Detection, Monitoring and Referral of Chronic Kidney Disease

1. Detection, Monitoring and Referral ofChronic Kidney Disease September 9, 2010 Louis Girard MD, MBT FRCPC Clinical Assistant Professor Division of Nephrology University of Calgary

2. Outline What is chronic kidney disease? When to screen chronic kidney disease? What tests to order? Role of proteinuria What to do with the results? RAAS inhibition These are the three key points that we hope clinicians will remember. - use case-finding approach to CKD in high-risk individuals - test using eGFR (kidney function) and assessment of urine protein (kidney damage) to identify individuals with CKD as well as the subgroup at risk of progressive disease - abnormal findings need serial monitoring as many will improve on repeat testing and serial monitoring helps to identify those with progressive renal diseaseThese are the three key points that we hope clinicians will remember. - use case-finding approach to CKD in high-risk individuals - test using eGFR (kidney function) and assessment of urine protein (kidney damage) to identify individuals with CKD as well as the subgroup at risk of progressive disease - abnormal findings need serial monitoring as many will improve on repeat testing and serial monitoring helps to identify those with progressive renal disease

3. Chronic kidney disease No uniform terms Provide a framework for therapeutic interventions Improve communication clinical information public education dissemination of research results Enhance conduct of research epidemiology clinical trials

4. K/DOQI CKD Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification Based on glomerular filtration rate, duration (3 months) and urinary and anatomical abnormalities Aimed to enhance identification and management

5. K/DOQI CKD Classification Among patients with CKD, the stage of the disease should be assigned based on the level of kidney function, irrespective of diagnosis, according to the K/DOQI CKD classification, as shown in the above table.Among patients with CKD, the stage of the disease should be assigned based on the level of kidney function, irrespective of diagnosis, according to the K/DOQI CKD classification, as shown in the above table.

6. CKD definition Kidney damage for ? 3 months, as defined by structural or functional abnormalities of the kidney Pathologic abnormalities Abnormalities in urine sediment irrespective of Abnormalities in imaging tests eGFR OR eGFR < 60 ml/min/1.73m2 for ? 3 months, with or without kidney damage

7. When to screen CKD? Population-based screening Vs. Case-finding approach

8. NKF-K/DOQI Estimates of Prevalence of CKD in the U.S. Using their definition and classification of stages of chronic kidney disease the K/DOQI workgroup was able to provide rough estimates of the prevalence of each stage in adults aged 20 or over from the Third National Health and Nutrition Examination Survey (NHANES III) in the United States. In the United States, there is a rising incidence and prevalence of kidney failure. There is an even higher prevalence of earlier stages of CKD.Using their definition and classification of stages of chronic kidney disease the K/DOQI workgroup was able to provide rough estimates of the prevalence of each stage in adults aged 20 or over from the Third National Health and Nutrition Examination Survey (NHANES III) in the United States. In the United States, there is a rising incidence and prevalence of kidney failure. There is an even higher prevalence of earlier stages of CKD.

9. So, for obvious reasons… CSN endorses a case finding approach to testing for CKD Focuses on high-risk groups

10. Who should be screened: High risk groups for CKD? Diabetes mellitus Hypertension Heart failure Atherosclerotic coronary, cerebrovascular or peripheral vascular disease Unexplained anemia Family history of ESRD First nations peoples

11. Case: Joe Joe is a 68 year old welder Past Medical History: appendectomy, hypertension, dyslipidemia, Type 2 DM Smoker- 1 pack a day since age 21 Etoh- a case of beer on the weekend Allergy- none known Family History- father MI age 50, mother HTN age 48 Medications- hydrochlorothiazide 25 mg po od, amlodipine 5mg po od, metformin 1000 mg po bid Weight 75 kg BP 149/84 mmHg Illustrating the power of eGFR using clinical cases Could discuss SCORED study (Arch Int Med Feb 2007; 167:374-381)– Here Joe has a history of hypertension as well as DM. SCORED also considered age as a risk factor Illustrating the power of eGFR using clinical cases Could discuss SCORED study (Arch Int Med Feb 2007; 167:374-381)– Here Joe has a history of hypertension as well as DM. SCORED also considered age as a risk factor

12. Which test would you choose to assess Joe’s renal function? Serum creatinine 24 hour urine collection Nuclear medicine scan eGFR Each item in this list has elements that preclude them from being dependably used and easily accessed in the day to day clinical assessment of patient renal function in a reliable and accurate manner. Commonly voiced concerns about 24hr urine collections include 1) instructions are routinely misunderstood leading to inaccurate collections and unreliable inaccurate results 2) Patients find it difficult to commit to an entire day’s worth of “testing” 3) routine under or over collections etc Nuclear medicine tests are not practical nor cost effective ways in which to follow renal function Serum Creatinine and urea measurements alone often are misinterpreted by health care professionals, the most common of which is that despite a value being in the “normal range” it reflects a GFR that is significantly reduced for that patient’s age , gender and body mass. This will be explored more in the presentation. Each item in this list has elements that preclude them from being dependably used and easily accessed in the day to day clinical assessment of patient renal function in a reliable and accurate manner. Commonly voiced concerns about 24hr urine collections include 1) instructions are routinely misunderstood leading to inaccurate collections and unreliable inaccurate results 2) Patients find it difficult to commit to an entire day’s worth of “testing” 3) routine under or over collections etc Nuclear medicine tests are not practical nor cost effective ways in which to follow renal function Serum Creatinine and urea measurements alone often are misinterpreted by health care professionals, the most common of which is that despite a value being in the “normal range” it reflects a GFR that is significantly reduced for that patient’s age , gender and body mass. This will be explored more in the presentation.

13. What is GFR?

14. GFR Glomerular filtration rate (GFR): is the volume of fluid filtered from the renal glomerular capillaries into the Bowman’s space per unit time Normal for a 20 year old is ~ 120ml/min Age-rated decline ~ 1ml/min/year after ?55yo

15. Methods to assess GFR Serum urea Serum creatinine Serum cystatin C Timed urine collections Creatinine clearance Inulin clearance Calculated approximations based on serum creatinine many formulas including Cockcroft Gault and MDRD Nuclear medicine methods There is a great article in BMJ October 2006 that reviews all these methods How to measure renal function in clinic practice. Traynor, Mactier, Geddes and Fox, BMJ 2006; 333: 733-737 Cystatin C- endogenous GFR marker; part of cystein protease inhibitors; freely filtered - problem is the high variability between patients and serum level increases with malignancy, HIV infection and steroid Inulin – exogenous polymer of fructose; expenseive and difficult to measure, time consuming. - bolus and infusion of inulin to achieve steady plasma level followed by collection of blood and urine sample over several hours for inulin excretionThere is a great article in BMJ October 2006 that reviews all these methods How to measure renal function in clinic practice. Traynor, Mactier, Geddes and Fox, BMJ 2006; 333: 733-737 Cystatin C- endogenous GFR marker; part of cystein protease inhibitors; freely filtered - problem is the high variability between patients and serum level increases with malignancy, HIV infection and steroid Inulin – exogenous polymer of fructose; expenseive and difficult to measure, time consuming. - bolus and infusion of inulin to achieve steady plasma level followed by collection of blood and urine sample over several hours for inulin excretion

16. The perfect marker Endogenous Freely filtered Not secreted or reabsorbed Inexpensive to measure

17. Problems with creatinine

18. Problems with timed collections Cumbersome Prone to error Cr clearance tends to overestimate GFR No longer recommended in most situations

19. Problems with other methods Cystatin C Inulin clearance Nuclear medicine (iothalamate, iohexol, EDTA) Complex Time-consuming Expensive Not practical for serial monitoring Cystatin C- endogenous GFR marker; part of cystein protease inhibitors; freely filtered - problem is the high variability between patients and serum level increases with malignancy, HIV infection and steroid Inulin – exogenous polymer of fructose; expensive and difficult to measure, time consuming. - bolus and infusion of inulin to achieve steady plasma level followed by collection of blood and urine sample over several hours for inulin excretion Cystatin C- endogenous GFR marker; part of cystein protease inhibitors; freely filtered - problem is the high variability between patients and serum level increases with malignancy, HIV infection and steroid Inulin – exogenous polymer of fructose; expensive and difficult to measure, time consuming. - bolus and infusion of inulin to achieve steady plasma level followed by collection of blood and urine sample over several hours for inulin excretion

20. Creatinine based approximations 1) Cockcroft-Gault equation CrCl (ml/min)= (140-age) x actual weight (kg) x 1.2 (if male) SCreat (µmol/L) 2) MDRD (Modification of Diet in Renal Disease) (6 variable or abbreviated version) eGFR (ml/min/1.73m2)=170 (PCr)-0.999 x (Age)-0.176 x (0.762 if female) x (1.21 if African American) x (serum urea)-0.170 x (Albumin)+0.318 Can use this slide to point out importance of adjusting for race in African Americans. These are the two main methods whereby an eGFR is generated by the lab. The CSN endorses the use of standardized methods to measure serum creatinine. Creatinine is measured in different ways in labs across Canada. It would be reasonable for the clinician to familiarize themselves with the methods employed in their local lab. Not all labs in Canada generate an eGFR value along with the serum creatinine. Pioneers in the area such as BC and Alberta have this but other areas do not have eGFR reporting at this time. Moreover, one lab may use the CG formula and another the MDRD equation. Again, the clinician is advised to familiarize themselves with the methods employed in their local lab. Both formulae have been validated in various populations with moderate to severe impairment of GFR; however they may be less reliable in patients with near normal (>60ml/min/1.73m2) GFR or in patients with markedly abnormal body composition (eg extreme obesity, cachexia, paralysis, amputations) There remain controversies as to the applicability of these equations to various ethnic groups, the very elderly and to the non-referred populations with modest decreases in renal function which are summarized on the next slide.Can use this slide to point out importance of adjusting for race in African Americans. These are the two main methods whereby an eGFR is generated by the lab. The CSN endorses the use of standardized methods to measure serum creatinine. Creatinine is measured in different ways in labs across Canada. It would be reasonable for the clinician to familiarize themselves with the methods employed in their local lab. Not all labs in Canada generate an eGFR value along with the serum creatinine. Pioneers in the area such as BC and Alberta have this but other areas do not have eGFR reporting at this time. Moreover, one lab may use the CG formula and another the MDRD equation. Again, the clinician is advised to familiarize themselves with the methods employed in their local lab. Both formulae have been validated in various populations with moderate to severe impairment of GFR; however they may be less reliable in patients with near normal (>60ml/min/1.73m2) GFR or in patients with markedly abnormal body composition (eg extreme obesity, cachexia, paralysis, amputations) There remain controversies as to the applicability of these equations to various ethnic groups, the very elderly and to the non-referred populations with modest decreases in renal function which are summarized on the next slide.

21. Why use eGFR? Better indicator of early CKD compared to serum creatinine Example: 65y Caucasian female Cr=95 umol/L eGFR= 54 ml/min/1.73m2 Stage 3 CKD The advantage of these equations over serum creatinine measurements alone is that the latter are recognized as being poor indicators of early CKD.The advantage of these equations over serum creatinine measurements alone is that the latter are recognized as being poor indicators of early CKD.

22. Problems with eGFR eGFR calculations may be less reliable in: individuals with near normal GFR (>60 ml/min/1.73m2) individuals with markedly abnormal body composition extreme obesity cachexia paralysis amputations Controversies exist as to the applicability of these formulae to various ethnic groups and the very elderly Remind them of adjusting MDRD for african-american raceRemind them of adjusting MDRD for african-american race

23. Back to Joe.. Labs Creatinine 118 µmol/L (40-100umol/L) eGFR=53 ml/min/1.73m2 Joe’s serum creatinine is in the normal range, but his kidney function is abnormal This highlights some of the problems with eGFR in that the CG equation is recognized for overestimating renal function. The MDRD equation has been validated for use in the CKD population but it is not as easy to use and not everyone has access to a computer in their clinic area. The point is made however that despite either equation’s pitfalls the patient is better served by having their eGFR calculated and then repeated in a serial fashion to determine if it is changing. Stable chronically reduced eGFR with minimal proteinuria does not necessarily need to be seen by a nephrologist. This highlights some of the problems with eGFR in that the CG equation is recognized for overestimating renal function. The MDRD equation has been validated for use in the CKD population but it is not as easy to use and not everyone has access to a computer in their clinic area. The point is made however that despite either equation’s pitfalls the patient is better served by having their eGFR calculated and then repeated in a serial fashion to determine if it is changing. Stable chronically reduced eGFR with minimal proteinuria does not necessarily need to be seen by a nephrologist.

24. Is it just about GFR? Should also assess proteinuria Marker of renal injury 24 hour urines are no longer recommended Urine dipsticks are affected by hydration status Quantify protein excretion with random urine for: Urine albumin to creatinine ratio Urine protein to creatinine ratio Can simplify it to explain that eGFR measures renal function (clearance) while proteinuria/albuminuria identifies renal injury and is associated with prognosisCan simplify it to explain that eGFR measures renal function (clearance) while proteinuria/albuminuria identifies renal injury and is associated with prognosis

25. Measuring Proteinuria

26. How to convert? To convert a protein to creatinine ratio (in mg/mmol) simply times the result by 8.83 This gives the estimated daily protein excretion in g/day for Prot:Creat mg/day microAlbu:Creat

27. Why is proteinuria important? Methods Alberta cohort from 2002-2007 920, 985 patients with at least one creatinine measured Excluded Dialysis and Transplant Proteinuria measured by dip or ACR Outcomes Mortality, MI and doubling of serum creatinine Methods Alberta cohort from 2002-2007 920, 985 patients with at least one creatinine measured Excluded Dialysis and Transplant Proteinuria measured by dip or ACR Outcomes Mortality, MI and doubling of serum creatinine

28. Why is proteinuria important? Secondary Analysis of the HOPE data; not dipstick positive Criteria: age > 55, previous CV disease or DM and 1 other risk factor, exclusion: dip stick positive urine, renal disease, CHF, hyperkalemia Secondary Analysis of the HOPE data; not dipstick positive Criteria: age > 55, previous CV disease or DM and 1 other risk factor, exclusion: dip stick positive urine, renal disease, CHF, hyperkalemia

29. Event Rates by Grade of ProteinuriaFramingham Heart Study: 16 Year Follow-up

30. Back to Joe His Creatinine 118 µmol/L eGFR=53 ml/min/1.73m2 Urine protein to creatinine ratio=0.01 g/mmol Est daily protein excretion= 88mg/day

31. What to do with the results? Now we know that Joe’s GFR is not normal and that he does not have proteinuria What to do next?

32. Questions… Is one eGFR or proteinuria measurement enough? Consider reversible factors Assess risk of progressive renal disease Who needs referral to Nephrology?

33. Natural history of elevated creatinine levels 1434 patients in a family medicine practice 58 patients had an elevated initial serum Cr levels (>130umol/L) and subsequent Cr levels within 4-5 years of follow-up This article was referenced because it is a primary care population in the Canadian setting. >50% with initially elevated Cr levels had Cr return to normal (including 50% of those with initial Cr >300) Only 7( 12%) patients progressed to a higher level over 4-5 years of followup In all 1434 patients average age was 63, 18% were diabetic, 47% were hypertensive, only 4% were referred to NephThis article was referenced because it is a primary care population in the Canadian setting. >50% with initially elevated Cr levels had Cr return to normal (including 50% of those with initial Cr >300) Only 7( 12%) patients progressed to a higher level over 4-5 years of followup In all 1434 patients average age was 63, 18% were diabetic, 47% were hypertensive, only 4% were referred to Neph

34. Serial eGFR measurements Decisions about investigation, treatment or referral should not be made based on a single measurement In a primary care setting, many patients will show improvement or normalization of kidney function upon repeat testing. The diagnosis of CKD is based on serial measurements of kidney function It is not possible to diagnose CKD on the basis of a single serum creatinine. These are statements from the position paperThese are statements from the position paper

35. CSN recommends … There will always be cases that do not fit with these recommendations (for example in a 35 year old otherwise well individual a finding of an eGFR below 60 would probably lead to repeat testing sooner than 2-4 weeks). Primary care givers are still asked to use their clinical judgement There will always be cases that do not fit with these recommendations (for example in a 35 year old otherwise well individual a finding of an eGFR below 60 would probably lead to repeat testing sooner than 2-4 weeks). Primary care givers are still asked to use their clinical judgement

36. Consider reversible factors Intercurrent illness Volume depletion Medications NSAIDs, aminoglycosides, IV contrast dye Adjust dosage of renally excreted drugs Obstruction An abdominal ultrasound may be indicated at eGFRs <60ml/min/1.73m2 May also mention fibrates, different forms of NSAIDs (suppositories, creams)May also mention fibrates, different forms of NSAIDs (suppositories, creams)

37. Back to Joe again… You repeat Joe’s eGFR in 2 weeks and then again in 3 months and it is unchanged Renal ultrasound is normal His urinalysis is normal

38. Given the stability of his eGFR, we can conclude that he has stable stage 3 CKD The cause of his CKD remains unclear at this time. Does he need a nephrology referral??

39. Natural history of CKD Community cohort of 10,000 pt >66yo with 2 creatinine measurement and mean f/u=2yr Patient characteristics: 65% stage 1 and 2 CKD; 31% are stage 3 CKD, only 4% are stage 4 and 5.Community cohort of 10,000 pt >66yo with 2 creatinine measurement and mean f/u=2yr Patient characteristics: 65% stage 1 and 2 CKD; 31% are stage 3 CKD, only 4% are stage 4 and 5.

41. Based on the recognition that many patients with an eGFR of 30 - 60 ml/min/1.73m2 do not have a high risk of progressive CKD CSN recommends: most patients with non-progressive CKD can be managed by non-nephrologists without referral Need to address two questions - why look for CKD if most will not be progressive - who does need referral to NephrologyNeed to address two questions - why look for CKD if most will not be progressive - who does need referral to Nephrology

42. Back to Joe… What now? Joe has non-progressive stage 3 CKD without proteinuria and his eGFR has been stable, So no referral needed now It is important to continue to serially follow his renal function.

43. Serial measurement is the cornerstone of CKD management.

45. Estimated prevalence of CKD in Canadians = 20 years old Stage 1 CKD > 90 ml/min 792,000 Stage 2 CKD 60 – 89 ml/min 720,000 Stage 3 CKD 30 – 59ml/min 1,032,000 Stage 4 CKD 15 – 29 ml/min 48,000 Stage 5 CKD < 15 ml/min 24,000 This reference is an excellent one for Primary Care Physicians on CKD. It also outlined the scope of the problem when it extrapolated figures from US data (which was taken from K/DOQI) and gave an idea of the numbers of Canadians who had CKD and expressed these according to their stage of CKD This slide also introduces the idea of the various stages of CKDThis reference is an excellent one for Primary Care Physicians on CKD. It also outlined the scope of the problem when it extrapolated figures from US data (which was taken from K/DOQI) and gave an idea of the numbers of Canadians who had CKD and expressed these according to their stage of CKD This slide also introduces the idea of the various stages of CKD

46. Question… Why should we be looking for CKD if most cases are non-progressive?

47. CKD Patients Are More Likely To Die Than Progress To ESRD 1996 cohort with 5 yr followup1996 cohort with 5 yr followup

48. This study shows nicely why we must pay attention to those patients with CKD. In addition to their renal disease they are at significantly greater risk for health complications related to cardiovascular disease. This study published in the NEJM in 2004 looked at 1,120,295 adults (55% were female) where a serum creatinine had been measured between 1996 and 2000 who had no history of been treated with dialysis or renal transplant. They examined the multivariate association between the estimated GFR (eGFR) and the risks of death, risk of cardiovascular event and hospitalizations. They found an independent, graded association was observed between a reduced eGFR and the risk of death, cardiovascular events and hospitalizations in a large community based population This study shows nicely why we must pay attention to those patients with CKD. In addition to their renal disease they are at significantly greater risk for health complications related to cardiovascular disease. This study published in the NEJM in 2004 looked at 1,120,295 adults (55% were female) where a serum creatinine had been measured between 1996 and 2000 who had no history of been treated with dialysis or renal transplant. They examined the multivariate association between the estimated GFR (eGFR) and the risks of death, risk of cardiovascular event and hospitalizations. They found an independent, graded association was observed between a reduced eGFR and the risk of death, cardiovascular events and hospitalizations in a large community based population

49. ESRD is not the problem Patients with CKD have high rates of cardiovascular disease Many patients die before progressing to ESRD Thus important to screen for CKD Risk of cardiovascular death is 100 X the risk of progressing to ESRDRisk of cardiovascular death is 100 X the risk of progressing to ESRD

50. CKD management Minimize further renal insult Implement renal protective measures BP target <130/80 Proteinuria target <0.5g/day HbA1C target <7% if DM Cardiovascular protection as per groups at highest CV risk Dyslipidemia and LDL reduction

51. BP management Consider Renin Angiotensin System blockade ACE-I, ARB, and DRI Particularly in patients with proteinuria and CKD Decrease proteinuria and reduce progression of CKD LVH

52. Mechanism of Action

53. Effect on GFR with ARB In their review of the ability of current agents to suppress the Renin System, Weber & Giles1 highlighted that despite the positive effects of angiotensin receptor blockers (ARBs) on outcomes in the Reduction of End-points in Non-insulin-dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) study2 and Irbesartan Diabetic Nephropathy Trial (IDNT)3, the decline in glomerular filtration rate (GFR) seen with ARB treatment in patients with Type 2 diabetic nephropathy was still higher than the expected decline due to ageing.1 Given that GFR is a strong predictor of both the risk of complications of kidney disease and the time to onset of kidney failure,4 these results indicate that patients treated with ARB therapy remain at elevated risk compared with healthy individuals. Consequently, further opportunity for therapeutic improvement remains. Weber & Giles speculated that more comprehensive suppression of the Renin System, such as that provided by Direct Renin Inhibition, may lead to improved organ protection over existing therapies.1 Abbreviations ARB = angiotensin receptor blocker GFR = glomerular filtration rate IDNT = Irbesartan Diabetic Nephropathy Trial RENAAL = Reduction of End-points in Non-insulin-dependent diabetes mellitus with the Angiotensin II Antagonist Losartan References 1. Weber MA, Giles TD. Inhibiting the renin-angiotensin system to prevent cardiovascular diseases: Do we need a more comprehensive strategy? Rev Cardiovasc Med 2006;7:45–54. 2. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861–869. 3. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851–860. 4. 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–S000. In their review of the ability of current agents to suppress the Renin System, Weber & Giles1 highlighted that despite the positive effects of angiotensin receptor blockers (ARBs) on outcomes in the Reduction of End-points in Non-insulin-dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) study2 and Irbesartan Diabetic Nephropathy Trial (IDNT)3, the decline in glomerular filtration rate (GFR) seen with ARB treatment in patients with Type 2 diabetic nephropathy was still higher than the expected decline due to ageing.1 Given that GFR is a strong predictor of both the risk of complications of kidney disease and the time to onset of kidney failure,4 these results indicate that patients treated with ARB therapy remain at elevated risk compared with healthy individuals. Consequently, further opportunity for therapeutic improvement remains. Weber & Giles speculated that more comprehensive suppression of the Renin System, such as that provided by Direct Renin Inhibition, may lead to improved organ protection over existing therapies.1 Abbreviations ARB = angiotensin receptor blocker GFR = glomerular filtration rate IDNT = Irbesartan Diabetic Nephropathy Trial RENAAL = Reduction of End-points in Non-insulin-dependent diabetes mellitus with the Angiotensin II Antagonist Losartan References 1. Weber MA, Giles TD. Inhibiting the renin-angiotensin system to prevent cardiovascular diseases: Do we need a more comprehensive strategy? Rev Cardiovasc Med 2006;7:45–54. 2. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861–869. 3. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851–860. 4. 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–S000.

54. Effect on Proteinuria of ACE-I or ARB This was a single-blind, longitudinal study in 11 patients with nondiabetic renal disease and mild-to-moderate hypertension (defined as diastolic blood pressure [DBP] ?90 mmHg and <115 mmHg), with normal or mildly impaired stable renal function (creatinine clearance ?60 mL/min) and stable proteinuria exceeding 2.0 grams per day. Patients were followed during seven periods, each of four weeks, in which they received once-daily placebo, losartan 50 mg, losartan 100 mg, placebo, enalapril 10 mg, enalapril 20 mg and placebo again, respectively. Blood pressure (BP) and 24-hour urinary protein excretion were assessed once-weekly during the first four periods, and at the end of the last three periods. Both losartan and enalapril provided significant reductions from baseline in proteinuria and BP (p<0.05). Furthermore, the efficacy of losartan and enalapril were similar with respect to the change from baseline in proteinuria and BP. The change from baseline in in urinary protein excretion was 46.3% for losartan 100 mg compared with 51.6% for enalapril 20 mg. Similarly, the mean change from baseline in BP was 15.1% for losartan 100 mg compared with 17.3% for enalapril 20 mg. Abbreviations BP = blood pressure DBP = diastolic blood pressure Reference Gansevoort RT, de Zeeuw D, de Jong PE. Is the antiproteinuric effect of ACE inhibition mediated interference in the renin-angiotensin system. Kidney Int 1994;45:861–867. This was a single-blind, longitudinal study in 11 patients with nondiabetic renal disease and mild-to-moderate hypertension (defined as diastolic blood pressure [DBP] ?90 mmHg and <115 mmHg), with normal or mildly impaired stable renal function (creatinine clearance ?60 mL/min) and stable proteinuria exceeding 2.0 grams per day. Patients were followed during seven periods, each of four weeks, in which they received once-daily placebo, losartan 50 mg, losartan 100 mg, placebo, enalapril 10 mg, enalapril 20 mg and placebo again, respectively. Blood pressure (BP) and 24-hour urinary protein excretion were assessed once-weekly during the first four periods, and at the end of the last three periods. Both losartan and enalapril provided significant reductions from baseline in proteinuria and BP (p<0.05). Furthermore, the efficacy of losartan and enalapril were similar with respect to the change from baseline in proteinuria and BP. The change from baseline in in urinary protein excretion was 46.3% for losartan 100 mg compared with 51.6% for enalapril 20 mg. Similarly, the mean change from baseline in BP was 15.1% for losartan 100 mg compared with 17.3% for enalapril 20 mg. Abbreviations BP = blood pressure DBP = diastolic blood pressure Reference Gansevoort RT, de Zeeuw D, de Jong PE. Is the antiproteinuric effect of ACE inhibition mediated interference in the renin-angiotensin system. Kidney Int 1994;45:861–867.

55. ACE-I/ARB Combo Significant controversy exists COOPERATE withdrawal ONTARGET New CHEP guidelines advise against their use What do we do with uncontrolled HTN and/or proteinuria? Supramaximal dosing Other RAAS blockade (DRI?, MRB?)

56. DRI effect on UACR The Aliskiren in the eValuation of prOteinuria In Diabetes (AVOID) study was a 6-month, double-blind, randomized, placebo-controlled study in 599 patients with mild-to-moderate hypertension, type 2 diabetes and nephropathy (urinary albumin-to-creatinine ratio [UACR] 200–3500 mg/g).1 Patients enrolled in the AVOID study received 3 months of losartan 100 mg once daily monotherapy, with optional addition of other antihypertensive agents as necessary, with the aim of achieving blood pressure (BP) <130/80 mmHg. After the 3 month open-label period, patients were randomized to receive aliskiren 150 mg or placebo once daily, in addition to continued losartan 100 mg and optimal antihypertensive therapy. After 3 months, the dosage of aliskiren was force-titrated from 150 to 300 mg for a further 3 months.1 A ?50% reduction in UACR from baseline has previously been shown to provide a significant reduction in the risk of cardiovascular (CV) events.2 In the AVOID study, when compared with the placebo group, a significantly greater proportion of patients in the aliskiren 300 mg treatment group had a ?50% reduction in UACR from baseline (p<0.001). After 6-months’ treatment, 24.7% in the aliskiren treatment group and 12.5% in the placebo group had a =50% reduction in UACR from baseline.1 Abbreviations AVOID = Aliskiren in the eValuation of prOteinuria In Diabetes BP = blood pressure CV = cardiovascular UACR = urinary albumin-to-creatinine ratio Reference 1. Parving H-H, Persson F, Lewis JB, et al. The combination of aliskiren, a direct renin inhibitor, and losartan in patients with type 2 diabetes and nephropathy. New Engl J Med 2008;358:2433–2446. 2. de Zeeuw D, Remuzzi G, Parving H-H, et al. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation 2004;110:921–927. The Aliskiren in the eValuation of prOteinuria In Diabetes (AVOID) study was a 6-month, double-blind, randomized, placebo-controlled study in 599 patients with mild-to-moderate hypertension, type 2 diabetes and nephropathy (urinary albumin-to-creatinine ratio [UACR] 200–3500 mg/g).1 Patients enrolled in the AVOID study received 3 months of losartan 100 mg once daily monotherapy, with optional addition of other antihypertensive agents as necessary, with the aim of achieving blood pressure (BP) <130/80 mmHg. After the 3 month open-label period, patients were randomized to receive aliskiren 150 mg or placebo once daily, in addition to continued losartan 100 mg and optimal antihypertensive therapy. After 3 months, the dosage of aliskiren was force-titrated from 150 to 300 mg for a further 3 months.1 A ?50% reduction in UACR from baseline has previously been shown to provide a significant reduction in the risk of cardiovascular (CV) events.2 In the AVOID study, when compared with the placebo group, a significantly greater proportion of patients in the aliskiren 300 mg treatment group had a ?50% reduction in UACR from baseline (p<0.001). After 6-months’ treatment, 24.7% in the aliskiren treatment group and 12.5% in the placebo group had a =50% reduction in UACR from baseline.1 Abbreviations AVOID = Aliskiren in the eValuation of prOteinuria In Diabetes BP = blood pressure CV = cardiovascular UACR = urinary albumin-to-creatinine ratio Reference 1. Parving H-H, Persson F, Lewis JB, et al. The combination of aliskiren, a direct renin inhibitor, and losartan in patients with type 2 diabetes and nephropathy. New Engl J Med 2008;358:2433–2446. 2. de Zeeuw D, Remuzzi G, Parving H-H, et al. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation 2004;110:921–927.

57. DRI on GFR The Aliskiren in the eValuation of prOteinuria In Diabetes (AVOID) study was a 6-month, double-blind, randomized, placebo-controlled study in 599 patients with mild-to-moderate hypertension, type 2 diabetes and nephropathy (urinary albumin-to-creatinine ratio [UACR] 200–3500 mg/g). Patients enrolled in the AVOID study received 3 months of losartan 100 mg once daily monotherapy, with optional addition of other antihypertensive agents as necessary, with the aim of achieving blood pressure (BP) <130/80 mmHg. After the 3 month open-label period, patients were randomized to receive aliskiren 150 mg or placebo once daily, in addition to continued losartan 100 mg and optimal antihypertensive therapy. After 3 months, the dosage of aliskiren was force-titrated from 150 to 300 mg for a further 3 months. In patients who received aliskiren in addition to optimal antihypertensive therapy for24 weeks, mean estimated glomerular filtration rate (eGFR) declined less from baseline(2.4 mL/min/1.73 m2) compared with those in the placebo group (3.8 mL/min/1.73 m2). The statistical analysis of the change from baseline in eGFR demonstrated that the decline in eGFR was numerically, but not statistically greater in the placebo group compared with the aliskiren group (p=0.07). These results suggest that aliskiren may preserve eGFR. Abbreviations AVOID = Aliskiren in the eValuation of prOteinuria In Diabetes BP = blood pressure eGFR = estimated glomerular filtration rate UACR = urinary albumin-to-creatinine ratio Reference Parving H-H, Persson F, Lewis JB, et al. The combination of aliskiren, a direct renin inhibitor, and losartan in patients with type 2 diabetes and nephropathy. New Engl J Med 2008;358:2433–2446. The Aliskiren in the eValuation of prOteinuria In Diabetes (AVOID) study was a 6-month, double-blind, randomized, placebo-controlled study in 599 patients with mild-to-moderate hypertension, type 2 diabetes and nephropathy (urinary albumin-to-creatinine ratio [UACR] 200–3500 mg/g). Patients enrolled in the AVOID study received 3 months of losartan 100 mg once daily monotherapy, with optional addition of other antihypertensive agents as necessary, with the aim of achieving blood pressure (BP) <130/80 mmHg. After the 3 month open-label period, patients were randomized to receive aliskiren 150 mg or placebo once daily, in addition to continued losartan 100 mg and optimal antihypertensive therapy. After 3 months, the dosage of aliskiren was force-titrated from 150 to 300 mg for a further 3 months. In patients who received aliskiren in addition to optimal antihypertensive therapy for24 weeks, mean estimated glomerular filtration rate (eGFR) declined less from baseline(2.4 mL/min/1.73 m2) compared with those in the placebo group (3.8 mL/min/1.73 m2). The statistical analysis of the change from baseline in eGFR demonstrated that the decline in eGFR was numerically, but not statistically greater in the placebo group compared with the aliskiren group (p=0.07). These results suggest that aliskiren may preserve eGFR. Abbreviations AVOID = Aliskiren in the eValuation of prOteinuria In Diabetes BP = blood pressure eGFR = estimated glomerular filtration rate UACR = urinary albumin-to-creatinine ratio Reference Parving H-H, Persson F, Lewis JB, et al. The combination of aliskiren, a direct renin inhibitor, and losartan in patients with type 2 diabetes and nephropathy. New Engl J Med 2008;358:2433–2446.

58. Joe: three years later You have continued to follow his eGFR and notice that it is now 42 ml/min/1.73m2 All clinical targets (BP, HBA1C, cholesterol) are stable No intercurrent illnesses His CKD is no longer stable

59. Who should be referred to a Nephrologist? Patients with acute renal failure Patients with eGFR <30ml/min/1.73m2 Patients with progressive loss of eGFR Persistent significant proteinuria (present on 2 out of 3 samples) on dipstick quantified PCR >100mg/mmol (~900mg/d) quantified ACR >60 mg/mmol (~500mg/d) Inability to achieve treatment targets or other difficulties in the management of the CKD patient Make a note about hematuriaMake a note about hematuria

60. Etiologies of CKD Ischemic Nephropathy Diabetes Chronic Glomerulonephritis Chronic Interstitial Nephritis Polycystic Kidney Disease Chronic Obstruction/Congenital Urologic

61. What information does a Nephrologist want? Complete medical Hx and med list eGFR (serial measurements) Urine Dip Urine protein quantification Renal US Lytes, Calcium, Phos SPEP and random UPEP if proteinuria is present

63. Summary Who should be tested for CKD? Diabetes mellitus Hypertension Heart failure Atherosclerotic coronary, cerebrovascular or peripheral vascular disease Unexplained anemia Family history of ESRD First nations peoples

64. Complications of CKD Cardiovascular Death LVH Hypertension Anemia Bone Metabolism Disorders Hyperkalemia Acidosis

65. Summary What tests should be ordered? eGFR to assess kidney function random urine sample to assess for significant persistent proteinuria CBC, Lytes, Ca, Phos, Albu What should be done with the results? follow serially assess for proteinuria implement risk reduction strategies

66. Nephrology referral is indicated when Patients with acute renal failure Patients with eGFR <30ml/min/1.73m2 Patients with progressive loss of eGFR Persistent significant proteinuria (present on 2 out of 3 samples) on dipstick quantified PCR >100mg/mmol (~900mg/d) quantified ACR >60 mg/mmol (~500mg/d) Inability to achieve treatment targets or other difficulties in the management of the CKD patient