2. Recent Advances in Management of CRF Yousef Boobess, M.D. Head, Nephrology Division Tawam Hospital

3. What is chronic renal failure ? Definitions Azotemia: Elevated blood urea and creatinine Chronic renal failure: The irreversible, substantial, and usually long- standing (>3 months) loss of renal function. Uremia: Azotemia with symptoms or signs of renal failure End-stage renal disease (ESRD): The degree of CRF that without renal replacement treatment would result in death.

4. Urinary abnormalities (GFR  90 ml/min) Mildly impaired (GFR 60 - 89 ml/min) Moderate CRF (GFR 30 - 59 ml/min) Severe CRF (GFR 15 - 29 ml/min) ESRD (GFR < 15 ml/min) STAGES OF Chronic Kidney Disease (CKD)

5. Epidemiology The number of ESRD patients is increasing rapidly, with very costly treatment Early recognition of renal disease and appropriate interventions may decrease Human suffering Financial costs associated with ESRD

6. Dialysis Sessions in Tawam

7. Incidence Rates of ESRD Therapy U.S. Renal Data System, (1997) 1982 1984 1986 1988 1990 1992 1994 1995 Years Rate per Million Population 300 250 200 150 100 50

8. Causes of ESRD in USA 1999 USRDS Report

9. Team Approach: Primary Helth Care (PHC) Physician and Nephrologist in CKD PHC Physician Early recognition of renal disease PHC Physicians treat patients with DM, HTN Timely referral to a Nephrologist Collaboration with a Nephrologist to provide long term care Patient education Nephrologist Diagnose and assess patients Assist in developing strategic guidance Recommend and implement patient care Provide role-specific patient education

10. Principles of Management of CKD Patients Early recognition of CKD Estimate the severity of CKD What is the cause of CKD? Detection and correction of any reversible cause. Avoidance of additional renal injury Institution of interventions to delay progression Treatment of complications Planning for renal replacement therapy

11. Principles of Management of CKD Patients Early recognition of CKD Estimate the severity of CKD What is the cause of CKD? Detection and correction of any reversible cause. Avoidance of additional renal injury Institution of interventions to delay progression Treatment of complications Planning for renal replacement therapy

12. Recognizing Renal Failure, Clinical Features Mild to Moderate renal failure: Usually no symptoms Severe renal failure: non specific Pale, fatigueability & shortness of breath Hypertension, headaches Polyuria/nocturia Body itch Poor appetite, nausea, vomiting Hyperventilation Swelling of the face and legs

13. Recognizing Renal Failure, Clinical Features Mild to Moderate renal failure: Usually no symptoms Severe renal failure: non specific Pale, fatigueability & shortness of breath Hypertension, headaches Polyuria/nocturia Body itch Poor appetite, nausea, vomiting Hyperventilation Swelling of the face and legs

14. Hyperventilation 13 y-o-f, came to ER with hyperventilation ER physician examined her  psychosis  valium, reassured the family & DC No improvement  taken to another hospital  Blood Chemistry & ABGs  ESRD with very severe metabolic acidosis (Bicarbonate ~ 2.7 mmol/l)

15. Recognizing Renal Failure, Investigations Urinalysis: Urine dipstick & microscopic exam => Ptu, Htu, pyuria, glycosuria Blood chemistry: s.Creatinine, urea (or BUN) Electrolytes (Na +, K +, CO 2, Ca ++, Ph -- ) GFR: Estimated or measured Ultrasound Morphologic evaluation

16. s.Creatinine Concentration Normal values: <115 umol/L in males (1.3 mg/dL) <90 umol/L in females (1 mg/dL) Changes in its level are more important: an increase from 55 to 110 umol/L represents a 50% decline in renal function Limitations

17. High s.Creatinine with Normal GFR Spurious elevation: Cephalosporin DKA Alcohol intoxication Blocking tubular secretion: Cimetidine or trimethoprim Increased creatinine production: Exogenous: ingestion of large quantities of cooked meat Endogenous: Muscular disorders, or increases in muscular mass

18. Normal s.Creatinine with CRF Poor production of creatinine: Severely malnourished patients Elderly Small children Ladies of small size

19. Glomerular Filtration Rate “ GFR ” Normal values: In males 120  20 mL/minute In females 115  20 mL/minute. Creatinine Clearance (24-h urine collection) Creatinine Clearance in Severe CKD: Overestimate GFR due to the tubular secretion To correct this overestimation: Take the average of urea and creatinine clearances Or give oral cimetidine 1200 mg, 3h before collection

20. Estimation of Creatinine Clearance Creat. Cl =1.23 x weight x(140-age)/(s.creat) In Male: In Female Cockcroft, Nephron, 1976; 16: 31-41 1.03

21. Determine the cause of CKD A specific diagnosis is needed: To consider specific TRT: obstructive uropathy, analgesic NP, drug- related IN, RPGN, SLE, vasculitis, accelerated HTN, tuberculosis, myeloma, amyloid,.. To be aware of potential complications: SLE, DM.. To advise the family: PKD or other familial renal disease.

22. Principles of Management of CKD Patients 1. Early recognition of CKD Estimate the severity of CKD What is the cause of CKD? 2. Detection and correction of any reversible cause. Avoidance of additional renal injury 3. Institution of interventions to delay progression 4. Treatment of complications 5. Planning for renal replacement therapy

23. Correcting any Reversible Cause

24. Correction a Reversible Cause “ Sarcoidosis ”

25. Volume Depletion Causes: Diarrhea, vomiting, iatrogenic (surgery, overzealous use of diuretics) Renal loss Worsening renal arterial stenosis, cholesterol emboli Volume repletion Restores renal function promptly Some degree of transient or permanent damage may occur

26. Principles of Management of CKD Patients 1. Early recognition of CKD Estimate the severity of CKD What is the cause of CKD? 2. Detection and correction of any reversible cause. Avoidance of additional renal injury 3. Institution of interventions to delay progression 4. Treatment of complications 5. Planning for renal replacement therapy

27. Slowing the Rate of Progression The earlier we alter factors that damage the kidneys, the better

28. Successful Intervention 0 0.001 0.002 0.003 0.004 0.005 0.006 0.007 05101520 1/s.cretinine Therapeutic Intervention Months, follow-up Rashed M., Tawam #125991

29. Intervention Renal Diet Protein Restriction High calories Law potassium Law salt Law phosphate

30. Intervention: Controlling BP in CKD Target BP: CKD: <130/85 mm Hg If proteinuria: <125/75 mm Hg Benefits Slows the progression of CKD, especially if proteinuria Reduces the cardiovascular complications Zabetakis PM, Nissenson AR. Am J Kid Dis. 2000;36(suppl):S31-S38.

31. BP Control and GFR Decline Parving HH et al. Br Med J 1989 Moschio G et al. NEJM 1996 Viberti GC et al. JAMA 1993

33. Prevalence of LV Disorders at Start of Dialysis Parfrey PS, et al.. Nephrol Dial Transplant. 1996;11:1277-1285 Echocardiograms of 413 incident hemodialysis patients

34. Consequences of CKD: (LVH) LVH is an independent predictor of cardiac death in dialysis patients. Hypertension, anemia and diabetics are modifiable predictors of LVH Increase in LVH risk: For each:  C cr of 25 mL/min => 3% increased risk of LVH.  Systolic BP by 5 mm Hg => 3% increased risk.  Hemoglobin by 1 g/dl => 6% increased risk of LVH Levin A, et al. Am J Kid Dis. 1996;27:347-354.

35. BP is Poorly Controlled in CKD Coresh J, et al. Arch Intern Med. 2001;161:1207-1216.

36. Blood Pressure Control Several classes of drugs are available Some can slow the decline of GFR: First-line treatment: ACE inhibitors & angiotensin receptor blockers There's still a great reluctance by PHC physicians to use them for fear that they will damage the kidneys rather than preserve function. Diuretics in combination with ACE inhibitors. JNC VI. Arch Intern Med. 1997;157:2413-2446.

38. Reno-protective Effect of ACEis ACEis (independent of their antihypertensive action): Decrease proteinuria Delay the progression of renal disease Mechanisms: Dilatation of EA =>reducing intra-glomerular pressure Restoration of glomerular perm-selectivity in proteinuric NPs ? Effect on the GH like of AII

39. Adverse Effects of ACEis Acute worsening of renal function if bilateral renal artery stenosis or if decreased effective circulating volume advices: monitor renal function after initiation of ACEi in high risk patients: renal scan with captopril test adjust the dose according to the renal function Hyperkalemia same considerations apply

40. Glycemic Control in Diabetics Tight control of blood glucose: Hb A1C <7% Delay the onset of microalbuminuria Decrease or stabilize protein excretion in patients who already had microalbuminuria ACE inhibitors, and ARBs: Delay the progression of kidney dysfunction. Zabetakis PM, Nissenson AR. Am J Kid Dis. 2000;36(suppl):S31-S38. The Diabetes Control and Complications Trial, long-term Sweden study, Japanese study

41. RENAAL Primary Components ESRD Months % with event 012243648 0 10 20 30 p=0.002 Risk Reduction: 28% P L ESRD or Death P (+ CT) L (+ CT) Months % with event 0122436 48 0 10 20 30 40 50 751714625 37569 762715610 34742 P L p=0.010 Risk Reduction: 20% Doubling of Serum Creatinine Months % with event p=0.006 Risk Reduction: 25% 751692583329 52 762689554 295 36 P (+ CT) L (+ CT) 012243648 0 10 20 30 P L P (+ CT) L (+ CT) 751714 625 37569 762715 610 34742 Brenner BM et al New Engl J Med 2001;345(12):861-869.

42. HyperlipidemiaHyperlipidemia In CRF: Mainly hypertriglyceridemia => Increases glomerulosclerosis by: Increasing mesangial proliferation and matrix production Altering glomerular hemodynamics Increasing local inflammation

43. Smoking Cessation All patients with renal disease should be encouraged to quit smoking DM is 3 to 4 times more common in smokers than in nonsmokers Smoking increases the relative risk for progression of CRF in nondiabetics Former smokers have an intermediate risk

44. Principles of Management of CKD Patients 1. Early recognition of CKD Estimate the severity of CKD What is the cause of CKD? 2. Detection and correction of any reversible causes. Avoidance of additional renal injury 3. Institution of interventions to delay progression 4. Treatment of complications 5. Planning for renal replacement therapy

45. Fluid and electrolyte disorders Sodium and Water Most often: Impaired Na excretion => Edema, HTN, CHF TRT: Moderate Na + restriction Loop diuretics In some patients: Salt wasting => volume depletion => worsening of CRF TRT: Na + replacement

46. Fluid and Electrolyte Disorders Potassium Balance Hyperkalemia Develops in advanced CRF Can occur earlier in patients with: Tubulointerstitial disease Diabetic NP and hyporeninemic hypoaldosteronism Drugs: as ACEis, A2 antagonist, b- blockers, NSAIDs, K + sparing diuretics, trimethoprim, salt substitutes.. TRT: Dietary K + restriction, loop diuretics, K + exchange resins..

47. Fluid and Electrolyte Disorders Acid-Base Disorders Metabolic acidosis: Occurs relatively early Treatment: Decrease protein intake Alkali supplementation if bicarbonate < 17mEq/L Na bicarbonate or Na citrate, 1 mEq/kg/day This will prevent: Excessive bone loss Muscle breakdown Tubulointerstitial inflammation

48. Hypocalcemia & Hyperphosphatemia Hypocalcemia Deficiency in Vit.D, Hyperphosphatemia Hyperphosphatemia Early in renal failure: Ph -- clearance => Ph -- => PTH => Ph -- clearance Frank hyperphosphatemia occur if GFR < 30 mL/min Management: Dietary phosphate restriction Phosphate binders: Ca carbonate, Renalgel,.. Vit D: Rocaltrol, One Alpha,..

49. AnemiaAnemia Present when GFR < 30-35 mL/min Causes: Reduced EPO production Others: iron deficiency, rapid destruction of RBC,.. Anemia is an independent risk factor for death in CHF Studies of Left Ventricular Dysfunction (SOLVD) 7000 patients 1% lower Hct was associated with 1% higher risk of mortality Al Ahmad. et al. J Am Coll Cardiol. 2001;38:955-962.

50. Independent Risk of a Fall in Mean Hb of 1 g/dL in Dialysis Patients Odds ratioP LV Dilation1.420.02 De novo cardiac failure 1.280.02 Recurrent cardiac failure 1.200.05 IHDNA Death1.140.02 Foley PS, et al. Am J Kidney Dis. 1996;28:53-61.

51. Cardio - Renal - Anemia Syndrome CKD CHFAnemia Vicious Circle of Destruction

52. Cardio - Renal - Anemia Syndrome CHF is a common and crucial contributor to the progression of CKD. (new concept) Treatment of anemia in patients with CHF may improve both the cardiac and the renal function => To save the heart and the kidney, treat the anemia

53. Treatment of Anemia Target Hgb 11 to 12 g/dL Epoetin: Dose: 50 U/kg/inj, iv or sc 1-3 times/week IV Iron Sucrose: Target: Serum ferritin: 100 - 500 ng/mL Transferrin saturation: 20 – 50%. Dose: 100 mg/session X 10, then reevaluate

54. Principles of Management of CRF Patients 1. Early recognition of CRF Estimate the severity of CKD What is the cause of CRF? 2. Detection and correction of any reversible cause. Avoidance of additional renal injury 3. Institution of interventions to delay progression 4. Treatment of complications 5. Planning for renal replacement therapy

55. Planning for Renal Replacement Therapy Options of RRT should be discussed: Difference modalities of dialysis HD, PD Transplantation Possibility of preemptive Tx Outcomes are optimal when RRT is initiated in a planned manner HD => need for A-V fistula (4-6 months) Tx: work-up

56. TRADITIONAL DIALYSIS START

57. Timely Dialysis Start

58. EARLY DIALYSIS START Early dialysis start (CrCl > 10 ml/min) vs late dialysis start (CrCl < 4 ml/min): => higher 12 yr survival (85% vs 51%) [Bonomini et al Kidney Int 17:S57 1985] => improved quality of life at 6 months post initiation of RRT [Korevaar et al AJKD Jan 2002]

59. Conclusion, 1 Early recognition of renal disease Early referral to Nephrologist Detect and correct any reversible cause Avoid any additional renal injury Use ACE inhibitors whenever it is indicated Lipid-lowering drugs

60. Conclusion, 2 Avoid: Nephrotoxic drugs: NSAIDs, aminoglycosides, radiocontrast In moderate to severe CRF: Diuretic therapy: often necessary Dietary potassium restriction Potassium exchange resins if hyperkalemia Alkali supplementation: if CO 2 < 16-17 mEq/L Phosphate binders, Vit D EPO, Iron