1. DIABETIC NEPHROPATHY MAY 2013 DR RAMESH B NAIK FRCP

2. Causes of ESRF in Patient Starting Dialysis UK (%) Diabetes30 Glomerulonephritis12 Pyelonephritis9 Polycystic Kidney Disease10 Hypertension8 Renovascular disease6 Uncertain17 Others8

3. Acceptance Rates for RRT 100-120 pmp/yr in UK USA – Whites 185 pmp/yr Blacks 758 pmp/yr Total – 242 pmp/yr Berkshire is 114 but Slough is 143 pmp/yr Age 1982 11% over 65 years old Now 50% - will be more Liberalisation of attitudes

4. PREVALENCE OF DIABETES Percentages All ethnic minorities5.6 Caribbean5.9 All South Asians5.9 Indian5.5 African Asian4.0 Pakistani7.6 Bangladeshi7.4 Chinese2.2 White2.2

5. Diabetic Renal Failure - Incidence Commonest cause of ESRF & rising Major implications for dialysis programmes EuropeUSA 19763% 198511%23% 199217% 199322%36% 200425-30%40-45% 1985 60% type I 1993 60% type II

6. Diabetic RF - Pathology Four Stages:- Hypertrophy / hyperfiltration Microalbuminuria Diabetic glomerulosclerosis ESRF

7. Microalbuminuria in Guidelines Existing UK guidance Joint British Societies 2 Guidelines (2005)  Recognise MAU, proteinuria and CKD as TOD  CKD defined by eGFR levels  Patients with raised blood pressure and TOD should be considered high risk and be managed accordingly  Diabetes and TOD – BP target 130/80 mm Hg

8. What is Microalbuminuria? Definitions and prevalence Levels of urinary albumin above the normal range, but lower than dipstick-positive proteinuria below are termed microalbuminuria Microalbuminuria is found in: 5-7% of the ‘healthy’ population 12-30% of the hypertensive population Morning urine sample (mg/l) Morning urine sample – Albumin to Creatinine Ratio (mg/mmol) Normal <20Males <2.5 Females <3.5 Microalbuminuria 20-200Males 2.5-25 Females 3.5-25 Macroalbuminuria (proteinuria) >200Males >25 Females >25

9. Microalbuminuria: both risk marker and independent risk factor Presence of Microalbuminuria Increased Risk of Renal Complications Increased Risk of Cardiovascular Events Increased Risk of New Onset Diabetes

10. GUIDELINES FOR DIABETIC RENAL DISEASE Persistent Microalbuminuria earliest marker of diabetic nephropathy  Associated with increased risk of  Retinopathy  Cardiovascular disease  Reversible in up to 50% if treated early

11. If negative, EMU for ACR If ACR positive, repeat 2x within 12 weeks If negative, repeat annually If positive dipstick proteinuria, or positive ACR WE MUST DO SOMETHING ANNUAL PROTEIN DIPSTICK

12.  All patients (regardless of BP)  Add ACEI/ARB (Check Renal Function)  To maximum dose  Lifestyle modification  Diet (Dietician)  Exercise  Smoking cessation  Glycaemic control ( HbA1C <7% )  BP 130/80 (or 125/75 if proteinuria >1gm) Which drugs ( CaCB Diuretics BB )  Aspirin. Statin  Metformin. Fibrates ( Avoid or Stop ) WHAT DO WE DO

13. Renal Clinic  Urine protein >1gm/24 hrs  Creatinine >150mmol//litre  Diagnostic uncertainty Diabetes Clinic  Difficulty achieving BP or HbA1C  Persistent dyslipidaemia

14. DIABETIC NEPHROPATHY DM more common in Europe and North America Long induction of 20-30 years from onset DM to RF Increased prevalence DM not impacted on numbers. Tidal wave yet to come! Lifestyle of increasing inactivity and high calorie intake favours development of T2DM in genetically susceptible individuals Ageing population has exposed more individuals to risk, decreasing mortality from CV causes means more survive to get ESRF

15. Genetic Factors are Important Some Ethnic groups have higher incidence of DM and diabetic nephropathy AA and native Americans in USA, A-C in Caribbean and UK, South Asians worldwide, every Polynesian population Higher incidence of older people in some regions of Germany e.g. in lower Neckar region 50% of dialysis population

16. ESRD IN DIABETES[2009] A. New pts with DM developing ESRD 44% in USA and 25% in UK B. Incident no. of patients in USA 355 pmp cf 110pmp in UK C. No. of prevalent patients rising. 572000 on ESRD RX [half DM] in USA; 50000 in UK [17.5% DM] D. Survival with ESRD and DM at 1 yr on dialysis 2002 76% 2009 84%

18. DIABETIC NEPHROPATHY

19. OBESITY, DM AND THE KIDNEY

20. Functional changes* Natural History of Type 2 Diabetic Nephropathy Proteinuria End-stage renal disease Clinical type 2 diabetes Structural changes † Rising blood pressure Rising serum creatinine levels Cardiovascular death Microalbuminuria Onset of diabetes25102030 Years * Renal haemodynamics altered, glomerular hyperfiltration † Glomerular basement membrane thickening , mesangial expansion , microvascular changes +/-

21. Prevalence of Diabetes amongst ESRF UK Renal Registry report 2004 Comorbidity at start of RRT% incidence Cardiovascular disease24.7 Cerebrovascular disease11.7 Peripheral vascular disease14.2 Diabetes (not cause of ESRF)7.4 Diabetic nephropathy18.8 Diabetes (either category)26.1 No comorbidity38.7

22. Mortality in Diabetic ESRF 5 year survival on dialysis 20% 5 year survival on transplantation 75-80% Causes of death CVS disease 50% Infection 15-20% Withdrawal from dialysis 20% Mailloux et al.JASN 1993;3(9)  65% of patients were >61 years at start of dialysis  50% of patients had diabetes and/or renovascular disease

23. Mortality in Diabetic ESRF Joanna Johnson et al.NDT 1999;14:2156-64 Quantitative metaanalysis RR of death in dialysis patients 1.029 with each year of increasing age 1.59 with cardiovascular disease 1.58 with peripheral vascular disease 1.91 with diabetes UK Registry report 2004 –RR of death at 1year was 1.65 with diabetes

24. Epidemiology of Cardiovascular Disease in Haemodialysis Patients Age (years) Annual Mortality (%) 0.01 0.1 1 10 100 25-3435-4445-5455-6465-74 75-84 >85 Dialysis M Dialysis F Healthy M Healthy F Foley AJKD 1998;32:S112-9

25. WET GANGRENE

27. 2/24/003/9/003/24/00 Anterior Leg (SHIN) Distal Calcific Uremic Aeteriolopathy (CUA)

28. CVD Mortality by Urinary Protein Excretion in Type 2 Diabetes U-Prot = urinary protein concentration A: U-Prot <150 mg/LB: U-Prot 150–300 mg/LC: U-Prot >300 mg/L Months Survival curves for CVD mortality 1.0 0.9 0.8 0.7 0.6 0.5 0 0102030405060708090 A B C Overall: p <0.001 Miettinen H et al. Stroke. 1996; 27: 2033–2039.

29. Valsartan lowers AER in type 2 diabetic patients with microalbuminuria 0 4 812 18 24 time (wks) HbA1 c (%) Percent change of AER (%) Mean AER (  g/min) Valsartan Amlodipine 65 25 35 45 55 8 8.2 8.4 8.6 8.8 9 20 10 0 -10 -20 -30 -40 -50 p<0.001 (changes in logged UEAR from baseline at week 24)

30. 30 IRMA 2 Normalisation of Urinary Albumin Excretion Rate at 2 years (<20  g/min) Subjects (%) 35 45 40 30 25 20 15 10 5 0 Control (n=201) 150 mg (n=195) 300 mg (n=194) Irbesartan 24 34 21 p =0.006 Parving H-H, et al. N Engl J Med 2001; 345(12): 870-878.

31. 31 Subjects (%) Irbesartan 14 18 16 12 10 8 6 4 2 0 Control (n=201) 150 mg (n=195) 300 mg (n=194) 9.7 5.2 14.9 RRR=39% p =0.08 RRR=70% p<0.001 IRMA 2 Primary Endpoint Development of Diabetic Nephropathy Parving H-H, et al. N Engl J Med 2001; 345(12): 870-878.

32. IDNT: Time to Doubling of SeCr Control defined as placebo SeCr, serum creatinine; RRR, relative risk reduction Patients (%) Follow-up (months) 061218243036424854 0 10 20 30 40 50 6070 Irbesartan (n=579) Amlodipine (n=567) Control (n=569) RRR=33% P=.003 P=NS RRR=37% P<.001 Adapted from Lewis EJ et al. N Engl J Med. 2001;345:851-860.

33. Summary Diabetic Nephropathy accounts for significant proportion of ESRF Increasing number of sick older diabetics Mortality higher compared to non diabetics Early intervention important to reduce complications associated with disease

34. Dialysis related problems Difficult vascular access Haemodynamic instability due to autonomic neuropathy Increased infection Unpredictable blood sugars Increased insulin sensitivity Increased insulin degradation Increased insulin secretion Decreased clearance of oral hypoglycemics Hyperglycemia from PD dialysate( 83 mmol/L in 1.36%) Weight gain on PD

35. Prevalence of Diabetes amongst ESRF Proportion of diabetics amongst ESRF  US 45%  Germany 36 %  Australia 22% Increasing proportion of Type 2Diabetes entering RRT (+11.9% annually data from European registry 1991-1999) Increasing number of older patients due to better survival Incidence of ESRF decreasing amongst Type 1 diabetes- Nishimura et al AJKD 2003;42(1)

36. Time Course of Type 2 Diabetic Renal Disease Early Stage Late Stage End Stage Microalbuminuria Proteinuria ESRD PRIME Kidney Disease IRMA 2IDNT Cardiovascular Morbidity and Mortality Prevention Protection