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Progressive Chronic Kidney Disease. Cherelle Fitzclarence August 2009. Overview. Case studies Discussion Take home messages. 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
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Progressive Chronic Kidney Disease • Cherelle Fitzclarence • August 2009
Overview • Case studies • Discussion • Take home messages
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Discussion • NHANES 3 study – T2DM with creat > 150 -1/3rd 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
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
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
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
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
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
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)
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)
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
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
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
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
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
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
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%
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
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
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
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
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
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
Discussion • BENEDICT study • ACEi decreased albumuria in T2DM with hypertension and normal albumin excretion • RENAAL study • Similar results with AR2B
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
Conclusion • Keep your chronic disease protocols handy
Acknowledgements • Information taken from chapter 11 Clinical Cases in Kidney Disease by David Harris and colleagues