Pakistan is an impoverished and underdeveloped country. Third World Country.

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1 Cost Effectiveness of Treatment of CKD Dr. Haren Kumar The Kidney Foundation Karachi - Pakistan

2 Pakistan facts sheet Population : 164,741,924 (> 160 Millions) Median Age : 20.9 years Life Expectancy : years Male=10,37,87,412 63% Female = 6,09,54,512 37% Literacy rate : 49.9% Population below : 24% (< US$ 1 = 17%) poverty line Under-nourished nourished : 24% population Excess to improved : 59% sanitation Per Capita Income : US$ 770 Physicians : 74 / 100,000 % of GDP on : 2% Education % on GDP on Health : 0.7% Pakistan is an impoverished and underdeveloped country. Third World Country.

3 Chronic Kidney Disease (CKD) CKD A Global Public Health Problem Incidence and prevalence of Kidney failure (ESKD) Rising Poor outcome High cost Even higher prevalence of earlier stages of CKD. Kidney Failure (ESKD) Cardiovascular Disease (CVD) Premature Death Ref: National Kidney Foundation K/DOQI. Clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. American Journal of Kidney Disease 2002; 39 (2 supplement): S 1-266

4 Chronic Kidney Disease (CKD) Convincing evidence: CKD can be prevented or delayed by early detection and treatment. CKD is under diagnosed and under treated: Resulting in lost opportunities for prevention. Reason: Lack of universal definition Classification of stages Application of simple test for detection and evaluation Ref: National Kidney Foundation K/DOQI. Clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. American Journal of Kidney Disease 2002; 39 (2 supplement): S A.S. Leved; R.Atkins; A.J. Collins et al. Chronic Kidney Disease as a global public health problem: Approaches and initiatives A position statement from Kidney Disease improving global outcomes. Kidney Int. 2007; 72(3):

5 CHRONIC KIDNEY DISEASE Kidney damage or a Glomerular Filtration Rate (GFR) of less than 60 ml per minute per 1.73m 2 (body surface area) for three months or more. Men- S. Creatinine > 1.5 mg/dl Women- S. Creatinine >1.3 mg/dl Presence of urinary albumin excretion > 300 mg/24 Hours OR Spot urine albumin to creatinine ratio > 200 mg albumin to 1 g of creatinine Ref: National Kidney Foundation K/DOQI. Clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. American Journal of Kidney Disease 2002; 39 (2 supplement): S 1-266

6 Glomerular Filtration Rate Assess the degree of kidney function impairment. Monitor disease progression and treatment response. Estimation: 24 Hours urine collection for creatinine clearance UV / P MDRD equation: GFR= 186X S.cr X age X(0.726 if female)x(1.210 if black) Cockcroft Gault equation: Ref: 140- Age (years)x Weight (Kg) GFR = 72 X S.cr (mg/dl) X (0.85 If female) Levey AS et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease study Group. Ann Intern Med 1999;130: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41.

7 Stages Of Chronic Kidney Disease The NKF Kidney Disease Outcome Quality Initiative (K/DOQI) classify chronic kidney disease into five stages based on the GFR & metabolic consequences. Stage Description GFR Metabolic Consequences 1 Kidney damage with normal or elevated GFR 2 Kidney damage with mildly decreased GFR 3 Moderately decreased GFR 4 Severely decreased GFR (Pre ESKD). 90 or higher - 60 to 89 PTH levels begins to rise. 30 to 59 Ca absorption decreases, Malnutrition develops, LVH & Anemia 15 to 29 Triglycerides, Hyperphosphatemia, Metabolic Acidosis, Hyperkalemia 5 Kidney Failure ESKD <15 Need for RRT Azotemia Ref: National Kidney Foundation K/DOQI Clinical practice guidelines for Chronic Kidney Disease; evaluation, classification and stratification. American Journal of Kidney Disease 2002;39 (2 supplement) S51

8 CKD- Magnitude of the Problem In USA 11% of Adult population is affected by CKD The prevalence of earlier stages of the disease is 10.8% The prevalence of Kidney Failure is 0.1% Thus 10 times higher prevalence of earlier stages of CKD Studies from Europe, Australia & Asia also confirms high prevalence of CKD Ref: National Kidney Foundation K/DOQI. Clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. American Journal of Kidney Disease 2002; 39 (2 supplement): S A.S. Leved; R.Atkins; A.J. Collins et al. Chronic Kidney Disease as a global public health problem: Approaches and initiatives A position statement from Kidney Disease improving global outcomes. Kidney Int. 2007; 72(3):

9 CKD-Magnitude of the Problem Pakistan Conservative estimate of Incidence of ESKD 100/million new patients each year Incidence/prevalence of CKD?? 15% - 20% of people above 40years of age have reduced GFR (24-32 million). 14% of people in Pakistan have either stage 3 or stage 4 CKD (21 million). 13% prevalence of CKD in India (initial phase SEEK study) These figures are 3 times higher then west. Ref: Jaffar TH, The growing burden of CKD in Pakistan. N.Engl J.Med 2006;354: Waqar H. Kazmi, Samina Khan. Press Conference August 23, Sakhuja V, Sud K. End stage Renal Disease in India & Pakistan. Kidney Int. suppl 2003;63:

10 Burden of Diabetes 177 million people suffer from Diabetes world wide. 300 million will suffer by the year % increase in developed countries. 170% increase in developing countries. Globally Pakistan is ranked 8 th in Diabetes. By the year 2010 it will be ranked 4 th in Diabetes. 10% Pakistani population have Diabetes. 10% Pakistani population have Impaired Glucose Tolerance. Ref: Diabetic care 1998; 21: Diabetic Association of Pakistan

11 Burden of Hypertension 12 million hypertensive in apopulation of 130 million in Pakistan (1998). 17.9% of population above the age of 15 suffers from Hypertension. One in three above the age of 45 suffers from hypertension. More than 60% of patients are unaware of hypertension. In only 3% of patients, blood pressure is adequately controlled. Ref: First Report of National Task Force (NTF-1) on Hypertension. Pakistan Hypertension League 1998.

12 Consequences of Diabetes and Hypertension One third of Diabetics will develop CKD because of Casual treatment and lack of understanding. 50% of hypertensive are also likely to develop CKD. Such is the burden of silent killers. We cannot look after all these patients by RRT. Thus most will die of uremia.

13 Delay The Progression of Chronic Kidney Disease (CKD) ESKD RRT Dialysis Haemodialysis CAPD Transplant Live Related Live Non Related Cadaveric Both modalities are expensive and not readily available. The only option is to slow the progression of CKD and decrease the ESKD Burden. The NKF suggests actions to slow disease progression.

14 Benefits of Delaying Progression Small changes in the rate of renal function loss (GFR) per year, result in a significant benefit to patients. A change in the annual decline of GFR from 5ml/min to 2ml/min adds nearly 30 years of life off dialysis to a 25 years old patient with CKD. Ref: Hebert LA et al. Reno protection: one or many therapies? : Kidney Int 2001;59:1212

15 Delay The Onset and Progression of Chronic Kidney Disease (CKD) Early Referral. Diabetes Mellitus. Hypertension Proteinuria Dyslipidemia Anemia Heart Failure Renal Osteodystrophy Nutrition Smoking Cessation Acute on CKD

16 Early Referral General physicians must be involved in the team to ensure timely referral of patients with CKD Patients with diabetes, hypertension, microalbuminuria, proteinuria and hematuria GFR > 125 ml/min, <60ml/min for more than 3 months S. creatinine > 1.5mg/dL (male) > 1.3mg/dL (female)

17 Diabetes Mellitus Diabetes Mellitus is the most common cause of CKD and Hyperglycemia is an independent risk factor for nephropathy. Type 1: Progressive Kidney Disease Type 2: 1/3 rd will develop nephropathy Strict glycaemic control Target HgbA1c < 7% Target Blood sugar mg/dL140mg/dL Life style changes Increasing activity Reduce obesity Stop smoking Yearly screening for microalbuminuria Blood pressure control with ACE or ARB Target Blood pressure /70-80 Ref: United States Renal Data System Annual data report. Bethesda, Md:National institute of Health, National institute of Diabetes and digestive and kidney diseases June UK prospective diabetes study UKPDS. Lancet 1998;352: The Diabetes Control and Complication Trial DCCT. N Engl J Med 1993;329: American Diabetes Association. Standards of medical care for patients with Diabetes Mellitus. Diabetes care 2003;26 (suppl 1) : S33-50

18 Treatment of Diabetics ESRD In Pakistan ESRD 100/million population ESRD 14,400 patients Diabetic ESRD 33% patients Cost Comparison DRUGS DIALYSIS $ 21=Rs.1,197/Patient / Year $3331=Rs.189,000 /Patient / year 4752 patients 4752 patients $ 99,792=Rs.5.6 million $ million=rs million 150 fold additional expenditure on Dialysis

19 Hypertension Several trials have demonstrated the benefits of strict Blood pressure control in slowing the progression of Kidney disease. 7th JNC recommends target Blood pressure< 130/80 in patients with CKD ACE and ARB preferentially lower intraglomerular pressure and reduce proteinuria Efficacy may increase when used in combination Some CKD patients may have initial in GFR ( 10ml/min) or in S.Cr and in potassium. S.Cr and Potassium levels 1-2 weeks after initiation of therapy Other measures: Weight reduction Walk Salt restriction < 2.4 g Na/ Day, 6 g NaCl/ Day Diuretics. Ref: Peterson et al. Blood pressure control, proteinuria and the progression of renal disease. MDRD study. Ann Intern Med 1995;123: Mogenson et al. (CALM) study. BMJ 2000; 321: Brenner et al. Effects of losartan on renal and cardiovascular outcomes in patients with type2 diabetes and nephropathy. N Engl J Med 2001;345:861-9 NKF. K/DOQI clinical practice guidelines for CKD.Am J Kidney Dis 2002; 39 (2 Suppl): 2; S 1-246

20 Treatment Cost Hypertension ESKD 100/million population ESKD 14,400 patients Hypertensive ESRD 22% = 3,168 patients More than 60% of population unaware of hypertension in Pakistan. Only 3% adequate BP control Pakistan. COST DRUGS DIALYSIS $310/Patient/Year $3,331/Patient/Year 3,168 Patients 3,168 Patients $982,080 $10.55 million Savings 9.57 millions $ (90.69%) 100 fold additional expenditure on dialysis

21 Proteinuria Control of Proteinuria is the mainstay of managing CKD Persistent proteinuria is associated with worsening renal functions because proteins damage the glomerular capillaries as they leak across Many studies with ACE inhibitors and ARBs show these drugs are effective in reducing proteinuria They appear to work independent of controlling blood pressure as they reduce intra glomerular pressure by acting on glomerular capillaries It may be necessary to use these drugs in larger doses to lower protein losses

22 Dyslipidemia Most patients with CKD have an abnormal lipid panel. Triglycerides(defective clearance) LDL/HDL ratio LDL Cardiovascular mortality is 20 times higher in dialysis patients than in the normal population even after adjustments are made for age,sex and diabetes mellitus A recent meta-analysis analysis of 13 small studies showed that lipid reduction preserves GFR & reduces proteinuria. NKF K/DOQI recommends treating dyslipidemia aggressively in patients with CKD. Target LDL < 100mg/dL Triglycerides < 200mg/dL Ref: Fried. LF. et al. Effect of Lipid reduction on the progression of renal disease: a meta analysis. Kidney Int 2001;59:260-9 Crook ED et al. Lipid abnormalities and renal disease:is dyslipidemia a predictor of progression of renal disease? Am J Med Sci:2003;325:340-8

23 Poly Pill Should be on the agenda of many developing countries Generic ACE Inhibitors Statin Aspirin Folic Acid Simultaneous control of BP, Dyslipidemia and Thrombogenic tendency Ref: Barsoum RS. Chronic Kidney Disease in the developing world. N. Engl J. Med 2006;354:

24 Anemia Normocytic, Normochromic anemia due to reduced erythropoietin production by decreased mass of functioning renal tubular cells Fatigue, reduced exercise capacity, decreased cognition and impaired immunity QOL (morbidity) Work load on the heart LVH and Cardiomyopathy Heart failure or IHD mortality Correction of anemia can limit the progression of CKD and possibly decrease both morbidity and mortality NKF K/DOQI recommends Target Hb G/dL Target Hematocrit 33% - 35% Monitor Iron levels. Ferritin > 100mg/dL and T.S > 20%. If below give iron supplements. Hypertension and thrombotic events are potential adverse affects of treatment and must be monitored closely Ref: Revicki DA et al. Health related QOL associated with RH Epo for predialysis chronic renal disease. Am J Kidney Dis 1995;25: Fink J et al. Use of EPO before the initiation of dialysis and its impact on mortality. Am J Kidney Dis 2001;37:348-55

25 Heart Failure Heart failure is usually associated with the later stages of CKD Most heavily linked to hypertension and anemia Other factors involved include fluid overload, vascular calcification, increased salt intake, malnutrition and dyslipidemia CHF may lead to reduced renal perfusion resulting in rapid deterioration of GFR in patients of CKD. Ref: Harnett JD et al. Congestive heart failure in dialysis patients: prevalence, incidence, prognosis and risk factors. Kidney Int 1995;47: Portoles J et al. Cardio vascular effects of RH Epo in predialysis patients. Am J Kidney Dis 1997;29:541-8

26 Renal Osteodystrophy Metabolic bone disease begins early in CKD PTH level begin to rise when Cr Ccl falls below 60ml/min Secondary Hyperparathyroidism Calcium Phosphorus Alkaline Phosphatase Lesions: Osteitis Fibrosa Cystica ( Secondary Hyperparathyroidism) Osteo malacia ( Defective mineralization) Adynamic bone disease ( Absence of cellular activity) Bone pain, increased risk of fracture, pruritis and vascular calcification Management: Restrict dietary phosphate; Colas, nuts, peas, beans and dairy product Calcium based phosphate binders: Calcium carbonate and Calcium acetate Vitamin-D; monitor Ca X PO4 product Correct Acidosis: Sodium bicarbonate Montor BP, Na and fluid overload Refractory hyperparathyroidism parathyroidectomy Ref: Ho LT, Sprague SM. Renal osteodystrophy in Chronic Renal Failure. Semin Nephrol 2002;22: Slatopolsky E et al. Effects of Calcitriol and non-calcemic Vitamin-D analogs in secondary hyperparathyroidism. Kidney Int (suppl 1) 1992;38:S43-9

27 Nutrition CKD Malnutrition and Hypoalbuminemia Poor outcomes The effect of dietary protein restriction on the progression of CKD is the subject of debate. MDRD study There does not appear to be a major benefit in renal protection from dietary protein restriction. NKF K/DOQI recommends: Protein intake g/kg/day Caloric intake Kcal/Kg/day Monitor: S.Albumin and Weight at least every 3 month Early referral to a nutritionist can help maintain optimal protein and caloric intake in patients with CKD Ref: Klahir S et al. The effects of dietary protein restrictions and blood pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease ( MDRD). N Eng J Med 1994;330: National Kidney Foundation. K/DOQI. Clinical practice guidelines for Chronic Kidney Disease; evaluation, classification and stratification. Am J Kidney Dis 2002;39 (suppl 1) : S1 266

28 Smoking Cessation Several mechanism exists by which smoking may damage the kidneys. GFR Hyperfiltration BP Glomerulorsclerosis Plasma Aldosterone BP and Direct profibrotic effect platelet aggregation Injury to renal endothelial cells In two large studies smoking emerged as an independent risk factor for the development of albuminuria Rate of progression of Diabetic Nephropathy to ESKD is greatly increased in smokers as compared to non-smokers. Data suggests that cessation of smoking can slow the rate of progression of diabetic nephropathy Smoking cessation should be strongly encouraged in patients of CKD Ref: Orth SR et al. The renal risk of smoking. Kidney Int 1997;S1: Mimran A et al. Albuminuria in normals and essential hypertensions. J Diabetes Complications 1994;8:150-6 Klein R et al. Incidence of gross proteinuria in older onset diabetes. A population based perspective. Diabetes 1993;42:381-9 Sawicki PT et al. Smoking is associated with progression of Diabetic Nephropathy. Diabetes care 1994;17:125-31

29 Acute on CKD Any acute condition will lead to further deterioration of compromised renal function and sudden decrease in GFR. Timely intervention and appropriate management may restore the GFR to its base line level. Infection Hypovolemia Nephrotoxic Drugs Hypertensive Crisis Cardiogenic Shock

30 Summary Slowing the progression of CKD is dependent upon; 1. Early recognition and referral 2. Strict glycaemic control. Target HgbA1c < 7% 3. Control of Hypertension. Target BP < 130/80 4. Lifestyle changes Weight reduction, activity and Sodium restriction 5. Reduce proteinuria 6. Use ACE and ARB s 7. Correct dyslipidemia. Target LDL < 100 mg/dl and Triglycerides < 200 mg/dl 8. Correction of Anemia. Target Hb g/dl 9. Avoid LVH and Heart failure 10. Avoid Renal Osteodystrophy.PO 4 restriction,ca supplements, Vit-D 11. Nutrition. Protein moderation ( g/kg/day) Calories Kcal/Kg/day 12. Smoking Cessation. 13. Aggressive management of Acute on CKD.

31 INCIDENT & PREVALENT RATES 160 Rate per million population Diabetes Hypertension Glomerulonephritis Cystic kidney '00 '04 Incident & prevalent rates of ESRD, by primary diagnosis Incident & December 31 point prevalent ESRD patients USRDS

32 Cost Effectiveness of Stage-4 CKD Pre ESKD GFR ml/min Timely referral to Nephrologists Frequent visits. Fluid & Diet restrictions Involve dietician Watch Acidosis, Hyperkalemia, Heart Failure Educate patient and family Discuss RRT options Creation of Permanent Vascular Access Native AVF Screening and Vaccination for Hepatitis B Monitor Drugs & Dosage Avoid Nephrotoxic Drugs

33 Cost Effectiveness of Stage-5 CKD Renal Failure GFR < 15 ml/min Urgent referral to Nephrologist Early initiation of dialysis preferable Avoid emergency Adequate dialysis 4 hours. 3 times/week Logistics: Near Home facility Rural/Urban Maximum utilization of machine & man power 1 machine 10 patients Technical: Dialysis Machine Simple, user friendly, low maintenance, backup Dialyzer Modified Cellulose/Polysulfone (ETO?) Dialyzer Re-use Manual / Automated Patient Education: Compliance Timing, Frequency, Discipline Fluid Diet Medication

34 Conclusion The management of CKD creates a series of challenges that have to be handled in a systematic and orderly fashion Three goals should always be kept in mind a. Delay the progression of disease b. Maintain quality of life c. Decrease morbidity and mortality

35 Thank You.