Pathogenesis and Treatment of Diabetic Nephropathy

1. Pathogenesis and Treatment of Diabetic Nephropathy Dr Simon Fletcher Consultant Nephrologist

2. Type 1 Diabetes An autoimmune disease characterised by antibody and cell mediated destruction of pancreatic islet cells. Circulating C-peptide is absent indicating a failure to produce insulin.

3. Type 2 Diabetes Characterised by a combination of insulin resistance and insulin deficiency. May be a component of the Metabolic Syndrome; Obesity, Insulin Resistance, Hypertension and Hyperlipidemia.

4. Diabetic Nephropathy Clinical syndrome characterised by persistent albuminuria (>300mg/24hrs) on at least 2 occasions separated by 3 months.

5.  Epidemiology  Incidence of Diabetic Nephropathy in Type 1 Diabetes 4-17% 20 years 16-30% 30 years 30-40% 40 years

6.  Epidemiology  Incidence of Diabetic Nephropathy in Type 2 Diabetes 5% at diagnosis 20% after 20 years

7. Incidence of ESRF in Diabetics USA 45% of patients requiring dialysis. Incidence of ESRF at 300 PMP Europe 20% of patients requiring dialysis. Incidence of ESRF at 150 PMP.

8. Susceptibility for Diabetic Nephropathy Genetic Gender Age of onset of Diabetes Intrauterine malnutrition

9. Ethnicity Pima Indians 50% will develop Type 2 diabetes Incidence of ESRF 60% after 15 years compared to 15% in Caucasians Type 2 diabetics. (Large Glomeruli)

10. Pima Indians 14% Incidence of nephropathy if no parent has proteinuria. 23% One parent has proteinuria. 46% Two parents have proteinuria.

11. Ethnicity Mexican Americans incidence ratio is 6:1, African Americans 4:1 compared with Caucasian Type 2 Diabetics. Correcting for socio-economic factors

12. Ethnicity The incidence of ESRD is 4 fold higher in diabetics from South Asia than Caucasians in the UK.

13. Gender Type 1 Diabetes Male to Female risk of Nephropathy 1.7:1 Type 2 Diabetes Male to Female risk of Nephropathy 5:1

14. Genetics ACE Gene Pleomorphisim DD Variation AT 2 Receptor gene X Chr AA Haplotype in Males Aldos-reductase Gene ZZ allele

15. Age of Onset of Diabetes Type 1 Diabetes Greatest risk age 11-20 years Affect of puberty on Renal hypertrophy Type 2 Diabetes Greatest risk age > 50 than those <40 Pima Indians < 20

16. Natural History of Diabetic Nephropathy Stage 1: Hyperfiltration and Hypertrophy Stage 2: Basement Membrane Changes Stage 3: Microalbuminuria Stage 4: Nephropathy Stage 5: ESRF Mogensen

18. Screening for Microalbuminuria Albumin excretion increased due to Strenuous exercise Oral Protein intake Urinary infection Fluid loading Pregnancy

19. Screening for Microalbuminuria Albumin excretion 25% more if erect than supine. 40% day to day variation in excretion rates

20. Urinary Albumin Excretion  Rates Normoalbuminuria < 30mg/day Microalbuminuria 30-300mg/day Overt Nephropathy > 300mg/day

21. Screening for Microalbuminuria 24hr collections of urine are time consuming, subject to error and are not practicable for repeated screening in large numbers of patients A practical alternative is a Albumin Creatinine Ratio on a random sample of urine.

22. Screening for Microalbuminuria Early morning Albumin Creatinine Ratio ACR <2.5 Normoalbuminuria ACR >2.5 Microalbuminuria ACR > 25 Proteinuria

23. UKPDS 5000 Type 2 Diabetics followed prospectively and after 10 years Microalbuminuria 25% Proteinuria 5% Raised Creatinine 0.8%

24. Screening for Microalbuminuria Type 1: Yearly after 5 years of diagnosis Type 2: Annually from diagnosis

27. Regression of Microalbuminuria 386 patients followed for 8 years 58% regression. Independent factors associated with regression. Lower cholesterol <5.1 Lower Systolic BP <115 Glycaemic control HbA1C<8 Recent onset of Microalbuminuria

28. Renal Pathology

33. Renal Pathology Kidneys larger 15% onset of Diabetes Increase in glomerular volume and Capillary loop volume. Glomerular Hyperplasia

34. Diffuse Glomerular Lesion Increase in the mesangial matrix and progressively expands into the capillary loops. Capillary wall thickening Mesangial expansion leads to capillary narrowing and peri-glomerular fibrosis

38. Nodular Glomerular Lesion Kimmelstiel and Wilson 1936 Diabetics with proteinuria renal impairment and hypertension Nodular lesions in the mesangium due to microaneurysmal dilation of the associated capillary and mesangiolysis

42. Arteriolar Lesions Hyaline Material replaces the entire wall of the afferent and efferent Arterioles at the hilum.

45. Pathogenesis of Diabetic Nephropathy

47. Role of Glucose Control

48. Direct Effect of Glucose Cell culture studies have shown that glucose can induce Cell hypertrophy and extra cellular matrix production.

49. Role of Glucose Control Good Glycaemic control (HbA1c <7.0) only 9% of Type 1 Diabetics will develop ESRF after 25 years as opposed to historical controls of 40%. (Krolewski et al N Eng J Med 1995) Diabetes Control and Complications Trial- Significant reduction in progression from Normoalbuminuria to Microalbuminuria in those with tight Glycaemic control. (DCCT N Eng J Med 1993)

51. Role of Glucose Control Euglycaemic control after Pancreas Transplantation regression of diabetic glomeruli after 10 years. (Fioretto et al N Eng J Med 1998) UKPDS- Reducing HbA1c by 0.9% in Type 2 Diabetics reduces the risk of nephropathy. (UKPDS Lancet 1998)

52. Protein Kinase C Renal injury due to hyperglycaemia increase reactive oxygen species. Activation of PK C and TGF b results in increased: Vascular Contractility Blood Flow Cellular Proliferation Vascular Permeability

53. Inhibition of PKC by Ruboxistaurin in Rats Reduces Glomerular Hyperfiltration Albuminuria Extra cellular Matrix accumulation

54. Inhibition of PKC by Ruboxistaurin in Humans Placebo controlled trials in Retinopathy: No difference at 12 months Placebo controlled trial in Type 2 Diabetics 123 patients with early nephropathy randomised and after 1 year there was no difference.

55. Transforming Growth Factor-� Central histological feature is Matrix accumulation in the Mesangium TGF � plays a pivotal Stimulated by PKC, AGE and Angiotensin ll Anti TGF � reduces extra cellular matrix production in rats

57. Effect of Advanced Glycation end Products on Nephropathy

59. Effect of Aminoguanidine in Diabetic Rats Inhibitor of AGE formation Reduction in Mesangial expansion Reduction in proteinuria (Ishii et al Science 1996)

64. Heamodynamic Changes Hyperfiltration is the earliest stage in Diabetic Nephropathy. Afferent arteriolar dilation mediated by Vasoactive Hormones and Cytokines Insulin Growth Factor 1 (IGF 1) Nitric oxide Prostaglandins

66. Renin-Angiotensin System ACE inhibitors can slow the progression of Diabetic Nephropathy in RATS (Zatz et al J Clin Invest 1986)

71. Mechanisms for the Renoprotective Effect of ACE Inhibitors Lower Systemic Blood Pressure Lower Intra glomerular Pressure and filtration rates Reduce Proteinuria

72. Mechanisms for the Renoprotective Effect of ACE Inhibitors Inhibit non Heamodynamic effects of Angiotensin on various cell types Reduction in Cytokine and Growth factor synthesis e.g. TGF � Mesangium: Reduced Cell proliferation Hypertrophy Matrix Expansion

73. Mechanisms for the Renoprotective Effect of ACE Inhibitors Reduction in Oxidative Stress Inhibit macrophage activation, proliferation and migration

75. Prevention of Diabetic Nephropathy

77. Stage 1 and 2 Hyperfiltration associated with glomerular hypertrophy.

78. Glycaemic Control

79. Type 1 DM DCCT 3 injections per day or insulin pump verses 2 per day. HbA1c 7% verses 9% over 9 years. 40% risk reduction of developing Microalbuminuria

81. Type 2 DM Ohkubo et al 110 non obese patients treated with intensive insulin reduced the risk of Microalbuminuria by 62% Glycaemic threshold HbA1c of 6.5% below which Microalbuminuria did not develop.

82. Pancreatic Transplantation 8 Patients with pancreas only transplants underwent serial biopsies 0,5 10 years. Prior to transplantation 3 normal, 3 micro 2 proteinuria At 10 years improved significantly the Histological changes

83. Glycaemic Control UKPDS Intensive treatment with insulin and oral hypoglycaemic agents HbA1c 7.O V 7.9 over 9 years 25-30% reduction in Microalbuminuria and 50% decrease in the doubling of Creatinine

84. ACE Inhibition Type 2 Enalapril better than placebo Schrier et al 2002

85. ACE Inhibition EUCLID- study no benefit of Lisinopril in this normoalbuminuric normotensive patients. Lancet 1997 Kventy et al- Peridopril retarded the Microalbuminuria which occurred in the control group. Q J Med 2001

86. Stage 3 Microalbuminuria and Hypertension. Mesangial Expansion, Glomerular basement thickening and Arteriolar Hyalinosis.

87. Glycaemic control DCCT- few patients had Microalbuminuria Microalbuminuria Collaborative Study Group no statistical evidence. Guy�s retrospective study in normotensive patients found intensification of insulin therapy of benefit

88. Antihypertensive therapy Hypertension BP > 140/90 classically develops 2-5 years after the onset of Microalbuminuria Many studies have shown that control of BP reduces proteinuria and development of renal failure (Parving et al BMJ 1987)

90. Role of ACE Inhibitors Microalbuminuria and Normotension Type 1 DM The ACE Inhibitors in Diabetic Nephropathy Trialists Group (Ann Int Med 2001) Meta-analysis of 12 placebo control trials 698 patients majority over 2 years 60% reduction in progression to proteinuria and a 3 fold increase in the return to normoalbuminuria

91. Role of ACE Inhibitors Microalbuminuria and Normotension Type 2 DM Ravid et al Treatment with Enalapril v Placebo reduced the risk of developing proteinuria and renal impairment Ahmed et al Reduction in the development of proteinuria with no discernable difference in BP in the Placebo group

92. Role of ACE I or ARB in Microalbuminuria and Hypertension Most studies have shown that ACE I will reduce proteinuria of any cause by 40-50% Reduce the rate of decline in renal function, (Collaboration Study)

96. Hyperlipidemia

97. Hyperlipidemia Type 1 Krolewski et al found in a cholesterol of less than 5.7 was an important risk factor. Diabetes Atherosclerosis Intervention Study in Type 2 found Fenofibrate reduced the progression of proteinuria

98. Stage 4 Nephropathy Proteinuria and progressive decline in renal function.

100. When would you make a referral to a Nephrologist? Microalbuminuria Proteinuria Creatinine 150 Creatinine 250 Creatinine 500