1. Management of Diabetic Nephropathy & What to prescribe! Theingi Aung Endocrinologist, RBH 4 th Feb 2015

2. Diabetic nephropathy…. General management Specific management Long term follow-up Referral to specialist

3. Diabetic nephropathy –T1DM T1D ~ 20-30% will have moderate albuminuria after mean duration diabetes 15 years Prior to intensive combined control incidence of overt nephropathy higher 25-45%, and progression from this to ESRD Lower rates due to intensive treatment of HbA1c and BP. In DCCT <2% of intensively treated developed renal insufficiency Stanton Am J Kidney Disease 2014(63)S3-21;Ritz NEJM 1999;341(15):1127; Nathan Arch Intern Med 2009;169: 1307

4. Diabetic nephropathy T2DM T2D similar renal risk - time to proteinuria from diabetes onset and time to ESRD from proteinuria onset similar for T1 and T2 UKPDS: 5100 patients, 10yrs after diagnosis-25% albuminuria; 5% severe albuminuria; 0.8% Cr>175 or needing RRT Am J Kidney Disease 2014(63)S3-21;Ritz NEJM 1999;341(15):1127; Adler Kidney Int 2003; 63(1):225

5. Risk Factors Non-modifiable - Genetic predisposition - Ethnicity - Age Modifiable - HbA1c - BP - lipids - Weight, diet, smoking, other factors

6. General management Smoking cessation Drug history – stop nephrotoxins - IV contrast, NSAIDs - assess metformin Cardio-renal patients – severe CCF Weight, consider bariatric intervention

7. Health benefit of modest (10%) weight loss Mortality20-25% fall in overall mortality 30-40% fall in diabetes related deaths 40-50% fall in obesity-related cancer deaths DiabetesUp to 50% fall in fasting blood glucose Reduces risk of developing diabetes by over 50% LipidsFall of 10% total cholesterol, 15% LDL and 30% TG Increase of 8% HDL Blood Pressure 10 mmHg fall in diastolic and systolic pressures

8. Diet modification Uncertain if dietary protein restriction improves long-term decline in GFR Small studies show some benefit

10. Diet – protein restriction Uncertain if dietary protein restriction slows long-term decline in GFR Small studies show some benefit Recent prospective study – benefit uncertain Practical difficulties with low-protein diet - compliance due to concurrent fat and simple CHO restriction - including risk protein malnutrition in diabetes Limit to a level not difficult for compliance: 0.6 -1g/kg/day Hansen Kidney Int 2002; 62:220; Brodsky JCEM 1992; 75:351

11. Diet – salt restriction Fall in blood pressure with salt restriction High salt intake can blunt antiproteinuric effect of ACEi/ARBs Salt restriction to <70meq/day beneficial Difficult to maintain <100meq/day (5-6g/day) recommended If not possible, co administration of diuretic partially corrects the loss of antiproteinuric effect due to high sodium intake Bakris Ann Intern Med 1996; 125:201; Houlihan Diabetes Care 2002; 25:663; Esnault J Am Soc Nephrol 2005; 16:474 Cochrane review/Database

12. Specific management Intensive combined therapy Target the many factors underlying disease Hyperglycaemia Hypertension Dyslipidaemia

13. Hyperglycaemia In T1 or T2D hyperglycaemia major determinant of progression of diabetic nephropathy Evidence best established in T1D Efficacy partly depends on stage at which begun and degree of normalisation of glucose metabolism

14. Benefit of strict glycaemic control on kidney Intensive therapy can Reverse glomerular hypertrophy and hyperfiltration Delay development of elevated albumin excretion Stabilize or even reverse microalbuminuria Can slow progression of GFR decline

16. Hyperglycaemia In pancreas transplant patients restoring euglycaemia prevented recurrent nephropathy in renal allografts Euglycaemic pancreatic transplant slow progressive renal disease even after dipstick-positive proteinuria Diabetes Care 2000; 23:B21; Bilous NEJM 1989; 321:80; DCCT NEJM 2011; 365:2366; Fioretto Kidney Int 2006: 69:907

17. Main tissue and organ targets of glucose-lowering drugs. Arnouts P et al. Nephrol. Dial. Transplant. 2013;ndt.gft462 © The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

18. Prescribing in diabetic nephropathy 1. Metformin Eliminated unchanged via the kidney, partly by glomerular filtration and partly by tubular secretion Avoid accumulation of excess metformin: a risk of lactic acidosis not recommended with eGFR<30 use with caution eGFR 30-44

19. Prescribing in diabetic nephropathy 2. Sulphonylureas Proportion of these metabolites will be eliminated via the kidney Risk of accumulation Use with care in CKD – risk hypoglycaemia Use lowest dose that adequately controls blood glucose

20. Prescribing in diabetic nephropathy 3. DPP4 inhibitors Sitagliptin –80% cleared by kidney – dose reduction with reduced GFR; –100mg standard dose – reduce to 50mg with GFR 30-50ml/min; reduce to 25mg with GFR<30 Saxagliptin –can prescribe upto 5mg daily; with GFR<50 reduce to 2.5mg Aloglitpin –reduce from 25 to 12.5mg with GFR<60; reduce to 6.25mg if GFR<30 Linagliptin –no dose reduction needed with reduced GFR Diabetes Care 2007;30(7):1862; Expert Opin Drug Metab Toxicol. May 2013;9(5):529

21. Prescribing in diabetic nephropathy 4.Sodium-glucose cotransporter 2 (SGLT2) inhibitors Dapaglifozin not recommended with eGFR<60 Canagliflozin reduce to 100mg with GFR 45-60; not recommended with eGFR<45 Empagliflozin reduce to 100mg with GFR 45-60; not recommended with eGFR<45

22. Prescribing in diabetic nephropathy 5.GLP1 receptor agonists Exenatide clearance is GFR dependant; use with caution at eGFR 30-50ml/min and avoid if GFR<30 Liraglutide not metabolized by kidney; no dose adjustment required with reduced eGFR inc those with ESRD – data limited in this group ABCD audit showed liraglutide safe and effective in GFR>30ml/min Br J Clin Pharmacol. 2007;64(3):317; Endocr Pract. 2011;17(3):345; Practical Diabetes 2013; 30(2): 71

23. Suggested use and dose adaptation of glucose-lowering drugs according to the CKD stages (see also Table 1 for details). *1.5 g with eGFR > 45 mL/min and 850 mg with eGFR 30–45 mL/min; **to be temporarily witheld in periods of unstable eGFR. Arnouts P et al. Nephrol. Dial. Transplant. 2013;ndt.gft462 © The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

24. Insulin prescribing in diabetic nephropathy In advanced CKD - reduced degradation insulin and marked reduction in insulin requirement Can partially reverse with dialysis Careful individualised therapy and dosing Reduce insulin dose with GFR<50 (~75%) Significantly reduce with GFR<10 (~50%)

25. Specific management Intensive combined therapy Target the many factors underlying disease Hyperglycaemia Hypertension Dyslipidaemia

26. Hypertension Strict blood pressure control is important for preventing progression of diabetic nephropathy and other complications in patients with type 2 diabetes In the United Kingdom Prospective Diabetes Study (UKPDS), each 10 mmHg reduction in systolic pressure was associated with a 12 percent risk reduction in diabetic complications (P<0.001); the lowest risk occurred at a systolic pressure below 120 mmHg

27. Hypertension Adler BMJ 2000;321:412

28. Hypertension: ACEi and T1D ACEi delays development of diabetic nephropathy NEJM 1993; 329:1456; Kidney Int 2001; 60

31. Hypertension: ACEi and T1D ACEi delays development of diabetic nephropathy Beneficial effect of preventing progression from microalbuminuria to overt nephropathy is longlasting (8y) and associated with preservation of GFR Beneficial effect seen in normotensive and hypertensive subjects Remission or regression can occur with aggressive control of BP particularly with ACEi NEJM 1993; 329:1456; Kidney Int 2001; 60

32. Renin Angiotensin system in T2D Much less data on effect of ACEi on nephropathy in T2D but similar benefit appears to be present More data on efficacy of angiotensin II receptor blockers (ARBs) IDNT and RENAAL trials showed ARBs superior to conventional therapy and amlodipine in slowing the progression of overt nephropathy Am J Kid Dis 2005;45:281; Kidney Int 2004;65:2309

34. RENAAL 1513 patients with type 2 diabetes with nephropathy randomly assigned to losartan (50 titrating up to 100 mg once daily) or placebo Every 10 mmHg increase in the baseline systolic blood pressure was associated with an enhanced risk of end- stage renal disease or death of 6.7 percent Lowering albuminuria within the first six months correlated with a decreased subsequent cardiovascular risk

35. ACEi vs ARBs No good head to head comparisons of ACEi and ARBs ACEi or ARBs appear beneficial for renoprotection in diabetic nephropathy MICRO-HOPE, ramipril reduced the risk for myocardial infarction, stroke, or cardiovascular death by 26% after 2 years Lancet 2000;355:253

36. Combination of ACEi & ARB better?

37. The Veterans Affairs Nephropathy in Diabetes study (VA NEPHRON-D) Randomized placebo-controlled double-blind trial 1448 with diabetic nephropathy All patients received 100 mg/day of losartan Randomly assigned to placebo or lisinopril (10 to 40 mg/day as tolerated); Primary endpoint was a composite of a 50 percent estimated GFR decline (or more than 30 mL/min/1.73 m2), end-stage renal disease, or death. The trial was discontinued early after a median of 2.2 years because of safety concerns.

38. Combination ACEi and ARB therapy not recommended Combined therapy with ACEi and ARB decreases proteinuria in T1 and T2D compared with either therapy alone Several combination trials now shown higher rates acute kidney injury (requiring dialysis) and hyperkalaemia (NEPHRON-D; ONTARGET) Thus combination ACEi and ARB not recommended NEJM 2013; 31:414; NEJM 2013; 369:1892

40. Other agents Direct renin inhibitors (aliskiren) – did not preserve renal function and increased adverse events (ALTITUDE) Aldosterone antagonists have additive antiproteinuric effect but significant risk hyperkalaemia; Finerenone-ARTS-DN Endothelin antagonists showed antifibrotic, anti-inflammatory, and antiproteinuric effects in experimental studies Avosentan administered in addition to standard treatment with an ACE inhibitor or an ARB, reduced proteinuria after 3-6months (ASCEND) NEJM 2012; 367:2204J Am Soc Neph 2009; 20:2641; Br J Clin Pharm 2013;76:573

43. Management HTN ACEi are superior to beta-blockers, diuretics, and calcium channel blockers in reducing urinary albumin excretion in normotensive and hypertensive T1 and T2D Treatment with an ACE inhibitor for 12 months has significantly reduced mean arterial blood pressure and the urinary albumin excretion rate in type 2 DM patients who have microalbuminuria In addition to beneficial cardiovascular effects, ACE inhibition shown benefit on progression of diabetic retinopathy and development of proliferative retinopathy Recommendation is to aim for BP 130/80 or lower. Almost all patients will need more than one agent. Combination ACEi and ARB not recommended

44. Standard of care in Diabetes-2015 (ADA position statement)

46. Specific management Intensive combined therapy Target the many factors underlying disease Hyperglycaemia Hypertension Dyslipidaemia

47. Hyperlipidaemia Aggressive lipid lowering important part of medical management all patients with diabetes High Lipid promote systemic atherosclerosis Contribute to glomerulosclerosis in CKD Lipid lowering may slow rate of progression of CKD including diabetic nephropathy Less progression to microalbuminuria in patients on fenofibrate treatment (DAIS) – possible mechanism suppression of inflammation and decreased type 1 collagen in mesangial cells Kidney Int 2006;70:177; Am J Kidney Dis 2012; 60:896

48. Standard of care in Diabetes-2015 (ADA position statement)

49. Other complications Patients with nehropathy and T1D almost always have other signs microvascular disease – retinopathy and neuropathy Retinopathy can be detected clinically and typically precedes onset of overt nephropathy Less clear in T2D, T2D with marked proteinuria and retinopathy most likely have diabetic nephropathy, those without retinopathy have high frequency of nondiabetic glomerular disease Clin Nephrol 2007; 67:293

50. Long term monitoring Regular outpatient follow-up Regular annual urinalysis is recommended for screening for microalbuminuria Ensuring optimal glucose control Optimizing blood pressure Screening for other associated complications of diabetes (eg, retinopathy, diabetic foot, cardiovascular disease) Referral to Diabetes renal clinic

52. Diabetes-Renal clinic at RBH Intervene before too late!! Diabetic nephropathy CKD 3 One-stop new patient clinic To review and investigate accordingly To develop individualised care plan for patients before refer them back to primary care physician ESRD/RRT – Nephrologist referral

53. Diabetic nephropathy…. General management Specific management Long term follow-up Referral to specialist

55. Primary prevention Treat associated risk factors such as hyperlipidemia, smoking, and hypertension (BP < 130/80 Hg) Early detection and optimal management of diabetes(HbA1c < 6.5%), especially in the setting of family history of diabetes Avoidance of potentially nephrotoxic substances such as NSAIDs and aminoglycosides No evidence that ACEi or ARBs are effective for the primary prevention of microalbuminuria in normoalbuminuric and normotensive T1D. These patients should be screened yearly for microalbuminuria and ACEi initiated if persistent moderately increased albuminuria is documented