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Membranous Nephropathy

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Dr Rusnawati Yahya …

Dr Rusnawati Yahya
Consultant Nephrologist
Hospital Kuala Lumpur

Published in Health & Medicine
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  • 1. Membranous Nephropathy
  • 2. Epidemiology
    • Uncommon in children.
    • 2-12% (< 5%) of pediatric patients undergoing biopsy for nephrotic syndrome.
    • Adults
    • Most common cause of nephrotic syndrome in adults
    • 30% all biopsies for nephrotic syndrome
    • Older population
    • 50% of all biopsies for nephrotic syndrome
  • 3. Epidemiology
    • Because of its frequency ,2 nd /3 rd common cause of ESRD within 1 o GN group
    • USRDS 1991-95:
    • 0.5% ESRD was due to idiopathic Membranous GN
    • Has been reported in < 1 year old and > 90 years old.
    • Uncommon in < 30 years old
    • Peak age 30-40 and 50-60
    • Men:women- 2-3:1
  • 4. Membranous Nephropathy Clinical Manifestations
    • Presentation:
    • Nephrotic : 60-70%
    • Asymptomatic proteinuria : 30-40%
    • Associated findings:
    • Hypertension : 10-20%
    • Renal insufficiency : 10%
    • Microhematuria : 50%
    • Renal vein thrombosis : 5-30%
  • 5. Aetiology
    • Systemic disease
      • SLE
      • Diabetes mellitus
    • Infections
      • Hep B /C
    • Drugs
      • Gold
      • Penicillamine
      • NSAID’s
    • Malignancies
      • Solid Organ tumors
    • Transplant
    • Uncommon
      • Autoimmune disease eg: Rheumatoids arthritis
      • Infections: syphilis, filariasis, malaria, leprosy, schistosomiasis.
      • Sarcoidosis
      • Sickle cell disease
      • Drugs: mercury, captopril, hydrocarbons
  • 6. Pathogenesis
    • Heymann nephritis in rats:
    • Podocytes is the target of injury.
    • Research has focused on :
    • 1. Responsible antigen
    • 2. Subsequent immune response
    • 3. The role of complement
    • 4. Delineation of the injury process
  • 7. Pathogenesis
    • Antigen target
    • Antigenic target has been localized to the membrane of glomerular epithelial cell, specifically a 515 kD glycoprotein called MEGALIN
    • MEGALIN:
        • A polyspecific receptor related to LDL receptor family
  • 8. Pathogenesis
    • Immune response
    • CD4+ T cell dependent and humoral response results in glomerular immunoglobulin deposition and complement activation.
    • The CD4+ help for antibody response is a function of Th2 cells which produce IL-4, 5, 6, 10 and 13.
    • A role of cell mediated injury is supported by observation:
    • - depletion of CD8+ cell reduces injury
    • - monoclonal anti CD4 and CD8 modifies the disease
  • 9. Pathogenesis
    • Immune response
    • Complement involvement:
    • Complement C5b-9 :Membrane attack complex (MAC) present within the immune deposits
    • Depletion of complement by cobra venom serum prevent subsequent proteinuria confirm role of complement .
    • Podocytes ? Retrieves MAC from the immune deposits by endocytosis, transport them across the cells and exocytosed to the urinary space--- Therefore detectable in the urine
  • 10. Pathogenesis
    • Subsequent injury process
    • Podocytes response to injury is not proliferative but hypertrophy and increased matrix production and finally glomeruloslerosis and interstitial fibrosis
  • 11. Pathology Light microscopy-H&E
    • GBM becomes thickened thru the accumulation of additional matrix material along the outer surface of GBM
    • Later immune deposits becomes surrounded by GBM material
  • 12. Pathology Light microscopy-silver stain
    • Spikes formation
  • 13. Pathology Immnunoflurescence
    • Subepithelial immune complex of Ig G and complement along the outer surface of capillary wall.
  • 14. Pathology Electron Microscopy
    • Electron dense deposit on the subepithelial surface of GBM
  • 15. Membranous Nephropathy Management controversy
    • Debate regarding its management continues since early 1970’s…..
    • Marked variability in its natural history
    • ?accurately predicts which patients is going to progress to ESRD
    • ? Ability to identify it early enough ,so the kidney retain the ability to improve with treatment but late enough to avoid therapy in patient that remits spontaneously
    • Do we have effective treatment??
  • 16. Idiopathic Membranous Nephropathy Natural History
    • 1/3 patients achieved spontaneous complete remission within 3 to 5 years.
    • 25% who enter remission suffer subsequent relapse.
    • 1/3 have partial remission (24HUP< 2g) with persistent proteinuria but no loss of GFR
    • 1/3 progress to ESRD over 5 to 10 years period
    • Patients that achieved remission/ maintain normal GFR for > 3 years , prognosis is excellent.
  • 17. Untreated Membranous Nephropathy Natural History Schieppati et al , NEJM 1993,329(2):85
  • 18. Idiopathic Membranous Nephropathy Natural history
    • 50% with persistent nephrotic range proteinuria has a progressive course
    • 15% of all patients are dead/on dialysis in 5 years.
    • 35% of all patients are dead/on dialysis in 10 years
    • >40% of all patients are dead/on dialysis in 15 years
    • Mean time to doubling in serum Cr is 30 months
  • 19. Membranous Nephropathy Management controversy
    • Generally good prognosis but 25% end stage at 8 years
    • Some authors recommend conservative approach given high rates of spontaneous remission and long term good prognosis
    • Some use immunosuppressive drugs to all patients with NS since several RCT demonstrated superior outcome with this regime
  • 20. Membranous Nephropathy Management controversy
    • The aggressive approach has been criticized as many patients who would evolved into spontaneous remission are exposed to the risk of immunosuppression
    • The conservative approach,would leave considerable amount of patients with progressive renal failure
    • Balance: select patients at high risk of progression for immunosupressive therapy.
  • 21. Membranous Nephropathy
    • Can we predicts those patients who will progress to end stage renal disease?
  • 22. Idiopathic Membranous Nephropathy Poor Prognostic Factors Reichert et al, AJKD 1998(31),1:1-11
    • Clinical features:
      • Age
      • Sex
      • race
      • HLA
      • Hypertension
      • Serum albumin
      • Serum cholesterol
      • Serum creatinine at presentation
  • 23. Idiopathic Membranous Nephropathy Poor Prognostic Factors(cont) Reichert et al, AJKD 1998(31),1:1-11
    • Urine protein
      • Nephrotic syndrome
      • 24HUP > 8g for > 6 months.
      • C5b-9 excretion
    • Biopsy appearances
      • Focal sclerosis
      • Tubulointerstitial disease
      • Electron microscopy (stages III and IV)
  • 24. Predicting CRI in IMN Pei et al, KI 1992(42):960
    • Level of persistent proteinuria over time improve PPV of predicting renal insufficiency
    92 79 30 62 25 X=8, Y=12 88 88 66 66 47 X=8, Y =6 77 87 49 42 55 X=8, Y at biopsy 86 83 50 55 42 X=6, Y=12 78 90 75 54 65 X=6, Y= 6 64 84 66 38 80 X=6, at biopsy 75 84 58 44 61 X=4, Y=12 62 92 85 44 92 X=4 , Y=6 37 89 87 32 127 X=4 at biopsy spec NPV sens PPV n PP (> x g/day, >y month)
  • 25. Membranous Nephropathy
    • Do we lose ability to effectively treat by waiting??
  • 26. Conservative vs immunosuppression in IMN Torres et al KI 2002 (61): p 219-227
    • Retrospective study
    • Biopsy proven MN who developed progressive renal insufficiency (1975-2000)
    • Secondary membranous excluded.
    • Renal insufficiency:
    • SCr > 1.5 mg/dl + Cr Cl ,60 ml/min in at least3 consecutive determination
    • Renal insufficiency was progressive in all patients. Other causes of renal failure ruled out before attributing to glomerular disease
  • 27. Conservative vs immunosuppression in IMN Torres et al KI 2002 (61): p 219-227
    • Therapeutic approaches:
    • First period 1975-1989:
    • conservative Mx for all.
    • Second period 1990-2000:
    • immunosuppressive to new patients with renal insufficiency of recent onset.
    • Prednisolone 1mg/kg/d x1/12
    • 0.5 mg/kg/d x 1/12
    • 0.5 mg/kg/eod x 4/12
    • chlorambucil 0.15 mg/kg x 14 weeks.
  • 28. Conservative vs immunosuppression in IMN Torres et al KI 2002 (61): p 219-227 <3g/dl >3.5 Nephrotic syndrome Normal normal 0.5-2.5 or 50% red fr baseline Partial remission normal Normal <0.5 Complete remission Renal function Serum albumin 24 HUP (g)
  • 29. Conservative vs immunosuppression in IMN Torres et al KI 2002 (61): p 219-227 NS 15.7% 68% 15.7% 0% 10% 75% 15% 0 Stage of MN I II III IV NS 51.8 + 36.5 46.8 + 37.5 Follow-up (months) NS 14 + 18.6 10.8 + 11.8 Interval between bx and renal insufficiency NS 102 + 13 103 + 12 MAP NS 8.9 + 3.6 6.9 + 3.1 Proteinuria NS 11:8 15:5 Sex (M:F) NS 55 + 20 53 + 16 Age Treated(n=19) Nontreated(n=20)
  • 30. Conservative vs immunosuppression in IMN Torres et al KI 2002 (61): p 219-227
  • 31. Conservative vs immunosuppression in IMN Torres et al KI 2002 (61): p 219-227 treated Non-treated
  • 32. Conservative vs immunosuppression in IMN Torres et al KI 2002 (61): p 219-227 Clinical status at end of follow-up 2 (10%) 5 (25%) Death 2 (10%) 13 (65%) Dialysis 4 (21%) 2 (10%) CRF 5 (26%) 0 24HUP>2.5g but N f(x) 2 (10%) 0 Partial remission 5 (26%) 0 Complete remission Treated (n=19) Non-treated (n=20)
  • 33. Conservative vs immunosuppression in IMN Torres et al KI 2002 (61): p 219-227 Probability of renal survival (censoring death) Non-treated treated
  • 34. Conservative vs immunosuppression in IMN Torres et al KI 2002 (61): p 219-227
    • No patients received immunosuppression until serum Cr 1.5 mg/dl or Cr Cl < 60 ml/min (mean 2.3 + 0.94)
    • Time to reach this point was 14 months after biopsy
    • Only 30% went to develop CRF compared to 75% if treated conservatively
    • Suggest that we can safely wait and observe the patient before beginning treatment and still alter the natural history
  • 35. Risk of Progression Categories
    • Low risk
    • normal renal function
    • Proteinuria < 4g/day for 6/12
    • Medium risk
    • normal renal function
    • proteinuria > 4g/d < 8g/d for 6/12
    • High risk
    • abnormal renal function or/and
    • persistent proteinuria >8g/d for >6/12
  • 36. Treatment Strategies
    • Specific immunosuppression
    • Non-specific –reduction of proteinuria
      • Dietary protein restriction
      • BP control
      • ACE inhibitor/AARB
    • Treatment of secondary effect
      • Control of oedema - diuretics
      • Hyperlipidaemia-statin
    • Treatment prophylaxis
      • Anticoagulation: against deep/renal vein thrombosis
      • PCP prophylaxis
      • Osteoporosis prophylaxis: high dose corticosteroid therapy
  • 37. Idiopathic Membranous Nephropathy Specific Immunosuppression
    • Steroid alone
    • Steroid & cytotoxic
    • Cyclosporine.
  • 38. Idiopathic Membranous Nephropathy Trials on Steroids RCT RCT RCT 77 51 38 placebo Pred 45 mg/m2 Pred 125 mg EOD x 8/52 Pred 100-125 mg EOD x8/52 and taper rx steroid N publications Author 81 158 NEJM 1989 (320):210 Cattran 52 103 QJM 1990 (74):133 Cameron 34 72 NEJM 1979 (301):1301 CSAINS
  • 39. Idiopathic Membranous Nephropathy Trials on Steroids Secondary membranous Impaired GTT Use of cytotoxic within 6/12 Cr Cl < 30 ml/min Secondary membranous Exclusion criteria Inclusion criteria Author 24HUP > 0.3g/day Cr Cl > 0.25 ml/sec Cattran adult >15, <65 NS(alb<30,24HUP >3.5) Cameron Proteinuria > 3.5 g/1.73m 2 on > 2 occasion CSAINS
  • 40. Idiopathic Membranous Nephropathy Trials on Steroids Definition (urine prot in g/24 hrs) Nephrotic syndrome Partial remisson Complete remission Author > 3.0 Reduction of more than 50% initial value <0.3 Cattran >3.5 Alb <30 0.0-3.5 0.0 Cameron > 2.0 0.2 -2.0 < 0.2 CSAINS
  • 41. Steroids CSAINS 1979 0.008 0.008 NS NS 0.052 NS NS
  • 42. Steroids Cattran et al, 1989
  • 43. Steroids Cattran et al, 1989 P=0.4
  • 44. Steroids Cameron et al. QJM 1990 ,74(27) :133-156
  • 45. Steroids alone MRC Trial Cameron et al. QJM 1990 ,74(27) :133-156
  • 46. Steroids alone MRC Trial Cameron et al. QJM 1990 ,74(27) :133-156
    • At 36 months, there were no significant difference between control and treatment group in:
    • Plasma Cr
    • Cr CL
    • 24 hr urine protein excretion
    • Conclusion:
    • no significant benefit of high dose short term steroid treatment in the medium term
  • 47. Steroid Alone Meta analysis Hogan et al, AJKD 1995(25): pg862 Outcome :Rate of complete remission 0.48-13.21 2.25 0.75 0.33 24 Kobayashi 0.99-2.44 1.55 total 0.75 1.75 5.33 RR 0.44-1.27 0.27 0.36 36 Cattran 0.54-5.65 0.15 0.08 36 Cameron 0.67-42.01 0.33 0.06 24 CSAIN 95% CI steroid Non-treated Follow-up (months) Study
  • 48. Idiopathic Membranous Nephropathy Steroid alone :summary
    • Therapy with corticosteroid alone does not:
    • increase the odds of complete remission
    • Influence renal survival.
  • 49. Trials in IMN Cytotoxic + steroid Steroid alone Steroid +CBL 91 NEJM1992(327):599 Ponticelli conservative conservative Conservative comparison Active treatment N publications Author Cycloph+ warfarin + dipyridamole 40 Clin Nephrol, 1992(37):229 Murphy cycloph 22 KI 1974, 6: 431 Donadio Steroid +CBL 92 KI 1995(48): 1600 Ponticelli
  • 50. IMN Steroids & cytotoxics versus conservative/no treatment Ponticelli, 1995(48):1600 PR: 24HUP: 0.21- 2.0 g, CR: 24HUP < 0.20 g Renal dysf(x): increase plasma Cr 50% fr baseline Later: renal survival and death End-points 10 years follow-up age<14 and > 65, Cr> 150umol/l,previous steroid or cytotoxic treatment, secondary membranous Exclusion criteria Nephrotic syndrome (24HUP > 3.5 g in 2 specimen, alb < 25g/L) – Inclusion criteria Conservative treatment Control gp N=39 methypred 1g x3/7 at month 0, 2, 4 then oral 0.4 mg/kg/d x27 days chlorambucil 0.2 mg/kg x 6/12 Treatment gp N=42
  • 51. IMN Steroids & cytotoxics versus conservative treatment Ponticelli, 1995(48):1600 Schieppati 10 YRS =0.72 Ponticelli 10 YRS untreated 0.70
  • 52. IMN Steroids & cytotoxics versus conservative treatment Ponticelli, 1995(48):1600 Probability of complete and partial remission Of nephrotic syndrome treated control
  • 53. IMN Steroids & cytotoxics versus conservative/no treatment Ponticelli, 1995(48):1600 Clinical status at end of follow-up 9 2 Dialysis 3 1 death 8 4 Renal dysfunction 6 9 Nephrotic syndrome 11 9 Partial remission 2 17 Complete remission 39 42 Total Conservative treated
  • 54. IMN Steroids & cytotoxics versus steroid alone Ponticelli NEJM1992(327):599-603 PR: 24HUP: 0.21- 2.0 g, CR: 24HUP < 0.20 g Renal dysf(x): increase plasma Cr 50% fr baseline End-points 2-4 years follow-up age<14 and > 65, Cr> 150umol/l,previous steroid or cytotoxic treatment, secondary membranous Exclusion criteria Nephrotic syndrome (24HUP > 3.5 g in 2 specimen, alb < 25g/L) Inclusion criteria Methylpred alone Control gp N=47 Cyclical –ponticelli regime Treatment gp N=45
  • 55. IMN Steroids & cytotoxics versus steroid alone Ponticelli 1992(327):599-603 0.002 0.029 0.011 0.102
  • 56. IMN Steroids & cytotoxics versus steroid alone Ponticelli 1992(327):599-603 Steroid + CBL steroid
  • 57. IMN: Cytotoxics versus conservative/no treatment Murphy, Clin Nephrol, 1992(37):229 24HUP, Cr ,albumin outcome Diuretics and antihypertensives Conservative treatment Cyclophosphamide 1.5 mg/kg/day for 6/12 Dipyridamole100-400 mg daily Warfarin for 2 years Specific treatment N=19 Open randomized study Secondary membranous, proven RVT Prior cytotoxic treatment Exclusion >18 with histological diagnosis of IMN within 3 months of biopsy Proteinuria > 0.5 g/24 hr Inclusion
  • 58. IMN:Cytotoxics versus conservative/no treatment Murphy Clin Nephrol, 1992(37):229 p<0.05
  • 59. IMN:Cytotoxics versus conservative/no treatment Murphy Clin Nephrol, 1992(37):229
    • No effect on renal f(x)
    • Reduction in proteinuria
    • Significant increase in remission of NS
    • Short follow-up
    Remission of nephrotic syndrome <0.05 P value 9 4 total 2 1 Complete Remis. 7 3 Partial Remis. treatment N=13 conservative N=13
  • 60. IMN:Cytotoxics versus conservative/no treatment Donadio, KI 1974 (6): 431 24HUP, Cr ,albumin outcome Diuretics and antihypertensives Conservative treatment Cyclophosphamide 1.5 -2.5 mg/kg/day for 1 year Specific treatment N=19 Open randomized study Secondary membranous, proven RVT Prior cytotoxic treatment Exclusion >18 with histological diagnosis of IMN within 3 months of biopsy Proteinuria > 2 g/24 hr Inclusion
  • 61. IMN:Cytotoxics versus conservative/no treatment Donadio, KI 1974 (6): 4
    • Downward trend in proteinuria
    • No significant difference in the 2 groups
    • 4/9 of treated gp had partial remission
    • 2/9 of non-treated gp had partial remission
    Treatment gp Proteinuria
  • 62. IMN:Cytotoxics versus conservative/no treatment Donadio, KI 1974 (6): 4
    • No changes in GFR
    • Inulin Cl : increased by 8 ml/min/1.73 m2 in treated gp
    • : increased by 2 ml/min/1.73 m2 in non-treated gp
    • : p=0.2
    Cr Clearance
  • 63. Idiopathic Membranous Nephropathy Trials on chlorambucil vs cyclophosphamide Ponticelli but monthly pulsed iv CYCL Ponticelli regime CBL 0.15 mg/kg 18 Annals int med 1994, 72(4):277 Reichert Similar but CBL substituted with cyclophos 2.5 mg/kg Ponticelli regime but chlorambucil 0.2 mg/kg 87 JASN 1998, 9(3):444 Ponticelli CBL substituted with cyclophos 1.5-2.0 mg/kg Ponticelli regime. CBL 0.15 mg/kg 32 QJM 1998 91(5):359 Branten Steroid & cyclophospha Steroid & chlorambucil N Publication Author
  • 64. Idiopathic Membranous Nephropathy Trials on chlorambucil vs cyclophosphamide Cr>150 umol/l,Age <18 Secondary membranous DM , RVT IMN . NS with deteriorating renal f(x) Reichert N=18 IMN with nephrotic syndrome Ponticelli Cr>150 umol/l,Age <18 Secondary membranous DM , RVT IMN . NS with deteriorating renal f(x) Branten N=32 Exclusion Inclusion criteria Author
  • 65. Steroids/cyclophosphamide vs steroid/chlorambucil Branten, QJM 1998 91(5):359 Greater efficacy with cyclophosphamide with better tolerability 26 (5-68) 38 (8-71) F/up (median ,range) <0.01 6/17 11/15 Adverse event <0.01 -121 - 6.3 Change in S Cr (umol/l) <0.05 1/17 4/15 Proportion of pt dev ESRD 15/17 164 + 86 to 274 + 126 cyclophosph <0.05 5/15 Remission of proteinuria 148 + 50 to 219 + 73 Serum Cr 6/12 preceeding rx P value chlorambucil
  • 66. Steroids/cyclophosphamide vs steroid/chlorambucil Reichert et al. QJM 1994 121(5): 328 Pulsed iv cyclophosphamide is ineffective in treating IMN <0.05 -3.1 -2.6 Urine prot: Cr index (g/10 mmol) at 6/12 <0.05 +322 -38.0 Change Serum Cr at 12/12(umol/l0 <0.05 +79.0 -74.0 Change Serum Cr at 6/12(umol/l) 4/9 1/9 Patient reaching ESRD NS -2.9 -2.8 Urine prot: Cr index (g/10 mmol) at 12/12 P value Cyclophosph Chlorambucil
  • 67. Steroids/cyclophosphamide vs steroid/chlorambucil Ponticelli JASN 1998, 9(3):444 Both treatment are effective in inducing remission and preserving renal function, ? Cyclophosphamide more effective and better tolerated 2 did not complete 0 zoster 6 did not complete 4 zoster Side effect NS 10/40 (25%) 11/36 (30.5%) Relapse between 6-30 months 0.116 40 (93%) 36 (82%) Remission (comp/part) P value Cyclophosphamide (n= 43) Chlorambucil (n=44)
  • 68. Steroids & cytotoxics :meta-analysis Imperial et al, JASN 1995,5:1553-1558
    • 5 controlled studies(4 randomized)
    • Treatment:
    • Chloramucil & prednisolone(6 months) or cyclophosphamide(6-12 months)
    • Outcome:
    • complete resolution of nephrotic syndrome 4x more likely with cytotoxic therapy
  • 69. IMN: Trials on Cyclosporin RCT 64 KI 1995, 47(4):1130 Cattran Prednisolone 0.15mg/kg/D & placebo Prednisolone 0.15mg/kg/D & cyclosporine (3.5mg/kg/day) CSA level of 125-225 RCT 51 KI 2001, 59(4):1484 Cattran Control gp Study gp n publications Author
  • 70. Cyclosporin Cattran 1995, KI Membranous n=64 Low protein diet <0.9g/kg/day Prog of renal failure Decrease in Cr Cl 8ml/min/year And persistent nephrosis Stable renal f(x) Placebo N=8 Cyclosporin N=9 for 12/12
  • 71. Cyclosporin Cattran KI 1995, 47(4):1130 Slope of Cr Clearance (ml/min/month) 49 8 9 N - - -0.5 Non-randomized NS -2.1 -2.2 Placebo <0.02 -0.7 -2.4 Cyclosporin P value Part 2 Part 1
  • 72. Cyclosporin Cattran KI 1995, 47(4):1130 cyclosporin placebo
  • 73. Cyclosporin Cattran KI 1995, 47(4):1130 P=0.02 P=0.03
  • 74. Cyclosporin Cattran et al, KI 2001,59(4):1484-90. Randomized double blind placebo controlled Study Complete remission (<0.3 g/day) Partial remission (50% reduction from baseline, and < 3.5 g/day with stable renal function) Stable f(x): Cr Cl within 15% of baseline) Outcome CSA at 3.5 mg/kg/day. Blood level 125 – 225 umol/l Pred 0.15 mg/kg/day Treatment Female unwilling to take effective birth control Comorbid condition with expected survival < 2 years Secondary membranous, DM malignancy Exclusion criteria Age 18-70, failure to achieve remission after 8 weeks of pred I mg/kg.proteinuria > 3.5g/day, Cr Cl> 42ml/min and BP< 135/85 Inclusion criteria
  • 75. Cyclosporin Cattran et al, KI 2001,59(4):1484-90 . P=0.001 P=0.004 P=0.007