common reason for initiation of RRT  The kidney is the only route for excretion of dietary intake, thus there is limited excretion as GFR falls, potentially leading to increased serum levels  Many patients with CKD also have a tendency to retain potassium because of stimulation of the Renin/Angio/Aldo system  Diabetics may have a type IV RTA (hyporeninemic hyperaldosteronism)  Use of ACE-I can exacerbate hyperkalemia
  55. 55. Hyperkalemia  Treatment  Restriction of intake  Diuretics  Kayexelate, long term use can lead to colonic mucosal defects
  56. 56. Hyperkalemia High Potassium foods Fruits Vegetables Other foods Apricot Artichoke Bran/bran products Avocado Asparagus Coffee, Tea Banana Beans Chocolate Cantaloupe, Honeydew Brussel sprouts Coconut, Granola Dates,Figs, dried fruits Lentils, legumes Molasses Mango,Papaya Limas, Peas, Okra Milk, Ice cream Orange, Nectarine Parsnips, Rutabaga Nuts/seeds Peaches, Prunes Potatoes Snuff/chewing tobacco Raisins, Persimmons Tomatoes Salt subs/Lite salt Juices of these Winter squash fruits Salt free veg. juice
  57. 57. Hyperkalemia Low Potassium foods Fruits Vegetables Starches Apples/applesauce Broccoli Rice Blackberries Beans, green/wax Noodles Blueberries/Cranberries Beets/carrots/corn Bread/bread products Cherries/grapes/gooseberries Cabbage/cauliflower Cereals Fruit cocktail Cucumber, lettuce Cakes, cookies Pears, canned/pineapple Eggplant/onions Pies (not chocolate or Plums/raspberries/Strawberries Summer squash high K fruit) Mandarin oranges/Tangerines Mushrooms, raw Rhubarb, Watermelon Parsley, radish, turnip Juices of these fruits Greens (collards, kale turnip, mustard) Peas, green
  58. 58. Cardiovascular Risk  Individuals with CKD are at increased risk for CVD, they should be considered in the “highest risk group for evaluation and management” according to NKF recommendations.  Remember, there are an estimated 7.5 million people in the US with stage 3 CKD and 363,000 at Stage 4 CKD but only 372,00 on dialysis with only a further 80,000 having received a kidney transplant.  If we consider the patients at Stages 3 and 4, they have a higher risk of death than progressing to need for dialysis !!!!
  59. 59. When to Refer to Nephrology: General Indications  Serum Creatinine >/= 1.7 mg/dl (M) and >/= 1.4 (F)  Poorly controlled HTN  Diabetes mellitus with atypical renal manifestations  Proteinuria or nephrotic syndrome without retinopathy  Renal insufficiency without proteinuria or retinopathy  Sudden onset of nephrotic syndrome or rapidly changing serum creatinine  Systemic disease associated with renal involvement  Heavy proteinuria  Urine-sediment abnormalities  Prior to onset of uremic symptoms
  60. 60. Goals of Early Referral  Patient education, soon Medicare reimbursement for CKD education  Choice of modality: HD vs PD vs Transplant  Planning of vascular access if HD is the chosen intervention and catheter placement if PD  Planning of timing of transplantation work-up  Institution of interventions to slow progression of renal disease
  61. 61. Avoidance of acute exacerbation of function  Volume depletion  IV Radiographic contrast  Gadolinium  Aminoglycosides and amphoterecin  NSAIDS/COX II inhibitors (Tordal)  ACE-I/ARB in certain populations  CyA / Tacrolimus in the transplant population  Obstructive uropathy
  62. 62. K-DOQI Action Plan for the Management of CKD Stage 1: GFR > 90 Clinical evaluation Slowing Progression CVD Risk Reduction Stage 2: GFR 60-89 Slowing Progression Stage 3: GFR 30-59 CVD Risk Reduction Treat Complication Symptom control & Stage 4: GFR 15-29 preparation for replacement therapy Stage 5: GFR < 15 Replacement Therapy
  63. 63. In Summary: Important Early Conservative Therapies  ACE Inhibitor, Angiotensin II Receptor Antagonist, and Beta Blocker Therapy, to control HTN  Adequate volume control with diuretics  Early Treatment of hyperphosphatemia with Phosphate binders  Early Treatment with Active Vitamin D  Early Treatment with Erythropoietin/Darbepoetin (PROCRIT/ARANESP)  Early Treatment with Iron Products  Aggressive control of glucose levels in Diabetics
  64. 64. THE END

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