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Diabetic Nephropathy

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Diabetic Nephropathy

  1. 1. Diabetic Nephropathy Angus Jones
  2. 2. Plan <ul><li>Pathogenesis/ Histopathology </li></ul><ul><li>Natural history </li></ul><ul><li>Screening and prevention </li></ul><ul><li>Investigation </li></ul><ul><li>Management </li></ul><ul><li>Selected drugs and renal failure </li></ul><ul><li>Astral trial </li></ul>
  3. 3. Diabetic Nephropathy <ul><li>Progressive increase in urine albumin excretion accompanied by rising BP and declining GFR </li></ul><ul><li>30-35% cumulative incidence </li></ul><ul><li>Up to 40% of end stage renal disease </li></ul><ul><li>Strong association with cardiovascular risk </li></ul>
  4. 5. Pathogenesis 1 <ul><li>Hyperglycaemia </li></ul><ul><ul><ul><li>Early histological lesions reversible </li></ul></ul></ul><ul><ul><ul><li>with normoglycaemia </li></ul></ul></ul><ul><li>Hypertension </li></ul><ul><ul><ul><li>Predicts microalbimunuria, </li></ul></ul></ul><ul><ul><ul><li>Development of proteinuria paralleled by gradual rise in BP </li></ul></ul></ul><ul><ul><ul><li>Correlation between BP and rate of decline of GFR </li></ul></ul></ul>
  5. 6. Pathogenesis 2 <ul><li>Proteinuria </li></ul><ul><ul><ul><li>Induces tubulointerstitial damage/contributes to progression </li></ul></ul></ul><ul><ul><ul><li>Highly selective in early disease </li></ul></ul></ul><ul><li>Inflammatory mediators </li></ul><ul><ul><ul><li>Protein kinase C </li></ul></ul></ul><ul><li>Genetic influence </li></ul>
  6. 8. Histopathology <ul><li>Pathological features occur in both glomerulus and interstitium </li></ul><ul><li>Macroscopic - increase in kidney size </li></ul><ul><li>Microscopic </li></ul><ul><ul><li>Thickening of GMB </li></ul></ul><ul><ul><li>Expansion of mesangium </li></ul></ul><ul><ul><li>Fibrosis in efferent and afferent arterioles (nodular or diffuse glomerular sclerosis) </li></ul></ul>
  7. 13. Natural history <ul><li>19-24% of patients with microalbuminuria go on to develop overt nephropathy </li></ul><ul><li>Progressive rise in urine albumin excretion, rising BP, declining GFR </li></ul><ul><li>Microalbuminuria can appear within 10 yrs of T1DM </li></ul>
  8. 14. Natural History 2 <ul><li>GFR decline once proteinuria present 12ml/min/year untreated </li></ul><ul><li>Patients of die of other causes (CVS disease) before ESRF </li></ul><ul><ul><li>CVS risk rises 2-3X with microalbuminuria, 9-10X with clinical proteinuria </li></ul></ul><ul><li>Higher rates of ESRF in T1DM </li></ul>
  9. 15. <ul><li>Factors associated with progression of renal disease: </li></ul><ul><ul><li>Hypertension </li></ul></ul><ul><ul><li>Poor glycaemic control </li></ul></ul><ul><ul><li>Baseline albumin excretion </li></ul></ul><ul><ul><li>Dyslipidaemia/smoking – less consistant </li></ul></ul>
  10. 16. Screening <ul><li>Annual Urine ACR (ideally first pass specimen) </li></ul><ul><ul><li>Repeat twice within 3-4/12 if positive if raised </li></ul></ul><ul><ul><li>≥ 2/3 raised = confirmed microalbuminuria </li></ul></ul><ul><li>Annual Creatinine and EGFR </li></ul>
  11. 17. Diagnosis Albumin: creatinine ratio (mg/mmol) Overnight urine collection (ug/min) 24hr urine collection (mg/24hr) Normoalbuminuria Female: Male: <2.5 <3.5 <20 <30 Microalbuminuria Female: Male: 2.5-30 3.5-30 20-200 30-300 Proteinuria Female: Male: >30 >30 >200 >300
  12. 20. Differential diagnosis of microalbuminuria <ul><li>Exercise </li></ul><ul><li>Acute illness/fevers </li></ul><ul><li>Menstruation </li></ul><ul><li>Pregnancy, puberty </li></ul><ul><li>Semen </li></ul><ul><li>Orthostatic proteinuria </li></ul><ul><li>UTI </li></ul><ul><li>Short term hyperglycaemia </li></ul><ul><li>Severe hypertension </li></ul><ul><li>LVF </li></ul><ul><li>Other renal diseases </li></ul><ul><li>40% normal day to day variation in albuminuria </li></ul>
  13. 21. Prevention <ul><li>Glucose control: </li></ul><ul><ul><li>1% reduction HBA1C – 20-40% reduction in risk of microalbuminuria </li></ul></ul><ul><ul><li>DCCT – 39% relative risk reduction microalbuminuria intensive group (A1C 7 vs 9.1%) </li></ul></ul><ul><ul><li>UKPDS 30% reduced RR at 9-12 yrs A1C 7 vs 7.9% </li></ul></ul><ul><ul><li>No lower HBA1C threshold found </li></ul></ul><ul><li>BP control </li></ul><ul><ul><li>UKPDS mean BP 144/82 vs 154/87 – 29% reduction in risk of microalbuminuria over 6 yrs </li></ul></ul>
  14. 22. Investigations <ul><li>Microalbuminuria/proteinuria (no haematuria) </li></ul><ul><ul><li>Type 1 </li></ul></ul><ul><ul><ul><li>Retinopathy present, diabetes >10 years, no further investigation needed </li></ul></ul></ul><ul><ul><li>Type 2 </li></ul></ul><ul><ul><ul><li>If no retinopathy look for another cause </li></ul></ul></ul>
  15. 23. Investigations <ul><li>Microalbuminuria/proteinuria – NICE guidence </li></ul><ul><li>Suspect renal disease, other than diabetic nephropathy and consider further investigation or referral when the albumin:creatinine ratio (ACR) is raised and any of the following apply: </li></ul><ul><ul><li>there is no significant or progressive retinopathy </li></ul></ul><ul><ul><li>blood pressure is particularly high or resistant to treatment </li></ul></ul><ul><ul><li>had a documented normal ACR and develops heavy proteinuria (ACR >100 mg/mmol) </li></ul></ul><ul><ul><li>significant haematuria is present </li></ul></ul><ul><ul><li>the glomerular filtration rate has worsened rapidly </li></ul></ul><ul><ul><li>the person is systemically ill. </li></ul></ul>
  16. 24. Investigations 2 <ul><li>Renal impairment in diabetic patient </li></ul><ul><ul><li>Evidence of significant proteinuria/no haematuria/other microvascular disease present -> treat as diabetic nephropathy </li></ul></ul><ul><ul><li>No evidence of albuminuria – look for other disease (renovascular disease common) </li></ul></ul>
  17. 25. Management 1 <ul><li>Preventing progression of renal disease: </li></ul><ul><ul><li>Little evidence that improving glucose control alters rate of progression </li></ul></ul><ul><ul><ul><li>Regression of histological changes seen 10 yrs post pancreatic transplantation </li></ul></ul></ul><ul><ul><li>BP control </li></ul></ul><ul><ul><ul><li>Can reverse decline in albuminuria and slow/stop? decline in GFR </li></ul></ul></ul><ul><ul><ul><li>Several drugs often required </li></ul></ul></ul><ul><ul><ul><li>Target BP <130/80 T1 and T2 </li></ul></ul></ul>
  18. 26. Management 2 <ul><li>ACE inhibitors </li></ul><ul><ul><li>1 ST line treatment </li></ul></ul><ul><ul><li>Additional decrease in proteinuria </li></ul></ul><ul><ul><li>Effect plateaus – 45% reduction 2 yrs </li></ul></ul><ul><ul><li>Renal, cardiovascular and mortality benefits </li></ul></ul><ul><li>Angiotensin 2 inhibitors </li></ul><ul><ul><li>Similar effects to ACE in short term studies </li></ul></ul><ul><ul><li>Long term studies A/W </li></ul></ul><ul><ul><li>Effect on non renal outcomes not yet demonstrated </li></ul></ul>
  19. 27. Management 3 <ul><li>Dual ACE/Angiotensin 2 blocker therapy? </li></ul><ul><ul><li>Greater reduction in proteinuria </li></ul></ul><ul><ul><li>Short term data only </li></ul></ul><ul><ul><li>High rates adverse events? </li></ul></ul><ul><li>Low protein diet (?) </li></ul><ul><ul><li><8g/kg </li></ul></ul>
  20. 28. Management 4 <ul><li>Reduce cardiovascular risk: </li></ul><ul><ul><li>Treat as per secondary prevention (aspirin/statin) </li></ul></ul><ul><li>Avoid nephrotoxic drugs </li></ul><ul><li>Glycaemic control in renal failure </li></ul><ul><li>Management of established renal disease: </li></ul><ul><ul><li>In conjuction with a renal physician </li></ul></ul><ul><ul><li>Referral guidelines </li></ul></ul>
  21. 29. Drugs and Renal Failure <ul><li>Metformin – 2008 NICE guidance: </li></ul><ul><ul><li>Review metformin dose if serum creatinine > 130 μmol/litre or estimated glomerular filtration rate (eGFR) < 45 ml/minute/1.73-m2. </li></ul></ul><ul><ul><li>Stop metformin if serum creatinine > 150 μmol/litre or the eGFR < 30 ml/minute/1.73-m2. </li></ul></ul>
  22. 30. Drugs and renal failure 2 <ul><li>Sitagliptin – avoid EGFR <50 </li></ul><ul><li>Exenetide – avoid EGFR <30 </li></ul><ul><li>Statins – caution ERGF <30 </li></ul><ul><li>ACE inhibitors </li></ul><ul><ul><li><25% non progressive creatinine rise on introduction allowable </li></ul></ul>
  23. 31. ASTRAL Trial <ul><li>806 patients with atherosclerotic renal vascular disease – intervention vs medical therapy alone </li></ul><ul><li>≥ 1 year follow up </li></ul><ul><li>No differences in the change in kidney function, blood pressure control or the rates of major cardiovascular illness </li></ul><ul><li>3 per cent of revascularisation - serious procedural complication </li></ul>
  24. 32. Summary <ul><li>Common cause of end stage renal failure </li></ul><ul><li>High mortality – CVS risk </li></ul><ul><li>Intensive BP and CVS risk factor control </li></ul>

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