Clinical Practice Guidelines Diabetic Nephropathy

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  • 1. Clinical Practice Guidelines Diabetic Nephropathy
  • 2. Introduction
    • Increased prevalence of DM
    • Diabetic nephropathy – commonest cause of ESRD
    • heavy burden on resources
  • 3. Adapted from Breyer JA et al. Am J Kid Dis 1992; 20(6): 535. Time (yrs ) 0 5 20 30 Onset of Diabetes Onset of Proteinuria End Stage Renal Disease STRUCTURAL CHANGES (Increasing glomerular basement membrane thickening and mesangial expansion) Hypertension OVERT NEPHROPATHY Rising Scr, Decreasing GFR INCIPIENT NEPHROPATHY Hyperfiltration, microalbuminuria, rising blood pressure PRECLINICAL NEPHROPATHY Course of Diabetic Nephropathy
  • 4.
    • Microalbuminuria :
    • first sign of nephropathy
    • a strong and independent predictor of cardiovascular disease
    Diabetic Nephropathy
  • 5. Guidelines 1: Screening for proteinuria
    • Screening for proteinuria should be performed yearly in the following patients*:
    • (a)Type 1 DM : 5 years after diagnosis of diabetes, or earlier in the presence of other CV risk factors
    • (b)Type 2 DM: at the time of diagnosis of diabetes
    • Grade C
    *Other factors affecting urinary albumin excretion should be excluded when screening for microalbuminuria and proteinuria
  • 6. Guidelines 2: Method of screening for proteinuria
    • Urine should be screened for proteinuria with conventional dipstick on an EMU specimen*
    •  
    • Grade C
    *Other factors affecting urinary albumin excretion should be excluded when screening for microalbuminuria and proteinuria
  • 7. Guidelines 3: Screening for microalbuminuria
    • If urine dipstick for proteinuria is -ve, screening for MA should be performed on an EMU specimen
    • (b) Urine dipstick for MA is an acceptable screening test
    • (c) If MA is detected, confirmation should be made with 2 further tests within a 3 to 6 month period
    •   Grade C
    *Other factors affecting urinary albumin excretion should be excluded when screening for microalbuminuria and proteinuria
  • 8. Factors affecting urinary albumin excretion
    • NSAIDs
    • ACE inhibitors
    • Strenuous exercise
    • Poorly controlled DM
    • Heart failure
    • UTI
    • Acute febrile illness
    • Uncontrolled HPT
    • Haematuria
    • Menstruation
    • Pregnancy
    Decreases AER Increases AER
  • 9. Algorithm : Screening for Proteinuria Urine dipstick for protein (a)    Type 1 : 5 years after diagnosis or earlier in the presence of other cardiovascular risk factos (b) Type 2 : at the time of diagnosis NEGATIVE POSITIVE (urine protein >300mg/l) on 2 separate occasions (exclude other causes e.g. UTI, CCF etc.) Overt nephropathy Quantify excretion rate e.g. 24-hr urine protein POSITIVE Screen for microalbuminuria on early morning spot urine   Retest twice in 3 –6 months (exclude other causes e.g. UTI, CCF etc.) NEGATIVE If 2 of 3 tests are positive, diagnosis of microalbuminuria is established 3-6 monthly follow-up of microalbuminuria  Optimise glycaemic control  Strict BP control  ACEI/ARB  Stop smoking  Lifestyle modification  Treat hyperlipidaemia  Avoid excessive protein intake  Monitor renal function  Monitor for other diabetic endorgan damage Yearly test
  • 10. Definition of abnormal urinary albumin excretion SPECIMEN COLLECTED >35 (F) >25 (M) >200 >200 >300 Overt proteinuria 3.5 to 35 (F) 2.5 to 25 (M) 20-200 20-200 30-300 Microalbuminuria <3.5 (F) <2.5 (M) <20 <20 <30 Normoalbuminuria Urine Albumin:Creatinine ratio* (mg/mmol) Urine Albumin concentration (mg/l) First voided morning specimen Timed collection (μg/min) 24hr collection (mg/24h) Albumin Excretion
  • 11.
    • Glycaemic control should be optimised, with:
    • FBS  6 mmol/l and/or
    • HbA1c  7%
    •  
    • Grade A
    Guidelines 4: Glycaemic control
  • 12. Screening methods Microalbuminuria testing
  • 13. Glycaemic Control Type 1 DM :DCCT RR = 34% RR = 43% RR = 56% 1 o Prevention cohort 2 o Prevention cohort Risk of micro & macroalbuminuria
  • 14. % relative risk reduction P=0.03 P<0.01 P<0.01 P=0.05 P=0.02 Over 10 years, HbA 1c was 7.0% (6.2-8.2) in the intensive group (n=2,729) vs HbA1c was 7.9% (6.9-8.8) in the conventional group (n=1,138). Glycaemic Control Type II DM: UKPDS
  • 15.
    • Target blood pressure in diabetics should be less than 130/80
    • Grade B
    Guidelines 5: Target blood pressure
  • 16. Target BP in diabetics
    • 49 % death rate
    •  Cl cr , MA, overt proteinuria
    132/78 138/86 75 80-89 470 ABCD
    • 24% DM related end-points
    • 32% death related to DM
    • 44% stroke
    144/82 154/87 < 150/85 < 180/105 1148 UKPDS
    • 51% major CV events
    • 67% CV mortality
    • ( < 80 cf < 90)
    81.1 83.2 85.2 < 80 < 85 < 90 1501 HOT Relative risk reduction Achieved BP Target BP n RCT
  • 17. Target BP in Overt Nephropathy MDRD Mean GFR decline and achieved follow-up BP according to baseline proteinuria Peterson et al, Ann Internal Med 1995
  • 18.
    • ACEIs or ARBs should be initiated for reduction of microalbuminuria unless contraindicated
    •  
    • ACEIs in type 1 & type 2 diabetics : Grade A
    • ARBs in type 2 diabetics : Grade A
    Guideline 6: Treatment of microalbuminuria
  • 19. Evidence for use of ACE Inhibitors in type 1 and type II Diabetes mellitus with microalbuminuria
  • 20. ACEI in Type I DM with microalbuminuria Lisinopril and Nifedipine both delays onset of DN Lisinopril, nifedipine vs placebo 98 (3yr) DBP 75-90 SBP 115-140 Italian MA Study Group Slows progression of renal disease Lisinopril vs placebo 97 (2yr) DBP 75-90 SBP <155 EUCLID Reduces risk of DN independent of BP lowering Captopril vs placebo 96 (2yr) DBP <90-95 SBP <140-160 MA Captopril Study Group Less progression of MA, preserves CrCl Captopril vs placebo 95 (2yr) <140/90 North American MA Study Group Captopril impedes progression to macroalbuminuria Captopril vs placebo 92 (2yr) DBP <90-95 SBP <140-145 European MAStudy Group ACE-I postponed nephropathy Captopril vs placebo 91 (4yr) <90 Mathiesen ER Comment AHA Year BP Study
  • 21. ACEI in normotensive type 2 DM with microalbuminuria 2000 1993 1996 year Decreases risk of overt DN Ramipril vs Placebo 142/80 3577 4.5 Micro-HOPE long-term stabilization of creatinine and urinary albumin loss Enalapril vs no treatment <140/90 93 5 Ravid M Decrease microalbuminuria Enalapril vs no rx <150/90 62 4 Sano T Results Treatment BP n Dur. (yrs) Authors
  • 22. ACEI in hypertensive type 2 DM with microalbuminuria Both equally effectiv Enalapril vs atenolol SBP >150 DBP >85 UKPDS Both lower AER to similar extent Cilazapril vs Amlodipine 3 yrs SBP >140 DBP 90-114 Velussi M Both lowers AER and improves GFR Enalapril vs Nitrendipine 27 mo DBP >90-104 Mosconi L 1992 Enalapril prevents DN and preserve GFR better Enalapril vs AHA 3 yrs DBP >90 Lebovitz H 1994 Captopril decrease microalbuminuria Captopril vs conservative 3 yrs DBP 92-110 Lacourciere Y 1993 Results treatment Dur BP Authors
  • 23. Evidence for use of ARB in type 1 and type II Diabetes mellitus with microalbuminuria
  • 24. ARB in Type I DM with microalbuminuria
    • No well conducted studies
  • 25. ARB in normotensive type 2 DM with microalbuminuria
    • Viberti G et al.
    • MicroAlbuminuria Reduction With VALsartan
    • (MARVAL) Study Investigators.
    • Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect.
    • Circulation 2002;106(6):672-8
  • 26. ARB in hypertensive type 2 DM with microalbuminuria
    • Irbesartan in patients with type 2 diabetes and microalbuminuria study group.(IRMA)
    • The effect of Irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes.
    • N Engl J Med 2001; 345: 870-8
    •  
    • Lozano J V et al.
    • Losartan reduces microalbuminuria in hypertensive microalbuminuric type 2 diabetics.
    • Nephrol Dial Transplant 2001; 16 (Suppl 6): 1-5
  • 27. Incidence of Diabetic Nephropathy (%) 0 3 6 12 18 22 24 201 201 164 154 139 195 195 167 161 148 194 194 180 172 159 129 142 150 36 45 49 Placebo (n) Irbesartan 150 mg (n) Irbesartan 300 mg Months of Follow-up Placebo 150 mg of irbesartan 300 mg of irbesartan P<0.001 for difference between 300 mg irbesartan group and placebo IRMA II : Incidence of Progression to Diabetic Nephropathy
  • 28. Are ARBs superior to ACE inhibitors in DM with microalbuminuria?
  • 29. ACEI vs ARB in microalbuminuria Results Medications F-up Type n Authors II II II 250 81% microalb 122 92 No difference between 2 active agents and superior to placebo Valsartan vs captopril vs placebo 52 wks Muirhead Telmisartan vs enalapril Lasartan vs enalapril DETAIL NEJM 2004 Lacourciere KI 2000 5 yrs 1 yr Similar rate of GFR decline Similar GFR decline
  • 30. DETAIL STUDY: GFR change from baseline Year Enalapril Telmisartan Number of Enalapril patients assessed Telmisartan (carried forward) 113 (39) 103 (41) 103 (0) 86 (0) 110 (22) 99 (23) 113 (23) 102 (21) 113 (30) 102 (31) Change in GFR (ml/min/1.73 m 2 )
  • 31.
    • In patients with proteinuria > 1 g/day, target blood pressure should be lowered to < 125/75
    •  
    • Grade B
    Guidelines 7: Target BP in overt nephropathy
  • 32. MDRD study.
    • Mean decline in GFR
    • Based on severity of proteinuria
    — low BP --- usual BP
  • 33.
    • In Type 1 diabetics with overt proteinuria, ACEIs should be initiated unless contraindicated
    • Grade A
    • In Type 2 diabetics with overt proteinuria, ARBs or ACEIs should be initiated unless contraindicated
    • ARBs : Grade A
    • ACEIs : Grade B
    Guideline 7: Treatment of overt nephropathy
  • 34. Evidence for use of ACE Inhibitors in type II Diabetes mellitus with overt nephropathy
  • 35. ACEI in Type II DM with overt nephropathy
    • Nielsen et al
    • Diabetes 1994;43(9):1108-13
    • Bakris et al
    • KI 1996;50:1641
    • Leibovitz et al.
    • KI suppl 1994;45:S150
  • 36. Evidence for use of ARB in type II Diabetes mellitus with overt nephropathy
  • 37. ARB in Type II DM with over nephropathy
    • RENAAL
    • Brenner BM, et al.
    • N Engl J Med. 2001;345(12):861-869
    • IDNT
    • Lewis EJ, et al.
    • N Engl J Med. 2001;345(12):851-860
  • 38. Cumulative % of patients with event Months 24 0 12 36 48 554 583 Placebo Losartan Risk reduction=16% P=0.02 762 751 689 692 295 329 36 52 Placebo † (n) Losartan † (n) *Composite of a doubling of serum creatinine, end stage renal disease, or death RENAAL : Patients Reaching the Primary Composite Endpoint*
  • 39. Proportion with primary endpoint 0 6 12 18 24 30 36 42 48 54 579 555 528 496 400 304 216 146 65 565 542 508 474 385 287 187 128 46 568 551 512 471 401 280 190 122 53 Irbesartan Amlodipine Placebo Months of Follow-up *Composite of a doubling of serum creatinine, end stage renal disease, or death P=0.02 for irbesartan compared to placebo IDNT : Proportion of Patients with the Primary Composite Endpoint*
  • 40. Adapted from Breyer JA et al. Am J Kid Dis 1992; 20(6): 535 . Time (yrs) 0 5 20 30 Onset of Diabetes Onset of Proteinuria End Stage Renal Disease RENAAL OVERT NEPHROPATHY INCIPIENT NEPHROPATHY PRECLINICAL NEPHROPATHY IRMA 2 IDNT Summary of Clinical Trials in Type II Diabetic Nephropathy Nielsen. Diabetes 1994 Leibovitz. KI suppl 1994 Bakris. KI 1996 MARVAL Mosconi L 1992 Lebovitz H 1994 Lacourciere Y 1993
  • 41.
    • Cigarette smoking should be actively discouraged
    • Grade B
    Guideline 9: Cessation of smoking
  • 42. Guidelines 10: Monitoring of serum lipids
    • Full lipid profile should be performed at least annually in adult diabetics
    • Grade C
  • 43.
    • In diabetics
    • therapeutic lifestyle changes should be instituted if LDL-cholesterol is > 2.6 mmol/l
    • drug therapy should be considered if LDL-cholesterol is > 3.4 mmol/l
    • Grade B
    Guideline 11: Correction of dyslipidaemia
  • 44.
    • Moderate protein restriction of 0.6 – 0.8 g/kg/day* may be considered in patients with overt nephropathy and/or renal impairment
    •  
    • Grade B
    * one matchbox sized cooked protein source is equivalent to 7g of protein Guideline 12: Dietary protein
  • 45. Hansen HP et al (KI July 2002): Moderate dietary protein restriction improves prognosis in type 1 diabetic patients with progressive diabetic nephropathy in addition to the beneficial effect of antihypertensive treatment. Dietary protein restriction in type 1 diabetic nephropathy
  • 46.
    • Sodium intake should be restricted to < 80mmol/day (or 5g sodium chloride)* in patients with hypertension and/or proteinuria
    •  
    • Grade C
    * equivalent to 1 teaspoon of salt Guideline 13: Sodium restriction
  • 47. Studies on salt restriction essential HPT & diabetic nephropathy Low sodium diet potentiates antiHPT and antiproteinuric effects of Losartan Lorsartan 80-85 Type II DM, HPT, microalbuminuric RCT 2002 Houlihan Albumin excretion was reduced from 2967mg/d to 1294mg/d in diltiazem group on low sodium diet Diltiazem and Nifedipine 50 vs. 250 Diabetic nephro-pathy Opened label 1996 George L Bakris Additional mean BP reduction of 9% Captopril 83 vs.183 Essential HPT RCT 1987 Mac Cregor GA Absolute BP lower for both agents while on a low sodium diet Enalapril and Isradipine 90 vs. 314 Essential HPT RCT 1998 Mathew R. Weir Reduction of 3.5-5.5mmHg SBP and 2-3.5mmHg DBP due to sodium restriction Nil 80 vs. 160 Essential HPT RCT 1989 Australian National Health Outcomes Antihypertensives Sodium restriction (mmol/day) Patient group Trial type Year Study
  • 48.
    • Referral to a nephrologist for pre-dialysis evaluation should be made if the serum creatinine exceeds 200 umol/L
    •  
    • Grade C
    Guideline 14: Referral to nephrologist
  • 49.
    • Earlier referral to a nephrologist may be indicated if:
    Referral to nephrologist
    • the diagnosis of diabetic nephropathy is in doubt
    • nephrotic syndrome or unexplained haematuria occurs
    • a sudden worsening of renal function occurs
    • blood pressure is difficult to control
    • hyperkalaemia arises
    • renal artery stenosis is suspected
  • 50. Studies on Early vs late referral AV access use at initiation of HD increased with earlier referral time 499 ER < 1 mo LR > 12 mo USA 1995-1998 CHOICE study LR > ER 78 106 ER > 3 mo LR < 1 mo Brazil 1992-1995 Sesso et al LR > ER 2264 ER > 4 mo LR < 4 mo Texas 2002 Stack et al LR > ER 325 325 ER > 4 mo LR < 4 mo Edinburgh 1987-1992 Eadington et al LR > ER 153 65 ER > 6 mo LR < 1 mo Paris 1989-1991 Jungers et al LR > ER 32 23 ER > 1 mo LR < 1 mo Oxford 1981 Ratcliffe et al Mortality risk Mean length of hospital stay (days) No of patients Timing of referral Location/ year Source
  • 51. Healthy individual Diabetes complications Diabetes mellitus Impaired OGTT Genetic Environmental Life style modification Diabetes Prevention Study Diabetes Prevention Program Da Qing Study Malmo Study Pharmaceutical agents STOP NIDDM study (Acarbose) DPP (Metformin) TRIPOD study (Troglitazone) Chinese Diabetes Prevention Study (Acarbose/Metformin) Prevention of Diabetes
  • 52. Lifestyle modification Regular Exercise Healthy Eating Prevention of Diabetes