1. Progressive Chronic Kidney Disease Cherelle Fitzclarence August 2009

2. Overview Case studies Discussion Take home messages

3. Case 1 50 yo diabetic – 5 yr hx Initial poor control but good last 3 years with combo of insulin and oral hypoglycaemics Monitors own sugars Post prandial BSL’s <10mmol/L HbA1c – 5-7% No peripheral neuropathy No retinopathy Albuminuria Hypertension

4. Case 1 cont. In large epidemiological surveys for diabetes and chronic kidney disease, which of the following are correct? –About 1 in 20 people have abnormalities on urinalysis –About 8% of the general population have evidence of diabetes mellitus –About 1 in 10 type 2 diabetics have evidence of diabetic nephropathy –Those with diabetes are at risk of end stage kidney disease

5. Case 1 cont. Question 1 In large epidemiological surveys for diabetes and chronic kidney disease, which of the following are correct? –About 1 in 20 people have abnormalities on urinalysis –About 8% of the general population have evidence of diabetes mellitus –About 1 in 10 type 2 diabetics have evidence of diabetic nephropathy –Those with diabetes are at risk of end stage kidney disease

6. Discussion Case 1 AusDiab 1 in 7 pts in Australia have diabetes. This can be as high as 1 in 3 in indigenous Australians CKD was defined by presence of blood or protein on urinalysis and/or serum creatinine >150 8% of the surveyed group had diabetes and half of them were unaware of Dx 30% of those surveyed had hypertension with half being unaware of Dx 1 in 3 type 2 diabetics will develop nephropathy

7. Take home message Type 2 Diabetes is now worldwide, the most common cause of end stage kidney disease Indigenous populations have much higher rates of end stage kidney disease (ESKD) Risk factors for ESKD –Hypertension –Diabetes –Family history –Ethnicity –Smoking –Obesity

8. Case 1 Question 2 Which of the following is the most appropriate investigation when screening for CKD? –24 hr urinary protein –24 hr urinary albumin excretion –Urinary prot/creat ratio on a spot urine –Urinary alb/creat ratio on a spot urine –MSU with dipstick, spot ACR, microscopy and culture

9. Case 1 Question 2 Which of the following is the most appropriate investigation when screening for CKD? –24 hr urinary protein –24 hr urinary albumin excretion –Urinary prot/creat ratio on a spot urine –Urinary alb/creat ratio on a spot urine –MSU with dipstick, spot ACR, microscopy and culture

10. Discussion CARI/KCAT reviewed evidence Combo screening the best – –U/A – MSU - m,c,s –ACR –BP –Serum creatinine (GFR) This should be done yearly in high risk groups – eg diabetics, ATSI Further discussion

11. Take home message Single urine dipstick for protein – limitations false positives, false negatives Kidney function should be measured at least yearly in those at increased risk CKD Screening should include measurement of BP, serum creatinine (GFR), MSU Protein creatinine ratio or albumin creatinine ration

12. Case 1 Question 3 Which of the following is/are true statements concerning tests for assessing CKD? –Serum creatinine is an accurate measure of renal function and if <120 excludes nephropathy –GFR estimated from a formula is an accurate measure of renal function –A deterioration in eGFR or more than 15% over a period of months is sign of acute renal failure –An eGFR of >20mls/min excludes clinically relevant renal disease

13. Case 1 Question 3 Which of the following is/are true statements concerning tests for assessing CKD? –Serum creatinine is an accurate measure of renal function and if <120 excludes nephropathy –GFR estimated from a formula is an accurate measure of renal function –A deterioration in eGFR or more than 15% over a period of months is sign of acute renal failure –An eGFR of >20mls/min excludes clinically relevant renal disease

14. Discussion Serum creatinine can stay in the normal range until more than 50% of GFR is lost Serum creatinine is dependent on age, weight, gender and muscle mass Small people with low muscle mass, elderly, female may have significant renal impairment despite a ‘normal’ creatinine GFR falls over hours, days or weeks in acute renal failure GFR falls over months, years in chronic renal failure eGFR is used to stage kidney disease

15. Discussion StageGFR mL/min/1.73 Expected CM’s 1>90None or the primary disease process 260-89None, hyperparathyroidism, increased risk CVD 330-59Nocturia, anaemia, increased creat, decreased vit D, dyslipidaemia, abN extracellular volume 415-29Uraemic symptoms, abnomalities electrolytes 5<15Severe uraemic symptoms, dialysis

16. Take home message eGFR is useful as a screening tool for CKD Should be used in conjunction with BP, U/A, ACR eGFR can be used to stage CKD

17. Case 1 continues Over next 12 months, renal disease progresses Creat 312 Risk factors for cardiovascular disease poorly controlled –BP >150 with 4 drug therapy on board ACEI, CCB, BB, Frusemide –Hyperlipidaemia despite statin therapy –ACR increasing despite ACEI

18. Case 1 Question 4 In slowing the progression of renal disease and avoiding the development of malnutrition in CKD patients with an eGFR 15-30 mls/min, which of the following statements is/are correct? –Nephrotic patients need a high protein diet –Reducing proteinuria to <1g/24 hours is associated with a reduction in rate of decline off renal function –Proteinuria is a good measure of renal dysfunction –Heavy proteinuria (>3g/24hrs) predicts the response to ACEI

19. Case 1 Question 4 In slowing the progression of renal disease and avoiding the development of malnutrition in CKD patients with an eGFR 15-30 mls/min, which of the following statements is/are correct? –Nephrotic patients need a high protein diet –Reducing proteinuria to <1g/24 hours is associated with a reduction in rate of decline off renal function –Proteinuria is a good measure of renal dysfunction –Heavy proteinuria (>3g/24hrs) predicts the response to ACEI

20. Discussion CARI guidelines advise against excessive protein restriction for slowing renal function decline High protein diets do little to correct the malnourished state Control of BP can signifcantly reduce proteinuria esp ACEI, AR2B, aldosterone antagonists

21. Take home message Low protein diets may slow progression CKD but only a small impact and may increase risk of malnutrition High protein diets are not effective in treating malnutrition and may accelerate CKD Lowering BP decreases proteinuria Degree of preservation of renal function achieved with AHA directly proportional to decrease in proteinuria ACEI/AR2B’s slow progression CKD more than explained just be AHA

22. Case 1 Question 5 When a pt with T2DM is assessed for diabetic nephropathy, which of the following is correct? –The absence of proteinuria excludes diabetic nephropathy –Hypertension usually indicates the presence of concomitant macrovascular disease –The severity of diabetic nephropathy is related to the severity of hypertension –The absence of diabetic retinopathy excludes diabetic nephropathy –Kimmelstiel-Wilson lesions must be present to diagnose diabetic nephropathy

23. Case 1 Question 5 When a pt with T2DM is assessed for diabetic nephropathy, which of the following is correct? –The absence of proteinuria excludes diabetic nephropathy –Hypertension usually indicates the presence of concomitant macrovascular disease –The severity of diabetic nephropathy is related to the severity of hypertension –The absence of diabetic retinopathy excludes diabetic nephropathy –Kimmelstiel-Wilson lesions must be present to diagnose diabetic nephropathy

24. Discussion NHANES 3 study – T2DM with creat > 150 -1/3 rd had no evidence of proteinuria Due to more of a Vasculopathy (particularly microvascular) than by classic histological changes of glomerular basement membrane thickening and mesangial expansion Vasculopathy is associated with hypertension and may not be associated with proteinuria Vasculopathy leads to progressive CKD, accelerated by diabetic control, hypertension, proteinuria

25. Take home message Not all T2DM with CKD have proteinuria Hypertension is common and is associated with progressive CKD If hypertension is resistant, think RAS Diabetic retinopathy and nephropathy are commonly but not always bound together

26. Case 1 Question 6 Which of the following is true regarding treatment aimed at slowing the progression of CKD and at preventing cardiovascular events such as AMI and CVA? –The target BP is <140/90 –Only ACEI and AR2B slow progression CKD –In large studies, ACEi have been shown to improve overall survival in diabetics with large and small vessel vasculopathy –The presence of renovascular diesease is a contraindication to the use of ACEI or AR2B

27. Case 1 Question 6 Which of the following is true regarding treatment aimed at slowing the progression of CKD and at preventing cardiovascular events such as AMI and CVA? –The target BP is <140/90 –Only ACEI and AR2B slow progression CKD –In large studies, ACEi have been shown to improve overall survival in diabetics with large and small vessel vasculopathy –The presence of renovascular diesease is a contraindication to the use of ACEI or AR2B

28. Discussion Target BP should be <130/80 If diabetic with protenuria <1g/24 hours target should be <120/75 BP decrease alone contributes to slowing CKD All antihypertensives good for this but AR2B and ACEI have greatest efficacy HOPE and PROGRESS show ACEI in high risk populations decrease cardiovascular events Atherosclerotic renovascular disease with evidence of RAS is not an absolute contraindication to the use of ACEI or AR2B but you need to be very careful

29. Take home message Target BP –Proteinuria <1g/24hours 130/80 –Proteinuria >1g/24hours 120/75 For diabetic CKD target BP <120/75 AR2B and ACEI preferred but any agent ok as long as BP controlled Atherosclerotic renovascular disease not absolute contraindication to ACEi

30. Case 1 Question 7 In general, which of the following results in 50yo indicate need for referral to Nephrologist? –Diabetic with eGFR <60 and poorly controlled hypertension –A non diabetic with an eGFR 30-60mls, proteinuria <0.5g/day, controlled BP –Proteinuria >1g/day with normal eGFR –Unexplained decline in kidney function (>15% drop GFR over 3 months)

31. Case 1 Question 7 In general, which of the following results in 50yo indicate need for referral to Nephrologist? –Diabetic with eGFR <60 and poorly controlled hypertension –A non diabetic with an eGFR 30-60mls, proteinuria <0.5g/day, controlled BP –Proteinuria >1g/day with normal eGFR –Unexplained decline in kidney function (>15% drop GFR over 3 months)

32. Discussion Late referral to Nephrologist associated with poorer outcomes, greater morbidity for RRT and pall care groups Guidelines only and controversial – if not sure err on side of caution In general, stable patients with eGFR >30 don’t require referral but a significant number can benefit from referral and progression may be able to be averted

33. Take home message Indications for referral to Nephrologist –Proteinuria > 1g/24 hrs –eGFR < 30mls in non diabetics –eGFR < 60mls in diabetics –Unexplained decline in kidney function –Glomerular haematuria with proteinuria –CKD with difficult to control hypertension –Otherwise unexplained anaemia

34. Case 1 Question 8 Pt’s Hb dropped to 90 and treatment with epo commenced. Which of the following are true? –Most common cause for anaemia in CKD with GFR<60 is bleeding from the upper GIT –If pt on EPO, iron therapy is not required if serum ferritin is >100 –Treating the anaemia of CKD is not required until HB<100 –Anaemia occurs earlier in the course of CKD in diabetic than non diabetic patients

35. Case 1 Question 8 Pt’s Hb dropped to 90 and treatment with epo commenced. Which of the following are true? –Most common cause for anaemia in CKD with GFR<60 is bleeding from the upper GIT –If pt on EPO, iron therapy is not required if serum ferritin is >100 –Treating the anaemia of CKD is not required until HB<100 –Anaemia occurs earlier in the course of CKD in diabetic than non diabetic patients

36. Discussion Small increased risk in GIH Anaemia of CKD is due to relative erythropoietin deficiency and show up in stage 3 and is more severe in diabetics Prior to epo, iron deficiency was rare due to blood transfusions Now relative iron deficiency is a problem EPO can only be prescribed once Hb <100 Aim Hb 120 Worse outcomes if Hb higher than this Renal anaemia is often iron responsive

37. Discussion Aims Prior to starting epo – ferritin >100 Once epo started – ferritin 400-600 Transferrin saturation >20% prior to epo therapy Transferrin saturation 30-40% post epo starting Adequate iron stores required for epo to work Iron deficiency is most common cause of hyporesponsiveness to epo

38. Take home message Impaired absorption of oral iron and increased utilization of iron with EPO therapy have contributed to the development of iron deficiency Optimize responsiveness to EPO – targets for ferritin 300-600 and saturation 30-40%

39. Case 1 CKD progresses and he needs dialysis. GP questions whether other therpay may have prevented such a rapid progression to ESKD Question 9 –For which of the following therapies is there level 1 evidence for efficacy in the CKD population Cholesterol lowering with statins both to slow progressive decline of renal function and to reduce the increased cardiovascular risk associated with CKD Uric acid reduction slows progression Exercise and weight loss improve insulin resistance and slow progression Aldosterone blockade can further slow progression AR2B can further slow progression in pts on ACEI

40. Case 1 CKD progresses and he needs dialysis. GP questions whether other therpay may have prevented such a rapid progression to ESKD Question 9 –For which of the following therapies is there level 1 evidence for efficacy in the CKD population Cholesterol lowering with statins both to slow progressive decline of renal function and to reduce the increased cardiovascular risk associated with CKD Uric acid reduction slows progression Exercise and weight loss improve insulin resistance and slow progression Aldosterone blockade can further slow progression AR2B can further slow progression in pts on ACEI

41. Discussion Decrease uric acid, cessation of smoking, weight loss all slow progression but evidence is poor; studies small, non randomised, case studies Statins thought to help but again studies not good – no RCT AR2B and ACEI combo thought to help if patient proteinuric – COOPERATE study

42. Take home message Allopurinol, weight loss, cessation of smoking, exercise may all slow progression of CKD but no level one evidence Beneficial effect of lipid though to be present but still waiting level 1 evidence AR2B and ACEi together can help delay progression in pt with proteinuria

43. Case 1 Question 10 In type 2 DM ACEi and AR2B have been shown to slow the development of progression of nephropathy in pts who are –Normoalbuminuric and normotensive –Normoalbuminuric and hpertensive –Microalbuminuric and hypertensive –Macroalbuminuric and hypertensive

44. Case 1 Question 10 In type 2 DM ACEi and AR2B have been shown to slow the development of progression of nephropathy in pts who are –Normoalbuminuric and normotensive –Normoalbuminuric and hypertensive *** –Microalbuminuric and hypertensive –Macroalbuminuric and hypertensive

45. Discussion BENEDICT study –ACEi decreased albumuria in T2DM with hypertension and normal albumin excretion –RENAAL study –Similar results with AR2B

46. Take home message ACEi and AR2B have been proven in hypertensive type 2 diabetics to slow progression of CKD, development of microalbuminuria, macroalbuminuria Don’t use combination in patients who are simply hypertensive

47. Conclusion Keep your chronic disease protocols handy

48. Acknowledgements Information taken from chapter 11 Clinical Cases in Kidney Disease by David Harris and colleagues