Applications of ACE Inhibitors in NonDiabetic Proteinuria

1
Applications of ACE Inhibitors in Non-Diabetic
Proteinuria

• Eric T. Pride, M.D.
• March 16, 1999
• Internal Medicine Resident
• Grand Rounds

2
Case Presentation

• Chief Complaint Swelling
• HPI 39 yo BF with hx of SLE, recurrent DVT/PE on
  chronic coumadin. Increase in lower extremity
  swelling with weight gain.
• PMHx SLE, venous thromboembolic disease, venous
  insufficiency.

3
Case Presentation (continued)

• Medications lasix, coumadin
• NKDA
• Surgical Hx (-)
• Family Hx (-) for CTD or DVT/PE
• Social Hx 1 ppd smoker, no ETOH

• ROS denies orthopnea, PND, chest pain, SOB, DOE
  or GI/GU complaints

4
Physical Exam

• Vital Signs Afebrile, HR 80, BP 130/100
• General NAD
• HEENT/neck (-)
• Heart RRR, normal S1/S2, no murmur, rub or gallop

• Lungs CTA bilaterally
• Abdomen soft, distended, BS
• Ext 3 LE edema
• Neuro nonfocal

5
Labs/Diagnostic Studies

• CBC Hgb 10, otherwise WNL
• BMP WNL (creatinine 1.0)
• U/A 3 protein, 0-1 RBC, 0-1 WBC, no casts

• Urine protein/creatinine ratio 3.5
• CXR (-)
• Renal U/S (-) for hydronephrosis, normal sized
  kidneys bilaterally

6
Therapeutic Decision

• Begin ACE Inhibitor!

7
Nephrotic Syndrome and Nephrotic Range Proteinuria

• In adults, nephrotic range proteinuria generally
  defined as urinary protein excretion gt 3.5 g/24
  hrs
• Nephrotic syndrome includes edema,
  hypoalbuminemia and hyperlipidemia

8
Protein Abnormalities in Heavy Proteinuria

• Decreased levels of IgG
• Decreased levels of factor B of complement
  activation
• May explain enhanced susceptibility to bacterial
  infections

9
Hypercoagulable State

• Decreased levels of AT III
• Increased fibrinogen synthesis
• Reduced functional activity of Proteins C and S

10
Anemia Associated with Nephrotic Range Proteinuria

• Can be present even with relatively normal GFR
• depression of serum transferrin concentrations
• urinary losses of erythropoietin

11
Hyperlipidemia

• Patients with chronic renal failure in the U.S.
  have a risk of death from cardiovascular disease
  3-4 times that of the general population
• Increased levels of LDL, VLDL, triglycerides and
  Lp(a)

12
The AIPRI Study

• Patients with both diabetic and non-diabetic
  renal disease
• 583 patients with renal insufficiency from
  various disorders
• 300 randomized to receive benazepril
• 283 randomized to receive placebo

13
The AIPRI Study

• Three year follow-up period
• Level of proteinuria not initially accounted for
• Primary endpoint was doubling of serum creatinine
  or the need for dialysis

14
The AIPRI Study -- Results

• After three years of follow-up
• 31 patients in the benazepril group and 57 in the
  placebo group reached the combined endpoint
  (plt0.001)
• 53 risk reduction for reaching the combined
  endpoint (95 CI 27-70)

15
The AIPRI Study -- Results

• Greater reduction in risk noted for patients with
  baseline proteinuria gt 1g/24 hrs
• How much effect related to the drugs
  antihypertensive effects?

16
Etiologies of Nephrotic Range Proteinuria

• Primary Glomerular Diseases
• Minimal change disease
• FSGS
• Membranous GN
• Focal and segmental GN
• Mesangial and proliferative GN

17
Etiologies of Nephrotic Range Proteinuria

• Drugs
• Mercury, gold
• Penicillamine
• Heroin
• NSAIDs
• Probenicid
• Captopril

18
Etiologies of Nephrotic Range Proteinuria

• Allergens, Venoms, Immunizations
• Infections
• Bacterial (post-Strep GN, endocarditis, TB)
• Viral (HBV, CMV, EBV, HIV)
• Protozoal and helminthic infections

19
Etiologies of Nephrotic Range Proteinuria

• Neoplastic (solid tumors/adenocarcinoma,
  leukemia/lymphoma)
• Multisystem Disease
• CTD (SLE, pulmonary-renal syndromes)
• Sarcoidosis
• Amyloidosis
• TEN, dermatitis herpetiformis

20
Etiologies of Nephrotic Range Proteinuria

• Diabetes Mellitus
• Miscellaneous
• Thyroid disease
• Pregnancy-associated
• Chronic renal allograft rejection

21
Treatment of Primary Glomerular Diseases

• Corticosteroids
• Cytotoxic agents

• SIDE EFFECTS !

22
Is There a Role for ACE Inhibitors?

• We shall see

23
Theories Why ACE Inhibitors Might Work

• Lower arterial blood pressure
• Lower intraglomerular pressure by effects of
  efferent arteriole
• Change permeability characteristics at the level
  of the glomerulus

24
(No Transcript)
25
NSAIDs for Proteinuria

• Can decrease proteinuria, presumably by effects
  on the afferent arteriole
• Detrimental effect on GFR

26
Apperloo et al, Kidney Int 1994

• Compared enalapril and atenolol in non-diabetic
  renal disease with proteinuria in excess of 600
  mg/day
• 29 patients
• Double-blind prospective study
• Effects on proteinuria and GFR
• Target DBP lt 95 mmHg

27
Apperloo et al -- Results

• Reduction of BP (plt0.001)
• Reduction in proteinuria from 3.19 to 2.41 g/24
  hrs (plt0.001)
• 12 week antiproteinuric response predicts GFR
  decline

• No significant change in cholesterol levels
• No mention of adverse outcomes
• No distinction between treatment modalities

28
Conclusions

• Improvements in GFR decline secondary to
  reductions in proteinuria
• BUT
• Can we separate the antiproteinuric effect from
  the blood pressure lowering effect?

29
Comparing Classes of Antihypertensives

• Kamper et al in the Am J Hypertension compared
  enalapril to conventional antihypertensive
  treatment
• beta blockers
• diuretics
• vasodilators

30
Kamper et al Am J Hypertension

• Effects on moderate to severe chronic nephropathy
  (median GFR 15 ml/min)
• Level of proteinuria not accounted for

31
Kamper et al -- Results

• Enalapril group
• significant reduction in albuminuria
• slightly slower rate of GFR decline (-0.20
  ml/min/month vs. -0.31 ml/min/month, plt0.05)
• no difference in progression to ESRD

• Enalapril group with significant increase in
  serum potassium (plt0.01)
• No significant difference in overall deaths,
  adverse effects or patients withdrawing from study

32
Wheres the Information on Nephrotic Range
Proteinuria?

• Im getting there

33
Gansevoort et al, Nephrol Dial Transplant

• Meta-analysis of trials comparing ACE inhibitors
  and other antihypertensive agents with regards to
  their antiproteinuric effects
• 41 studies
• 1124 patients
• 558 with non-diabetic renal disease

34
Gansevoort et al -- Results

• ACE inhibitors showed superior antiproteinuric
  effects compared to baseline levels
• -39.9 (95 CI -42.8 to -36.8) vs.
  -17.0 (95 CI -19.0 to -15.1)
• plt0.001

35
Gansevoort et al -- Results

• Similar reductions in BP
• Similar results when only RCTs included

36
Maki et al, Arch Int Med

• Meta analysis of 14 RCTs comparing ACE
  inhibitors to control patients and other
  antihypertensive agents
• Lowering BP lowers proteinuria
• ACE inhibitors and nondihydropyridine CCB had
  similar antiproteinuric effects

37
Maki et al, continued

• Effects on GFR varied without trend towards
  significance
• Results given on logarithmic scale
• difficult to translate into clinically meaningful
  terms

38
Non-Pharmacologic Means to Reduce Proteinuria

• Low-Protein Diet

39
How About the 70/2/2 Renal Diet?

• Weve all ordered it

40
ACE Inhibitors and Protein Restricted Diets

• Reductions in proteinuria
• Less impressive effects on GFR
• Did see a decrease in serum cholesterol levels
• Compliance???

41
Praga et alAm J Kidney Diseases

• Captopril in non-diabetic primary renal diseases
• Exclusion criteria
• uncontrolled HTN
• systemic diseases
• evolution to ESRD in pretreatment period
• noncompliance with pretreatment protocol

• Patients with nephrotic range proteinuria (gt3.5
  g/24 hrs)
• Follow-up period 12 months

42
Praga et al -- Methods

• 5 patients were not included in the final
  analysis secondary to intolerances to ACE
  inhibitors (cough, hypotension, hyperkalemia)
• 46 patients completed the study
• divided into two groups based on response AFTER
  the study

43
Results

• Group A (gt45 reduction in proteinuria from
  baseline)
• improved serum albumin
• improvement in slope of 1/SCr
• improvement in serum cholesterol
• no change in BP

44
Results

• Group B(lt45 reduction from baseline)
• improvement in serum cholesterol
• no change in BP

• Overall reduction in proteinuria from 6.3 /- 2.5
  to 3.9 /- 3.1 g/24hrs (plt0.001)

45
What Does This Mean?

• Unclear rationale for dividing the patients after
  the treatment period
• Do patients who demonstrate a significant
  reduction in proteinuria have a slowing of the
  progression of their renal insufficiency?

46
The Randomized Controlled Trials

• What youve all been waiting for!

47
Nosarti et alAm J Nephrology 1997

• Small study
• 27 patients
• 22 entered study phase (5 lost to follow up and
  not accounted for)
• Effects of perindopril for 1 year on primary
  renal diseases

48
Nosarti et al -- Study Design

• Exclusion criteria
• age lt18, age gt70
• diabetes mellitus
• CHF
• renovascular disease
• liver disease
• pregnancy

• 11 patients in perindopril group, 6 in control
  group
• Patients with membranous GN and MPGN
• Similar pretreatment BP, albumin, serum creatinine

49
Nosarti et al -- Study Design

• Primary endpoint
• Effect on levels of proteinuria

50
Nosarti et al -- Results

• Responders had a significant lowering of
  albuminuria (6.1 /- 1.0 to 1.2 /- 0.5 g/24hrs,
  plt0.01)
• In responders a significant lowering of
  albuminuria was associated with increases in
  serum albumin

51
Nosarti et al -- Results

• No significant changes in creatinine clearance in
  either group
• Responders tended to have lower pretreatment
  levels of proteinuria

52
Nosarti et al -- Take Home Points

• Initial degree of proteinuria may predict
  antiproteinuric response
• 5 patients not accounted for
• Lack of clinically relevant findings
• Small study
• No difference when perindopril group looked at as
  a whole

53
Remuzzi et al -- Lancet 1997REIN Study

• RCT on the effects of ramipril in proteinuric,
  non-diabetic nephropathy
• 352 patients
• Intention to treat
• Randomized after classification (but before
  treatment)
• Stratum 1 (proteinuria 1-3 g/24hrs)
• Stratum 2 (proteinuria gt3 g/24hrs)

54
REIN Study -- End Points

• Primary End Points
• Effects on rate of GFR decline
• Extent to which effects on GFR decline is
  dependent on antiproteinuric effects

55
REIN Study -- End Points

• Secondary End Points
• total and cardiovascular mortality
• progression to ESRD
• effects on proteinuria

56
REIN Study -- Design

• Randomization
• receive either ramipril or placebo plus
  conventional antihypertensive treatment
• goal DBP lt 90 mmHg

• Baseline Characteristics
• similar baseline
• BP
• GFR
• serum creatinine
• lipid status

57
REIN Study -- Exclusion Criteria

• Age lt18 or gt70
• Treatment with corticosteroids, NSAIDs or
  immunosuppressive drugs
• Acute MI or CVA in past 6 months
• Severe uncontrolled HTN
• Renovascular disease
• Pregnancy
• Diabetes mellitus

58
REIN Study -- Results

• Study opened for patients in stratum 2 after 27
  months because of a significant difference in GFR
  decline
• Ramipril group 0.39 /- 0.10 ml/min/month
• Placebo group 0.89 /- 0.11 ml/min/month
• P 0.001
• Stratum 1 patients allowed to continue according
  to original protocol guidelines

59
REIN Study -- Results

• Urinary protein excretion decreased significantly
  by month 1 in ramipril group
• 23 reduction by month 1
• 55 reduction by month 36
• no significant reduction in placebo plus
  conventional treatment group
• P lt 0.01

60
Renal Survival

• Results encouraging!
• Nephrologists excited! (As much as nephrologists
  get excited)

61
REIN Study -- Renal Survival

• Significant reduction in patients achieving
  doubling of serum creatinine in ramipril group
• 18 in ramipril group vs. 40 in placebo plus
  conventional treatment group (P 0.02)
• Trend towards significance with regards to the
  development of ESRD
• 17 in ramipril group vs. 29 in placebo group (P
  0.20)

62
Renal Survival

• No significant difference between groups with
  regards to BP reduction
• No significant difference in adverse outcomes,
  deaths, or cardiovascular events

63
The Lipid Issue

• The most potential benefit?

64
Mechanisms of Hyperlipidemia in Nephrotic
Syndromes

• Not completely understood
• May be secondary to both increased production and
  abnormal catabolism of lipoproteins
• Low oncotic pressure implicated as cause for
  elevations in LDL, VLDL and Lp(a)
• Impaired clearance of circulating lipoproteins
  secondary to reduced lipoprotein lipase activity?
• Reductions in serum cholesterol related to
  reductions in protein excretion?

65
Whats Lp(a) Got to do With Anything?

• Patients with both proteinuric and
  non-proteinuric renal diseases demonstrate
  elevations in lipoprotein a (Lp(a))
• Lp(a) made of two major protein components
• apo(a)
• apo B100

66
(No Transcript)
67
Effects of Lp(a)

• Structure of apo(a) homologous to plasminogen and
  can bind plasminogen receptors
• Apo(a) is resistant to activation by tissue
  plasminogen activator and thus may interfere with
  fibrinolysis and clot lysis
• Lp(a) responds poorly to traditional lipid
  lowering therapies

68
Diabetic Nephropathy and Lp(a)

• Significant decrease in Lp(a) in patients with
  overt nephropathy treated with fosinopril
• May provide the best clinical rationale for using
  these medications

69
Take Home Points
70
Take Home Points

• ACE inhibitors in non-diabetic proteinuria
• Treatment of the underlying disease process
  preferred, when feasible
• ACE inhibitors
• May reduce rates of GFR decline
• May reduce the need for renal replacement
  therapies (dialysis, renal transplantation)

71
Take Home Points

• ACE inhibitors likely beneficial in patients with
  proteinuria and hypertension
• Effects on lipids might prove to reduce
  cardiovascular mortality

72
Take Home Points

• Need to be cautious of well-documented
  deleterious effects (decreased GFR, hyperkalemia,
  cough)
• Differences in tissue levels of different ACE
  inhibitors?

73
Final Take Home Point
74

• Know the day of your grand rounds!

75
Acknowledgements

• Michael Pursley, M.D.
• Bill Colyer, M.D.
• CLINT

76
(No Transcript)