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糖尿病腎病變 Diabetic Nephropathy

糖尿病腎病變 Diabetic Nephropathy. 蔡宜潔醫師 Feb. 24, 2008. Outline. Introduction of diabetic nephropathy Manifestations of diabetic nephropathy Staging of diabetic nephropathy Microalbuminuria Diagnosis of diabetic nephropathy Treatment of diabetic nephropathy. Introduction of

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糖尿病腎病變 Diabetic Nephropathy

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  1. 糖尿病腎病變Diabetic Nephropathy 蔡宜潔醫師 Feb. 24, 2008

  2. Outline • Introduction of diabetic nephropathy • Manifestations of diabetic nephropathy • Staging of diabetic nephropathy • Microalbuminuria • Diagnosis of diabetic nephropathy • Treatment of diabetic nephropathy

  3. Introduction of Diabetic nephropathy • The leading cause of end-stage renal disease • Diabetic nephropathy- → 30~40% type 1 DMvs. 20% type 2 DM after years • Majority of diabetic p’ts with ESRD→Type 2 DM • Prevalence of type 2 DM >> type 1DM (10~15x) • Susceptibility to DMN • Ethnicity- South Asian, African> Caucasian • Gender- ♂>♀(1.7:1) • Age of DM onset (11~20 y/o in type 1 DM p’t) Cf. >50y/o in type 2 DM p’t: incidence↑

  4. Manifestations of Diabetic nephropathy • Natural history of DM nephropathy →Better defined in type 1 DM →5 stages • Clinical and morphologic features →Similar in type 1 DM and type 2 DM • Glomerular hypertension and hyperfiltration are the earliest renal abnormalities • Course of GFR change: more variable in type 2 DM → GFR decline: 5~10cc/min/year (1~20 cc/min/year in type 2 DM)

  5. DM nephropathy stages • Stage 1:hyperfiltration phase • Stage 2:silent phase • Stage 3:microalbuminuria phase • Stage 4:macroalbuminuria phase • Stage 5:ESRD

  6. Stage of Diabetic nephropathy Stage 1-Hyperfiltration phase • Describes the renal hypertrophy and hyperfiltration that present at the time of diagnosis of type 1 DM . • GFR and UAER- elevated by 20-40% (UAER: urine albumin excretion rate) →GFR and UAER↓while insulin therapy

  7. Stage of Diabetic nephropathy Stage 2- Silent phase • Clinically silent (GFR↑) • Early histologic change (GBM/Matrix ↑) • Hyperfiltration related to • Degree of hyperglycemia (up to 250 mg/dL), higher levels of glycemia- GFR↓ • Better glucose control- hyperfiltration↓ • Typically lasts for 5-15 years

  8. Stage of Diabetic nephropathy Stage 3- Microalbuminuria phase • Incipient nephropathy • Occurs after 6 -15 years of diabetes • UAER: 30-300mg/d • Always small but detectable BP↑ • Impairment of nocturnal BP “dipping” • GFR is elevated or reduced into normal range • Initial hyperfiltration  greater subsequent rate of decline in GFR

  9. Sleep Blood pressure (mm Hg) 175 Non-dipper 155 135 Dipper 115 95 75 55 7:00 11:00 15:00 19:0 23:00 3:00 7:00 Time of day 24Hr BP Profile in Hypertension (Dipper vs non-dipper)

  10. Stage of Diabetic nephropathy Stage 4- Macroalbuminuria phase • Established or overt nephropahty • Characteristics • Clear histologic changes • HTN- established in most patients • Proteinuria→ increase 15~40 % per year • GFR decline→10(2~20)mL/min per year • The rate of decline in GFR is correlated with blood pressure levels • Microscopic hematuria: 66% of patient

  11. Stage of Diabetic nephropathy Stage 4- Macroalbuminuria phase • Macroproteinuric phase → a steady decline in renal function • GFR↓(about 1 mL/min↓per month) • A plot of the reciprocal of the serum creatinine level against time • usually yields a straight line and allows prediction of the rate of deterioration

  12. Stage of Diabetic nephropathy Stage 5- ESRD • ESRD developed in • 50% of type 1 diabetic patient with overt nephropathy within 10 years • Within a median of 7 years from the development of persistent proteinuria

  13. The importance of Microalbuminuria • Accurate measurement of UAER →Identification of incipient “early” nephropahty →Modify the natural history of DMN • Normal urine contains some albumin • < 30 mg/day • UAER↑- affected by • exercise • fever • oral protein intake, oral fluid intake • pregnancy • time of day (25% higher at daytime than night)

  14. Diagnosis of Microalbuminuria • Sample: overnight urine • Microalbiminuria (MicroA): • 30mg/day< UAER <300mg/day • Persistent microA: • MicroA found in 2/3 consecutive urine samples within 3-6 months • DM < 6 years: other causes should be suspected

  15. Screening of Microalbuminuria • Screening • An early morning urine sample • Screening recommendations • Type 1 DM: Age >12 y/o, DM Dx >5 years • Type 2 DM: At diagnosis • Both: Annually until 70 y/o

  16. Microalbiminuria • The predictive value of overt DMN • A marker of overt nephropathy risk in type 1 DM patients. • Type 1 DM> 15 years with microA: 28% developed overt DMN within 10 years. • Systemic hypertension • A significant relationship between BP and urine albumin excretion rate(UAE).

  17. Microalbiminuria • Diabetic retinopathy • Type 1 DM patients: strong association between UAE and DMR. • Close ophthalmologic monitoring advised. • Atherosclerosis: • DM patients with overt DMN: increased risk of CV mortality. • Micro A: potentially atherogenic changes

  18. Regression of Microalbuminuria • Low systolic blood pressure • BP < 130/80 mmHg • Low cholesterol • Low HbA1C • HbA1C < 7 American Familial Physician 72: 96-99, 2005

  19. Microalbuminuria Monitor Creatinine Screen for Eye Disease Investigate for Other Renal Disease Microalbuminuria Screen for Heart Disease Screen for Vascular Disease Optimize BP Optimize Lipids Optimize Glucose Discourage Smoking

  20. Diagnosis of Diabetic nephropathy • Usually depend on clinical grounds without a renal biopsy • Supportive clues are • 1.DM hx >10 years • 2.Presence of normal or enlarged kidneys • 3.Evidence of proliferative diabetic retinopathy • 4.A bland urinary sediment. • 5.Typical DM nephropathy course • Retinopathy is found in 90 and 60 percent of patients with type 1 DM and type 2 DDM, respectively, who develop nephropathy

  21. “Typical “ overt nephropathy • Type 1 DM for > 10 years • Retinopathy • Previous microalbuminuria • No macroscopic hematuria • No RBC casts • Normal renal echo No Biopsy

  22. “Atypical“ proteinuria • Type 1 DM for <10 years • No retinopathy • Nephrotic range proteinuria without previous microalbiminuria • Macroscopic hematuria • Red cell casts Renal biopsy

  23. Pathologic change of Diabetic nephropathy • The earliest morphologic abnormalities in diabetic nephropathy: • Thickening of the glomerular basement membrane (GBM) • Expansion of the mesangium due to accumulation of extracellular matrix. • With time • matrix accumulation becomes diffuse and is evident as eosinophilic, periodic acid Schiff (+) glomerulosclerosis on biopsy

  24. Pathologic change of Diabetic nephropathy • Prominent areas of nodular matrix expansion (nodular glomerulosclerosis) → Classic Kimmelstiel-Wilson nodule

  25. Treatments of Diabetic nephropathy • Therapy is aimed at retarding the progression of nephropathy through • Blood sugar control • Systemic blood pressure control • Glomerular capillary pressure↓(ACE inhibitor/ARB) • Dietary protein intake • Lipids

  26. Treatment goal (1) Blood sugar control • Normoalbuminuria • Intensive glycemic control- reduce the risk for development of microA at this stage • Type 1 DM : Strict glycemic control with HbA1C(7% vs. 9%)→ risk of microA↓(35~45%) • Hypoglycemic episodes↑ • Type 2 DM: HbA1C (7% vs. 7.9%)→ risk of microA↓(25~30%) • Microalbuminuria and overt DMN • Benefit of strict glycemic control- contraversial • Concurrence of HTN: confounding factor

  27. Treatment goal (2) Antihypertensive therapy • MDRD study • Lower BP (125/75mmHg)→slower rate of progression in proteinuria (>1g/day) • JNC 6 • Lower target BP for DM patient • Treatment at a BP of 130/85mmHg • Goal BP of 125/75 in proteinuria patient • JNC 7 • Goal BP of 130/80 in DM patient

  28. Treatment goal (3) ACEI in DMN • Glomerular pressure↓→Damage↓ • Independent of effects on systemic BP • Normoalbuminuria • EUCLID study- no benefit (Lisinopril) • Other recent studies- benefit(+) • Microalbuminuria with normal BP • Progression to proteinuria↓(type 1&2) • Microalbuminria/proteinuria with HTN • Most study: proteinuria↓(type 1&2) • Slow the deterioration of renal function

  29. Treatment goal (3) ACEI in DMN • Many studies clearly document the benefit of ACEI in normotensive and hypertensive microalbuminuric patient with type1 & type 2 DM →All diabetic patients should receive an ACE inhibitor upon the development of microalbuminuria, even in the absence of systemic hypertension unless contraindicated • ARB have the similar beneficial effects as ACEI (RENNAL, IDNT, IRMAII)

  30. Treatment goal (4) Dietary protein intake • Low protein diet 0.6g/kg/day (c/w 1g/kg/day) was associated with a 75% reduction in the rate of decline of the GFR in type 1 DM • MDRD: the effects of dietary protein restriction were inconclusive • American Diabetes Association: nonpregnant diabetic --- restrict protein to 0.8 g/kg ideal body weight /day

  31. Treatment goal (5) Lipids • Lipids may accelerate renal injury via cytokine-dependent pathways • HMG CoA reductase inhibitors retard the progression of diabetic nephropathy --- controversial now

  32. Management of Stage V • The nephrotic stage transforms almost imperceptibly into the azotemic stage. • The interval between diagnosis of DM and development of ESRD: type 1 DM 22 yrs, type 2 DM 10-12 yrs. • Early dialysis if ESRD- consensus (not evidence based) • Serum Cre: 5.5mg/dL or GFR 10~20cc/min • DM more vulnerable to uremic symptoms, fluid retention, hyperkalemia at an earlier stage than non DM subjects

  33. STAGES OF DM nephropahty • STAGE-1 HYPERFILTRATION • STAGE-2SILENT STAGE • STAGE-3INCIPIENT NEPHROPATHY • STAGE-4OVERT NEPHROPATHY • STAGE-5CHRONIC RENAL FAILURE → ESRD

  34. 高血壓腎病變Hypertensive Kidney Disease

  35. Outline • Introduction • Definition of Hypertension • Risk factors of Hypertensive nephrosclerosis • Pathogenesis of hypertensive nephrosclerosis • Diagnosis of hypertensive kidney disease • Prognosis • Therapy

  36. Introduction ofHypertensive Kidney Disease Chronic Kidney Disease 雞生蛋 ? 蛋生雞 ? Hypertension

  37. Introduction ofHypertensive Kidney Disease • About 6% essential HTN have CKD and are at risk for progression to ESRD • Hypertension is as a cause of 30% ESRD patients in US • The incidence of ESRD attributed to HTN is 5x higher in African Americans than in non-African American Kidney Int 64: 2331-2341, 2003

  38. Introduction ofHypertensive Kidney Disease • Hypertensive kidney disease= Nephrosclerosis = benign nephrosclerosis= nephroangiosclerosis • Renal damage is thought secondary to essential hypertension which affecting preglomerular microvasculature Kidney Int 68: S52-S56, 2005

  39. Definition of Hypertension From JNC 7 JAMA 289: 2561, 2003

  40. Risk factors forHypertensive Nephrosclerosis • Systolic blood pressure • Proteinuria • Decreased glomerular filtration rate • Race • Age • Sex • Lipid abnormalities • Insulin resistance • Hyperuricemia • Hyperhomocysteinemia • Smoking • Others Kidney Blood Press Res 25: 341-353, 2002

  41. Risk factors forHypertensive Nephrosclerosis • SBP • Systolic blood pressure was an independent risk factor for all-cause ESRD • Proteinuria • In AASK study: Urine protein/Cr ratio > 0.22  2x higher rate of decline in GFR • Every 1g/24h increase in urinary protein increased the risk by 1.4 times • Decreased glomerular filtration rate • In AASK study: • In patients with GFR < 40 ml/min/1.73m2 and proteinuria > 300mg/day, despite BP < 122/77 mmHg, renal disease continued to progressed • Each doubling of the serum Cr concentration increased the risk 2.6 times Kidney Int 64: 2331-2341, 2003 Nephrol Dial Transplant 28: 517-523, 2003

  42. Risk factors forHypertensive Nephrosclerosis • Race • Prevalence is higher in black with more severe histology • The incidence of hypertension induced renal failure: • Black: 33.8% • White: 21% • Age • Age was the factor most closely associated with HN among white patients • The incidence of HN as a cause of ESRD: • >64 years old: 31% • <64 years old: 19.2% • The histological change is similar in aging process and hypertension-related injury • Starting from the age of 30-40, kidney manifest significant functional changes Kidney Blood Press Res 25: 341-353, 2002

  43. Risk factors forHypertensive Nephrosclerosis • Sex • HN is more common in male • The role of androgens in mediating renal injury in renin-dependent hypertension? • But in black, female? • Lipid abnormalities • Particularly hypercholesterolemia, may play a role in the development of glomerulosclerosis • Lipid related renal injury • Glomerulosclerosis • Interstitial inflammation and fibrosis • Impair both arterial and artiolar endothelial function • Lipid abnormalities seem to be a modulator of progressive renal disease rather than a primary initiator, synergistic effect with HTN Kidney Blood Press Res 25: 341-353, 2002

  44. Risk factors forHypertensive Nephrosclerosis • Insulin resistance • Hypertensive patients with hyperinsulinemia excrete greater amounts of urinary albumin • Mechanism of renal injury: unclear • Enhance sympathetic activity • Increased renal Na retention • Increase cholesterol and TG synthesis • Direct injury on endothelial cells • Hyperuricemia • Hyperuricemia is believed to influence the development of proteinuria and to have a worse renal outcome in hypertensives • Postmortem examination of kidney with hypertension showed interstitial uric acid deposits similar to gout nephropathy Kidney Blood Press Res 25: 341-353, 2002

  45. Risk factors forHypertensive Nephrosclerosis • Hyperhomocysteinemia • Hyperhomocysteinemia is considered a new risk factor for cardiovascular disease • More frequently in essential hypertension than without • Mechanism is not fully understood • Induced oxidative stress • Endothelial injury • Enhancement of vascular monocyte adhesion • Smoking • Microalbuminuria is twice as prevalent in smoking as nonsmokers with primary HTN • Smoking related vascular renal injury make smokers more vulnerable to hypertensive renal involvement Kidney Blood Press Res 25: 341-353, 2002

  46. Risk factors forHypertensive Nephrosclerosis • Others • Heavy metals: lead • Salt intake: • Salt↑ ↓ renal plasma flow, ↑glomerular capillary pressure • Salt↑glomerular TGFβ1 ↑ promotes glomerulosclerosis • Genes: candidate genes linked to the renin-angiotensin system • Perinatal programming: low birth weight may be related to low nephron numbers Kidney Blood Press Res 25: 341-353, 2002

  47. Pathogenesis • Incompletely understood • Genetic predisposing factors may contribute • Angiotensin II plays an important role Kidney Int 64: 2331-2341, 2003

  48. Pathology • Benign nephrosclerosis: essential hypertension related • Microvascular changes with hyalinosis of preglomerular vessel (arcuate and interlobular arteries) walls  afferent arteriole vasconstriction  glomerular injury  renal scarring • As a form of intrarenal renovascular disase • Malignant nephrosclerosis: malignant hypertension related • Fibrinoid necrosis • Myointimal hyperplasia Kidney Int 68: S52-S56, 2005

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