1. DIABETES CASE PRESENTATIONS 3 rd – Chronic complications

2. 1. Diabetic retinopathy Early subclinical abnormalities of the retinal vessels: Early subclinical abnormalities of the retinal vessels: thickening of the basement membrane thickening of the basement membrane loss of pericytes (the contractile cells that control vessel calibre and flow) loss of pericytes (the contractile cells that control vessel calibre and flow) increased blood flow increased blood flow increased capillary permeability (leakage) increased capillary permeability (leakage)

3. Simplified grading of diabetic retinopathy Background (Level 1) Background (Level 1) Microaneurysms Microaneurysms Retinal haemorrhages  any exudates (hard exudates) Retinal haemorrhages  any exudates (hard exudates) Preproliferative (Level 2) Preproliferative (Level 2) Venous beading Venous beading Venous loop or reduplication Venous loop or reduplication Intraretinal microvascular abnormalities (IRMA) Intraretinal microvascular abnormalities (IRMA) Multiple deep, round haemorrhages Multiple deep, round haemorrhages Cotton-wool spots Cotton-wool spots Proliferative (Level 3) Proliferative (Level 3) New vessels on disc (NVD) New vessels on disc (NVD) New vessels elsewhere (NVE) New vessels elsewhere (NVE) Preretinal or vitreous hemorrhage Preretinal or vitreous hemorrhage Preretinal fibrosis  tractional retinal detatchment Preretinal fibrosis  tractional retinal detatchment Maculopathy Maculopathy Exudate within a disc area (DA) of fovea Exudate within a disc area (DA) of fovea Retinal thickening within DA of fovea Retinal thickening within DA of fovea Microaneurysm or hemorrhage within DA of fovea Microaneurysm or hemorrhage within DA of fovea

4. Screening for diabetic retinopathy Regular examination of the eye in the diabetic patient is essential Regular examination of the eye in the diabetic patient is essential visual acuity measurement visual acuity measurement examination of the fundus through dilated pupils examination of the fundus through dilated pupils digital fundus photography digital fundus photography yearly examinations for those with no retinopathy yearly examinations for those with no retinopathy from puberty / 5 yrs after diagnosis for T1DM from puberty / 5 yrs after diagnosis for T1DM from diagnosis for T2DM from diagnosis for T2DM 6-monthly for those with background retinopathy 6-monthly for those with background retinopathy

5. Treatment for DR Strict glycaemic control Strict glycaemic control Strict blood pressure control Strict blood pressure control ACE inhibitors ACE inhibitors Early detection Early detection Prompt treatment Prompt treatment Panretinal photocoagulation Panretinal photocoagulation Education Education

6. 2. Diabetic nephropathy Pathological changes: glomerulus + tubular interstitium Pathological changes: glomerulus + tubular interstitium Glomerulus: Glomerulus: at diagnosis of DM - enlarged because of the increased capillary surface area at diagnosis of DM - enlarged because of the increased capillary surface area subsequently, glomerular enlargement is caused by basement membrane thickening and (usually) expansion of the mesangium subsequently, glomerular enlargement is caused by basement membrane thickening and (usually) expansion of the mesangium Tubular interstitium: Tubular interstitium: total kidney volume is also increased, mainly through expansion of tubular tissue total kidney volume is also increased, mainly through expansion of tubular tissue basement membrane thickening basement membrane thickening atrophy atrophy interstitial fibrosis interstitial fibrosis arteriosclerosis arteriosclerosis

7. Glomerular filtration rate (GFR): Glomerular filtration rate (GFR): early in diabetes – increased because of the increased filtration area early in diabetes – increased because of the increased filtration area later declines in parallel with mesangial expansion and the resultant glomerular occlusion later declines in parallel with mesangial expansion and the resultant glomerular occlusion The natural history of diabetic nephropathy is marked by increasing loss of protein (mostly albumin) in the urine The natural history of diabetic nephropathy is marked by increasing loss of protein (mostly albumin) in the urine

8. Urinary albumin excretion AER 24-h urine collection Overnight urine collection (10-12h) albumin:creatinine ratio albumin:creatinine ratio Normoalbuminuria < 30 mg/24 h < 20 μg/min < 30 mg/g Microalbuminuria 30-300 mg/24 h 20-200 μg/min 30-300 mg/g Proteinuria > 300 mg/24 h > 200 μg/min > 300 mg/g albumin excretion rate AER = albumin excretion rate

9. The stages and determinants of DN Normoalbuminuria Microalbuminuria Intermitent proteinuria ProteinuriaEnd-stage renal disease Sustained normoalbuminuria Sustained microalbuminuria Diabetes duration Baseline AER Glycaemic control Genetic susceptibility Ethnic minorities BP Glycaemic control BP 50 % 30 % 20 %

10. Mogensen classification (1) Stage I (renal hyperfunction / hypertrophy) from diagnosis of DM from diagnosis of DM good glycemic control → reversible good glycemic control → reversible GFR  by 20-50 % (>150 ml/min/1,73 m2) GFR  by 20-50 % (>150 ml/min/1,73 m2) possible microalbuminuria (transitory!) possible microalbuminuria (transitory!)  size of kidneys (ultrasonography) and of glomerules (biopsy)  size of kidneys (ultrasonography) and of glomerules (biopsy) Electronic microscope: normal basal membrane Electronic microscope: normal basal membrane normal BP normal BP

11. Mogensen classification (2) Stage II – asymptomatic, normoalbuminuria first 5 yrs from diagnosis of DM first 5 yrs from diagnosis of DM 5-7 yrs from onset of disease: 30-50 % → stage III 5-7 yrs from onset of disease: 30-50 % → stage III biopsy: thickening of glomerular basal membrane, mesangium expansion biopsy: thickening of glomerular basal membrane, mesangium expansion GFR still ↑ (by 20-50 %) GFR still ↑ (by 20-50 %) normal urine albumin excretion normal urine albumin excretion possible microalbuminuria (transitory!) possible microalbuminuria (transitory!) normal BP normal BP

12. Mogensen classification (3) Stage III (early diabetic nephropathy) 6-15 yrs from diagnosis of DM 6-15 yrs from diagnosis of DM blood glucose and BP comtrol → stops/decreases progression blood glucose and BP comtrol → stops/decreases progression persistent microalbuminuria (30-300 mg/24 hrs) persistent microalbuminuria (30-300 mg/24 hrs) GFR still , but decreases by 3-5 ml/min/yr GFR still , but decreases by 3-5 ml/min/yr BP normal or mildly  (  by 3 mmHg/yr) BP normal or mildly  (  by 3 mmHg/yr)

13. Mogensen classification (4) Stage IV (clinical diabetic nephropathy) 15-25 yrs after onset of DM 15-25 yrs after onset of DM proteinuria (albuminuria > 300 mg/24 hrs) proteinuria (albuminuria > 300 mg/24 hrs) GFR  progressively (by 8-12 ml/min/yr) GFR  progressively (by 8-12 ml/min/yr) 3 sub-classes: 3 sub-classes: early (GFR > 130 ml/min) early (GFR > 130 ml/min) intermediate (GFR < 100 ml/min) intermediate (GFR < 100 ml/min) advanced (GFR < 70 ml/min) advanced (GFR < 70 ml/min) BP  (by 5 mmHg/yr) BP  (by 5 mmHg/yr)

14. Mogensen classification (5) Stage V (end-stage renal failure) 25-30 yrs after onset of DM 25-30 yrs after onset of DM variable proteinuria variable proteinuria urine albumin excretion < 10 g/24 hrs urine albumin excretion < 10 g/24 hrs GFR < 10 ml/min GFR < 10 ml/min BP constantly  BP constantly  Microscope: important glomerular modifications Microscope: important glomerular modifications

15. Screening for diabetic nephropathy Annual determining of microalbuminuria: Type 1 DM: Type 1 DM: from puberty from puberty 5 yrs after diagnosis 5 yrs after diagnosis Type 2 DM : Type 2 DM : from diagnosis from diagnosis How? How? minimum 3 samples in 3-6 months minimum 3 samples in 3-6 months avoid conditions that can produce transient urinary albumin excretions avoid conditions that can produce transient urinary albumin excretions persistent microalbuminuria = 2 out of 3 results of 30-300 mg/24 hrs, 20-200 µg/min or urine albumin/creatinine = 30-300 mg/g persistent microalbuminuria = 2 out of 3 results of 30-300 mg/24 hrs, 20-200 µg/min or urine albumin/creatinine = 30-300 mg/g

16. Tratament of diabetic nephropathy Objectives: Good glycemic control Good glycemic control Treat high BP Treat high BP Diet Diet Treat dyslipidemia Treat dyslipidemia Prevent / treat related comorbidities Prevent / treat related comorbidities Treat renal anemia Treat renal anemia Prevent / treat renal bone disease Prevent / treat renal bone disease

17. Treating hypertension in patients with diabetic nephropathy Non-pharmacologically: Non-pharmacologically: exercise exercise weight loss weight loss low-sodium diet low-sodium diet low-protein diet low-protein diet smoking cessation smoking cessation avoid alcohol avoid alcohol coffee coffee Drugs: Drugs: ACE inhibitors ACE inhibitors ARBs ARBs diuretics diuretics Calcium blockers Calcium blockers beta-blockers beta-blockers  -adrenergic blockers  -adrenergic blockers

18. 3. Diabetic neuropathy Acute reversible Acute reversible hyperglycemic neuropathy hyperglycemic neuropathy Persistent Persistent Symmetrical Symmetrical Distal symmetrical neuropathy (chronic sensory and autonomic polyneuropathy) Distal symmetrical neuropathy (chronic sensory and autonomic polyneuropathy) Acute painful neuropathy Acute painful neuropathy Focal and multifocal Focal and multifocal Mononeuropathies (diabetic amyotrophy) Mononeuropathies (diabetic amyotrophy)

19. Symptoms in distal symmetrical neuropathy Asymptomatic in some Asymptomatic in some Numbness Numbness Altered sensation Altered sensation paraesthesiae paraesthesiae allodynia allodynia Pain Pain

20. Signs in distal symmetrical neuropathy None None Loss of Loss of vibration sense vibration sense pin prick pin prick touch touch temperature temperature joint position sense joint position sense Wasting and weakness rare Wasting and weakness rare Autonomic involvement: Autonomic involvement: warm feet (dilated arteriovenous shunts) warm feet (dilated arteriovenous shunts) dry feet (absent sweating) dry feet (absent sweating) Complications Complications ulcer ulcer oedema oedema Charcot arthropathy Charcot arthropathy

21. Aetiology of foot ulceration in diabetic patients Neuropathy Autonomic MotorSensory A-V Shunting Absent sweating Reduced tissue nutrition Ischaemia Micro- vascular disease Arterial disease Abnormal foot posture (raised arch, clawed toes) Reduced pain sensation Increased pressure loading -Charcot joint - Orthopaedic deformity Callus formation Ulceration Trauma Infection

23. Charcot arthropathy severe neuropathy severe neuropathy long-standing diabetes long-standing diabetes initiating event = injury, causing bone fracture initiating event = injury, causing bone fracture gross deformity gross deformity cubic foot cubic foot acute Charcot foot acute Charcot foot